Patent Grant
9149610
Many diseases that affect organs develop over a decade or more. During this time, the function of the organ diminishes. The end-stage of many of these diseases is a transplant or some other treatment to supply artificially the organ's function—dialysis in the case of kidney disease such as end-stage renal disease, for example. A number of factors including immune system disorders or diabetes can cause these types of diseases.
Different diseases call for different treatments depending upon the dysfunction of the organ. For many of these diseases, the standard for treatment, short of a transplant, is drug-based. Drug-based treatments are usually systemic and typically use a pill or infusion of a solution of the drug in a carrier. These delivery methods are systemic because the patient's whole system is treated. But systemic treatment requires supplying the whole system drugs at levels high enough to be effective at the target organ. Achieving effective levels at the target organ frequently requires delivering toxic levels throughout the remainder of the system.
On the other hand, locally delivering the drug can alleviate some of the problems with systemic treatment. For instance, local delivery sidesteps supplying the drug system-wide allowing for effective local drug levels while maintaining much lower system-wide levels, levels that are frequently benign to the patient.
But local delivery presents its own set of challenges. Typically, with local delivery, the drug enters the bloodstream upstream of the desired treatment site. Another technique involves injecting the drug into a (temporarily) unperfused region of the vasculature near or in the diseased organ. This technique can use an occlusion device upstream of the deliver region to inhibit or stop blood flow. In either case, the natural laminar flow of blood does not always promote effective mixing between the drug and blood.
Ineffective mixing can prevent the drug from evenly reaching its target organ or region's cells. For example, delivery upstream of an arterial branch coupled with ineffective mixing can result in more drug being delivered down one branch than another.
What is needed is a delivery technique for local delivery that provides effective mixing between the blood and the drug. This need is especially acute for delivery to the kidney because the kidney contains a highly branched arterial vasculature.
The present invention is directed towards a method of delivering drug or therapeutic agent containing solutions to an organ having branched vessels wherein the method uses at least one step that improves the uniformity of the delivery of the drug or therapeutic agent among the branched vessels.
The step can be any one or any combination of normalizing the viscosity of the therapeutic agent solution towards that of blood; delivering a delivery catheter with a delivery port that has a geometry that causes increased mixing between the blood and therapeutic agent solution; delivering a delivery catheter with at least one delivery port wherein the delivery fosters increased turbulence around the delivery port; decreasing the infusion rate of the therapeutic agent solution; or increasing the number of delivery ports.
In some embodiments of the present invention, a step that improves the uniformity of the delivery of the drug or therapeutic agent among the branched vessels is a step that causes the range of therapeutic agent concentrations delivered to the vessels to be small enough so that the total drug delivery to the vessel that receives the lowest concentration exceeds the minimum therapeutic dose, while the total drug delivery to the vessel that receives the highest concentration is 50-200; 75-175; or 90-150 percent of the maximum therapeutic dose.
In some embodiments of the present invention, a step that improves the uniformity of the delivery of the drug or therapeutic agent among the branched vessels is a step that causes the range of therapeutic agent concentrations delivered to the vessels to be small enough so that the total drug delivery to the vessel that receives the highest concentration falls within the maximum therapeutic dose, while the total drug delivery to the vessel that receives the lowest concentration is 100-300; 150-250; 175-225 percent of the minimum therapeutic dose.
In some embodiments of the present invention, a step that improves the uniformity of the delivery of the drug or therapeutic agent among the branched vessels is a step that causes the range of therapeutic agent concentrations delivered to the vessels to be small enough so that the average amount of drug delivered to each vessel falls within a range defined as a 85, 90, 95, 98, or 99 percent confidence interval calculated from the standard deviation of the average amount of drug delivered for the vessel with the highest such standard deviation.
The following description of several embodiments describes non-limiting examples that further illustrate the invention. All titles of sections contained herein, including those appearing above, are not to be construed as limitations on the invention, but rather they are provided to structure the illustrative description of the invention that is provided by the specification.
The features, aspects, and advantages of the invention will become more apparent from the following detailed description, appended claims, and accompanying drawings.
Unless defined otherwise, all technical and scientific terms used in this document have the same meanings as commonly understood by one skilled in the art to which the disclosed invention pertains. The singular forms a, an, and the include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to “fluid” refers to one or more fluids, such as two or more fluids, three or more fluids, etc.
For purposes of this document, the portion of a delivery device designed to create turbulence in the blood flow is sometimes called a diffusion member or an expandable diffusion member.
In one embodiment, the treatment agent is delivered according to conditions that create turbulent blood flow within a vessel region where the treatment agent is delivered (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 flow profile otherwise modified from a normal or steady state flow. Modified flow profiles may include rapid variations of pressure, flow direction or velocity. For example, in some embodiments, turbulent blood flow arises from partially occluding the vessel lumen by about 60% to about 90%.
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 Ilium, and into the segmental arteries leading to the glomerular capillaries within the renal cortex. Thus, when the delivery device releases the treatment agent from a single point into one of these streams of a healthy kidney, most of the treatment agent is carried only to the kidney region at the end of the stream. In this respect, only a small portion of the kidney receives the treatment agent.
Moreover, the disease may reduce or stop altogether blood flow to those diseased regions especially in need of the treatment agent. In such cases, even when the treatment releases the treatment agent into a path normally destined for the diseased region, it may not reach that region. Treatment may overcome such problems by creating turbulence within the flow profile followed by treatment agent delivery into the turbulent blood flow. In particular, the turbulent conditions will facilitate mixing of the treatment agent with the blood and disrupt the streams typically found within the kidney causing more even distribution of the treatment agent throughout the kidney.
Liquid Flowing Streams
When blood or similar fluids experience flow parameters similar to those seen in a blood vessel, these fluids flow through a vessel lumen in substantially laminar flow—there is little mixing from point to point within the stream, if one looks at a cross-section of the lumen, the mixing between areas in one quadrant or stream and another quadrant or stream is very low. This means that introduction of a therapeutic-agent solution at a single point can result in a heterogeneous mix between the blood and solution. For instance, solution introduction at a lower rate will not substantially disturb the laminar flow behavior of the blood as it moves through the vessel lumen. Thus, downstream of the injection site, the blood is heterogeneous: some sectors contain blood mixed with more therapeutic-agent solution while others contain blood mixed with substantially less therapeutic-agent solution. Of course, one of ordinary skill in the art would expect that over time (distance traveled from the injection site), the blood from these various sectors would eventually mix yielding a substantially homogeneous blood-therapeutic-agent mixture.
This lack of mixing is inconsequential for systemic delivery. Systemic delivery of the injected therapeutic-agent solution provides longer times for the solution and blood to mix. But mixing must occur more quickly for local delivery. Local delivery methodologies frequently employ therapeutic-agent delivery within centimeters of the drug's target region. At typical blood flow rates, this short distance may yield mixing times of a few seconds or less.
It the goal is to uniformly treat a region, the blood and therapeutic-agent solution should mix before the treatment region receives the blood—therapeutic-agent mixture.
Blood from one quadrant or another will travel along one path or another in regions of high tortuosity. If the blood in one quadrant has not mixed with the therapeutic-agent solution, then pathways in the high tortuosity region that are fed by that blood quadrant will not see the same therapeutic-agent concentration as pathways that are fed from other sectors. This difference in therapeutic-agent concentration unavoidably leads to differences in treatment for tissues located along one pathway and those located along another pathway.
So, regional treatment may be better served by locating therapeutic-agent solution delivery points well ahead of the targeted region. But this is only a successful strategy if there is a sufficient vessel length ahead of the treatment region.
For instance, one may desire a longer vessel length within which to accomplish mixing between a therapeutic-agent solution and the blood. But another goal of regional delivery is for the therapeutic agent to substantially remain or arrive at the treatment region without substantial delivery to ancillary regions. There are instances when delivering far enough upstream of the target region to achieve adequate mixing of the therapeutic-agent solution and the blood would likewise require delivering the therapeutic-agent solution upstream of a vessel branch that would allow some of the therapeutic agent to follow the unintended branch rather than the intended one.
This circumstance, among others, leads to other strategies for promoting uniform regional drug delivery.
One class of strategies employs a turbulence-inducing element near the point at which the therapeutic-agent solution enters the vessel. In principle, having a turbulence-inducing member causes the non-mixing sectors discussed above in the laminar-blood-flow portion to mix. This mixing promotes adequate homogenization along a shorter path than if no turbulence-inducing elements were present.
