# Patent

## Title
Method and apparatus for delivering an agent to a kidney

## Abstract

A method is described including introducing a delivery device to a point within a renal artery or a renal segmental artery and delivering a treatment agent from the delivery device according to conditions that create a turbulent blood flow and wherein the treatment agent is capable of inhibiting a biological process contributing to nephropathy. In other embodiments, an apparatus and kit are described including a delivery device for insertion to a point within a renal artery or renal segmental artery and delivery of a treatment agent capable of inhibiting a biological process contributing to nephropathy.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
The application is a continuation of co-pending U.S. patent application Ser. No. 11/756,376, filed May 31, 2007 and incorporated herein by reference.


BACKGROUND
1. Field
Delivery systems for delivery of a treatment agent to a kidney for inhibiting nephropathy or end-stage renal disease.
2. Background
Nephropathy is a disease that typically develops over a prolonged period (e.g., 10-15 years) during which time the ability of the kidneys to properly function diminishes. Once the disease has progressed to end-stage renal disease (ESRD), a kidney transplant or dialysis may be the only treatment option. The disease is caused, for example, by immune disorders (e.g., IgA nephropathy) or diabetes (e.g., diabetic nephropathy). In either case, nephropathy is characterized by the trapping of protein deposits, such as, the protein immunoglobulin A (IgA), inside glomerular capillaries of the kidney. These glomerular capillaries serve as the kidney's filtration system to filter waste and water from the blood. The protein deposits prevent the glomerular capillaries from properly filtering the blood resulting in high protein levels in the urine.
Once the glomerular capillaries are damaged, they cannot be repaired. Thus, treatment of nephropathy typically involves slowing the progression of the disease rather than curing it. Treatment may consist of, for example, administration of therapeutics, such as angiotensin converting enzyme (ACE) inhibitors which reduce urine protein levels. A solution of the therapeutic may be delivered to the kidneys systemically. Systemic delivery, however, has several disadvantages. In particular, in systemic delivery techniques, the whole organism is treated therefore greater amounts of drugs must be supplied which are sometimes toxic to the organism.
Local delivery techniques may be used to overcome some of the disadvantages of systemic delivery techniques, however, a separate set of problems arise. Typically, in local delivery techniques the therapeutic is injected into a blood stream at a point upstream from the treatment site or into an unperfused vessel region after first occluding the vessel region to inhibit blood flow. In either case, due to the natural laminar flow profiles within the renal artery and kidney and reduced blood flow to diseased kidney regions, the blood flow may not evenly distribute the therapeutic to the desired treatment site.
SUMMARY
According to an embodiment, methods and apparatus for delivery of a treatment agent to a kidney for inhibiting nephropathy or end-stage renal disease are described. Representatively, in one embodiment, a method includes introducing a delivery device to a point within a renal system. The point may be within a renal artery, a renal segmental artery or a renal cortex. The delivery device may include, but is not limited to, a catheter assembly or a stent implant. A treatment agent may be delivered from the delivery device to a treatment site according to conditions that create a turbulent blood flow to facilitate even distribution of the treatment agent at the treatment site. By distributing the treatment agent to the kidney in this manner, the beneficial effects of the treatment agent are maximized at a desired treatment site within the renal system. Delivery of the treatment agent according to conditions that create a turbulent blood flow may include, delivering a treatment agent to a lumen modified to alter a blood flow or injecting a treatment agent into a blood flow in a direction perpendicular to the direction of flow such that a typical laminar flow profile of the blood is altered. Additionally, in one embodiment, delivery further comprises delivering the treatment agent according to conditions that prevent back flow of the treatment agent into, for example, an aorta. In this aspect, a balloon or sheath of the delivery device may be expanded in a vessel region upstream from a point of treatment agent delivery. Alternatively, backflow may be prevented by releasing the treatment agent from a delivery port of the delivery device at a flow rate less than a natural flow rate of the artery. The treatment agent may include a property to inhibit a biological process contributing to nephropathy. Such biological processes may include, but are not limited to, changes in glomerular basement membrane, changes in mesangial matrix deposition and podocyte apoptosis.
In another embodiment, an apparatus is described. Representatively, the apparatus includes a primary cannula having dimensions suitable for insertion into a renal artery and/or a branch thereof such as a renal segmental artery. The primary cannula may include a first end, a second end and a medial portion along a length of the catheter body between the first end and the second end. An aperture may be positioned within the medial portion of the primary cannula such that when the apparatus is positioned within the renal artery the first end is within the renal artery and the aperture is within an aorta. The first end may include a first port and a second port. The first port is in fluid communication with the aperture and both the first port and the aperture are dimensioned to divert blood flowing from an aorta to the renal artery into the aperture and out of the first port. The first end may include a second port that may be adapted for advancing a guidewire therethrough.
According to another embodiment, an apparatus is described that may include a balloon expandable intralumenal framework to create a turbulent flow within a vessel. Representatively, the apparatus may include a balloon expandable intralumenal framework comprising a first end and a second end defining a length dimension less than a length of a renal artery. The framework may include axially-oriented anchor portions along the length dimension capable of anchoring to a vessel lumen. The anchor portions may be wound around a distal end of a primary cannula such that blood may flow through a channel winding around the primary cannula to alter a speed of the blood flow and provide a turbulent flow. The apparatus may further include an inflation cannula for expanding a balloon of the framework and a delivery cannula for delivering a treatment agent within the turbulent flow. In this aspect, the apparatus facilitates mixing and even distribution of the treatment agent throughout the kidney.
According to another embodiment, an apparatus is described having a dilating balloon assembly including pores along a portion of a balloon of the balloon assembly to modify the flow of blood within a vessel lumen and a direction of flow of a treatment agent released from a delivery cannula of the apparatus. The apparatus includes a guidewire cannula having dimensions for insertion into a renal artery and/or a renal segmental artery. A dilatable balloon assembly is connected to the guidewire cannula having a balloon including a distal taper wall. The distal taper wall consists of pores along only a region of the distal taper wall defined by a diameter of a lumen of the artery. The apparatus further includes a delivery cannula having an end within the balloon for dilating the balloon assembly and delivering a treatment agent such that the treatment agent is released into the vessel lumen through the pores.
In still further embodiments, an apparatus is described having a sheath extending from an end of a catheter body to provide a turbulent flow within a vessel and reduce backflow of a treatment agent delivered from the apparatus. The apparatus may include a primary cannula having dimensions for insertion into a renal artery and a lumen dimensioned for inserting a delivery cannula having a sheath extending from an end of the delivery cannula therethrough. The sheath may include an outer diameter substantially equivalent to an inner diameter of a renal artery to retain a same perimeter of the inner diameter of the renal artery when the sheath is deployed. The sheath may be of a material that allows blood flow to a region of the renal artery distal to the sheath to create a turbulent blood flow.
In one embodiment, another apparatus is described including an implant for delivery of a treatment agent. Representatively, in one embodiment the implant may be an intravascular stent implant. The stent implant includes a plurality of struts connected together by a plurality of links. The intravascular stent implant may be dimensioned to be deployed in a renal artery. Alternatively, the intravascular stent implant may be dimensioned to be deployed in a segmental artery. The implant may include a treatment agent for delivery to a kidney. The treatment agent may have a property to inhibit a biological process contributing to nephropathy.



BRIEF DESCRIPTION OF THE DRAWINGS
The features, aspects, and advantages of the invention will become more thoroughly apparent from the following detailed description, appended claims, and accompanying drawings in which:
FIG. 1 illustrates a flow chart of a method for delivering a treatment agent to a kidney.
FIG. 2 shows a cross-sectional side view of a kidney and a method for delivering a treatment agent to the kidney.
FIG. 3 shows a cross-sectional side view of a blood vessel of a renal region and one embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 4 shows a cross-sectional side view of a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 5 shows a cross-sectional side view of a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment to a kidney.
FIG. 6 shows a cross-sectional side view of a blood vessel of a renal region and a perspective view of another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 7 shows a cross-sectional side view of a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 8 shows a cross-sectional side view of a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 9 shows a cross-sectional side view of another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 10 shows a cross-sectional side view of a blood vessel of a renal region and a top side perspective view of the delivery device of FIG. 9 wherein the delivery device is in an expanded configuration.
FIG. 11 shows a cross-sectional side view of another embodiment of a delivery system to deliver a treatment agent to a kidney.
FIG. 12 shows a cross-sectional side view through line A-A′ of one embodiment of a strut of the stent delivery system of FIG. 11.
FIG. 13 shows a cross-sectional side view through line A-A′ of another embodiment of a strut of the stent delivery system of FIG. 11.
FIG. 14 shows a cross-sectional side view through line A-A′ of another embodiment of a strut of the stent delivery system of FIG. 11.



