Patent Application
20120259314
The invention relates generally to intraluminal methods and devices for the treatment of a chronic total occlusion (CTO) within a body vessel.
Stenotic lesions may include a hard, calcified substance and/or a softer thrombus material, each of which forms on the lumen walls of a blood vessel and restricts blood flow. Intraluminal treatments such as balloon angioplasty, stent deployment, atherectomy, and thrombectomy are well known and have proven effective in the treatment of such stenotic lesions. These treatments often involve the insertion of a therapy catheter into a patient's vasculature, which may be tortuous and may have numerous stenoses of varying degrees along its length. In order to place a distal end of a catheter at the treatment site, a guidewire is typically introduced and tracked from an incision, through the vasculature, and across the lesion. Then, a balloon catheter, perhaps containing a stent at its distal end, can be tracked over the guidewire to the treatment site. Ordinarily, a distal end of the guidewire is quite flexible so that it may be rotatably steered and pushed through the bifurcations and turns of the typically irregular passageway without damaging the vessel walls.
In some instances, the extent of occlusion of the lumen is so severe that the lumen is completely or nearly completely obstructed, which may be described as a total occlusion. If such an occlusion persists for a long period of time, the lesion may be referred to as a chronic total occlusion or CTO. Furthermore, in the case of diseased blood vessels, the lining of the vessels may be characterized by the prevalence of atheromatous plaque, which may form total occlusions. The extensive plaque formation of a chronic total occlusion typically has a fibrous cap surrounding softer plaque material. This fibrous cap may present a surface that is difficult to penetrate with a conventional guidewire, and a typically flexible distal tip of the guidewire may be unable to cross the lesion.
Thus, for treatment of total occlusions, stiffer guidewires have been employed to recanalize through the total occlusion. However, due to the fibrous cap of the total occlusion, a stiffer guidewire still may not be able to cross the occlusion and may prolapse into the vessel when force is applied. As well when using a stiffer guidewire, greater care must be taken to avoid perforation of the vessel wall.
Further, even if the guidewire can penetrate the proximal cap of the total occlusion, it may not be able to completely cross the occlusion. In a CTO, there may be a distortion of the regular vascular architecture such that there may be multiple small non-functional channels throughout the occlusion rather than one central lumen for recanalization. Thus, the conventional approach of looking for a single channel in the center of the occlusion may account for many of the failures. Furthermore, these spontaneously recanalized channels may be responsible for failures due to their dead-end pathways and misdirecting of the guidewires. Once a “false” tract is created by a guidewire, subsequent attempts with different guidewires may continue to follow the same incorrect path, and it is very difficult to steer subsequent guidewires away from the false tract.
Another equally important failure mode, even after a guidewire successfully crosses a chronic total occlusion, is the inability to advance a balloon, other angioplasty device, or other intravascular device over the guidewire due to the fibrocalcific composition of the chronic total occlusion, which occur as fibrous caps mainly at the “entry” and “exit” segments of the chronic total occlusion.
Embodiments hereof relate to a method of recanalizing a chronic total occlusion. The method includes positioning distal ends of a catheter and a guidewire proximally adjacent to the occlusion. An occlusion weakening therapy effective to soften and/or loosen the occlusion is delivered to the occlusion via at least one lumen of a catheter. The occlusion weakening therapy includes at least a first therapeutic agent targeted to soften and/or loosen a first material or component of the occlusion and a second therapeutic agent targeted to soften and/or loosen a second material or component of the occlusion, and the first and second therapeutic agents are selectively deliverable together or separately depending on the type of material encountered in the occlusion that needs to be crossed or recanalized by the guidewire. The distal end of the guidewire is advanced into the occlusion until the distal end of the guidewire crosses the occlusion to exit distal thereof.
Another method according to an embodiment hereof includes positioning distal ends of a catheter and guidewire proximally adjacent to the occlusion and delivering an occlusion weakening therapy through the distal end of the catheter at or within the occlusion. The occlusion weakening therapy is effective to quickly soften and/or loosen the occlusion for crossing shortly after delivery thereof. The distal end of the guidewire is advanced into the occlusion after the delivery of the occlusion weakening therapy until the distal end of the guidewire is located through the occlusion at a point distal to the occlusion. In an embodiment, the guidewire may be advanced into the occlusion within a thirty minute time period required to weaken the occlusion.