Turbulence-inducing elements come in a variety of forms. Typically, the turbulence-inducing element functions by partially occluding the vessel or by forcing the blood to change directions as it flows by the element.
Another strategy for improving uniform regional drug delivery is to prepare the therapeutic-agent solution so that its viscosity more closely matches that of the blood, e.g. around 3-4 centipoise. Fluids flowing together through a vessel that have mismatched viscosities remain segregated for a longer time as they move through the vessel. The closer the viscosity match between the blood and therapeutic-agent solution, the easier or quicker the two mix.
Yet another strategy is to supply the therapeutic-agent solution at multiple positions near the distal end of a drug delivery device or catheter. This is believed to have at least two important effects: multiple injection positions promote turbulence in the blood flowing past the delivery device and multiple injection positions cause the therapeutic-agent solution to enter more individual streams or sectors within the blood flow.
Decreasing the speed of delivering the therapeutic-agent solution promotes more uniform therapeutic-agent delivery. Also, the geometry of the delivery port can be selected to encourage mixing. Such geometries can include structures with delivery ports that occupy a larger cross sectional area of the vessel, which allows for greater coverage of the fluid flow and improves mixing.
In one aspect, conditions creating turbulent blood flow may include partially occluding a region of the lumen so as to provide a constricted pathway for blood flow (e.g., about 60% to about 90% lumen occlusion). The narrowed pathway causes the speed of the blood flowing through that region to increase resulting in turbulent blood flow. The treatment agent may then be injected into that region. 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 stream of treatment agent alters the normal direction of blood flow, disturbing the normal flow path, and causing turbulence. This turbulence mixes the treatment agent with the blood for delivery to the treatment site. In addition, this turbulence may disrupt the downstream laminar flow profiles within the kidney. The homogenous distribution of the treatment agent throughout the blood flowing to the kidney and disruption of flow profiles within the kidney facilitates a substantially uniform distribution of the treatment agent solution throughout the kidney tissues or the tissues of other organs.
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, one may advance the delivery device 224 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 using retroperitoneal insertion. In this aspect, a distal end of delivery device 224 may be inserted through the back of the 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 with delivery device 224, it localizes within an area proximal to glomerular capillaries within 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
Useful treatment agents will be discussed below after discussing several embodiments of delivery devices according to embodiments of the invention.
Referring to
In operation, the device 310 is placed into a desired vessel 320 upstream of the desired treatment region or organ. The expandable diffusion member 340 is deployed creating a region of increased turbulence in the blood flow near the expandable diffusion member 340. Upstream of the expandable diffusion member 340 within the region of increased blood turbulence or upstream of that region, the therapeutic agent can be released from drug delivery lumen 360.
When the drug reaches the turbulent region, it mixes more thoroughly with the blood than it would have if the expandable diffusion member 340 were not present. Past the turbulent region, the blood and drug mixture returns to laminar flow 370. In some embodiments, the expandable diffusion member 340 creates a turbulent region that ranges from upstream of the diffusion member 340 to downstream of the member. After drug delivery, the expandable diffusion member 340 is retrieved.
Further back from the self-expanding structure 2090 and also coaxial to the main wire 2030 is a mounting ring 2040 that attaches to the main wire 2030.
As depicted in
In some embodiments, the self-expanding structure 2090 is composed of struts 2060 and a flexible membrane 2050. In these or other embodiments, the flexible membrane 2050 is composed of polyurethane, nylon, or pebax. It can take a number of different forms. In some embodiments, the flexible membrane 2050 becomes taut when deployed; in other embodiments, the flexible membrane 2050 remains at least somewhat slack when deployed. Similarly, the attachment of flexible membrane 2050 to the strut 2060 can also take a number of different forms. In some embodiments, the flexible membrane 2050 is attached or bonded to strut 2060 within the entire contact region between the flexible membrane 2050 and the strut 2060. In other embodiments, the flexible membrane 2050 is attached or bonded to strut 2060 at the distal end of strut 2060. The struts 2060 are composed of a flexible or elastic material such as nitinol, a polymer, or polymer-coated stainless steel.
In some embodiments, such as shown in
In some embodiments, the struts 2060 are serpentine such as shown in FIG. 7—serpentine struts 2111.
In operation, the therapeutic agent delivery device 2010, as shown in
Without wishing to be bound by any particular theory, the deployed self-expanding structure 2090 is believed to disturb the local blood flow causing a turbulent region near the therapeutic agent delivery device 2010.
After the deployment of the self-expanding structure 2090, drugs or other therapeutic agents are delivered through the passageway 2080. This constitutes delivery of the therapeutic agent or drug upstream of the turbulent blood, region. In an alternative embodiment, such as shown in
Another embodiment of the invention is also directed at a device adapted for percutaneous delivery into the vasculature of a mammal and adapted to expand the expandable diffusion member within the vessel of the mammal. This class of embodiments includes an infusion catheter for delivering drugs or other therapeutic agents to the mammal's vasculature. In some embodiments, the therapeutic agents are diabetic nephropathy treatment agents. In
Coils 3030 connect to the outside of the infusion catheter's walls 3020 near the distal end of the infusion catheter 3002. The coils 3030 have a substantially rectangular shape and are cut from nitinol foil or sheets, but those of ordinary skill in the art will recognize that these coils 3030 can take just about any shape. The coils 3030 are shown collapsed in
The device 3000 also comprises a sheath 3010 that is movably affixed to the distal end of the device 3000, but is manipulable from a control handle (not shown) connected to the proximal end of the device 3000. When in the closed position, the sheath 3010 maintains the coils 3030 in a collapsed configuration. When in the open position, the sheath 3010 no longer interferes with the coils 3030, and they assume the shape shown in
As shown in
In operation, the delivery catheter 1200 is delivered percutaneously (in some embodiments) to blood vessel 320 over guidewire 1220. After delivery, appropriate tension on guidewire 1220 causes diffusion member 1240 to adopt its operational or unfolded position. Once placed into its operational position, drugs or pharmaceuticals travel down drug delivery lumen 1230 through the diffusion member 1240 and then out through delivery port 1360 for delivery.
The edge 1245 of the diffusion member 1240 interferes with blood flow and creates a region of turbulent blood flow 1250 that at least partially extends across the end of diffusion member 1240 moving through the space where delivery ports 1360 deposit the drug or pharmaceutical composition at delivery. The confluence of the turbulent blood flow 1250 and the released drug or pharmaceutical compound promotes quicker mixing between the blood and the drug or pharmaceutical.
As shown in
In operation, the delivery catheter 1200 is delivered percutaneously (in some embodiments) to blood vessel 320 over guidewire 1220. After delivery, appropriate tension on guidewire 1220 causes diffusion member 1240 to adopt its operational or unfolded position. Once placed into its operational position, drugs or pharmaceuticals travel down drug delivery lumen 1230 through the diffusion member 1240 and then out through delivery port 1360.
The tabs with trailing edges 1410 act similarly to the plain edge, edge 1245 of
As shown in
In operation, the delivery catheter 1200 is delivered percutaneously (in some embodiments) to blood vessel 320 over guidewire 1220. After delivery, appropriate tension on guidewire 1220 causes diffusion member 1240 to adopt its operational or unfolded position. Once placed into its operational position, drugs or pharmaceuticals travel down drug delivery lumen 1230 through the diffusion member 1240 and then out through delivery port 1360.
The edge 1745 of the diffusion member 1240 interferes with blood flow and creates a turbulent blood flow region 1250 that at least partially extends across the end of diffusion member 1240 moving through the region where delivery ports 1360 deposit the drug or pharmaceutical composition. The confluence of the turbulent blood flow 1250 and the released drug or pharmaceutical compound promotes quicker mixing between the blood and drug or pharmaceutical.
As can be seen in
Without wishing to be bound by any theory, the data supports the observation that injection rate does correlate with absorbance uniformity. In
Despite this correlation for distally injected drugs solutions, the absorbances for the middle and proximal injection positions do not correlate with injection rate. This difference seems to indicate that injection position more strongly affects absorbance uniformity than does injection rate. Perhaps the higher injection rates yield, less uniform mixing of the blood initially, but having a longer mixing time or perhaps distance overcomes this initially poor mixing.