DETAILED DESCRIPTION
FIG. 1 shows a flow chart of a method for delivering a treatment agent to a kidney. In one embodiment, the method includes introducing a delivery device to a point within a renal artery or a renal segmental artery that supplies the renal cortex (block 102). Alternatively, the point may be within a renal cortex of a kidney. The delivery device is intended to broadly include any medical device for insertion into a physiological lumen to permit injection and/or withdrawal of fluids of varying viscosities to maintain patency of a lumen of a blood vessel or an area defining the lumen, or for other purposes. The delivery device may further include any medical device for insertion into a physiological lumen capable of releasing a treatment agent. The point to which the delivery device is introduced may be a treatment site or a region adjacent to a treatment site. The treatment site may be a diseased region within a renal vessel or other tissue of a kidney.
In one embodiment, the treatment agent is delivered according to conditions that create a turbulent blood flow within a region of treatment agent delivery (block 104). The term “turbulent blood flow” as used herein generally refers to a flow profile characterized by a chaotic or agitated blood flow or otherwise modified flow profile which may include rapid variations of pressure, flow direction and/or velocity. For example, in some embodiments, turbulent blood flow is created in a vessel lumen by partially occluding the vessel lumen by about 60 percent (%) to about 95%. Typically, the flow profile of blood flowing through the renal artery to the kidney is laminar, meaning the fluid flows in parallel layers, or streams, with little or no disruption between the layers. This profile continues along the kidney opening, or hilum, and into the segmental arteries leading to the glomerular capillaries within the renal cortex. Thus, when the treatment agent is released from a single point of a delivery device into one of these streams of a healthy kidney most, if not all, of the treatment agent is carried only to the kidney region at the end of the stream. In this aspect, only a small portion of the kidney receives the treatment agent. Moreover, blood flow to the diseased regions especially in need of the treatment agent may be reduced or stop all together as a result of the disease. In such cases, even where the treatment agent is released into a path normally destined for the diseased region, it will not reach the desired treatment region. Such problems may be overcome where turbulence is created within the flow profile and the treatment agent is dispersed into the turbulent blood flow. In particular, the turbulent conditions will facilitate mixing of the treatment agent with the blood and disrupt the pathways typically found within the kidney so that the treatment agent is more evenly distributed throughout the kidney.
In one aspect, conditions creating a turbulent blood flow may include partially occluding a region of the artery lumen so as to provide a constricted pathway for blood flow (e.g., about 60% to about 95% lumen occlusion). The narrowed pathway causes the speed of the blood flowing through the narrower region to increase resulting in turbulent blood flow. The treatment agent may then be injected into the turbulent blood flow. Turbulent blood flow may further be created within a lumen of a delivery device. In this aspect, a fluid, such as a saline or blood, may be delivered through the lumen of the device and a treatment agent may be injected into the flowing fluid. In other embodiments, the conditions creating a turbulent blood flow may include injecting a treatment agent within a vessel lumen in a direction perpendicular to the direction of blood flow. In this aspect, the normal direction of blood flow is altered by the stream of treatment agent bisecting the normal flow path resulting in a turbulent flow. Due to the turbulence, the treatment agent is homogenously distributed throughout the blood for delivery to the treatment site. In addition, the turbulence may disrupt the downstream laminar flow profiles within the kidney. The homogenous distribution of the treatment agent throughout blood flowing to the kidney and disruption of flow profiles within the kidney facilitate an even distribution of the treatment agent solution throughout the kidney tissues.
Delivery of the treatment agent to the treatment site may further be maximized by preventing backflow of the treatment agent. The term “backflow” as used herein generally refers to a flow of treatment agent in a direction opposite to that in which it is desired to be delivered. For example, in some cases the treatment site is unable to retain the full volume of treatment agent being delivered. In this aspect, the extra volume of treatment agent is rejected and, where delivery is within the renal artery, flows into the adjacent aorta (i.e. backflow). In one embodiment, such backflow may be prevented by partially or fully occluding a vessel region upstream from the treatment site before delivering the treatment agent. Blocking may be accomplished, by expanding, for example, a balloon or a sheath of the delivery device within the vessel. The balloon or sheath essentially serves as a backstop to any unabsorbed treatment agent delivered to the treatment site that may begin to flow toward the balloon or sheath. Alternatively, backflow may be prevented by releasing the treatment agent from a delivery port of the delivery device at a flow rate less than a natural flow rate of the artery. For example, it is estimated that a flow rate of blood through the renal artery to the kidney is about 500 milliliters per minute (ml/min), thus in order to prevent backflow, the treatment agent may be delivered within the renal artery at a flow rate less than about 500 ml/min.
In other embodiments, delivery of an effective amount of the treatment agent to the treatment site may be maximized by altering a particle size of the treatment agent. As illustrated in FIG. 2, a lower branch of aorta 200 feeds blood to kidney 204 through renal artery 202. Renal artery 202 branches off into renal segmental arteries 206, 208, 210 and 212 and arterioles 214. Each arteriole 214 in turn leads to a tuft of capillaries 216, also known as a glomerulus. Blood from segmental arteries 206, 208, 210 and 212 flows into the glomerulus at the end of each segmental artery 206, 208, 210 and 212 where it is filtered to remove fluid and solutes from the blood. In one embodiment, as illustrated in FIG. 2, a distal end of delivery device 224 may be positioned at a point within renal artery 202. Alternatively, delivery device 224 may be positioned at a point within renal segmental arteries 206, 208, 210 and 212. A proximal portion of delivery device 224 remains outside of the body to facilitate loading of the treatment agent within delivery device 224. Representatively, a femoral artery may be punctured and delivery device 224 may be advanced through the femoral artery, to aorta 200 and then into renal artery 202. Alternatively, delivery device 224 may be advanced through a brachial artery, down aorta 200 and into renal artery 202. In still further embodiments, an external iliac artery may be punctured and delivery device 224 may be advanced through the external iliac artery to a common iliac artery, to aorta 200 and then into renal artery 202.
It is further contemplated that delivery device 224 may be introduced to a point within kidney 204 via a retroperitoneal insertion technique. In this aspect, a distal end of delivery device 224 may be inserted through a back of a patient adjacent kidney 204. Delivery device 224 may then be advanced through a surface of kidney 204 to a point within renal cortex 218 adjacent to glomerulus 216. In this aspect, when the treatment agent is delivered via delivery device 224, the treatment agent is localized to an area proximal to glomerular capillaries within the kidney to facilitate treatment of the kidney. Alternatively, delivery device 224 may be introduced through a back region of the patient and into renal artery 202. In this embodiment, the treatment agent may then be delivered by delivery device 224 through renal artery 202 to a desired treatment site.
In an embodiment illustrated in FIG. 2, a treatment agent loaded within delivery device 224 may be released into, for example, renal artery 202 such that the treatment agent flows through segmental artery 208 and into glomerulus 216. In one embodiment, the treatment agent may be loaded into a carrier having a large enough diameter such that the carrier becomes lodged within a narrow lumen of a capillary within the glomerulus 216. This aspect is shown in the exploded view of glomerulus 216 of FIG. 2. In this embodiment, treatment agent 220 flows into glomerulus 216 and becomes lodged within the lumen. For example, in some embodiments the treatment agent may have a diameter from about 8 microns to about 15 microns. Thus, release of the treatment agent from within the carrier is localized to glomerulus 216. Thus, delivery of the treatment agent may be confined to a specific treatment site within the kidney.
Treatment Agents
As used herein, treatment agents are intended to include, but are not limited to, drugs, biologically active agents, chemically active agents, therapeutic agents, and the like, and pharmaceutical compositions thereof, which can be used to deliver a treatment agent to a treatment site within a kidney as described herein. The treatment agents are delivered alone or in combination to the treatment site.
In one embodiment, the treatment agent may include a property to inhibit a biological process contributing to nephropathy. Such biological processes may include, but are not limited to, changes in glomerular basement membrane, changes in mesangial matrix deposition and podocyte attachment and/or apoptosis.
In one embodiment, the treatment agent may include a drug. The drug may have a property to inhibit undesirable effects of the renin-angiotensin system in the kidneys. The renin-angiotensin system responds to a decrease in the perfusion of the juxtaglomerular apparatus found in afferent arterioles of the glomerulus of the kidney by constricting glomerular arterioles. Such constriction causes blood to build up in the glomerulus and increase glomerular pressure. Representative drugs that may act to inhibit this process include, but are not limited to, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and renin inhibitors.
In still further embodiments, the treatment agent may include a drug to inhibit protein kinase C. Representative drugs may include, but are not limited to, ruboxistaurin (LY333531), enzastaurin (LY317615), bisindolylmaleimide IX, chelerythrine, edelfosine, edelfosina, ET18OCH3, H-7, HA-100, H89, HA-1004, Ro 31-8220, rottlerin, staurosporine and quercetin.
The transforming growth factor-beta system contributes to the progression of renal damage due to stimulation of extracellular matrix deposition. Thus, in further embodiments, the treatment agent may include an agent having a property to inhibit transforming growth factor beta, its receptor and SMAD and other signaling molecules downstream of the receptor. Representative inhibitors may include, but are not limited to antisense molecules, ribozymes, siRNA, antibodies, receptor kinase inhibitors and other small molecule inhibitors such as halofuginone, sirolimus, everolimus, biolimus ABT578 and nuclear receptor agonists such as estradiol, retinoids, and peroxisome proliferator-activated receptors (PPAR) agonists.
It is further recognized that connective tissue growth factor (CTGF) is present in glomeruli in patients with diabetic nephropathy. CTGF is a member of the centrosomin (CCN) family of proteins, which regulate biological processes including stimulation of cell proliferation, migration, and adhesion. It is believed that expression of CTGF in diabetic kidneys contributes to the development of glomerulosclerosis by affecting matrix synthesis and its turnover. In this aspect, the treatment agent may include an agent having a property to inhibit connective tissue growth factor. Representative agents having a property to inhibit connective tissue growth factor may include, but are not limited to antibodies, interleukin-1 (IL-1) alpha and beta, Rho A GTPase inhibitors, and p38 MAP kinase inhibitors.
In some embodiments, the treatment agent may be modified to enhance uptake of the agent into the desired tissue. In this aspect, the treatment agent may be delivered to the desired tissue in a formulation which may include vasoactive agents as enhancers of vascular permeability called excipients, such as thrombin, bradykinin and histamine. These excipients have properties which increase endothelial porosity and thereby enhance uptake of the treatment agent into the tissue.
The treatment agent may be delivered in a form including, but not limited to, a solution. For example, in some embodiments, a desired amount of treatment agent is mixed with saline or an iodine free-contrast media to form the solution.
In some embodiments, the treatment agent may be delivered to the desired tissue in a carrier. In one aspect, the carrier may be a sustained-release carrier which allows for controlled release of the treatment agent over time at the desired treatment site. “Carrier” includes a matrix that contains one or more treatment agents. A suitable carrier may take the form of a nanoparticle (e.g., nanosphere), microparticle (e.g., microsphere) or liposome as the situation may dictate. The carrier with the treatment agent encapsulated inside may be incorporated into a solution including an oily solution for delivery to the desired tissue.
The carrier may be a bioerodable carrier (hereinafter interchangeably referred to as sustained-release carriers) infused with a treatment agent. Suitable materials for sustained-release carriers include, but are not limited to, encapsulation polymers such as poly(L-lactide), poly(D,L-lactide), poly(glycolide), poly(lactide-co-glycolide), polycaprolactone, polyanhydride, polydiaxanone, polyorthoester, polyamino acids, or poly(trimethylene carbonate), and combinations thereof.
Treatment agents, including treatment agents combined with a carrier (e.g., a sustained release carrier), having a size greater than about 10 microns have the potential, when introduced into the renal artery, of being trapped in the glomerular capillaries. In this aspect, the treatment agent may be released over time at a point within the glomerular capillaries. In other embodiments, the carrier size may be between about 1 micron to 100 microns, still further between about 8 microns to about 15 microns and in some embodiments between about 1 micron to 2 microns. In other embodiments, the carrier size may be between about 10 microns and 14 microns. In still further embodiments where the treatment agent is delivered at a point outside of a vessel lumen, such as the kidney cortex, the treatment agent or a carrier encapsulating the treatment agent may be any size capable of being delivered through a lumen of the delivery device, such as for example, a size as small as one nanometer (nm) to as large as about 100 microns.
Various methods may be employed to formulate and infuse the carrier with one or more treatment agents. The embodiments of the composition of infused carrier may be prepared by conventional methods where all components are combined then blended. In some embodiments, carriers may be prepared using a predetermined amount of a polymer or a pre-polymer that is added to a predetermined amount of a solvent or a combination of solvents. The solvent is mutually compatible with the polymer and is capable of placing the polymer into solution at the concentration desired in the solution. Examples of solvents may include, but are not limited to, dimethylsulfoxide (DMSO), Dimethyl Acetamide (DMAC), chloroform, acetone, water (buffered saline), xylene, acetone, methanol, ethanol, 1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide, dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone, propylene glycol monomethylether, isopropanol, N-methylpyrrolidinone, toluene and mixtures thereof.