The foregoing and other features and advantages of the invention will be apparent from the following description of embodiments hereof as illustrated in the accompanying drawings. The accompanying drawings, which are incorporated herein and form a part of the specification, further serve to explain the principles of the invention and to enable a person skilled in the pertinent art to make and use the invention. The drawings are not to scale.
Specific embodiments of the present invention are now described with reference to the figures, wherein like reference numbers indicate identical or functionally similar elements. The terms “distal” and “proximal” are used in the following description with respect to a position or direction relative to the treating clinician. “Distal” or “distally” are a position distant from or in a direction away from the clinician. “Proximal” and “proximally” are a position near or in a direction toward the clinician.
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses of the invention. Although the description of the invention is in the context of treatment of blood vessels such as the coronary and peripheral arteries, the invention may also be used in any other body passageways where it is deemed useful. Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description.
Guidewire 114 slidingly extends through guidewire lumen 108 of catheter shaft 106 with distal end or tip 120 of guidewire 114 extending beyond distal end 112 of catheter shaft 120 as shown in
Catheter 105 is utilized for delivering an occlusion weakening therapy that includes one or more active therapeutic agents to soften and/or loosen the material of a CTO. Atherosclerotic plaques vary considerably in their composition from site to site, but certain features are common to all of them. For example, plaques contain many cells which primarily are derived from cells of the vessel wall that have divided and grown into the surface layer of the blood vessel, creating a mass lesion. Plaques also contain cholesterol and cholesterol esters, commonly referred to as fat, which may lie freely in the space between the cells and in the cells themselves. A large amount of collagen is also present in the plaques, particularly advanced plaques of the type which cause clinical problems such as CTO. Additionally, human plaques contain calcium to varying degrees, hemorrhagic material including clot and grumous material composed of dead cells, and other debris. Relatively large amounts of water are also present, as is typical of all tissue. In various embodiments hereof, the occlusion weakening therapy delivered via catheter 105 includes one or more enzyme(s) and at least one chelating agent to quickly weaken the CTO, to facilitate the passing of guidewire 114 and subsequently allow for secondary interventions such as a balloon angioplasty and/or stenting. In an embodiment, the occlusion weakening therapy delivered softens or loosens the CTO within a time period of thirty minutes or less. Guidewire 114 is used to mechanically penetrate and pass through the weakened lesion during and/or shortly after administration of the occlusion weakening therapy, thereby combining mechanical force and multiple active therapeutic agents to achieve crossing of the CTO.
The particular combination of enzyme(s) and chelating agent(s) operate to quickly weaken the CTO because each therapeutic agent targets a different aspect or material of a CTO. In addition, the chelating agent enhances the activity/performance of the enzyme as compared to occlusion weakening therapy including only enzyme(s) as the active therapeutic agent. More particularly, the enzyme(s) of the occlusion weakening therapy operate to loosen or break up tissue material of a CTO. “Tissue material” as utilized herein is intended to mean connective tissue of a chronic total occlusion that may include cells primarily derived from vessel wall cells or other cells and collagen, elastin, fibronecting, laminin or other fibrous proteins, proteoglycans, hyaluronic acid, cholesterol and cholesterol esters, water, polysaccharides and/or necrotic debris, although the specific composition of atherosclerotic plaques and CTOs vary between individuals. Enzyme(s) may be selected to act on any of the above-mentioned extracellular matrix components. In one embodiment, enzyme(s) may be selected to act to degrade the collagen content of the CTO, as collagen is a predominant component of atherosclerotic plaque and is a main supportive structure of plaque of a CTO such that the plaque body collapses when the collagen degrades. Suitable examples include, but are not limited to, different proteases or elastases such as but not limited to papain, collagenase, serrapatase, or elastase which can digest proteins in the presence of extracellular matrix. In one embodiment, the one or more enzyme(s) of the occlusion weakening therapy may be selected from: matrix metalloproteinases, serine elastases, trypsin, neutral protease, chymotrypsin, aspartase, cysteinase and clostripain. Matrix metalloproteinases (MMPs) is a group of zinc-containing enzyme(s) that are responsible for degradation of several extracellular matrix (ECM) components, including collagen, fibronectin, elastin, proteoglycans and laminin. These ECM components are important components of the occluding atherosclerotic plaque. MMPs play an important role in normal embryogenesis, inflammation, wound healing and tumour invasion. These enzyme(s) are broadly classified into three general groups: collagenases, gelatinases and stromelysins. Collagenase is the initial mediator of the extracellular pathways of interstitial collagen degradation, with cleavage at a specific site in the collagen molecule, rendering it susceptible to other neutral proteases (e.g. gelatinases) in the extracellular space. In one embodiment, the enzyme containing formulation includes a matrix metalloproteinase selected from: collagenase, type 1A collagenase, gelatinases, and stromelysins. In another embodiment, the enzyme containing formulation includes collagenase, whether alone or in combination with other enzyme(s).