The experimental section contains a description of these catheter designs. Each design was used three times for each regimen. The COV is a measure of the variance of the standard deviations of the six vessels in a kidney model. Thus, smaller values indicate smaller standard deviations of absorbance among the vessels. And therefore, they indicate higher uniformity in drug distribution among the vessel and ultimately better mixing upstream of the vessel branches.
For most of the catheter designs, the data shows similar COVs for each of the separate runs, which indicates that the experiments yield reproducible results.
The date illustrates the catheter design matters to drug mixing. Generally, the SC design induces less turbulence than the SCLS design followed by BOIC-2-atm and BOIC-4-atm. Therefore, apparently increasing turbulence around the injection position increases mixing between the blood and the drug solution.
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. Treatments agents may contain a mixture of active agents.
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 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), enzastau (LY317615), bisindolylmaleimide IX, chelerythrine, edelfosine, edelfosina, ET180CH3, H7, 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 some 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. Probably, 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 its uptake into the desired tissue. In this aspect, the treatment agent may be delivered to the desired tissue in a formulation that may include vasoactive agents as enhancers of vascular permeability called excipients, such as thrombin, bradykinin and histamine. These excipients have properties that 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 that 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 encapsulated treatment agent may be incorporated into a solution including an oily material 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, polydioxanone, polyorthoester, polyamino acids, or poly (trimethylene carbonate), and combinations of these materials.
Treatment agents, including treatment agents combined with a carrier (e.g., a sustained release carrier), having a size greater than about 10 microns can become trapped in the glomerular capillaries when introduced into the renal artery. 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 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 dissolving the polymer into solution at the desired concentration. 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-methyl pyrrolidinone, toluene and mixtures of these materials.
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. Specific weight ratios depend 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, such as a biological process contributing to nephropathy, when released within the renal system. The treatment agent may be dissolved or suspended. If the treatment agent is not completely soluble in the composition, operations including mixing, stirring, 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 or nanoparticles, the microparticles or nanoparticles may be sustained release carriers prepared by a water/oil/water (WOW) double emulsion method. The WO phase, an aqueous phase containing treatment agent, is dispersed into the oil phase containing 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 (WO) emulsion is then dispersed to an aqueous solution containing a polymeric surfactant, e.g., polyvinyl alcohol) (PVA), and further homogenized to produce a WOW emulsion. After stirring for several hours, the microparticles or nanoparticles are collected by filtration.
In some embodiments, the sustained-release carrier is a liposome. “Liposomes” are approximately spherical artificial vesicles 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 to induce 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, CD1 Ib/CD1 8 (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 progress, 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 to the cells or membrane.
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 synthesized 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 glutaral-dehye 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, if it does not subsequently react with the aldehyde crosslinker. Another approach for forming cationic carriers may include using a polylysine graft of PLGA.
In still further embodiments, a surface of the carrier may beh 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 useful proteins include nephrin and podocin.
The data set out below were collected on a kidney model. This model allows the investigation of the degree of mixing between the blood and the administered therapeutic-agent solution. For accurate data collection, the model has several components: a model of the kidney vasculature; a fluidics system; an infusion system; a sample collection system, and ancillary data analysis systems or methods.
The vascular model contains an anatomically correct, 1:1 scale model of the renal arteries of a human kidney. This model is constructed from silicone. The vascular anatomy model was constructed in two different versions: one with a tortuous anatomy and one with a straight anatomy. The tortuous anatomy features a curved renal artery section between the model aorta and the arterial branches within the model kidney. And the straight anatomy features a straight and slightly shorter section in place of the curve renal artery section of the tortuous version.
At the ends of the six main kidney vessels, the anatomical model transitions back to standard tubing. Each tube is segregated so that solution can be collected individually so that the concentration of the therapeutic agent can be determined for each of the arteries in the model separately.
The fluidics system provides the fluid input to the model and sends the fluid output from the model arteries to the sample collection portion. To provide a realistic model of mixing in the kidney vasculature, the fluid flow through the model arteries should simulate the fluid flow through a real kidney. Fluid flow through this model kidney is marked by a flow rate and a pulsating pressure (just as in a real kidney, which exhibits a systolic and diastolic blood pressure).
For the data collected below, the flow rate was set to 600 mL per minute and the blood pressure was set at approximately 120 over 80 mmHg.
A standard roller pump provided the baseline flow rate. The pulsing pressure came from a pulsing pump. The pressures and flow rates are measured and controlled with pressure sensors.
Carrier Fluid for this data collection is either water or a water solution with 36% glycerol (which has a viscosity of around four centipoise). See Example 1.
For supplying the model drug solution, the model used an automated infusion pump. The pump for the infusion system was a Harvard syringe pump. For a typical experiment, the volume of model drug solution was one milliliter typically delivered at a rate of 5 mL per minute. The model drug solution for these data was a 35% solution of red food coloring in water. Thus, the model drug is red food coloring.
As discussed above, each model artery discharges into a dedicated collection vessel. Once collected, the concentration of drug (red dye) is measured using absorbance spectroscopy (Spectramax unit). The closer the concentrations of dye in the samples from each model artery are to each other, the more uniform the drug delivery down each artery. Thus, lower standard deviations of the concentrations from each of the individual model arteries indicate better mixing.
To represent homogeneity of mixing between the six independent vessels, the coefficient of variation (COV) is calculated. The COV is the ratio of the standard deviation to the mean. It can be used to compare the amount of variance between populations with different means. The absolute value of the coefficient of variation is referred to as the relative standard deviation (RSD) and is measure of precision among a set of data points. As it pertains to this invention, the COV or RSD is a measure of the variance of the standard deviations of the six vessels in a kidney model. A smaller COV or RSD value indicates smaller standard deviations of absorbance among the six vessels and thus, indicates higher uniformity in drug distribution among the vessel and ultimately better mixing.
These examples use a variety of delivery catheters:
A “Veripath catheter” is a Veripath brand catheter, which is a delivery catheter with a tapered tip and a single delivery port located at the distal end of the catheter;
A “VSH” is a Veripath brand catheter modified with side holes, which is a delivery catheter with a tapered tip and a delivery port located at the distal end of the catheter. The catheter has 15 additional holes placed near the distal end of the catheter but emerging from the sides of the catheter rather than the tip. Each of the holes is approximately 250 μm in diameter;
An “SCLS” is a Support Catheter Lifestream brand catheter. This catheter has 8 holes of around 300 micrometers diameter that are formed in the side of the catheter tip and spaced back from the tip of the catheter, which also as a single delivery located at the distal end of the catheter body;
An “SCE” is a Support Catheter Esprit brand catheter. This catheter has 9 holes of around 320 micrometers diameter that are formed in the side of the catheter tip and spaced back from the tip of the catheter, which also has a single delivery located at the distal end of the catheter body;
An “SC” is an Abbott Support Catheter, which is a single lumen catheter used for assisting guide wire delivery or infusing therapeutic agents;
An “AN” is an Accunet brand embolic protection device;
An “SB” is a spiral balloon infusion catheter with an independent infusion lumen.
A “PSB” is a Porous Spiral Balloon with a holes in a proximal taper;
A “BOIC2” is a balloon occlusion infusion catheter inflated to 2.0 atmospheres of pressure;
A “BOIC4” is a balloon occlusion infusion catheter inflated to 4.0 atmospheres of pressure;
The circulating fluid in this example was a blood substitute (mixture of water and glycerol) with a viscosity of roughly 4 centipoise. An infusion catheter was tracked to the entry of the renal artery proximal to the branching of the main renal artery into the six smaller diameter branches. Each of the six branches emptied into separate vials. The model drug fluid contained red dye so that after its infusion, each of the six vials would receive a certain concentration of dye. Therefore, using an absorbance measurement device (SpectraMax), the absorbance value is linkable to an amount of dye. With this system, the lower the standard deviation between vials, the better or more uniform the mixing of the drug in the blood upstream of the arterial branch.
Two fluids (water and the blood substitute) containing the same concentration of dye were chosen as the model drug fluid to understand the influence of viscosity on mixing. The data verified that solutions with viscosity more alike the main fluid stream would exhibit better mixing. In this case, the model drug fluid, which was the blood substitute+dye, mixed more completely than when the model drug fluid was water+dye.
Table 1 and Table 2 show the data.
In Table 1 and Table 2, above, the data points are the absorbance values from each of the six branches. The % RSD values are the most important values to note. The experiments with the lower % RSD exhibited more uniform mixing. Therefore, as the data shows, the glycerol and dye solution (which is actually glycerol+water+dye) has a lower % RSD than the water and dye solution.