By way of example, and not limitation, the polymer may comprise from about 0.1% to about 35%, more narrowly about 2% to about 20% by weight of the total weight of the total solution, and the solvent may comprise from about 65% to about 99.9%, more narrowly about 80% to about 98% by weight, of the total weight of the total solution. A specific weight ratio is dependent on factors such as the material from which the delivery device is made and the geometrical structure of the device.
Sufficient amounts of treatment agent are dispersed or dissolved in the carrier. The amount of treatment agent introduced into the carrier may be any amount sufficient to inhibit a biological process contributing to nephropathy when released within the renal system. The treatment agent may be in solution or suspension. If the treatment agent is not completely soluble in the composition, operations including mixing, stirring, and/or agitation may be employed to effect homogeneity. The treatment agent may be added so that the dispersion is in fine particles. The mixing of the treatment agent may be conducted in an anhydrous atmosphere, at ambient pressure and at room temperature.
In some embodiments using microparticles and/or nanoparticles, the microparticles and/or nanoparticles may be sustained release carriers prepared by a water/oil/water (W/O/W) double emulsion method. The W1 phase, an aqueous phase containing treatment agent, is dispersed into the oil phase consisting of polymer dissolved in organic solvent (e.g., dichloromethane) using a high-speed homogenizer. Examples of sustained-release polymers that may be used include, but are not limited to, poly(D,L-lactide-co-glycolide) (PLGA), poly(D,L-lactide) (PLA) or PLA-PEEP co-polymers, poly-ester-amide co-polymers (PEA) and polyphophazines. The primary water-in-oil (W/O) emulsion is then dispersed to an aqueous solution containing a polymeric surfactant, e.g., poly(vinyl alcohol) (PVA), and further homogenized to produce a W/O/W emulsion. After stirring for several hours, the microparticles and/or nanoparticles are collected by filtration.
In some embodiments, the sustained-release carrier is a liposome. “Liposomes” are artificial vesicles that are approximately spherical in shape and can be produced from natural phospholipids and cholesterol. In one method, phospholipids are mixed with cholesterol in chloroform. Suitable phospholipids include, but are not limited to, dimyristoyl phosphatidyl choline or dipalmitoyl phosphatidyl ethanolamine. In some embodiments, a hydrophobic treatment agent may be added with an optional co-solvent. After mixing, the solvent (and optional co-solvent) may be evaporated with heat or ambient temperature in a round bottom flask. Resultant lipids may be deposited on the glass surface. In some embodiments, a hydrophilic treatment agent and water may be added to the flask and sonicated to form liposomes. The resultant solution may be pressure filtered through ceramic pore size controlled filters to reduce liposome particle size. In still further embodiments, the carrier is a microbubble formed by any technique deemed desirable.
In some embodiments, a surface of the carrier may be modified to enhance affinity of the encapsulated treatment agent to tissue lining the walls of the glomerular capillaries. In this aspect, the surface may be coated with binding agents. The binding agent may include a protein or small molecule that will facilitate retention of the carrier and encapsulated treatment agent at the treatment site so as to induce and/or modulate a therapeutic response through interaction with a specific binding site (e.g., a receptor within a cell or on a cell surface). Representative binding agents and their associated receptors include, but are not limited to, CD11b/CD18 (MAC-1) or aL/beta2 integrin (LFA-1) and intracellular adhesion molecule-1 (ICAM-1) receptor, integrin avb3 which binds to RGD-containing peptide and E-selectin which binds to Sialyl-Lewis glycoprotein.
A surface charge of the carrier may further be modified (e.g., positively, negatively or neutral) to accommodate and enhance binding characteristics to the glomerular tissue. The endothelial cells and basement membrane along the normal glomerular capillary walls are typically electronegatively charged. As diseases such as glomerulosclerosis and diabetic nephropathy progresses, however, these cells slowly lose the electronegative charge. It is believed that modifying the carriers to have an electropositive charge will enhance binding of the carrier and encapsulated agent within the capillary. In this aspect, a carrier encapsulating the treatment agent may be modified by any standard method suitable for providing the carrier surface with an electropositive charge. In one embodiment, positively charged carriers may be made by coating carriers with Chitosan. Alternatively, positively charged carriers may be made, for example, entirely of Chitosan in a water-in-oil emulsion process and crosslinked with glutaraldehye or genipin. In this aspect, the treatment agent may be swell loaded in the crosslinked spheres. Still further, if the treatment agent is soluble at pH 5, the treatment agent may be incorporated into the initial Chitosan solution, provided it does not subsequently react with the aldehyde crosslinker. Another approach for forming cationic carriers may include using a poly-lysine graft of PLGA.
In still further embodiments, a surface of the carrier may be coated with active agents or other species to enhance the range of functionalities of the product. For example, the surface may be coated with a monoclonal antibody that selectively binds to proteins expressed within the glomerulus (glomerular endothelium, basement membrane, podocytes) and tubules (tubular epithelium and basement membrane). A representative example is the monoclonal antibody anti CD90/Thy 1 that binds to OX-7 a glomerular basement membrane protein. Other proteins to target include nephrin and podocin.
Delivery Devices
FIG. 3 shows blood vessels of a renal region and one embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 3 shows a renal artery 302 extending from aorta 304 and having a delivery device 300 disposed therein. Delivery device 300 includes a proximal portion 308 and a distal portion 310. Proximal portion 308 may be external to renal artery 302 and to the patient. Representatively, delivery device 300 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 314 to a location in a renal artery or renal segmental artery of a patient. Alternatively, delivery device 300 may be introduced to the point within the renal system of the patient by inserting delivery device 300 through a region of the patient's back adjacent a kidney and then advancing delivery device 300 into the kidney renal cortex or a renal artery. FIG. 3 shows distal portion 310 of delivery device 300 positioned at a point within renal artery 302. Alternatively, delivery device 300 may be positioned at a point within a renal segmental artery or a renal cortex.
In one embodiment, delivery device 300 includes a primary cannula 312 having a length that extends from proximal portion 308 (e.g., located external to a patient during a procedure) to distal portion 310. Primary cannula 312 has a lumen therethrough sized to accommodate a guidewire cannula 316 and a delivery cannula 318. It is contemplated that primary cannula 312 may be a single lumen catheter as illustrated in FIG. 3 or, in some embodiments, a dual lumen catheter. In some embodiments where delivery device 300 is introduced to a location within a renal artery, guidewire cannula 316 and delivery cannula 318 may have a width of about 5 French to about 7 French (3 French=1 mm). In other embodiments where delivery device 300 is introduced to a location within a renal segmental artery, guidewire cannula 316 and delivery cannula 318 may have a width of about 2 French to about 4 French.
Delivery cannula 318 may extend from proximal portion 308 of delivery device 300 to distal portion 310. Delivery cannula 318 may have a distal end that is occluded 320. Holes 322 are disposed along a length of the distal end so that the treatment agent is emitted from holes 322 in a direction perpendicular to the direction of blood flow. Delivery of the treatment agent perpendicular to the direction of blood flow, in addition to the narrowing of the vessel lumen due to device 300, disrupts the blood flow thereby creating turbulent conditions. The turbulence facilitates mixing of the treatment agent into the blood flow and even distribution of the treatment agent at the desired treatment site, for example, distal to deliver device 300. Additionally, emitting the treatment agent out of the sides of the device in this manner does not increase a flow rate of fluid (e.g., mixture of blood and treatment agent) delivered to the treatment site therefore backflow from the delivery of the mixture of blood and treatment agent into the treatment site is minimized.
Guidewire cannula 316 has a lumen sized to accommodate a guidewire 314. Delivery device 300 may be an over the wire (OTW) configuration wherein guidewire cannula 316 extends from a proximal end (e.g., external to a patient during a procedure) to a distal end of delivery device 300. Guidewire cannula 316 may also be used for delivery of a treatment agent such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomeruli of the kidney when guidewire 314 is removed with delivery device 300 in place. In such case, separate delivery cannula (i.e., delivery cannula 318) is unnecessary. Alternatively, delivery cannula 318 may be used to deliver one treatment agent while guidewire cannula 316 is used to deliver another treatment agent.
In another embodiment, catheter assembly 300 is a rapid-exchange-type (RX-type) delivery device and only a portion of catheter assembly 300 (e.g., a distal portion 310) is advanced over guidewire 314. In a RX-type of delivery device, typically, the guidewire cannula extends from the distal end of the delivery device to the proximal guidewire port which is typically spaced a substantial distance from the proximal end of the delivery device.
FIG. 4 shows a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 4 shows a renal artery 402 branching off of aorta 404 and having a delivery device 400 disposed therein. Delivery device 400 includes a proximal portion 406 and a distal portion 408. Proximal portion 406 may be external to renal artery 402 and to the patient. Representatively, delivery device 400 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 410 to a location in a renal artery or renal segmental artery of a patient. FIG. 4 shows distal portion 408 of delivery device 400 positioned at a point within renal artery 402. Alternatively, delivery device 400 may be positioned at a point within a renal segmental artery.
In one embodiment, delivery device 400 includes a primary cannula 412 having a length that extends from proximal portion 406 (e.g., located external to a patient during a procedure) to connect with a proximal end or skirt of a balloon 420. Primary cannula 412 has a lumen therethrough that includes a guidewire cannula 414, a delivery cannula 416 and an inflation cannula 418. Delivery cannula 416 may extend from proximal portion 406 of delivery device 400 to distal portion 408. Inflation cannula 418 further extends from proximal portion 406 of delivery device 400 to distal portion 408. Inflation cannula 418 has a distal end that terminates within balloon 420. In one embodiment, catheter assembly 400 is introduced into renal artery 402 and balloon 420 is inflated via inflation cannula 418.
Primary cannula 412, as well as those described in reference to other embodiments, may be a polymer material that may include markers to allow the cannula to be identified using fluoroscopic or angiographic techniques. For example, a metal band (e.g., stainless steel, platinum, or tungsten loaded polymer) that may be detected by fluoroscopic or angiographic techniques.
Balloon 420 is connected to a distal end of delivery device 400 and is in fluid communication with inflation cannula 418. Balloon 420 includes balloon wall or membrane 422 which is selectively inflatable to dilate from a collapsed configuration to a desired and controlled expanded configuration. Balloon 420 can be selectively expanded by supplying a fluid into inflation cannula 418 at a predetermined rate of pressure through a delivery port 424. Balloon wall 422 is selectively deflatable, after inflation, to return to the collapsed configuration or a deflated profile. In one embodiment, balloon wall 422 can be defined by three sections, distal taper wall 426, medial working length 428, and proximal taper wall 430. In one embodiment, proximal taper wall 430 can taper at any suitable angle θ, typically between about 10° to less than about 90°, when balloon 420 is in the expanded configuration.
Distal taper wall 426, medial working length 428, and proximal taper wall 430 of balloon wall 422 can be bound together by seams or be blown out of a single seamless material. Balloon 420 can be made from any suitable material, including, but not limited to, polymers and copolymers of polyolefins, polyamides, polyesters and the like. The specific material employed must be mutually compatible with the fluids employed in conjunction with balloon 420 and must be able to withstand the pressures that are developed within balloon 420. Balloon wall 422 can have any suitable thickness so long as the thickness does not compromise properties that are critical for achieving optimum performance. Such properties include high burst strength, low compliance, good flexibility, high resistance to fatigue, the ability to fold, the ability to cross and re-cross a desired region of treatment or an occluded region in a lumen, and low susceptibility to defect caused by handling. By way of example, and not limitation, the thickness can be in the range of about 0.0005 inch to about 0.003 inch, the diameter of balloon 320 in the expanded configuration can be in the range of about 2 millimeters (mm) to about 10 mm, and the length can be in the range of about 3 mm to about 40 mm. The specific specifications, however, may vary depending on the procedure for which balloon 420 is to be used and the anatomy and size of the target lumen in which balloon 420 is to be inserted.
Balloon 420 may be expanded by the introduction of a liquid into inflation cannula 418. In one embodiment, liquids containing therapeutic and/or diagnostic agents may be used to inflate balloon 420. In other embodiments, delivery cannula 416 may have a distal end terminating in balloon 420 and inflation cannula 418 may be removed. In this embodiment, balloon 420 may have micropores. In this aspect, a treatment agent such as those described above may be introduced through a delivery lumen (e.g., inflation cannula 418) to expand the balloon (e.g., balloon 420). The treatment agent will expand balloon 420 at relatively low pressure (e.g., 2-3 atm) and diffuse through the pores to a treatment site, such as glomerular capillaries, within the kidney. In some embodiments, the balloon may be expanded to a dimension which partially occludes artery 402 such that blood continues to flow past balloon 420. Partial occlusion may provide a turbulent blood flow distal to delivery device 400 due to the narrowing of the region through which the blood must pass. Partial occlusion may include from about 60% to about 95% lumen occlusion. In this aspect, the treatment agent may be infused into the turbulent blood flow through the pores or an end of delivery cannula 416 distal to balloon 420 into a turbulent blood flow distal to delivery device 400. In this aspect, a homogenous distribution of the treatment agent within the blood flowing to the kidney is achieved. Still further, since the balloon is inflated, backflow is minimized.