In addition to enhancing the performance of the enzyme(s), the chelating agent of the occlusion weakening therapy operates to soften the calcification of a CTO. Chelating agents or chelants are chemicals that bind with or “sequester” certain metal ions such as calcium (Ca2+). In a CTO, calcium may be loosely held in plaque deposits by an electrostatic charge which prevents the body from dissolving the plaque. The calcium of a calcified lesion binds with the chelating agent(s) of the occlusion weakening therapy, removing the metallic ion from a CTO by holding it in solution and thereby softening or dissolving the calcification of the CTO. Further, when utilized in combination with enzymes, the effects of the chelating agent(s) to soften and/or remove calcification are accelerated because enzyme(s) are simultaneously acting to loosen or break up tissue of the CTO. Non-exhaustive examples of suitable chelating agents include ethylenediaminetetraacetic acid (EDTA, a polyamino carboxylic acid), ethylene glycol tetraacetic acid (EGTA, a polyamino carboxylic acid), citric acid, and other substances that chelate with Ca+ ions.
In one embodiment shown in
In another embodiment shown in
In another embodiment shown in
Other types of catheter construction are also amendable to the present invention, such as, without limitation thereto, a catheter coaxial construction including coaxial outer and inner shafts such that a first annular lumen for delivery of occlusion weakening therapy is defined between an inner surface of the outer shaft and an outer surface of the inner shaft and a second lumen is defined by an interior surface of the inner shaft, which also serves as a guidewire lumen. As well various multi-lumen extrusion catheter shaft constructions and catheters having a rapid exchange configuration may be adapted for use herein.
Referring to
Shortly after release of occlusion weakening therapy 504, guidewire 414 is distally advanced towards and/or within occlusion 402. Thus, distal end 420 of guidewire 414 penetrates and is manipulated into occlusion 414 shortly after release of occlusion weakening therapy 504. Advantageously, occlusion weakening therapy 504 softens and/or loosens occlusion 402 shortly after administration thereof to render occlusion 402 crossable in a relative short period of time, i.e., less than thirty minutes. In one embodiment, occlusion weakening therapy 504 softens and/or loosens and renders occlusion 402 crossable in less than five minutes. Such a reduced treatment time is substantially shorter than prior art approaches to weakening a chronic total occlusion, which typically require a waiting period of one to three days between application of a weakening agent and advancement of the guidewire. The shortened treatment time may be due to the specific combination of enzyme(s) and chelating agent(s) of occlusion weakening therapy 504. More particularly, as previously described herein, in addition to being effective in the softening and/or degrading of calcification of occlusion 402, certain chelating agents such as EDTA promote or increase the enzyme's performance. In addition, the shortened treatment time is due to the relatively higher concentrations of enzyme(s) utilized in occlusion weakening therapy 504. Some known approaches for weakening a CTO typically utilize relatively diluted concentrations of enzyme(s), i.e., 300 ug/ml, due to concerns regarding higher concentrations remaining/mixing into a patient's bloodstream. In accordance with methods hereof, occlusion weakening therapy 504 utilizes higher concentrations of enzyme(s), i.e., approximately 7 mg/ml, and one or more excess enzyme removal steps to remove excess enzyme(s) from the patient to alleviate any concerns regarding the higher concentrations. As will be described in more detail herein, the enzyme removal process may include utilizing an extendable needle or cannula at distal end 420 of guidewire 414 to guide delivery of occlusion weakening therapy 504 into occlusion 402, utilizing an expandable suction cup at distal end 420 of guidewire 414 to act as a shield that prevents occlusion weakening therapy 504 from entering into the bloodstream, utilizing an inflatable balloon at distal end 420 of guidewire 414 to act as a shield that prevents occlusion weakening therapy 504 from entering into the bloodstream, and/or aspirating excess solution and debris shortly after delivery of occlusion weakening therapy 504.