In summary, the uniformity or level of mixing can be seriously influenced by the viscosity of the model drug fluid and the difference between that viscosity and the viscosity of the main fluid stream (usually blood). The more similar the viscosities of the model drug fluid and the main fluid stream, the better the mixing. Therefore, one can tune the level of mixing desired by adjusting the viscosity of the deliverable.
This set of experiments varies the distance from the delivery port of the catheter to the first branch point in the multi-branched vessels. The data is set out in Table 3, Table 4, and Table 5.
Each set of experiments uses a Veripath catheter. The model renal flow rate is 10 mL per second.
Table 3 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a proximal position—15 mm downstream of the aorta-renal-artery branch.
Table 4 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a middle position—40 mm downstream of the aorta-renal-artery branch.
Table 5 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a distal position—60 mm downstream of the aorta-renal-artery branch.
This set of experiments varies the distance from the delivery port of the catheter to the first branch point in the multi-branched vessels. The data is shown in Table 6, Table 7, and Table 8.
Each set of experiments uses a VSH catheter. The model renal flow rate is 10 mL per second.
Table 6 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a proximal position—15 mm downstream of the aorta-renal-artery branch.
Table 7 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a middle position—40 mm downstream of the aorta-renal-artery branch.
Table 8 shows the absorbance data for a variety of model infusion rates and model drug volumes with the delivery port located at a distal position—60 mm downstream of the aorta-renal-artery branch.
This set of experiments uses water as the carrier or system fluid. The model drug solution (red dye) is injected at a rate of 1 or 5 mL/min through a delivery catheter that is either a SCLS or SCE. The output of the catheter is located at a middle position (Mid) that is 40 mm downstream of the aorta-renal-artery branch or at a distal position (Distal) that is 60 mm downstream of the aorta-renal-artery branch.
The model kidney vasculature is the tortuous form. Table 9 sets out the data from this example.
This set of experiments uses water as the carrier or system fluid. The model drug solution (red dye) is injected at a rate of 1 or 5 mL/min through a delivery catheter that is either a SCLS or SCE. The output of the catheter is located at a middle position (Mid) that is 40 mm downstream of the aorta-renal-artery branch or at a distal position (Distal) that is 60 mm downstream of the aorta-renal-artery branch.
The model kidney vasculature is the straight form.
The data in Table 9 shows the standard deviation of the absorbances for the various delivery positions.
The kidney model uses a carrier fluid that models the fluid characteristics of blood.
This set of experiments uses a 36% glycerol in water solution as the carrier or system fluid. The model drug solution (red dye) is injected at a rate of 1 or 5 mL/min through a delivery catheter that is either a VSH or SCE. The output of the catheter is located at a middle position (Mid) that is 40 mm downstream of the aorta-renal-artery branch or at a distal position (Distal) that is 60 mm downstream of the aorta-renal-artery branch.
The model kidney vasculature is the tortuous form.
The data in Table 9 shows the standard deviation of the absorbances for the various delivery positions.
The kidney model uses a carrier fluid that models the fluid characteristics of blood.
This set of experiments uses a 36% glycerol in water solution as the carrier or system fluid. The model drug solution (red dye) is injected at a rate of 1 or 5 mL/min through a delivery catheter that is either a VSH or SCE. The output of the catheter is located at a middle position (Mid) that is 40 mm downstream of the aorta-renal-artery branch or at a distal position (Distal) that is 60 mm downstream of the aorta-renal-artery branch. The model kidney vasculature is the straight form.
The data in Table 9 shows the standard deviation of the absorbances for the various delivery positions. Lower standard deviations in absorbance indicate more uniform absorbances vessel branch to vessel branch. From the data, drug uniformity depends on infusion rates, distances between the injection position and the vessel branch points, carrier fluid viscosity, and catheter shape. Table 9 further supports that increasing mixing follows from adding multiple deliver ports at the distal end of the catheter. VSH is the same catheter as V but modified with side holes on the distal end. Once again, a lower COV indicates less variance between the six independent vessels and better overall mixing. The data also shows that this improved, mixing is most critical when the distance between the delivery site and vessel branching is small.
The experiments that go along with Example 8, Example 9, and Example 10 vary the catheter type, the infusion rates, the infusion volumes of model drug solutions, and the anatomy model. The data for these examples is set out in Table 11.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and water as the carrier fluid. It uses an SCE delivery catheter. The data shows the effect of varying the injection point between mid and distal positions, as described above. The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between a and 5 mL per minute.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and water as the carrier fluid. It uses an SCLS delivery catheter. The data shows the effect of varying the injection point between mid and distal positions, as described above. The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between a and 5 mL per minute.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and water as the carrier fluid. It uses an VSH delivery catheter.
The data shows the effect of varying the injection point between mid and distal positions, as described above.
The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between a and 5 mL per minute.
The experiments that go along with Example 11 and Example 12 vary the catheter type, the infusion rates, infusion volumes of model drug solutions, the catheter type, and the anatomy model. The data for these examples is set out in Table 12.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and a 36% glycerol in water solution as the carrier fluid. It uses an SCE delivery catheter.
The data shows the effect of varying the injection point between mid and distal positions, as described above.
The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between 1 and 5 mL per minute.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and a 36% glycerol in water as the carrier fluid. It uses an SCLS delivery catheter.
The data shows the effect of varying the injection point between mid and distal positions, as described above.
The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between a and 5 mL per minute.
The experiments that go along with Example 13 and Example 14 vary the catheter type, the infusion rates, infusion volumes of the model drug solutions, the catheter type, and the anatomy model. The data for these examples is set out in Table 13.
This set of experiment uses a straight anatomy as the kidney vasculature model and a 36% glycerol in water solution as the carrier fluid. It uses an VSH delivery catheter.
The data shows the effect of varying the injection point between mid and distal positions, as described above.
The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between 1 and 5 mL per minute.
This set of experiment uses a tortuous anatomy as the kidney vasculature model and a 36% glycerol in water as the carrier fluid. It uses an SCE delivery catheter.
The data shows the effect of varying the injection point between mid and distal positions, as described above.
The data shows the effect of varying the infusion volume of the model drug solution between 0.2 and 1 mL and of varying the infusion rate between a and 5 mL per minute.
For the data set out in Table 14, the absorbances for 3 experiments using each of the catheters listed below were measured for each of the six model kidney vessels. From these data, the mean, standard deviation, and coefficients of variance (COV) were calculated for each of the 3 experiments. Smaller COVs indicate more uniform absorbances within the six model kidney vessels. More uniform absorbances indicate better mixing of the model drug solution and model blood upstream of the point in the model kidney the six vessels branch from.
For the data labeled normal flow in Table 14, the experiments used a model blood pressure of 120/80, a model renal flow rate of 612 ml/min and a model heart rate of 62 beats per minute. This data is also depicted in
The injection position was middle, as described above.
The rate that the model drug solution was infused was 5 ml per minute and the model drug solution volume was 1 ml.
For the data labeled slow flow in Table 14, the experiments used a model blood pressure of 100/60, a model renal flow rate of 432 ml/min and a model heart rate of 62 beats per minute.
The injection position was middle, as described above.
The rate that the model drug solution was infused was 5 ml per minute and the model drug solution volume was 1 ml.
In this experiment, SC is a single lumen delivery device similar to the V catheter in previous examples. SCLS is the SC catheter with side holes in the distal end similar to the VSH catheter in previous examples. Data from Table 14 shows that an expandable diffusion member such as a balloon improves mixing more than a simple, single lumen delivery device or one with side holes improves mixing. Balloon expansion causes partial obstruction of the vessel resulting in turbulent flow around the balloon, which improves mixing. The degree of obstruction plays a role in the degree of mixing as the BOIC2 (inflated to 2 atm) is about 60% of the vessel ID versus the BOIC4 (inflated to 4 atm) is about 90% of the vessel ID.
While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from the embodiments of this invention in its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as fall within the true, intended, explained, disclose, and understood scope and spirit of this invention's multitudinous embodiments and alternative descriptions.