In another embodiment, delivery device 400 may include a perfusion shaft (illustrated with a broken line in FIG. 4) to allow blood to continue to flow to a vessel region distal to balloon 420 when balloon 420 is fully inflated to occlude the vessel lumen. In this embodiment, primary cannula 412 is omitted and guidewire cannula 414 includes holes through portions of a wall of guidewire cannula 414 located proximal and distal to balloon 420. In this aspect, guidewire 410 is positioned proximal to an end of guidewire cannula 414 (e.g., about 10 centimeters from the end), and more specifically proximal to the openings, such that blood is free to flow into holes proximal to balloon 420, through guidewire cannula 414 and out the holes of guidewire cannula 414 distal to balloon 420. In this aspect, although the vessel lumen is completely occluded, blood continues to flow to a region upstream from balloon 420 and a turbulent blood flow is created within this region. In this embodiment, balloon 420 may be a porous balloon such that upon delivery of a treatment agent solution through inflation cannula 418 to inflate balloon 420, the solution diffuses through pores of balloon 420 and into the region of turbulent blood flow. In this aspect, delivery cannula 416 may be omitted. Alternatively, balloon 420 may be nonporous and delivery cannula 416 is used to deliver a treatment agent to the region of turbulent blood flow downstream from balloon 420. Although a substantially round balloon is shown in FIG. 4, it is contemplated that for this embodiment, balloon may have any shape deemed desirable for occluding the lumen of blood vessel 402, for example, conical/square, tapered stepped, and offset.
In one embodiment, balloon 420 is a conventional nonporous balloon. In other embodiments, balloon 420 is a porous material such as PEBAX®, Nylon or polyethylene terephthalate (PET) that has tens or hundreds of micropores around its circumference for treatment agent diffusion. A suitable pore size may range, for example, from about 4 microns to about 400 microns, in some embodiments from about 10 microns to about 100 and in some embodiments from about 8 microns to about 15 microns. Still further, the pore size may have a size of at least four times the diameter of a particle to be delivered. Pores may be created by mechanical means or by laser perforation. Pore distribution along a balloon surface may be inhomogeneous to tailor distribution of treatment agent delivery. Balloon 420 may also be retractable into optional sheath (not shown) to tailor a length of a treatment agent delivery region. In an alternative embodiment, the sheath may have an opening on one side to preferentially deliver a treatment agent to one side of the vessel.
Guidewire cannula 414 extends through balloon 420. Guidewire cannula 414 has a lumen sized to accommodate a guidewire 410. Delivery device 400 may be an over the wire (OTW) configuration wherein guidewire cannula 414 extends from a proximal end (external to a patient during a procedure) to a distal end of delivery device 400. Guidewire cannula 414 may also be used for delivery of a treatment agent as previously described such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomerular tissue of the kidney when guidewire 410 is removed with delivery device 400 in place. In such case, separate delivery cannula (i.e., delivery cannula 416) may be unnecessary or a delivery cannula may be used to deliver one treatment agent while guidewire cannula 414 is used to deliver another treatment agent.
In another embodiment, delivery device 400 is a RX-type catheter assembly and only a portion of delivery device 400 (e.g., a distal portion 408 including balloon 420) is advanced over guidewire 410. In a RX-type of catheter assembly, typically, the guidewire cannula/lumen extends from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
FIG. 5 shows a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 5 shows a renal artery 502 branching off of aorta 504 and having a delivery device 500 disposed therein. Delivery device 500 includes a proximal portion 506 and a distal portion 508. Proximal portion 506 may be external to renal artery 502 and to the patient. Representatively, delivery device 500 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 510 to a location in a renal artery or renal segmental artery of a patient. FIG. 5 shows distal portion 508 of delivery device 500 positioned at a point within renal artery 502. Alternatively, delivery device 500 may be positioned at a point within a renal segmental artery near the renal cortex.
In one embodiment, catheter assembly 500 includes a primary cannula 512 having a length that extends from proximal portion 506 (e.g., located external to a patient during a procedure) to connect with a proximal end or skirt of a balloon 520. Primary cannula 512 has a lumen therethrough that includes a guidewire cannula 514, a delivery cannula 516 and an inflation cannula 518. Primary cannula 514 may be a polymer material that may include markers to allow the cannula to be identified using fluoroscopic or angiographic techniques. For example, a metal band (e.g., stainless steel, platinum, or tungsten loaded polymer) that may be detected by fluoroscopic or angiographic techniques.
Delivery cannula 516 may extend from proximal portion 506 of delivery device 500 to distal portion 508. A distal end of delivery cannula 516 may be occluded 522 so as to prevent fluids from being released out the end. In this aspect, openings 524 may be provided along a length of the distal portion 508 of delivery cannula 516 between balloon 520 and occluded end 522 for delivery of a treatment agent.
Inflation cannula 518 extends from proximal portion 506 of delivery device 500 to distal portion 508. Inflation cannula 518 has a distal end that terminates within balloon 520. Balloon 520 is incorporated at a distal end of delivery device 500 and is in fluid communication with inflation cannula 518. In one embodiment, catheter assembly 500 is introduced into renal artery 502 and balloon 520 is inflated via inflation cannula 518.
Balloon 520 includes balloon wall or membrane 526 which is selectively inflatable to dilate from a collapsed configuration to a desired and controlled expanded configuration. Balloon 520 can be selectively dilated (inflated) by supplying a fluid into inflation cannula 518 at a predetermined rate of pressure through a delivery port 534. Balloon wall 526 is selectively deflatable, after inflation, to return to the collapsed configuration or a deflated profile. In one embodiment, balloon wall 526 can be defined by three sections, distal taper wall 528, medial working length 530, and proximal taper wall 532. In one embodiment, proximal taper wall 528 can taper at any suitable angle θ, typically between about 10° to less than about 90°, when balloon 520 is in the expanded configuration.
Distal taper wall 528, medial working length 530, and proximal taper wall 532 of balloon wall 526 can be bound together by seams or be blown out of a single seamless material. Balloon 520 can be made from any suitable material, including, but not limited to, polymers and copolymers of polyolefins, polyamides, polyesters and the like. The specific material employed must be mutually compatible with the fluids employed in conjunction with balloon 520 and must be able to stand the pressures that are developed within balloon 520. Balloon wall 522 can have any suitable thickness so long as the thickness does not compromise properties that are critical for achieving optimum performance. Such properties include high burst strength, low compliance, good flexibility, high resistance to fatigue, the ability to fold, the ability to cross and re-cross a desired region of treatment or an occluded region in a lumen, and low susceptibility to defect caused by handling. By way of example, and not limitation, the thickness can be in the range of about 10 microns to about 30 microns, the diameter of balloon 320 in the expanded configuration can be in the range of about 2 millimeters (mm) to about 10 mm, and the length can be in the range of about 3 mm to about 40 mm, the specific specifications depending on the procedure for which balloon 520 is to be used and the anatomy and size of the target lumen in which balloon 520 is to be inserted.
Balloon 520 may be expanded by the introduction of a liquid into inflation cannula 518. In one embodiment, liquids containing a treatment agent may be used to inflate balloon 520. In this embodiment, balloon 520 may have micropores. A treatment agent such as those described above may be introduced through a delivery lumen (e.g., delivery cannula 516 or inflation cannula 518) to expand the balloon (e.g., balloon 520). The treatment agent will expand balloon 520 at relatively low pressure (e.g., 2-3 atm) and diffuse through the pores to a treatment site, such as glomerular capillaries, within the kidney. In this aspect, one or more treatment agents may be delivered through pores of balloon 520 and another through openings 524 of delivery cannula 516. Balloon 520 is inflated to a diameter which partially occludes artery 502 such that blood continues to flow to a region of artery 502 distal to balloon 520. In this aspect, the treatment agent is released from openings 524 or micropores 520 and is delivered to the stream of blood flowing around balloon 520 or distal to balloon 520 in a direction perpendicular to the direction of blood flow. The partial occlusion of the lumen of renal artery 502 and/or delivery of a treatment agent in a direction perpendicular to blood flow create turbulent delivery conditions which facilitate mixing and even distribution of the treatment agent.
In one embodiment, balloon 520 is a conventional nonporous balloon material or a porous material such as PEBAX®, Nylon or PET that has tens or hundreds of micropores around its circumference for treatment agent diffusion. A suitable pore size may range, for example, from about 4 microns to about 400 microns, in some embodiments from about 10 microns to about 100 and in some embodiments from about 8 microns to about 15 microns. Still further, the pore size may have a size of at least four times the diameter of a particle to be delivered. Pores may be created by mechanical means or by laser perforation. Pore distribution along a balloon surface may be inhomogeneous to tailor distribution of treatment agent delivery. Balloon 520 may also be retractable into optional sheath (not shown) to tailor a length of treatment agent delivery. In an alternative embodiment, the sheath may have an opening on one side to preferentially deliver a treatment agent to one side of the vessel.
Guidewire cannula 514 extends through balloon 520. Guidewire cannula 514 has a lumen sized to accommodate a guidewire 510. Delivery device 500 may be an over the wire (OTW) configuration wherein guidewire cannula 514 extends from a proximal end (external to a patient during a procedure) to a distal end of delivery device 500. Guidewire cannula 514 may also be used for delivery of a treatment agent such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomerular tissue of the kidney when guidewire 510 is removed with delivery device 500 in place. In such case, separate delivery cannula (i.e., delivery cannula 516) may be unnecessary or a delivery cannula may be used to deliver one treatment agent while guidewire cannula 514 is used to deliver another treatment agent.
In another embodiment, delivery device 500 is a RX-type catheter assembly and only a portion of delivery device 500 (a distal portion 508 including balloon 520) is advanced over guidewire 510. In a RX-type of catheter assembly, typically, the guidewire cannula/lumen extends from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
FIG. 6 shows a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 6 shows a renal artery 602 extending from aorta 604 and having a delivery device 600 disposed therein. Delivery device 600 includes a proximal portion 606 and a distal portion 608. Proximal portion 606 may be external to renal artery 602 and to the patient. Representatively, delivery device 600 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 614 to a location in a renal artery or renal segmental artery of a patient. In still further embodiments, an external iliac artery may be punctured and delivery device 600 may be advanced through the external iliac artery to a common iliac artery, to aorta 604 and then into renal artery 602. Alternatively, delivery device 600 may be introduced to the point within the renal artery of the patient by inserting delivery device 600 through a region of the patient's back adjacent a kidney and then into the renal artery. In still further embodiments, delivery device 600 may be introduced to a point within a renal cortex of a kidney adjacent glomerular capillaries by inserting delivery device 600 through a region of the patient's back and advancing the delivery device through a region of a retroperitoneal cavity surrounding a kidney into a region of a renal cortex adjacent to glomerular capillaries. FIG. 6 shows distal portion 608 of delivery device 600 positioned at a point within renal artery 602.
In one embodiment, delivery device 600 includes a primary cannula 612 having a length that extends from proximal portion 606 (e.g., located external to a patient during a procedure) to distal portion 608. A medial portion 622 of primary cannula 612 extends between a first end 630 and a second end 632 of primary cannula 612. An aperture 620 may be formed within a wall of primary cannula 612 along medial portion 622. Aperture 620 may be positioned along the wall of primary cannula 612 at a distance from first end 630 of primary cannula 612 such that when first end 630 is positioned within renal artery 602, aperture 620 is positioned within aorta 604. When delivery device 600 is positioned in this manner, aperture 620 is within a stream of blood flowing from aorta 604 and into renal artery 602. In this aspect, blood flowing from aorta 604 to renal artery 602 may be diverted through aperture 620 and into a lumen of primary cannula 612 such that it flows toward first end 630 of primary cannula 612. Aperture 620 may have dimensions suitable to allow a plurality of blood cells to flow therethrough. In one embodiment, aperture 620 is substantially the same size or greater than a size of a first port 628. Representatively, in some embodiments, aperture 620 may have a diameter of from about 0.25 mm to about 3 mm depending upon the diameter of the inner lumen of the catheter or first port 628. It is further contemplated that the diameter of aperture 620 may be adjusted or selected depending on the amount of blood desired to flow therethrough. This diversion of the blood flow into the lumen of primary cannula 612 creates a turbulent blood flow within the lumen. A treatment agent may be released into the turbulent blood flow such that it mixes with the blood to provide a treatment agent and blood solution which flows out first port 628 to the treatment site.