Catheter 405 is continually advanced and occlusion weakening therapy 504 released as necessary until distal end 420 of guidewire 414 is located at a point distal to occlusion 402 as shown in
One or more enzyme removal features may be incorporated into a catheter used in delivering a occlusion weakening therapy in accordance herewith to remove any excess amount of enzyme(s). In any embodiment described herein, a suction member such as a syringe or vacuum may be attached to the proximal end of the catheter for aspirating excess solution and any debris through a lumen of the catheter. In a single or multi-lumen catheter such as those described herein, aspiration may occur through the same lumen utilized for delivery of the occlusion weakening therapy. Alternatively, the catheter is at least a multi-lumen catheter that includes at least one lumen for delivery of the occlusion weakening therapy and an additional lumen dedicated to aspiration of excess solution and debris. In one embodiment, aspiration of excess solution and debris occurs approximately 10-20 minutes after delivery of the occlusion weakening therapy. Aspiration of excess solution prevents the occlusion weakening therapy from entering a patient's bloodstream. Thus the relatively higher concentrations of enzyme(s) that are utilized in the occlusion weakening therapy in order to speed up the treatment time for weakening the CTO are substantially prevented from entering a patient's bloodstream. In addition, aspiration of debris such as digested tissue that breaks off or separates from the CTO prevents these potentially dangerous fragments from entering a patient's bloodstream.
Referring to
When expanded in situ, suction cup 1035 assists in fixing or securing the location of a distal tip 1012 of catheter 1005 in close proximity to a CTO while also positioning a guidewire 1014 slidingly received within catheter 1005 towards the center of the proximal end of the CTO such that the guidewire may be utilized to penetrate into the CTO. In addition, the delivered occlusion weakening therapy is essentially trapped between the expanded suction cup 1035 and the CTO during the recanalization procedure. Proximal or upstream blood flow is blocked from mixing with the delivered occlusion weakening therapy by expanded suction cup 1035. Aspiration or suction may be applied through a lumen of catheter 1005 to remove any excess solution and debris to prevent the same from entering a patient's bloodstream, thus creating a suction or vacuum force within the space between the proximal end of the CTO and expanded suction cup 1035. Thus higher concentrations of the enzyme(s) that are utilized in the occlusion weakening therapy in order to speed up the treatment time for weakening a CTO are substantially prevented from entering a patient's bloodstream.
The following description relates to specific examples of blended solutions that are operable as occlusion weakening therapy to quickly soften and/or loosen a CTO as described herein. Although the examples are blended solutions having one or more enzyme (s) and a chelating agent, in other embodiments the enyzme(s) and chelating agent(s) may be utilized as separate solutions that are selectively delivered to a CTO depending upon what the make-up of the CTO is when encountered as described above.
In one example, a blended solution of enzyme(s) and the chelating agent EDTA may be prepared as described herein. A base buffer of an EDTA solution may be prepared ahead of time. The base buffer of an EDTA solution includes weighing out 0.0606 g of cysteine-HCL and charging it into a 100 ml volumetric flask. 2.915 g of EDTA disodium salt is added to the volumetric flask and the flask is filled to the 100 ml mark. The flask is placed on a stir plate and stirred. The fully dissolved solution is poured into an Erlenmeyer flask and the pH of the solution is adjusted to 6.25. The solution is bubbled with an inert gas, such as argon, to remove oxygen therefrom. The base buffer may be stored in a −20° C. freezer until use. 2 mL of the base EDTA buffer is combined with 2 mL of 10 mg/mL papain solution, an enzyme that breaks up protein. 20 ml of the base EDTA buffer is combined with 30 mg of collagenase I, an enzyme that breaks up protein. A calcium chloride (CaCl2) solution is also formulated by weighing out 10 g of calcium chloride in a 100 ml Erlenmeyer flask, adding 90 ml of DI water, and dissolving the solution by stirring it at room temperature. The CaCl2 solution is a salt that enhances or increases the performance of enzymes. 1125 μl of the papain solution/base EDTA buffer, 1125 μl of the collagenase I/base EDTA buffer, and 750 μl of the CaCl2 solution are combined and vortexed.
