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Publication numberUS20080208167 A1
Publication typeApplication
Application numberUS 12/114,717
Publication date28 Aug 2008
Filing date2 May 2008
Priority date15 Apr 2003
Also published asEP1631299A2, EP2332553A1, EP2340843A1, US7294334, US7641643, US8383158, US8795652, US20040208845, US20040213756, US20150011502, US20150018747, WO2004091592A2, WO2004091592A3
Publication number114717, 12114717, US 2008/0208167 A1, US 2008/208167 A1, US 20080208167 A1, US 20080208167A1, US 2008208167 A1, US 2008208167A1, US-A1-20080208167, US-A1-2008208167, US2008/0208167A1, US2008/208167A1, US20080208167 A1, US20080208167A1, US2008208167 A1, US2008208167A1
InventorsJohn Stankus, Eugene T. Michal
Original AssigneeJohn Stankus, Michal Eugene T
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Methods and compositions to treat myocardial conditions
US 20080208167 A1
Abstract
Methods, devices, kits and compositions to treat a myocardial infarction. In one embodiment, the method includes the prevention of remodeling of the infarct zone of the ventricle. In other embodiments, the method includes the introduction of structural reinforcing agents such as those agents containing aloe-derived pectin. In other embodiments, the structural reinforcing agent may be accompanied by other therapeutic agents. These agents may include, but are not, limited to pro-fibroblastic and angiogenic agents.
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Claims(31)
1. A method comprising identifying an infarct region within the ventricle of a subject; and
delivering near or in the infarct region material comprising aloe-derived pectin.
2. A method comprising identifying an infarct region within the ventricle of a subject; and
delivering to the infarct region material comprising aloe-derived pectin.
3. The method of claim 1 wherein delivering aloe-derived pectin prevents thinning of the ventricle.
4. The method of claim 1 wherein delivery of the aloe-derived pectin occurs within 2 weeks of a myocardial infarction (MI).
5. The method of claim 1 wherein delivery of the aloe-derived pectin occurs within 5, 10, 15, or 20 weeks of a myocardial infarction (MI).
6. The method of claim 1 wherein the aloe-derived pectin material further comprises at least one of cells, proteins, peptides, growth factors or microparticles containing at least one of cells, proteins, peptides, or growth factors or nanoparticles containing at least one of cells, proteins, peptides or growth factors.
7. The method of claim 6 wherein the aloe-derived pectin material comprises cells and proteins, cells and growth factors, or proteins and growth factors.
8. The method of claim 1 wherein said subject with the MI displays at least 20 percent ventricular damage.
9. The method of claim 1 wherein the aloe-derived pectin displays a pseudoplastic characteristic.
10. The method of claim 1 wherein delivering aloe-derived pectin comprises: delivering the aloe-derived pectin material to the infarct region in a liquid phase and once delivered the aloe-derived pectin material is capable of transitioning to a solid phase in the presence of an endogenous material.
11. The method of claim 1 further comprising delivering at least one matrix metalloproteinase inhibitor (MMPIs) to the ventricle.
12. The method of claim 1 wherein delivering the aloe-derived pectin comprises introducing the aloe-derived pectin to the ventricle through a procedure.
13. The method of claim 12 wherein the procedure to the ventricle region is selected from at least one of minimally invasive such as sub-xiphoid, percutaneous, or surgical approach such as open-chest procedure in conjunction with Coronary Bypass Graft (CABG).
14. The method of claim 13 wherein the percutaneous introduction of the aloe-derived pectin into the ventricle comprises at least one of the following modes consisting of intracoronary infusion, intraventricular catheter, intravenous pressure perfusion, transvascular needle catheter, and retrograde venous perfusion.
15. The method of claim 1 wherein delivering the aloe-derived pectin comprises delivering a composition suspended in a solution.
16. The method of claim 1 wherein delivering aloe-derived pectin near the infarct region is capable of increasing the compliance of the ventricle.
17. A kit comprising a delivery lumen; agents delivered from the delivery lumen; and at least one agent comprising a structural reinforcing agent wherein said structural reinforcing agent is capable of forming a matrix product within a ventricle wherein the structural re-inforcing agent comprises a material comprising aloe-derived pectin.
18. The kit of claim 17 further comprising forming a matrix product within or near an infarct region of a ventricle.
19. The kit of 17 further comprising a delivery device.
20. The kit of 17 wherein the structural reinforcing agent comprises a material in a liquid phase and once delivered the material is capable of transitioning to a solid phase in the presence of an endogenous material in or near an infarct region.