Primary cannula 612 may be a polymer material that may include markers to allow the cannula to be identified using fluoroscopic or angiographic techniques. For example, a metal band (e.g., stainless steel, platinum, or tungsten loaded polymer) that may be detected by fluoroscopic or angiographic techniques.
The lumen of primary cannula 612 includes a guidewire cannula 614, a flush cannula 616 and a delivery cannula 618. First end 630 may include a first port 628 in fluid communication with aperture 620 so that blood flowing into aperture 620 flows through the lumen of primary cannula 612 and out first port 628 to the treatment site. Still further, first port 628 may be in fluid communication with delivery cannula 618 and flush cannula 616. First end 630 may include a second port 626. Second port 626 is dimensioned to receive a guidewire 610 extending through guidewire cannula 614.
Delivery cannula 618 may extend from proximal portion 606 of delivery device 600 to distal portion 608. A distal end of delivery cannula 618 may terminate within distal portion 608 such that a treatment agent delivered from the distal end of delivery cannula 618 is released within the turbulent blood flow created within the lumen of distal portion 608 of primary cannula 612. Alternatively, the distal end of delivery cannula 618 extends through first port 628 such that a treatment agent delivered from delivery cannula 618 is released within the turbulent conditions that may be created within the lumen of renal artery 602.
Flush cannula 616 may extend from proximal portion 606 of delivery device 600 to distal portion 608. Alternatively, flush cannula 616 may be a cannula which terminates within proximal portion 606 of delivery device 600. Blood or another fluid, such as saline, may be loaded into flush cannula 616 at a proximal end of delivery device 600 and infused through the lumen of primary cannula 612 to push or wash out treatment agent and/or blood debris within primary cannula 612. Still further, the delivery of blood and/or other solutions through flush cannula 612 may create a turbulent blood flow either within the lumen of primary cannula 612 or vessel within which delivery device 600 is positioned.
Guidewire cannula 614 has a lumen sized to accommodate a guidewire 610. Delivery device 600 may be an over the wire (OTW) configuration wherein guidewire cannula 614 extends from a proximal end (e.g., external to a patient during a procedure) to a distal end of delivery device 600. Guidewire cannula 614 may also be used for delivery of a treatment agent such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomerular tissue of the kidney when guidewire 610 is removed with delivery device 600 in place. In such case, separate delivery cannula (delivery cannula 618) is unnecessary or a delivery cannula may be used to deliver one treatment agent while guidewire cannula 614 is used to deliver another treatment agent.
In another embodiment, catheter assembly 600 is a RX-type catheter assembly and only a portion of catheter assembly 600 (a distal portion 608) is advanced over guidewire 610. In a RX-type of catheter assembly, typically, the guidewire cannula/lumen extends from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
FIG. 7 shows a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 7 shows a renal artery 702 extending from aorta 704 and having a delivery device 700 disposed therein. Delivery device 700 includes a proximal portion 706 and a distal portion 708. Proximal portion 706 may be external to renal artery 702 and to the patient. Representatively, delivery device 700 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 714 to a location in a renal artery or renal segmental artery of a patient. FIG. 7 shows distal portion 708 of delivery device 700 positioned at a point within renal artery 702. Alternatively, delivery device 700 may be positioned at a point within a renal segmental artery near the renal cortex.
In this embodiment, delivery device 700 includes primary cannula 712 that has a lumen of a sufficient size to accommodate a guidewire cannula 714 and a delivery cannula 716. In this manner, delivery device 700 may be advanced over guidewire 710 within guidwire cannula 714 to a region of interest or a treatment site. In one embodiment, primary cannula 712 extends from a proximal end of the delivery device intended to be exterior to a patient during a procedure to a distal end of a delivery device. Primary cannula 712 may be a polymer material that may include markers to allow the cannula to be identified using fluoroscopic or angiographic techniques. For example, a metal band (e.g., stainless steel, platinum, or tungsten loaded polymer) that may be detected by fluoroscopic or angiographic techniques.
In the embodiment shown in FIG. 7, delivery device 700 includes an intralumenal framework having a balloon 720 wrapped/spiraled at a distal end around primary cannula 712. In the embodiment shown, balloon 720 includes distal spiral 720A and proximal spiral 720B. Although a distal spiral 720A and proximal spiral 720B are illustrated in FIG. 7, any number of spirals are contemplated. Distal spiral 720A and proximal spiral 720B are connected to primary cannula 712 to anchor device 700 to artery 702 when balloon 720 is expanded. A distal end of inflation cannula 718 positioned along primary cannula 712 terminates within balloon 720 and a proximal end extends to proximal portion 706. In this aspect, a fluid may be delivered through inflation cannula 718 to balloon 720 to expand balloon 720. When balloon 720 is expanded, a corkscrew type channel is formed around primary cannula 712 which allows blood to flow around primary cannula 712 from a region proximal to balloon 720 to a region distal or upstream from delivery device 700. Since the channel is much narrower then the vessel lumen, the flow profile of blood flowing through the channel becomes turbulent resulting in a turbulent blood flow. A treatment agent may then be delivered through delivery cannula 716 which terminates distal to balloon 720 as shown or within distal spiral 720A and released within the turbulent conditions to facilitate even distribution of the treatment agent throughout the kidney.
In one embodiment, balloon 720 may be connected to primary cannula 712 at a distal end by strap 724 and by strap 722 at a portion of primary cannula 712 intended to be positioned proximal to a region of interest. Alternatively, straps 724 and 722 may be omitted and balloon 720 may be bonded to primary cannula 712. In one embodiment, a total inflatable size or length of balloon 720 is on the order of 10 mm to 40 mm. In other embodiments, the total inflatable size or length of balloon 720 is any length less than about 10 mm found suitable to facilitate positioning of delivery device 700 within a renal segmental artery, for example, 8 mm. Representatively, the spacing of adjacent spirals is equivalent to approximately 50 percent of the total inflatable size of the balloon (e.g., from about 5 mm to about 20 mm).
In one embodiment, a material for balloon 720 and its properties are selected so that the balloon expands along its entire length. Suitable materials for balloon 720 include materials that will achieve expansion at inflation pressures on the order of, for example, 6 atm or less. Suitable materials include, but are not limited to, PEBAX® or polytetrafluoroethylene (ePTFE). In another embodiment, only the distal portion of balloon 720 is intended to expand, notably a portion including spiral 720A and spiral 720B. Accordingly, the properties of balloon 720 may be modified along its length making a portion proximal to spiral 720A and spiral 720B resistant to expansion at pressures less than six atmospheres.
In one embodiment, delivery device 700 may be placed at a region of interest using a sheath (not shown) that surrounds primary cannula 712 and balloon 720. In this aspect, a distal portion of primary cannula 712 and balloon 720 may be exposed from the sheath, perhaps by retracting the sheath once delivery device 700 is placed at the region of interest.
The lumen of primary cannula 712 includes guidewire cannula 714 and delivery cannula 716. Delivery cannula 716 may extend from proximal portion 706 of delivery device 700 to distal portion 708. Guidewire cannula 714 has a lumen sized to accommodate a guidewire 710. Delivery device 700 may be an over the wire (OTW) configuration wherein guidewire cannula 714 extends from a proximal end (external to a patient during a procedure) to a distal end of delivery device 700. When guidewire 710 is removed from guidewire cannula 714, guidewire cannula 714 may also be used for delivery of a treatment agent such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomerular tissue of the kidney. In such case, a separate delivery cannula (i.e., delivery cannula 716) is unnecessary or delivery cannula 716 may be used to deliver one treatment agent while guidewire cannula 714 is used to deliver another treatment agent.
In another embodiment, catheter assembly 700 is a RX-type catheter assembly and only a portion of catheter assembly 700 (a distal portion 708) is advanced over guidewire 710. In an RX type of catheter assembly, typically, the guidewire cannula/lumen extends from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
FIG. 8 shows a blood vessel of a renal region and another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 8 shows a renal artery 802 branching off of aorta 804 and having a delivery device 800 disposed therein. Delivery device 800 includes a proximal portion 806 and a distal portion 808. Proximal portion 806 may be external to renal artery 802 and to the patient. Representatively, delivery device 800 may be inserted through a femoral artery and through, for example, a guide catheter and with the aid of a guidewire 810 to a location in a renal artery or segmental artery of a patient. FIG. 8 shows distal portion 808 of delivery device 800 positioned at a point within renal artery 802.
In one embodiment, delivery device 800 includes a primary cannula 812 having a length that extends from proximal portion 806 (e.g., located external through a patient during a procedure) to connect with a proximal end or skirt of a balloon 820. Primary cannula 812 has a lumen therethrough that includes a guidewire cannula 814 and a delivery cannula 816. Delivery cannula 816 may extend from proximal portion 806 of delivery device 800 to distal portion 808. Delivery cannula 816 has a distal end that terminates within balloon 820. In one embodiment, delivery device 800 is introduced into renal artery 802 and balloon 820 is inflated via delivery cannula 816.
Balloon 820 is incorporated at distal end 808 of delivery device 800 and is in fluid communication with delivery cannula 816. Balloon 820 includes balloon wall or membrane 822 which is selectively inflatable to dilate from a collapsed configuration to a desired and controlled expanded configuration. Balloon 820 can be selectively expanded by supplying a fluid into delivery cannula 816 at a predetermined rate of pressure through a delivery port 832. Balloon wall 822 is selectively deflatable, after inflation, to return to the collapsed configuration or a deflated profile. In one embodiment, balloon wall 822 can be defined by three sections, distal taper wall 826, medial working length 828, and proximal taper wall 830. In one embodiment, proximal taper wall 830 can taper at any suitable angle θ, typically between about 10° to less than about 90°, when balloon 820 is in the expanded configuration.
Distal taper wall 826, medial working length 828, and proximal taper wall 830 of balloon wall 822 can be bound together by seams or be made out of a single seamless material. Balloon 820 can be made from any suitable material, including, but not limited to, polymers and copolymers of polyolefins, polyamides, polyesters and the like. The specific material employed must be mutually compatible with the fluids employed in conjunction with balloon 820 and must be able to stand the pressures that are developed within balloon 820. Balloon wall 822 can have any suitable thickness so long as the thickness does not compromise properties that are critical for achieving optimum performance. Such properties include high burst strength, low compliance, good flexibility, high resistance to fatigue, the ability to fold, the ability to cross and re-cross a desired region of treatment or an occluded region in a lumen, and low susceptibility to defect caused by handling. By way of example, and not limitation, the thickness can be in the range of about 10 microns to about 30 microns, the diameter of balloon 820 in the expanded configuration can be in the range of about 2 millimeters (mm) to about 10 mm, and the length can be in the range of about 3 mm to about 40 mm, the specific specifications depending on the procedure for which balloon 820 is to be used and the anatomy and size of the target lumen in which balloon 820 is to be inserted.
Balloon 820 may be expanded by the introduction of a liquid into delivery cannula 816. Liquids containing therapeutic and/or diagnostic agents may be used to inflate balloon 820. In one embodiment, balloon 820 may be made of a material that is permeable to such therapeutic and/or diagnostic liquids such as those described above with respect to FIG. 4. To inflate balloon 820, the fluid can be supplied into delivery cannula 816 at a predetermined pressure, for example, from about 1 atm to about 2 atm. Balloon 820 may be expanded to a diameter which partially occludes artery 802 such that blood flowing from aorta 804 may flow past balloon 820 to a vessel region distal to delivery device 800. The blood flow through this region and distal to delivery device 800 is turbulent due to the narrowed region between balloon 820 and the wall of vessel 802 through which the blood must flows. Expansion of balloon 820 as described may further minimize backflow of the treatment agent into the aorta during delivery of the treatment agent to the treatment site.
To facilitate homogenous distribution of the treatment agent throughout the kidney, pores or openings 824 may be provided along distal taper wall 826 of balloon 820. Pores 824 may have any diameter suitable for delivery of a treatment agent therethrough. In one embodiment, the pores may be confined to only a region of distal taper wall 826 defined by a diameter of the lumen of renal artery 802. Any number of pores 824 may be distributed along distal taper wall 826. The treatment agent may be supplied into delivery cannula 816 at the predetermined pressure, and released through pores 824 in multiple directions. The treatment agent then mixes with the turbulent blood flow within this region. Distribution of the treatment agent through pores 824 creates multiple streams of the treatment agent from pores 824. In this aspect, the treatment agent may be distributed more homogenously throughout the blood flowing to the kidney regions.
In one embodiment, balloon 820 is a conventional balloon material such as PEBAX®, Nylon or PET that has tens or hundreds of micropores around its circumference for treatment agent diffusion. A suitable pore size may range, for example, from about 4 microns to about 400 microns, in some embodiments from about 10 microns to about 100 and in some embodiments from about 8 microns to about 15 microns. Still further, the pore size may have a size of at least four times the diameter of a particle to be delivered. Pores may be created by mechanical means or by laser perforation. Pore distribution along a balloon surface may be inhomogeneous to tailor distribution of treatment agent delivery. Balloon 820 may also be retractable into optional sheath (not shown) to tailor a length of treatment agent delivery. In an alternative embodiment, the sheath may have an opening on one side to preferentially deliver a treatment agent to one side of the vessel.