Additionally, various embodiments have been described above. For convenience's sake, combinations of aspects composing invention embodiments have been listed in such a way that one of ordinary skill in the art may read them exclusive of each other when they are not necessarily intended to be exclusive. But a recitation of an aspect for one embodiment is meant to disclose its use in all embodiments in which that aspect can be incorporated without undue experimentation. In like manner, a recitation of an aspect as composing part of an embodiment is a tacit recognition that a supplementary embodiment exists that specifically excludes that aspect. All patents, test procedures, and other documents cited, in this specification are fully incorporated by reference to the extent that this material is consistent with this specification and for all jurisdictions in which such incorporation is permitted.
Moreover, some embodiments recite ranges. When this is done, it is meant to disclose the ranges as a range, and to disclose each and every point within the range, including end points. For those embodiments that disclose a specific value or condition for an aspect, supplementary embodiments exist that are otherwise identical, but that specifically exclude the value or the conditions for the aspect.
Finally, headings are for the convenience of the reader and do not alter the meaning or content of the disclosure or the scope of the claims.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2701559 | Cooper | Feb 1955 | A |
| 3105492 | Jeckel | Oct 1963 | A |
| 3657744 | Ersek | Apr 1972 | A |
| 3868956 | Alfidi et al. | Mar 1975 | A |
| 3952747 | Kimmell, Jr. | Apr 1976 | A |
| 3993078 | Bergentz et al. | Nov 1976 | A |
| 4130904 | Whalen | Dec 1978 | A |
| 4140126 | Choudhury | Feb 1979 | A |
| 4159719 | Haerr | Jul 1979 | A |
| 4323071 | Simpson et al. | Apr 1982 | A |
| 4387952 | Slusher | Jun 1983 | A |
| 4503569 | Dotter | Mar 1985 | A |
| 4504354 | George et al. | Mar 1985 | A |
| 4512338 | Balko et al. | Apr 1985 | A |
| 4516972 | Samson | May 1985 | A |
| 4531933 | Norton et al. | Jul 1985 | A |
| 4553545 | Maass et al. | Nov 1985 | A |
| 4560374 | Hammerslag | Dec 1985 | A |
| 4580568 | Gianturco | Apr 1986 | A |
| 4616652 | Simpson | Oct 1986 | A |
| 4619246 | Molgaard-Nielsen et al. | Oct 1986 | A |
| 4649922 | Wiktor | Mar 1987 | A |
| 4650466 | Luther | Mar 1987 | A |
| 4655771 | Wallsten | Apr 1987 | A |
| 4665918 | Garza et al. | May 1987 | A |
| 4681110 | Wiktor | Jul 1987 | A |
| 4693243 | Buras | Sep 1987 | A |
| 4706671 | Weinrib | Nov 1987 | A |
| 4733665 | Palmaz | Mar 1988 | A |
| 4739762 | Palmaz | Apr 1988 | A |
| 4740207 | Kreamer | Apr 1988 | A |
| 4748982 | Horzewski et al. | Jun 1988 | A |
| 4760849 | Kropf | Aug 1988 | A |
| 4762128 | Rosenbluth | Aug 1988 | A |
| 4767418 | Deininger et al. | Aug 1988 | A |
| 4768507 | Fischell et al. | Sep 1988 | A |
| 4776337 | Palmaz | Oct 1988 | A |
| 4793348 | Palmaz | Dec 1988 | A |
| 4795458 | Regan | Jan 1989 | A |
| 4800882 | Gianturco | Jan 1989 | A |
| 4830003 | Wolff et al. | May 1989 | A |
| 4848343 | Wallsten et al. | Jul 1989 | A |
| 4856516 | Hillstead | Aug 1989 | A |
| 4870966 | Dellon et al. | Oct 1989 | A |
| 4877030 | Beck et al. | Oct 1989 | A |
| 4878906 | Lindemann et al. | Nov 1989 | A |
| 4886062 | Wiktor | Dec 1989 | A |
| 4887997 | Okada | Dec 1989 | A |
| 4892539 | Koch | Jan 1990 | A |
| 4893623 | Rosenbluth | Jan 1990 | A |
| 4907336 | Gianturco | Mar 1990 | A |
| 4913141 | Hillstead | Apr 1990 | A |
| 4921479 | Grayzel | May 1990 | A |
| 4921484 | Hillstead | May 1990 | A |
| 4922905 | Strecker | May 1990 | A |
| 4923464 | DiPisa, Jr. | May 1990 | A |
| 4943346 | Mattelin | Jul 1990 | A |
| 4950227 | Savin et al. | Aug 1990 | A |
| 4963022 | Sommargren | Oct 1990 | A |
| 4969458 | Wiktor | Nov 1990 | A |
| 4969890 | Sugita et al. | Nov 1990 | A |
| 4986831 | King et al. | Jan 1991 | A |
| 4988356 | Crittenden et al. | Jan 1991 | A |
| 4990155 | Wilkoff | Feb 1991 | A |
| 4994071 | MacGregor | Feb 1991 | A |
| 4998539 | Delsanti | Mar 1991 | A |
| 5002560 | Machold et al. | Mar 1991 | A |
| 5007926 | Derbyshire | Apr 1991 | A |
| 5015253 | MacGregor | May 1991 | A |
| 5019085 | Hillstead | May 1991 | A |
| 5019090 | Pinchuk | May 1991 | A |
| 5026377 | Burton et al. | Jun 1991 | A |
| 5034001 | Garrison et al. | Jul 1991 | A |
| 5035706 | Giantureo et al. | Jul 1991 | A |
| 5037377 | Alonso | Aug 1991 | A |
| 5037392 | Hillstead | Aug 1991 | A |
| 5037427 | Harada et al. | Aug 1991 | A |
| 5053008 | Bajaj | Oct 1991 | A |
| 5059211 | Stack et al. | Oct 1991 | A |
| 5061273 | Yock | Oct 1991 | A |
| 5061275 | Wallsten et al. | Oct 1991 | A |
| 5062829 | Pryor et al. | Nov 1991 | A |
| 5064435 | Porter | Nov 1991 | A |
| 5071407 | Termin et al. | Dec 1991 | A |
| 5073694 | Tessier et al. | Dec 1991 | A |
| 5078720 | Burton et al. | Jan 1992 | A |
| 5078726 | Kreamer | Jan 1992 | A |
| 5078736 | Behl | Jan 1992 | A |
| 5084065 | Weldon et al. | Jan 1992 | A |
| 5089005 | Harada | Feb 1992 | A |
| 5089006 | Stiles | Feb 1992 | A |
| 5092877 | Pinchuk | Mar 1992 | A |
| 5100429 | Sinofsky et al. | Mar 1992 | A |
| 5102417 | Palmaz | Apr 1992 | A |
| 5104404 | Wolff | Apr 1992 | A |
| 5108416 | Ryan et al. | Apr 1992 | A |
| 5108417 | Sawyer | Apr 1992 | A |
| 5116318 | Hillstead | May 1992 | A |
| 5116360 | Pinchuk et al. | May 1992 | A |
| 5116365 | Hillstead | May 1992 | A |
| 5122154 | Rhodes | Jun 1992 | A |
| 5123917 | Lee | Jun 1992 | A |
| 5133732 | Wiktor | Jul 1992 | A |
| 5133733 | Rasmussen et al. | Jul 1992 | A |
| 5135536 | Hillstead | Aug 1992 | A |
| 5158548 | Lau et al. | Oct 1992 | A |
| 5161547 | Tower | Nov 1992 | A |
| 5163951 | Pinchuk et al. | Nov 1992 | A |
| 5163952 | Froix | Nov 1992 | A |
| 5163958 | Pinchuk | Nov 1992 | A |
| 5171262 | MacGregor | Dec 1992 | A |
| 5180368 | Garrison | Jan 1993 | A |
| 5183085 | Timmermans | Feb 1993 | A |
| 5192297 | Hull | Mar 1993 | A |
| 5192307 | Wall | Mar 1993 | A |
| 5192311 | King et al. | Mar 1993 | A |
| 5195984 | Schatz | Mar 1993 | A |