21. A kit comprising a delivery lumen and agents comprising aloe-derived pectin, wherein the agents are capable of increasing the compliance of a ventricle.
22. The kit of claim 21 further comprising a delivery device.
23. A method comprising delivering a liquid phase of a structural reinforcing agent to a ventricle wherein the structural reinforcing agent is capable of transitioning to a solid when an environmental temperature is approximately a body temperature of a mammalian subject and wherein the structural reinforcing agent comprises a material comprising aloe-derived pectin.
24. The method of claim 23 wherein delivering a liquid phase of a structural reinforcing agent to a ventricle comprises delivering a liquid phase of a structural reinforcing agent to or near an infarct region of a ventricle.
25. A method comprising delivering a first material and a second different material to a ventricle wherein a first material and a second different material are components of a final product and wherein the first or second material comprises aloe-derived pectin.
26. The method of claim 25 wherein the final product prevents thinning of the ventricle.
27. A kit comprising at least two delivery lumen; agents delivered from each delivery lumen; and a first material and a second different material wherein the first material and the second different material are components of a final product and are capable of forming the final product within a ventricle and wherein the first or second material comprises aloe-derived pectin.
28. The kit of claim 27 wherein the first material and the second material are housed in separate lumen.
29. The kit of claim 27 wherein a final product is formed within or near an infarct region of a ventricle from the first material and the second material.
30. The kit of claim 27 further comprising a delivery device.
31. The kit of claim 30 wherein the delivery device comprises a dual chamber delivery device comprising separate chambers for the first material and the second different material.
Description
    RELATED APPLICATIONS
  • [0001]
    This application is a continuation-in-part of application 10/414,602, filed on Apr. 15, 2003, and fully incorporates the contents of that application.
  • FIELD
  • [0002]
    The treatment of myocardial infarction, and more particularly, in one embodiment, to the reinforcement of the infarct regional wall of a heart chamber and/or the inhibition of the thinning of the infarct regional wall of a heart chamber.
  • BACKGROUND
  • [0003]
    Ischemic heart disease typically results from an imbalance between the myocardial blood flow and the metabolic demand of the myocardium. Progressive atherosclerosis with increasing occlusion of coronary arteries leads to a reduction in coronary blood flow. Blood flow can be further decreased by additional events such as changes in circulation that lead to hypoperfusion, vasospasm or thrombosis.
  • [0004]
    Myocardial infarction accounts for approximately 20% of all deaths. It is a major cause of sudden death in adults.
  • [0005]
    Myocardial Infarction (MI) is one form of heart disease that often results from the sudden lack of supply of oxygen and other nutrients. The lack of blood supply is a result of closure of the coronary artery that nourishes the particular part of the heart muscle. The cause of this event is generally caused by arteriosclerosis “hardening of the arteries” in coronary vessels.
  • [0006]
    Formerly, it was believed that an MI was caused from a slow procession of closure from for example 95% then to 100% but an MI can also be a result of minor blockages where, for example, there is a rupture of the cholesterol plaque resulting in blood clotting within the artery. Thus, the flow of blood is blocked and downstream cellular damage occurs. This damage can cause irregular rhythms that can be fatal, even though the remaining muscle is strong enough to pump a sufficient amount of blood. As a result of this insult to the heart tissue, scar tissue tends to naturally form.
  • [0007]
    Even though relatively effective systemic drugs exist to treat MI such as ACE-inhibitors and Beta-blockers, a significant portion of the population that experiences a major MI ultimately develops heart failure. An important component in the progression to heart failure is remodeling of the heart due to mechanical forces resulting in uneven stress and strain distribution in the left ventricle. Once an MI occurs remodeling of the heart begins. The principle components of the remodeling event include myocyte death, edema and inflammation, followed by fibroblast infiltration and collagen deposition, and finally scar formation. The principle component of the scar is collagen. Since mature myocytes of an adult are not regenerated the infarct region experiences significant thinning. Myocyte loss is the major etiologic factor of wall thinning and chamber dilation that may ultimately lead to progression of cardiac myopathy. Myocyte death can and does occur. In other areas, remote regions experience hypertrophy (thickening) resulting in an overall enlargement of the left ventricle. This is the end result of the remodeling cascade. These changes in the heart result in changes in the patient's lifestyle and their ability to walk and to exercise. These changes also correlate with physiological changes that result in increase in blood pressure and worsening systolic and diastolic performance.