Guidewire cannula 814 extends through balloon 820. Guidewire cannula 814 has a lumen sized to accommodate a guidewire 810. Delivery device 800 may be an over the wire (OTW) configuration wherein guidewire cannula 814 extends from a proximal end (external to a patient during a procedure) to a distal end of delivery device 800. Guidewire cannula 814 may also be used for delivery of a treatment agent such as an agent having a property to inhibit nephropathy or a formulation including vasoactive agents which enhance binding characteristics to glomerular tissue of the kidney when guidewire 810 is removed with delivery device 800 in place. In such case, separate delivery cannula (delivery cannula 816) is unnecessary or delivery cannula 816 may be used to deliver one treatment agent while guidewire cannula 814 is used to deliver another treatment agent.
In another embodiment, delivery device 800 is a RX-type catheter assembly and only a portion of delivery device 800 (a distal portion 808 including balloon 820) is advanced over guidewire 810. In a RX-type of catheter assembly, typically, the guidewire cannula/lumen extends from the proximal end of the catheter assembly. The proximal guidewire port is typically spaced a substantial distance from the proximal end of the catheter assembly.
FIG. 9 shows another embodiment of a delivery system to deliver a treatment agent to a kidney. In this embodiment, delivery device 900 is a hollow guidewire having an assembly for partially occluding and creating turbulence within a vessel lumen. Delivery device 900 includes hollow hypotube body 910 including proximal portion 905 and distal portion 915. Proximal portion 905 is intended to be resident outside of a patient during a procedure while distal portion 915 may be percutaneously inserted, for example, into a femoral or radial artery and advanced to a point within a renal artery and/or a renal segmental artery near a renal cortex for delivery of a treatment agent to a treatment site via a transluminal route (e.g., an arterial route). A suitable treatment site may be diseased glomerular tissue upstream from a renal artery and renal segmental renal artery. Hypotube body 910 of delivery device 900 includes a hollow lumen to allow a treatment agent to be introduced at a proximal port 920 through the lumen of hypotube 910 and exit at distal end 930 of hypotube 910. In one embodiment, hypotube 910 can be made of a metal, like 316L stainless steel, nitinol (NiTi), other metal alloy, or polymer, or combination thereof, with an outer diameter and overall length of the hypotube comparable to most guidewires used for interventional procedures, including, but not limited to, an outer diameter of 0.012 inches, 0.014 inches, 0.018 inches and 0.035 inches. A suitable length includes, but is not limited to, 180 centimeters to 300 centimeters typical of guidewires for rapid exchange and over-the-wire applications, respectively, in interventional procedures.
In one embodiment, delivery device 900 includes a tube or cannula (not shown) extending through the lumen of hypotube 910. The cannula has a lumen therethrough and may be of a flexible polymer material. In this embodiment, a proximal end of the cannula is defined by port 920 to introduce a treatment agent therethrough. A distal end of the cannula extends to distal end 915 of hypotube 910. In this manner, a treatment agent introduced through delivery port 920 is dispersed through a lumen of the cannula and exits delivery device at distal end 930.
In another embodiment, delivery device 910 includes solid tip 950 of a flexible material such as might be used in guidewires in interventional procedures. Such a tip may have a length on the order of up to a few centimeters. In this embodiment, an exit point for a treatment agent such as a treatment agent introduced through the cannula of hypotube 910 may be at a position proximal to tip 950. FIG. 9 shows port 955 (shown in dashed lines) proximal to tip portion 950 (e.g., within 1-2 centimeters from tip portion 950).
Delivery device 900 also includes assembly 960 positioned on hypotube 910. In one embodiment, a distal end of assembly 960 is positioned within a few centimeters of tip 950 (e.g., positioned proximal to an exit point that is proximal to tip 950). In this embodiment, assembly 960 is an expandable cage-like structure that is shown in a collapsed configuration in FIG. 9. FIG. 9 also shows restraining sheath 970 disposed over hypotube 910 from proximal portion 905 to a distal portion beyond assembly 960. Restraining sheath 970 extends co-axially along hypotube 910.
In one embodiment, assembly 960 has an expandable cage that may be deployed by a physician by retracting restraining sheath 970 proximally to expose assembly 960. Once restraining sheath 970 is retracted, the self expanding cage of assembly 960 may immediately begin to expand. In a blood vessel, the assembly will expand until the device contacts a wall of the blood vessel. In one embodiment, delivery device 900 also includes obturator 975 affixed to a distal end of assembly 960. Obturator 975 may be implemented to inhibit possible “snow plowing” of assembly 960 or restraining sheath 970 as it is being delivered through the vasculature.
As noted above, assembly 960, in one embodiment, is an expandable cage-like structure. Suitable cage-like structures are described in the context of embolic filtering devices described in, for example, commonly assigned U.S. Publication No. 2003/0120303, filed Dec. 21, 2001; U.S. Publication No. 2003/0212361, filed Mar. 10, 2003; U.S. Publication No. 2004/0098032, filed Jun. 29, 2001; and U.S. Pat. No. 6,656,202, filed Jun. 29, 2001.
FIG. 10 shows a blood vessel of a renal region and a top side perspective view of the delivery device of FIG. 9 wherein the delivery device is in an expanded configuration. Representatively, delivery device 900 is advanced through aorta 904 to renal artery 902 such that assembly 960 is positioned proximal to the kidney. Conventional imaging techniques may be used to position delivery device. In this manner, although not shown, delivery device 900 may include radiopaque markers that are visible under a fluoroscope or other markers (e.g., magnetic resonance imaging markers) to position delivery device 900 at a desired site within a renal artery or segmental artery. Following the positioning of delivery device 900 within the artery, assembly 960 may be deployed as desired. In this embodiment, assembly 960 is deployed by proximally retracting restraining sheath 970 to expose assembly 960 within the blood vessel. In one embodiment, assembly 960 expands immediately upon retraction of restraining sheath 970 without any external aid of force applied to assembly 960. In this aspect, cage structure 980 of assembly 960 may be made of a self expanding material, such as nitinol (NiTi). Assembly 960 expands to an outer diameter of the blood vessel in which delivery device 900 is placed. The wall of a blood vessel may be used to constrain the expansion. It is further contemplated that assembly 960 may be expanded by any suitable technique, for example, with the aid of a balloon assembly.
Assembly 960 may include a sheath 985. Sheath 985 may be of a porous material that permits some blood flow through the porosity and in doing so creates turbulence. In other embodiments, sheath 985 may be selected of a material that inhibits permeation of blood flow past the assembly. In this aspect, assembly 960 when deployed, may partially occlude a blood vessel such that blood may flow around sheath 985 to create a turbulent blood flow. Sheath 985 may only partially envelope an underlying cage structure 980 so as not to completely inhibit blood flow when sheath 985 of a porous material is in an expanded state.
The following description of an embodiment of cage structure 980 is similar to the description of a cage structure for an embolic filtering device described in, for example, commonly assigned U.S. Publication No. 2003/0120303, filed Dec. 21, 2001. It is appreciated that the cage structure presented herein is representative of similar structures described in the referenced application as well as the other applications and patent referenced above.
In one embodiment, cage structure 980 of assembly 960 includes a pair of self-expanding proximal struts 9802 and 9804 that help to deploy assembly 960 and the remainder of the expandable cage. Proximal struts 9802 and 9804 are connected to first circumferential member 9806 which is adapted to move from an unexpanded delivery position to the expanded deployed position. Second circumferential member 9808 is, in turn, connected to first circumferential member 9806. The deployment of first circumferential member 9806 and second circumferential member 9808 results in assembly 960 being placed against a wall of an artery or other blood vessel, even if the lumen of the blood vessel is non-circular. A pair of distal struts 9810 and 9812 connected to second circumferential member 9808 extend distally toward obturator 975. First circumferential member 9806 and second circumferential member 9808 are connected to, and spaced apart, from each other by short connecting struts 9814. It should be appreciated that a single circumferential member could be used to create an expandable cage. Also, additional circumferential members could be added to create a larger expandable cage. Additionally, while two proximal struts and distal struts are shown in the cage design of FIG. 10, the cage could also be made with single proximal and distal struts or additional struts could be implemented.
In one embodiment, each circumferential member includes four bending regions, 9816, 9818, 9820 and 9822 formed on the circumferential member to enhance the performance of the circumferential member to bend as it moves between an unexpanded and an expanded position. Each bending region 9816, 9818, 9820 and 9822 is placed on the circumferential member approximately 90 degrees apart. Each of the proximal struts includes a first end 9824 attached to collar 990 which is rotatably mounted to hypotube 910. Each proximal strut includes second end 9826 connected to one of the proximal bending regions 9816 and 9818 of first circumferential member 9806. This proximal bending regions 9816 and 9818 are spaced approximately 180 degrees apart from each other along a circular diameter defined by circumferential member 9806 in an expanded state. Each of distal struts 9810 and 9812, in turn, have first end 9828 connected to and extending towards obturator 975 and a second end 9830 attached to distal bending regions 9820 and 9822 of second circumferential member 9808. These distal bending regions 9820 and 9822, in turn, are spaced approximately 180 degrees apart from each other and are offset 90 degrees from proximal bending regions 9816 and 9818.
Each of the bending regions is substantially U-shaped which help to create a natural bending point on the circumferential member. While the flexibility of the circumferential member is already high, these bending regions only help to increase the ability of the circumferential member to collapse or expand when needed. In this manner, the shape of the hinge region creates a natural hinge that helps to actuate the expandable cage between an unexpanded and an expanded position. As shown in FIG. 10, U-shaped bending regions 9816 and 9822 are positioned directly opposite the U-shaped portion of bending regions 9818 and 9820. The positioning of the direction of the U portion also enhances the ability of the circumferential member to bend. Circumferential member 9816 and circumferential member 9818, while being bendable, nevertheless may maintain sufficient radial strength to remain in the deployed position to hold assembly 960 open in a blood vessel for occluding blood flow.
The shape of the bending regions are shown as substantially U-shaped portions, however, any one of a number of different shapes could be utilized to create a natural bending point on a circumferential member. For example, a V-shaped region could also be formed and would function similarly to a U-shaped portion to facilitate the collapse and expansion of a circumferential member as needed. Alternative shapes and sizes of the bending regions could also be utilized. Although four bending regions are shown on each circumferential member, it is appreciated that the number of bending regions could be increased or decreased as needed. For example, it is possible to utilize only two bending regions. Additional bending regions also could be utilized in the event that additional proximal or distal struts are used to form the expandable cage. Moreover, different sizes, shapes and location of the bending regions can be utilized on any circumferential member.
In the embodiment shown in FIG. 10, expandable cage structure 980 of assembly 960 is shown rotatably mounted to a distal end of hypotube 910 to allow the entire assembly 960 to remain stationary once deployed in a blood vessel. This feature prevents the assembly from rotating in the event that the proximal end of hypotube 910 is rotated by the physician during use. As a result, the possibility that the deployed assembly can be rotated to cause trauma to a wall of a blood vessel minimized. First end 9824 of proximal struts 9802 and 9804 are attached to collar 990 which is rotatably mounted on hypotube 910 between a pair of stop fittings 9902 and 9904. Stop fittings 9902 and 9904 allow expandable cage structure 980 to spin on hypotube 910 but restrict the longitudinal movement of the cage on the hypotube. A distal end of cage structure 980 may be connected to obturator 975 which may similarly be free to rotate on hypotube 910.
An expandable cage such as shown in detail with reference to FIG. 10 may be made in a variety of ways. One particular method of making cage 980 is to cut a thin-walled tubular member, such as NiTi hypotube, to remove portions of the tubing in a desired pattern for each strut, leaving relatively untouched the portions of the tubing which are to form each strut. The tubing may be cut into the desired pattern by means of a machine-controlled laser. The tubing used to make cage 980 could possibly be made of suitable biocompatible materials such as spring steel. Elgiloy is another material which could possibly be used to manufacture cage 980. Also, certain polymers could be used.
In one embodiment, a strut size is relatively small, so the tubing from which the cage is formed may have a small outside diameter. Typically, the tubing has an outside diameter on the order of from about 0.020 to about 0.100 inches in an unexpanded condition. Also, cage 980 can be cut from large diameter tubing. Fittings are attached to both ends of the lased tube to form the final cage geometry. One suitable wall thickness of tubing is about 0.076 millimeters (about 0.002 inches to about 0.003 inches). As can be appreciated, the strut widths and/or depths at the bending point may be less. Further details of manufacturing a cage such as shown in FIG. 10 may be found with reference to the above-noted applications and patent describing embolic filtering devices.