| 5197978 | Hess | Mar 1993 | A |
| 5207644 | Strecker | May 1993 | A |
| 5217482 | Keith | Jun 1993 | A |
| 5222971 | Willard et al. | Jun 1993 | A |
| 5226913 | Pinchuk | Jul 1993 | A |
| 5234456 | Silvestrini | Aug 1993 | A |
| 5242394 | Tremulis | Sep 1993 | A |
| 5242399 | Lau et al. | Sep 1993 | A |
| 5242452 | Inoue | Sep 1993 | A |
| 5254084 | Geary | Oct 1993 | A |
| 5256146 | Ensminger et al. | Oct 1993 | A |
| 5279565 | Klein et al. | Jan 1994 | A |
| 5282823 | Schwartz et al. | Feb 1994 | A |
| 5282824 | Gianturco | Feb 1994 | A |
| 5290295 | Querals et al. | Mar 1994 | A |
| 5290305 | Inoue | Mar 1994 | A |
| 5292331 | Boneau | Mar 1994 | A |
| 5304120 | Crandell et al. | Apr 1994 | A |
| 5304200 | Spaulding | Apr 1994 | A |
| 5306250 | March et al. | Apr 1994 | A |
| 5314444 | Gianturco | May 1994 | A |
| 5314472 | Fontaine | May 1994 | A |
| 5330500 | Song | Jul 1994 | A |
| 5336178 | Kaplan et al. | Aug 1994 | A |
| 5344426 | Lau et al. | Sep 1994 | A |
| 5354279 | Hofling | Oct 1994 | A |
| 5354308 | Simon et al. | Oct 1994 | A |
| 5356433 | Rowland et al. | Oct 1994 | A |
| 5360401 | Turnland et al. | Nov 1994 | A |
| 5368566 | Crocker | Nov 1994 | A |
| 5372600 | Beyar et al. | Dec 1994 | A |
| 5378239 | Termin et al. | Jan 1995 | A |
| 5383892 | Cardon et al. | Jan 1995 | A |
| 5405378 | Strecker | Apr 1995 | A |
| 5415637 | Khosravi | May 1995 | A |
| 5419777 | Hofling et al. | May 1995 | A |
| 5421955 | Lau et al. | Jun 1995 | A |
| 5423745 | Todd et al. | Jun 1995 | A |
| 5423885 | Williams | Jun 1995 | A |
| 5445646 | Euteneuer et al. | Aug 1995 | A |
| 5449373 | Pinchasik et al. | Sep 1995 | A |
| 5456667 | Ham et al. | Oct 1995 | A |
| 5456694 | Marin et al. | Oct 1995 | A |
| 5458615 | Klemm et al. | Oct 1995 | A |
| 5476476 | Hillstead | Dec 1995 | A |
| 5484449 | Amundson et al. | Jan 1996 | A |
| 5507768 | Lau et al. | Apr 1996 | A |
| 5514154 | Lau et al. | May 1996 | A |
| 5545132 | Fagan et al. | Aug 1996 | A |
| 5549626 | Miller et al. | Aug 1996 | A |
| 5571135 | Fraser et al. | Nov 1996 | A |
| 5603721 | Lau et al. | Feb 1997 | A |
| 5609574 | Kaplan et al. | Mar 1997 | A |
| 5611775 | Machold et al. | Mar 1997 | A |
| 5626604 | Cottone, Jr. | May 1997 | A |
| 5639274 | Fischell et al. | Jun 1997 | A |
| 5653690 | Booth et al. | Aug 1997 | A |
| 5653691 | Rupp et al. | Aug 1997 | A |
| 5653727 | Wiktor | Aug 1997 | A |
| 5693029 | Leonhardt | Dec 1997 | A |
| 5713860 | Kaplan et al. | Feb 1998 | A |
| 5713863 | Vigil et al. | Feb 1998 | A |
| 5716396 | Williams, Jr. | Feb 1998 | A |
| 5720726 | Marcadis et al. | Feb 1998 | A |
| 5733303 | Israel et al. | Mar 1998 | A |
| 5733325 | Robinson et al. | Mar 1998 | A |
| 5735893 | Lau et al. | Apr 1998 | A |
| 5755781 | Jayaraman | May 1998 | A |
| 5769816 | Barbut et al. | Jun 1998 | A |
| 5782855 | Lau et al. | Jul 1998 | A |
| 5800521 | Orth | Sep 1998 | A |
| 5810871 | Tuckey et al. | Sep 1998 | A |
| 5817152 | Birdsall et al. | Oct 1998 | A |
| 5830217 | Ryan | Nov 1998 | A |
| 5836965 | Jendersee et al. | Nov 1998 | A |
| 5851210 | Torossian | Dec 1998 | A |
| 5855563 | Kaplan et al. | Jan 1999 | A |
| 5855600 | Alt | Jan 1999 | A |
| 5873852 | Vigil et al. | Feb 1999 | A |
| 5876374 | Alba et al. | Mar 1999 | A |
| 5882335 | Leone et al. | Mar 1999 | A |
| 5891108 | Leone et al. | Apr 1999 | A |
| 5893852 | Morales | Apr 1999 | A |
| 5902332 | Schatz | May 1999 | A |
| 5904670 | Schreiner | May 1999 | A |
| 5924997 | Campbell | Jul 1999 | A |
| 5951599 | McCrory | Sep 1999 | A |
| 5984964 | Roberts et al. | Nov 1999 | A |
| 5997468 | Wolff et al. | Dec 1999 | A |
| 6030413 | Lazarus | Feb 2000 | A |
| 6066168 | Lau et al. | May 2000 | A |
| 6102904 | Vigil et al. | Aug 2000 | A |
| 6129754 | Kanesaka et al. | Oct 2000 | A |
| 6146358 | Rowe | Nov 2000 | A |
| 6190405 | Culombo et al. | Feb 2001 | B1 |
| 6210392 | Vigil et al. | Apr 2001 | B1 |
| 6245026 | Campbell et al. | Jun 2001 | B1 |
| 6273910 | Limon | Aug 2001 | B1 |
| 6273913 | Wright et al. | Aug 2001 | B1 |
| 6280413 | Clark et al. | Aug 2001 | B1 |
| 6280414 | Shah et al. | Aug 2001 | B1 |
| 6283947 | Mirzaee | Sep 2001 | B1 |
| 6287336 | Globerman et al. | Sep 2001 | B1 |
| 6325826 | Vardi et al. | Dec 2001 | B1 |
| 6334871 | Dor et al. | Jan 2002 | B1 |
| 6358247 | Altman et al. | Mar 2002 | B1 |
| 6402778 | Wang | Jun 2002 | B2 |
| 6440162 | Cox et al. | Aug 2002 | B1 |
| 6450971 | Andrus et al. | Sep 2002 | B1 |
| 6451044 | Naghavi et al. | Sep 2002 | B1 |
| 6482178 | Andrews et al. | Nov 2002 | B1 |
| 6494862 | Ray et al. | Dec 2002 | B1 |
| 6577895 | Altman | Jun 2003 | B1 |
| 6592569 | Bigus et al. | Jul 2003 | B2 |
| 6602226 | Smith et al. | Aug 2003 | B1 |
| 6652579 | Cox et al. | Nov 2003 | B1 |
| 6656202 | Papp et al. | Dec 2003 | B2 |
| 6663880 | Roorda et al. | Dec 2003 | B1 |
| 6685648 | Flaherty et al. | Feb 2004 | B2 |
| 6695813 | Boyle et al. | Feb 2004 | B1 |
| 6695830 | Vigil et al. | Feb 2004 | B2 |
| 6733474 | Kusleika et al. | May 2004 | B2 |
| 6905476 | Ponzi | Jun 2005 | B2 |
| 6997903 | Wijay et al. | Feb 2006 | B2 |
| 7097440 | Papp et al. | Aug 2006 | B2 |
| 7217255 | Boyle et al. | May 2007 | B2 |
| 7241304 | Boyle et al. | Jul 2007 | B2 |
| 20010000799 | Wessman et al. | May 2001 | A1 |
| 20010007059 | Mirzaee | Jul 2001 | A1 |
| 20010010014 | Trozera | Jul 2001 | A1 |
| 20010012951 | Bates et al. | Aug 2001 | A1 |
| 20010032011 | Stanford | Oct 2001 | A1 |
| 20010047138 | Kokate et al. | Nov 2001 | A1 |
| 20020009535 | Michal et al. | Jan 2002 | A1 |
| 20020062147 | Yang | May 2002 | A1 |
| 20020077564 | Campbell et al. | Jun 2002 | A1 |
| 20020082515 | Campbell et al. | Jun 2002 | A1 |
| 20020090388 | Humes et al. | Jul 2002 | A1 |
| 20020091408 | Sutton et al. | Jul 2002 | A1 |
| 20020091409 | Sutton et al. | Jul 2002 | A1 |
| 20020091436 | Phelps et al. | Jul 2002 | A1 |
| 20020095141 | Belef et al. | Jul 2002 | A1 |
| 20020099406 | St. Germain | Jul 2002 | A1 |
| 20020099407 | Becker et al. | Jul 2002 | A1 |
| 20020103501 | Diaz et al. | Aug 2002 | A1 |
| 20020107541 | Vale et al. | Aug 2002 | A1 |