  • [0008]
    FIGS. 1A-1C illustrate blood flow by longitudinal cross sectioning of the artery. FIG. 1A illustrates a normal unobstructed artery. FIG. 1B illustrates artery damage due to a tear or spasm. This FIG. illustrates a minor insult to the interior wall. FIG. 1C illustrates an artery with plaque build-up that reduces the blood flow demonstrated by the blocked blood cell above the atherosclerotic mass. Fat and cholesterol build up at the site of damage. This mass can be detected by methods currently available, such as an ECG, SPECT, MRI, angiogram.
  • [0009]
    FIGS. 2A-2B illustrate the progression of heart damage once the build-up of plaque induces an infarct to occur. The most common pathogenesis of this disease is occlusive intracoronary thrombus where a thrombus is covering an ulcerated stenotic plaque. This causes approximately 90% of transmural acute myocardial infarctions. Other possible triggers of an MI are vasospasms with or without coronary atherosclerosis and possible association with platelet aggregation. Another possible trigger is embolisms from left-sided mural thrombosis, vegetative endocarditis or a paradoxic embolism from the right side of the heart through a patent foramen ovale. FIG. 2A illustrates a site where blockage and restricted blood flow can occur from any of the indicated causes. FIG. 2B illustrates the extensive damage to the left ventricle that can be a result of the lack of oxygen and nutrient flow carried by the blood to the inferior region left ventricle of the heart. This area will likely undergo remodeling and eventually a scar will form and a non-functional (an area that does not contract) area will exist.
  • [0010]
    Significant atherosclerotic build-up can reduce the arterial lumen and reduce blood flow. Build-up is capable of rupturing resulting in a total or partial occlusion of the artery. Complete coronary occlusion will lead to an acute MI. Thus the T-cells, platelets, fibrin and multiple other factors and cells are blocked from progression through the blood stream and the result is an inadequate vascular supply as seen. This leads to myocyte death. Myocyte death, in addition to fibrosis in the form of collagen deposition, can lead to a compromised left ventricle and overload on the remaining myocytes. This process is further complicated by compensation of the remaining myocytes that hypertrophy (enlarge). This can cause the left ventricle to enlarge and if the cycle continues can result in eventual heart failure.
  • [0011]
    The morphological appearance of the infarcted heart tissue post MI can vary. A transmural infarct involves the entire thickness of the left ventricular wall from the endocardium to the epicardium. It may extend into the anterior free wall and the posterior free wall. This damage may include extensions into the right ventricular wall. A subendocardial infarct may have multiple focal regions and necrosis area may be confined to the inner one-third to one-half of the left ventricular wall. The evolutionary changes in a subendocardial infarct do not evolve the same as in a transmural MI.
  • [0012]
    Over time post-MI morphological changes occur. The gross morphological changes that occur over approximately a 7-week period are pallor of the myocardium that leads to some hyperemia then a yellowing central to the damaged region. At approximately 15 days, the area is mostly yellow with soft vascular margins. This area eventually turns white from fibrosis. On a microscopic level, the initial examination reveals wavy myocardial fibers. Coagulation and necrosis with loss of cross striations occur followed by contraction bands, edema, hemorrhage, and neutrophilic infiltrate. Within 24-72 hours there is total loss of nuclei and striations and heavy neutrophilic infiltrate. Then macrophage and mononuclear infiltration begin resulting in a fibrovascular response. Once this fibrovascular response occurs then prominent granulation of the tissue follows. This ultimately leads to fibrosis and a scar is formed by about 7 weeks post MI.
  • [0013]
    FIGS. 3A-3B illustrate the occlusion of an artery that may lead to an MI. FIG. 3A illustrates the cross-section of a normal coronary artery with unobstructed lumen 301. The normal arterial wall 302 is made up of an intimal layer 303, a media layer 304, and an adventitia layer 305. Within the arterial lumen, the intima is in direct contact with the flow of blood. This region is mostly made up of endothelial cells. The media layer is mostly smooth muscle cells and extracellular matrix proteins. Finally, the adventitia layer is primarily made up of collagen, nerves, blood vessels and lymph vessels. FIG. 3B illustrates a coronary artery with atherosclerosis. In this example, this artery is about 50 percent occluded (only 50 percent of the arterial lumen is free of obstruction). Thus, the obstructed artery may lead to damage observed in a ventricle of an MI subject.