In still further embodiments, cage 980 may be made from formed tubing with micro-holes that allow agent delivery through the holes. In this aspect, cage 980 may be made from a NiTi hypotube wherein a distal end of the hypotube within renal artery 970 includes perfusion holes 9832 such that a treatment agent delivered to the NiTi hypotube perfuses through holes 9832. In one embodiment, perfusion holes 9832 may be formed along regions of NiTi hypotube cage 980 facing a center of the blood vessel such that when a treatment agent is delivered through holes 9832 and into the blood flowing distal to sheath 985, further turbulence is provided. In this aspect, hypotube 910 may have a distal end terminating within a lumen of NiTi hypotube cage 980 to allow a treatment agent to be introduced at a proximal port 920 through the lumen of hypotube 910 and exit through holes of NiTi hypotube cage 980. In this embodiment, distal end 930 may be eliminated. Alternatively, two hypotubes, one in fluid communication with distal end 930 and the other in fluid communication with NiTi hypotube cage 980 may be provided such that a treatment agent may be delivered from both distal end 930 and perfusion holes of NiTi hypotube cage 980. NiTi hypotube cage 980 may be similar in some respects to the device described in copending U.S. patent application Ser. No. 11/407,707, titled Devices and Methods for Intravascular Drug Delivery, filed on Apr. 19, 2006, incorporated herein by reference.
In some embodiments, cage 980 is composed of a bioabsorbable polymer or biostable polymer. A polymer or coating is “bioabsorable” or “biodegradable” when it is capable of being completely or substantially degraded or eroded when exposed to either an in vivo environment or an in vitro environment having physical, chemical, or biological characteristics substantially similar to those of the in vivo environment within a mammal. A polymer or coating is “degradable or erodable” when it can be gradually broken down, resorbed, absorbed and eliminated by, for example, hydrolysis, enzymolysis, metabolic processes, bulk or surface erosion, and the like within a mammal. It is to be appreciated that traces of residue of polymer may remain following biodegradation. A “biostable” polymer is a polymer that is not bioabsorbable.
Suitable polymers used in embodiments of a material for cage 980, include, but are not limited to, hydrophobic, hydrophilic, ampiphilic, biodegradable, or a combination thereof. Examples of hydrophobic polymers include, but are not limited to, poly(ester amide), polystyrene-polisobutylene-polystyrene block copolymer (SIS), polystyrene, polyisobutylene, polycaprolactone, poly(L-lactide), poly(D,L-lactide), polylactic acid (PLA), poly(lactide-co-glycolide), poly(glycolide), polyalkylene, polyfluoroalkylene, polyhydroxyalkanoate, poly(3-hydroxybutyrate), poly(4-hydroxybutyrate), poly(3-hydroxyvalerate), poly(3-hydroxybutyrate-co-3-hydroxyvalerate), poly(3-hydroxyhexanoate), poly(4-hydroxyhexanoate), mid-chain polyhydroxyalkanoate, poly(trimethylene carbonate), poly(orthoester), polyphosphohazene, poly(phosphoester), poly(tyrosine derived arylates), poly(tyrosine derived carbonates), polydimethyloxanone (PDMS), polyvinylidene fluoride (PVDF), polyhexafluoropropylene (HFP), polydimethylsiloxane, poly(vinylidene fluoride-co-hexafluoropropylene (PVDF-HFP), poly(vinylidene fluoride-co-chlorotrifluoroethylene) (PVDF-CTFE), poly(butyl methacrylate), poly(methyl mathacrylate), poly(vinyl alcohol) (PVA), poly(ethylene-co-vinyl acetate), poly (ethylene-co-vinyl alcohol), poly(ester-urethane), poly(ether-urethane), poly(carbonate-urethane), poly(silicone-urethane), poly(2-hydroxyethyl methacrylate), SOLEF® polyvinylidene fluoride (PVDF), poly(urea-urethane), and combinations thereof.
Examples of hydrophilic polymers include, but are not limited to, polymers and co-polymers of hydroxyethly methacrylate (HEMA); poly(methyl methacrylate) (PMMA); poly (ethylene glycol) acrylate (PEGA); PEG methacrylate; phosphorylcholine; 2-methacryloyloxyethyl phosphorylcholine (MPC); n-vinyl pyrrolidone (VP); carboxylic acid bearing monomers such as methacrylic acid (MA), acrylic acid (AA); hydroxyl bearing monomers such as HEMA, hydroxypropyl methacrylate (HPMA), hydroxypropylmethacrylamide, alkoxymethacrylate, alkoxyacrylate, and 3-trimethylsilylpropyl methacrylate (TMSPMA), poly(ethylene glycol) (PEG), poly(propylene glycol) (PPG), SIS-PEG-polystyrene-PEG, polisobutylene-PEG, PCL-PEG, PLA-PEG, PMMA-PEG, PDMS-PEG, PVD-PEG, PLURONIC® surfactants (poly-propylene oxide-co-polyethylene glycol), poly (tetramethylene glycol), hydroxyfunctinal poly(vinyl pyrrolidone), polyalkylene oxide, dextran, detrin, sodium hyaluronate, hyaluronic acid, heparin, elastin, chitosan; and combinations thereof.
Examples of biodegradable polymers include, but are not limited to, polymers having repeating units such as, for example, an α-hydroxycarboxylic acid, a cyclic diester of an α-hydroxycarboxylic, a dioxanone, a lactone, a cyclic carbonate, a cyclic oxalate, an epoxide, a glycol, an anhydride, a lactic acid, a glycolic acid, a clycolic acid, a lactide, a glycolide, an ethylene oxide, an ethylene glycol, or combinations thereof.
In some embodiments, the biodegradable polymers include, but are not limited, to polyesters, polyhydroxyalkanoates (PHAs), poly(ester amides), amino acids, PEG and/or alcohol groups, polycaprolactones, poly(L-lactide), poly(D,L-lactide, poly(D,L-lactide-co-PEG) block copolymers, poly(D,L-lactide-co-trimethylene carbonate), polyglycolides, poly (lactide-co-glycolide), polydioxanones, polyorthoesters, polyahydrides, poly(glycolic acid-co-trimethylene carbonate), polyphosphoesters, polyphosphoester urethans, poly(amino acids), polycyanoacrylates, poly(trimethylene carbonate), poly(imino carbonate), polycarbonates, polyurethanes, copoly(ether-esters) (e.g., PEO/PLA), polyakylene oxalates, polyphosphazenes, PHA-PEG, and any derivatives, analogs, homologues, salts, copolymers and combinations thereof.
A composition including a treatment agent (or multiple treatment agents) and a stimuli-responsive polymer may be included in a cage coating on cage 980 or included in the body of cage 980 such as, for example, a biodegradable polymeric cage. The release profile of the particles of treatment agent and polymer can be controlled by tailoring the chemical composition and crystallinity of the polymer as the coating or the bioabsorbable stent material (e.g., the more crystalline the slower the release rate).
In the embodiment described, expandable cage structure 980 is covered by sheath 985. Sheath 985 may be of a porous material, such as, but not limited to PEBAX®, Nylon or PET that has tens or hundreds of micropores around its circumference for treatment agent diffusion. Alternatively, pores of a desired dimension may be formed in a suitable material by mechanical means or by laser perforation. In still further embodiments, sheath 985 may be a polymeric material such as, but not limited to, polyurethane or GORTEX®, a commercially available material. Other suitable materials include expanded ePTFE. The material may be elastic or non-elastic. A suitable wall thickness of sheath 985 can be about 0.0005-0.005 inches. The wall thickness may vary depending on the particular material selected. The material can be made into a cone or similarly size shape utilizing blow-mold technology or dip technology. Additionally, a material for sheath 985 can have a “set” put in a much like the set used in a dilation balloon to make the sheet rewrap more easily when placed in a collapsed position.
A suitable material for restraining sheath 970 can be polymer material such as crosslinked high density polyethylene (HDPE). Restraining sheath 970 can alternatively be made from a material such as a polyolefin that has sufficient strength to hold the compressed assembly 960 and has relatively low frictional characteristics to minimize any friction between the occlusion device and the sheath. Friction can be further reduced by applying a coat of silicone lubricant, such as MICROGLIDE®, to the inside surface of the restraining sheath before the sheath is placed over assembly 960.
FIG. 11 shows another embodiment of a delivery system to deliver a treatment agent to a kidney. FIG. 11 shows a renal artery 1110 extending from aorta 1116 and having a delivery device 1100 disposed therein. Delivery device 1100 is similar in some respects, for example, to commonly owned U.S. application Ser. No. 10/802,435, titled Stent Deployable at a Low Pressure and a Stent Delivery System, filed on Mar. 16, 2004.
In this embodiment, the delivery device is a stent implant 1100. Stent implant 1100 is mounted onto a delivery catheter 1102. In one embodiment, stent 1100 is mounted on a distal portion of delivery catheter 1102. Stent 1100 includes a plurality of radially expandable cylindrical elements (a plurality of struts) 1104 disposed generally coaxially and interconnected by connecting elements (a plurality of links) 1106 disposed between adjacent struts 1104. The delivery catheter 1102 has an expandable portion or a balloon 1108 for expanding of stent 1100 within renal artery 1110. Stent 1100 is configured so that it can be deployed within renal artery 1110 at a low pressure so as to reduce injury and/or trauma to the vessel. For example, stent 1100 may be deployed at lower than 6 atm, in some embodiments, lower than about 3 atm, and in some other embodiments, even lower than about 1 atm. One approach for stent 1100 to be deployed at a substantially low pressure (e.g., ≦6 atm, ≦3 atm, and ideally, ≦1 atm) is to configure stent 1100 with substantially narrow struts 1104. In this aspect, struts 1104 of stent 1100 may be in the range of about 0.0018 inches to about 0.025 inches. Narrower struts 1104 allow stent 1100 to deploy at low pressure. In one embodiment, stent 1100 has a tubular shape. When stent 1100 is expanded, its diameter (tubular diameter) expands as bar arm portions 1118 and crown portions 1120 straighten due to the pressure that is applied to expand stent 1100.
It is within the scope and contemplation of the present invention that strut 1104 widths and lengths can be varied in conjunction with the different materials used to make stent 1100 able to deploy. For instance, when a stiffer material is used to makes stent 1100, stent 1100 is configured to be thinner and longer than when a less stiff material is used. Materials that may be used to make stent implant 1100 include, but are not limited to, cobalt chromium (CoCr) alloy, cobalt alloy, nickel alloy, tantanum alloy, nickel titanium alloy, stainless steel, or other corrosion resistant alloy or a biodegradable material. Still further, stent 1100 may be made of a polymer material such that a treatment agent may be embedded in a matrix of the polymer material. In some embodiments, stent 1100 may be coated with a permeabilizing reagent for increasing the permeability of membrane junctions or cell membranes. Suitable permeabilizing agents may include ethylene vinyl alcohol copolymer (commonly known by the generic name EVOH or by the trade name EVAL®), poly(hydroxyvalerate); poly(L-lactic acid); polycaprolactone to name a few. In some embodiments, stent 1100 is composed of a bioabsorbable polymer or biostable polymer similar to that described above in regard to cage 980 of FIG. 9.
As illustrated in the exploded view of strut 1104, each of struts 1104 further include bar arm portions 1118 and crown portions 1120. Depots 1122 are provided in struts 1104 for carrying and release of a treatment agent. An opening of each depot 1122 may be positioned on a side of strut 1104 adjacent a flow of blood along a lumen of renal artery 1110 such that the treatment agent is released in the direction of the artery lumen as opposed to a wall of the artery. Various embodiments of depots 1122 of stent 1100 will be described in more detail with reference to FIGS. 12-14.
FIG. 12 shows a cross-sectional side view through line A-A′ of one embodiment of a strut of the stent delivery system of FIG. 11. In this embodiment, a cross section along A-A′ of depot 1122 of delivery device 1200 is shown having a depth less than the thickness of the wall of strut 1104. In this aspect, depot 1122 has a single opening positioned along a lumen of renal artery 1100. FIG. 13 shows a cross-sectional side view through line A-A′ of another embodiment of a strut of the stent delivery system of FIG. 11. In this embodiment, a cross section along A-A′ of depot 1122 of delivery device 1300 is shown. Similar to the depot of FIG. 12, the depth of depot 1122 of delivery device 1300 is less than the thickness of the wall of strut 1104. In some embodiments, depot 1122 may have a rectangular dimension of from about 0.002 inches to about 0.005 inches in width and about 0.002 inches to about 0.100 inches in length. The depot can also be a round depot and have a diameter of from about 0.002 inches to about 0.006 inches. Depot 1122, may have a depth of from about 0.002 inches to about 0.005 inches. A membrane 1302 extends across the opening of depot 1122 to modify a release rate of a treatment agent loaded within depot 1122. The treatment agent may be loaded within depot 1122 through the opening of depot 1122 and then membrane 1302 placed over the opening prior to insertion of the delivery device into the vessel. Membrane 1302 may be a polymer material. In one embodiment, a material of membrane 1302 may include, but is not limited to, a hydrophilic polymer such as PVA. Still further, the material of membrane 1302 may be a cross-linked PVA to modify a rate of release of the treatment agent eluted from depot 1122. It is further contemplated that the specifications of membrane 1302, for example, a thickness, may be modified to achieve a desired release rate. Alternatively, membrane 1302 may be coated with any material having a property to modify a release rate.
FIG. 14 shows a cross-sectional side view through line A-A′ of another embodiment of a strut of the stent delivery system of FIG. 11. In this embodiment, a cross section along A-A′ of depot 1122 of delivery device 1400 is shown. In this embodiment, depot 1122 of delivery device 1400 has a depth substantially equivalent to the thickness of strut 1104 such that depot 1122 has an opening on each side of strut 1104. The greater depth of depot 1122 allows a greater amount of the treatment agent to be loaded into depot 1122 for delivery. It is further contemplated that a diameter of depot 1122 may be altered to increase the space within depot 1122 within which the treatment agent is loaded. A film or cap 1402 is provided along an opening of depot 1122 adjacent the wall of renal artery 1110. Membrane 1302 similar to that described in reference to FIG. 13, may be positioned across an opening of depot 1122 opposite to the opening cap 1402 is placed over. In this aspect, the treatment agent may be loaded in one of the openings of depot 1122 and retained within depot 1122 by cap 1402 and membrane 1302. Alternatively, depot 1122 may include only cap 1402 adjacent a wall of vessel 1110 such that a treatment agent loaded into depot 1122 is released into the flow of blood instead of the wall of renal artery 1110. Cap 1402 may be made of any material suitable for sealing the opening and retaining the treatment agent. The specific material employed must be mutually compatible with the fluids employed in conjunction with depot 1122. Representatively, the material suitable for cap 1402 may include, but is not limited to, polymers and copolymers of polyolefins, polyamides, polyesters and the like.
In the preceding detailed description, specific embodiments are illustrated, including a variety of devices and method for delivering a treatment agent to a kidney region according to conditions which create a turbulent blood flow within a region of agent delivery. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention as set forth in the claims. For example, the devices are described for delivering a treatment agent to a kidney region. It is contemplated that, the devices and method may be suitable for delivering a treatment agent to a treatment site within any blood vessel or organ of the body. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.