In another example, a base buffer of an EDTA solution may be prepared ahead of time as described above in Example 1. 2 mL of the base EDTA buffer is combined with 2 mL of 10 mg/mL papain solution, an enzyme that breaks up protein. 20 ml of the base EDTA buffer is combined with 30 mg of collagenase I, an enzyme that breaks up protein. 2.5 ml of the base EDTA buffer is combined with 50 mg of collagenase III solution, an enzyme that breaks up protein. A calcium chloride (CaCl2) solution is also formulated by weighing out 10 g of calcium chloride in a 100 ml Erlenmeyer flask, adding 90 ml of DI water, and dissolving the solution by stirring it at room temperature. The CaCl2 solution is a salt that enhances or increases the performance of enzymes. 1125 μl of the papain solution/base EDTA buffer, 1125 μl of the collagenase I/base EDTA buffer, 750 μl of the CaCl2 solution, and 500 μl of the collagenase III/base EDTA buffer are combined and vortexed.
In another example, a base buffer of an EDTA solution may be prepared ahead of time as described above in Example 1. 5 ml of the base EDTA buffer is combined with 100 mg of collagenase I, an enzyme that breaks up protein. A calcium chloride (CaCl2) solution is also formulated by weighing out 10 g of calcium chloride in a 100 ml Erlenmeyer flask, adding 90 ml of DI water, and dissolving the solution by stirring it at room temperature. The CaCl2 solution is a salt that enhances or increases the performance of enzymes. 1125 μl of 20 mg/ml papain solution, 1125 μl of the 20 mg/ml collagenase I/base EDTA buffer, and 750 μl of the CaCl2 solution are combined and vortexed.
In another example, a base buffer of an EDTA solution may be prepared ahead of time as described above in Example 1. 5 ml of the base EDTA buffer is combined with 100 mg collagenase I, an enzyme that breaks up protein. 2.5 ml of the base EDTA buffer is combined with 50 mg of collagenase III, an enzyme that breaks up protein. A calcium chloride (CaCl2) solution is also formulated by weighing out 10 g of calcium chloride in a 100 ml Erlenmeyer flask, adding 90 ml of DI water, and dissolving the solution by stirring it at room temperature. The CaCl2 solution is a salt that enhances or increases the performance of enzymes. 1125 μl of 20 mg/ml papain solution, 1125 μl of the 20 mg/ml collagenase I/base EDTA buffer, 750 μl of the CaCl2 solution, and 500 μl of the 20 mg/mL collagenase III solution/base EDTA buffer are combined and vortexed.
In another example, a base buffer of an EDTA solution may be prepared ahead of time as described above in Example 1. 2.5 ml of the base EDTA buffer is combined with 50 mg collagenase III, an enzyme that breaks up protein to prepare a 20 mg/mL collagenase III/base EDTA buffer solution.
Serrapeptase (CAS #37312-62-2, EC 3.4.24.40) with a known purity is used as received from the manufacturer/supplier. Serrapeptase is an enzyme from silkworms which breaks up proteins found in tissue of a CTO. The enzyme is weighed and dissolved in a sufficient quantity of PBS to make a solution with a concentration of approximately 20 to 25 mg of enzyme/mL of buffer.
While various embodiments according to the present invention have been described above, it should be understood that they have been presented by way of illustration and example only, and not limitation. It will be apparent to persons skilled in the relevant art that various changes in form and detail can be made therein without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the appended claims and their equivalents. It will also be understood that each feature of each embodiment discussed herein, and of each reference cited herein, can be used in combination with the features of any other embodiment. All patents and publications discussed herein are incorporated by reference herein in their entirety.