| 20020107561 | Pinheiro | Aug 2002 | A1 |
| 20020111648 | Kusleika et al. | Aug 2002 | A1 |
| 20020111659 | Davis et al. | Aug 2002 | A1 |
| 20020115942 | Stanford et al. | Aug 2002 | A1 |
| 20020120286 | DoBrava et al. | Aug 2002 | A1 |
| 20020120287 | Huter | Aug 2002 | A1 |
| 20020121472 | Garner et al. | Sep 2002 | A1 |
| 20020123720 | Kusleika et al. | Sep 2002 | A1 |
| 20020123755 | Lowe et al. | Sep 2002 | A1 |
| 20020128679 | Turovskiy et al. | Sep 2002 | A1 |
| 20020128680 | Pavlovic | Sep 2002 | A1 |
| 20020128681 | Broome et al. | Sep 2002 | A1 |
| 20020128706 | Osypka | Sep 2002 | A1 |
| 20020133092 | Oslund et al. | Sep 2002 | A1 |
| 20020138094 | Borillo et al. | Sep 2002 | A1 |
| 20020138095 | Mazzocchi et al. | Sep 2002 | A1 |
| 20020143360 | Douk et al. | Oct 2002 | A1 |
| 20020143361 | Douk et al. | Oct 2002 | A1 |
| 20020151927 | Douk et al. | Oct 2002 | A1 |
| 20020151959 | Von Oepen | Oct 2002 | A1 |
| 20020156456 | Fisher | Oct 2002 | A1 |
| 20020156457 | Fisher | Oct 2002 | A1 |
| 20020161390 | Mouw | Oct 2002 | A1 |
| 20020161392 | Dubrul | Oct 2002 | A1 |
| 20020161393 | Demond et al. | Oct 2002 | A1 |
| 20020161395 | Douk et al. | Oct 2002 | A1 |
| 20020165574 | Ressemann et al. | Nov 2002 | A1 |
| 20020165576 | Boyle et al. | Nov 2002 | A1 |
| 20020169414 | Kletschka | Nov 2002 | A1 |
| 20020169458 | Connors, III | Nov 2002 | A1 |
| 20020169472 | Douk et al. | Nov 2002 | A1 |
| 20020169474 | Kusleika | Nov 2002 | A1 |
| 20020173815 | Hogendijk et al. | Nov 2002 | A1 |
| 20020173817 | Kletschka et al. | Nov 2002 | A1 |
| 20020183763 | Callol et al. | Dec 2002 | A1 |
| 20030105515 | Skubitz et al. | Jun 2003 | A1 |
| 20030109824 | Anderson et al. | Jun 2003 | A1 |
| 20030114921 | Yoon | Jun 2003 | A1 |
| 20030125802 | Callol et al. | Jul 2003 | A1 |
| 20030181973 | Sahota | Sep 2003 | A1 |
| 20040002650 | Mandrusov et al. | Jan 2004 | A1 |
| 20040024445 | Dickson | Feb 2004 | A1 |
| 20040044400 | Cheng et al. | Mar 2004 | A1 |
| 20040059179 | Maguire et al. | Mar 2004 | A1 |
| 20040064091 | Keren et al. | Apr 2004 | A1 |
| 20040064099 | Chiu | Apr 2004 | A1 |
| 20040086550 | Roorda et al. | May 2004 | A1 |
| 20040093010 | Gesswein et al. | May 2004 | A1 |
| 20040102831 | Murray, III | May 2004 | A1 |
| 20040147939 | Rabkin et al. | Jul 2004 | A1 |
| 20040162516 | Mandrusov et al. | Aug 2004 | A1 |
| 20040214772 | Quay et al. | Oct 2004 | A1 |
| 20040230156 | Schreck et al. | Nov 2004 | A1 |
| 20040267353 | Gregorich | Dec 2004 | A1 |
| 20050015048 | Chiu et al. | Jan 2005 | A1 |
| 20050058711 | Massengale et al. | Mar 2005 | A1 |
| 20050070844 | Chow et al. | Mar 2005 | A1 |
| 20050070991 | Pienknagura | Mar 2005 | A1 |
| 20050090888 | Hines et al. | Apr 2005 | A1 |
| 20050240141 | Aliski et al. | Oct 2005 | A1 |
| 20050240147 | Makower et al. | Oct 2005 | A1 |
| 20050245882 | Elkins et al. | Nov 2005 | A1 |
| 20050288632 | Willard | Dec 2005 | A1 |
| 20060030814 | Valencia et al. | Feb 2006 | A1 |
| 20060064009 | Webler et al. | Mar 2006 | A1 |
| 20060079859 | Elkins et al. | Apr 2006 | A1 |
| 20060106366 | Wang | May 2006 | A1 |
| 20060189960 | Kesten et al. | Aug 2006 | A1 |
| 20060224234 | Jayaraman | Oct 2006 | A1 |
| 20060265043 | Mandrusov et al. | Nov 2006 | A1 |
| 20070067009 | Gandhi et al. | Mar 2007 | A1 |
| 20070129752 | Webler et al. | Jun 2007 | A1 |
| 20070213671 | Hiatt | Sep 2007 | A1 |
| 20070225634 | Ferren et al. | Sep 2007 | A1 |
| 20070250035 | El-Nounou et al. | Oct 2007 | A1 |
| 20070258903 | Kleiner et al. | Nov 2007 | A1 |
| Number | Date | Country |
|---|---|---|
| 3640745 | Jun 1987 | DE |
| 3823060 | Jan 1989 | DE |
| 19605864 | Aug 1996 | DE |
| 0062300 | Oct 1982 | EP |
| 0221570 | May 1987 | EP |
| 0338816 | Oct 1989 | EP |
| 0361192 | Apr 1990 | EP |
| 0364787 | Apr 1990 | EP |
| 0372789 | Jun 1990 | EP |
| 0380668 | Aug 1990 | EP |
| 0407951 | Jan 1991 | EP |
| 0408245 | Jan 1991 | EP |
| 0421729 | Apr 1991 | EP |
| 0423916 | Apr 1991 | EP |
| 0428479 | May 1991 | EP |
| 0517075 | Dec 1992 | EP |
| 0540290 | May 1993 | EP |
| 0541443 | May 1993 | EP |
| 807424 | Nov 1997 | EP |
| 1588731 | Oct 2005 | EP |
| 2677872 | Dec 1992 | FR |
| 2070490 | Sep 1981 | GB |
| 2135585 | Nov 1983 | GB |
| 58-501458 | Sep 1983 | JP |
| 62-213762 | Sep 1987 | JP |
| 62-231657 | Oct 1987 | JP |
| 62-235496 | Oct 1987 | JP |
| 63-214264 | Sep 1988 | JP |
| 01083685 | Mar 1989 | JP |
| 1299550 | Dec 1989 | JP |
| 2-174859 | Jul 1990 | JP |
| 2-255157 | Oct 1990 | JP |
| 03009745 | Jan 1991 | JP |
| 03009746 | Jan 1991 | JP |
| 3-57465 | Mar 1991 | JP |
| 3-151983 | Jun 1991 | JP |
| 4-25755 | Feb 1992 | JP |
| 63-246178 | Oct 1998 | JP |
| WO-8901798 | Mar 1989 | WO |
| WO-8908433 | Sep 1989 | WO |
| WO-9107139 | May 1991 | WO |
| WO-9206734 | Apr 1992 | WO |
| WO-9209246 | Jun 1992 | WO |
| WO-9640325 | Dec 1996 | WO |
| WO-9742998 | Nov 1997 | WO |
| WO-9966970 | Dec 1999 | WO |
| WO-0067825 | Nov 2000 | WO |
| WO-0141861 | Jun 2001 | WO |
| WO-0182835 | Nov 2001 | WO |
| WO-03068306 | Aug 2003 | WO |
| Entry |
|---|
| Abbott Cardiovascular Systems, Final Office Action mailed Jun. 5, 2014 for U.S. Appl. No. 13/446,768. |
| Abbott Cardiovascular Systems, Final Office Action mailed Jul. 30, 2014, U.S. Appl. No. 12/902,405. |
| Abbott Cardiovascular Systems, First Action Interview Pilot Program Pre-Interview Communication mailed Dec. 3, 2014, U.S. Appl. No. 13/154,258. |
| Abbott Cardiovascular Systems, Non-Final Office Action mailed Dec. 5, 2014, U.S. Appl. No. 12/902,405. |
| Non-Final Office Action mailed Jan. 13, 2015 for U.S. Appl. No. 13/446,768. |
| “70th Scientific Assembly and Annual Meeting: Scientific Program”, Radiology, Special Edition, vol. 153(P), Washington, D.C., (Nov. 1984), 206. |
| “72nd Scientific Assembly and Annual Meeting: RSNA Scientific Program”, Radiology, Special Edition, vol. 161(P), Chicago, IL, (Nov. 1986), 40. |
| “PE Plus Peripheral Balloon Dilation Catheter”, C.R. Bard, Inc., USCI Division, (Aug. 1985). |
| Abbott Cardiovascular Systems, Final office action dated Jun. 30, 2009 for U.S. Appl. No. 10/802,435. |