## Claims

1. A method comprising:
introducing a delivery device to a point within a renal artery, the delivery device comprising a primary cannula, a guidewire cannula and a delivery cannula, the primary cannula having a proximal end and a distal end and a lumen sized to receive the guidewire cannula and the delivery cannula, the delivery cannula being non-expandable and positioned along a length of the guidewire cannula, wherein the guidewire cannula and the delivery cannula have substantially the same width and wherein the guidewire cannula has an open end and the delivery cannula has an occluded distal end and at least one longitudinally disposed opening defined by a wall of the delivery cannula at a position proximal to the distal end of the delivery cannula, and wherein the delivery cannula is positioned with respect to the primary cannula such that the at least one longitudinally disposed opening is distal to the distal end of the primary cannula; and
delivering a treatment agent from the at least one longitudinally disposed opening in a direction perpendicular to a direction of blood flow to create a turbulent blood flow into the kidney in addition to any turbulent conditions from the presence of the delivery device in the renal artery, wherein said treatment agent is capable of inhibiting a biological process contributing to nephropathy.

2. The method of claim 1, wherein introducing the delivery device to a point comprises advancing the delivery device through an aorta into the renal artery.

3. The method of claim 1, wherein introducing the delivery device to a point comprises advancing the delivery device through a region of a retroperitoneal cavity surrounding the kidney into a region of a renal cortex adjacent to glomerular capillaries within the kidney.

4. The method of claim 1, wherein the treatment site is in one of a glomerular capillary or a renal cortex.

5. The method of claim 1, wherein the conditions creating a turbulent blood flow comprise modifying a flow of blood through a vessel lumen by injecting an amount of blood through the lumen.

6. The method of claim 1, wherein delivering the treatment agent further comprises delivering the treatment agent according to conditions that prevent back flow of the treatment agent into an aorta.

7. The method of claim 6, wherein conditions that prevent back flow comprise expanding one of a balloon or a sheath of the delivery device in a region of a lumen of the artery between the treatment site and a distal end of the delivery device before delivering the treatment agent to the treatment site.

8. The method of claim 6, wherein conditions that prevent back flow comprise releasing the treatment agent from a delivery port of the delivery device into a vessel lumen at a flow rate which is less than a natural flow rate of the vessel.

9. The method of claim 1, wherein the delivery device further comprises:
a dilatable balloon assembly coupled to the guidewire cannula, the dilatable balloon assembly comprising a balloon having a proximal wall, wherein the proximal wall consists of pores along only a region of the proximal wall defined by a diameter of a lumen of a renal artery; and
an inflation cannula having an end within the balloon for dilating the balloon assembly.

10. The method of claim 1, wherein delivering includes release of the treatment agent over time.

11. The method of claim 1, wherein the treatment agent comprises a vasoactive agent to increase endothelial porosity and enhance uptake of the treatment agent into tissue.

12. The method of claim 1, wherein the treatment agent is encapsulated within a carrier selected from one of a nanoparticle, a microparticle and a liposome.

13. The method of claim 12, wherein a surface of the carrier comprises a property to enhance binding of the carrier to the treatment site.

14. The method of claim 12, wherein a diameter of the carrier is between 8 microns and 15 microns.

15. The method of claim 12, wherein a diameter of the carrier is between 1 micron and 2 microns.

16. The method of claim 1, wherein the delivery device comprises a balloon and a condition that creates turbulent blood flow comprises expanding the balloon to a diameter that partially occludes the renal artery.