| Abbott Cardiovascular Systems, Non final office action dated Dec. 3, 2009 for U.S. Appl. No. 10/802,435. |
| Abbott Cardiovascular Systems, International Preliminary Report on Patentability dated Dec. 10, 2009 for PCT/US2008/005947. |
| Abbott Cardiovascular Systems, Non final office action dated Feb. 24, 2010 for U.S. Appl. No. 11/756,376. |
| Abbott Cardiovascular Systems, Final office action dated Jun. 2, 2010 for U.S. Appl. No. 10/802,435. |
| Abbott Cardiovascular Systems, Final Office Action mailed Nov. 22, 2010 for U.S. Appl. No. 11/756,376. |
| Abbott Cardiovascular Systems, Non-final Office Action mailed May 24, 3011 for U.S. Appl. No. 11/756,376. |
| Abbott Cardiovascular Systems, Non final office action mailed Aug. 10, 2012 for U.S. Appl. No. 13/446,761. |
| Abbott Cardiovascular Systems, Final Office Action dated Mar. 28, 2013 for U.S. Appl. No. 13/446,761. |
| Abbott Cardiovascular Systems, “PCT Invitation to Pay Additional Fees and Partial Search Report mailed Aug. 27, 2008”, PCT Application No. PCT/US2008/005947, 9 pages. |
| Abbott Cardiovascular Systems, “PCT Search Report and Written Opinion mailed Nov. 20, 2008”, PCT Application No. PCT/US2008/005947, 26 pages. |
| Bonzel, T., et al., “The Sliding Rail System (Monorail): Description of a New Technique for Intravascular Instrumentation and Its Application to Coronary Angioplasty”, Kardiologie, Supplemental 6, (1987), 119-122. |
| Charnsangavej, D., et al., “Endovascular Stent for Use in Aortic Dissection: An in Vitro Experiment”, Radiology, vol. 157, No. 2, (Nov. 1985), 323-324. |
| Charnsangavej, Chusilp, et al., “Stenosis of the Vena Cava: Preliminary Assessment of Treatment with Expandable Metallic Stents”, Radiology, vol. 161, (Nov. 1986), 295-298. |
| Cragg, et al., “Non-Surgical Placement of Arterial Endoprostheses: A New Technique Using Nitinol Wire”, Radiology Journal, (Apr. 1983), 261-263. |
| Dotter, Charles T., “Transluminal Expandable Nitinol Coil Stent Grafting: Preliminary Report”, Radiology Journal, (Apr. 1983), 259-260. |
| Dotter, Charles T., “Transluminally Placed Coilspring Endarterial Tube Grafts”, Investigative Radiology, (Sep./Oct. 1969), 329-332. |
| Duprat, et al., “Flexible Balloon-Expanded Stent for Small Vessels”, Radiology Journal, (1985), 73-77. |
| Finci, Leo, et al., “Percutaneous Transluminal Coronary Angioplasty of a Bifurcation Narrowing Using the Kissing Wire Monorail Balloon Technique”, The American Journal of Cardiology, vol. 60, (Aug. 1987), 375-376. |
| Furui, Shigeru , et al., “Hepatic Inferior Vena Cava Obstruction: Treatment of Two Types with Gianturco Expandable Metallic Stents”, Radiology, (Sep. 1990), 665-670. |
| Garasic, Joseph M., et al., “Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury”, Circulation, vol. 101, (Feb. 2000), 812-818. |
| Harrington, J.D., et al., “The Palmaz-Schatz Stent”, Handbook of Cardiovascular Interventions/Vascular Interventions, 563-572, Nov. 1996. |
| Kaltenbach, M., et al., “Zeitschrift fur Kardiologie”, Abstracts, German Journal of Cardiology, Band 80, Supplementum 3, (Apr. 1991), 28-29. |
| Lawrence, David D., Jr. , et al., “Percutaneous Endovascular Graft: Experimental Evaluation”, Radiology, vol. 163, (May 1987), 357-360. |
| Maass, et al., “Radiological Follow-Up of Transluminally Inserted Vascular Endoprosthese: An Experimental Study Using Expanding Spirals”, Radiology Journal, (1984), 659-663. |
| Mirich, et al., “Percutaneously Placed Endovascular Grafts for Aoertic Aneurysms: Feasibility Study”, Radiology, Part 2, (1989), 1033-1037. |
| Palmaz, et al., “Expandable Intraluminal Graft: A Preliminary Study”, Raiodiology Journal, (1985), 73-77. |
| PCT Search Report, PCT/US2007/009418, (Oct. 4, 2007). |
| Rosch, Josef, et al., “Experimental Intrahepatic Portacaval Anastomosis: Use of Expandable Gianturco Stents”, Radiology, vol. 162, (Feb. 1987), 481-485. |
| Rosch, Josef, et al., “Gianturco Expandable Stents in Experimental and Clinical Use”, Twelfth Annual Course of Diagnostic Angiography and Interventional Radiology (Pittsburgh, PA), (Mar. 1987), 121-124. |
| Rosch, Josef, et al., “Gianturco Expandable Wire Stents in the Treatment of Superior Vena Cava Syndrome Recurring after Maximum-Tolerance Radiation”, Cancer, vol. 60, (Sep. 1987), 1243-1246. |
| Rosch, Josef, et al., “Modified Gianturco Expandable Wire Stents in Experimental and Clinical Use”, Annales de Radiologie, vol. 31, No. 2, (1988), 100-103. |
| Rosch, Jr., M.D. , et al., “Transjugular Intrahepatic Portacaval Shunt: An Experimental Work”, The American Journal of Surgery, vol. 121, (May 1971), 588-592. |
| Strupp, G., et al., “Clinical and Angiographic Short and Medium Term Results after Coronary Stenting”, Zeitschrift fur Kardiologie, vol. 81, (1992), 500-506. |
| Van Der Geissen, Willem J., et al., “Coronary Stenting with a new, Radiopaque Balloon-Expandable Endoprosthesis in Pigs”, Circulation, vol. 83, No. 5, (May 1991), 93-149. |
| Wallace, Michael J., et al., “Tracheobronchia Tree: Expandable Metallic Stents Used in Experimental and Clinical Applications (Work in Progress)”, Radiology, vol. 158, (Feb. 1986), 309-312. |
| Wright, et al., “Percutaneous Endovascular Stents: An Experimental Evaluation”, Radiology Journal, (1985), 69-72. |
| Yoshioka, et al., “Development and Clinical Application of Biliary Endoprosthesis Using Expandable Metallic Stents”, Japan Radiological Society, vol. 48, No. 9, (1988), 1183-1185. |
| Yoshioka, et al., “Self-Expanding Endovascular Graft: An Experimental Study in Dogs”, American Journal of Roentgeriology, vol. 151, (Oct. 1988), 673-676. |
| Zeltinger, J., et al., “Advances in the Development of Coronary Stents”, Biomaterials Forum, (2004), pp. 8-9, 24. |
| Number | Date | Country | |
|---|---|---|---|
| 20110245766 A1 | Oct 2011 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13154258 | Jun 2011 | US |
| Child | 12902405 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11756376 | May 2007 | US |
| Child | 13158757 | US | |
| Parent | 12902405 | Oct 2010 | US |
| Child | 11756376 | US |