  • [0014]
    After an MI has occurred, three layers of tissue can be distinguished. The infarct region has (1) the region of significant necrosis/apoptosis tissue (2) the border zone that consists of a large concentration of apoptotic and necrotic tissue as well as viable tissue and (3) the unaffected region that consists of mainly viable tissue. In the border zone the cells exist in an oxygen-deprived state due to the damage from the MI.
  • [0015]
    FIGS. 3C-3J illustrate the details of a post-MI remodeling of the ventricle. The progression of heart failure after an MI is a result of the remodeling of the heart after the infarct. The remodeling process causes the infarcted region of the heart to stretch and become thinner causing the left ventricular diameter to increase. As the heart continues to remodel, the stresses on the heart increase. FIG. 3C, on a cellular level, a normal myocardium is illustrated. FIG. 3C illustrates the cross striations 306 and central nuclei 307 of a healthy myocyte population.
  • [0016]
    FIGS. 3D-3J depict the progression of the remodeling of the ventricle post MI. FIG. 3D illustrates an early acute MI. Here, there are prominent pink contraction bands that are indicated by reference number 308. FIG. 3E illustrates the increasing loss of striations and some contraction bands. The nuclei in this illustration are dying by a process called karyolysis 309. Karyolysis is a stage of cell death that involves fragmentation of the cell's nucleus; the nucleus breaks down into small dark beads of damaged chromatin. In addition, the neutrophils are infiltrating the damaged myocardial region. FIG. 3F illustrates an acute MI. The loss of nuclei and loss of cross striations are evident. There is extensive hemorrhaging on the infarct border 310. FIG. 3G illustrates the prominent necrosis and hemorrhaging 310, as well as the neutrophilic infiltrate 311. Subsequently, a yellowish center is formed within the damaged area with necrosis and inflammation surrounded by the hyperemic border. After 3-5 days post-MI, the necrosis and inflammation are extensive. There is a possibility of rupture at this point. FIG. 3H illustrates approximately one week after the MI with capillaries, fibroblasts and macrophages filled with haemosiderin 312. Haemosiderin is a long-term stored reserve of iron in tissues. In two to three weeks, granulation is the most prominent feature observed. FIG. 3I illustrates extensive collagen deposition 313 seen after a couple of weeks. Collagenous scarring occurs in subendocardial locations in remote myocardial infarct regions. FIG. 3J illustrates the myocytes 314 after several weeks of healing post MI. They are hypertrophied with large dark nuclei 315 and interstitial fibrosis 316. These enlarged cells contribute to the enlarged left ventricle.
  • [0017]
    A complication of an MI is an aneurysm that looks like a bulge in the left ventricular wall. The aneurysm is made up of non-functional tissue that is unable to contract. Therefore, the ejection and stroke volume of the heart are reduced. Additionally, parts of this mass can form a mural thrombus that can break off and embolize to the systemic circulation.
  • SUMMARY
  • [0018]
    Compositions and methods to treat myocardial infarction of the ventricle are described. In one embodiment, a composition is described that is capable of reinforcing the ventricular wall and may be capable of releasing an agent to recruit the natural cell population in order to stabilize the region. In another embodiment, a method is described to increase the compliance of a ventricle. A treatment agent is advanced through a delivery device to the infarct zone. In some embodiments, a delivery device is described to accurately deliver one or more treatment agents. In some embodiments, the treatment agent is delivered via a multiple of small volumes to the region. These delivery methods may use imaging of the ventricular wall to guide the deposition of the treatment agent to the site of the infarct zone such as deposition of the gel-forming agents. In these or other embodiments the gel-forming agent comprises aloe-derived pectin. The aloe-derived pectin can be delivered directly to or near the infarct region. The delivery near the infarct region may include delivery to a border region surrounding the infarct region. In other embodiments, treatment agents may induce angiogenesis.
  • [0019]
    In another embodiment, a method includes multi-component treatments of the infarct zone. One multi-component method includes the formation of a scaffold to facilitate the attachment of fibroblasts and to deliver growth factors and other treatment agents. In addition, the in-growth of new capillaries is encouraged by the sustained release of angiogenic factors by the microparticles that form the scaffold. The treatment agents may be released for up to two months period. This technique would offer maximum benefit for the regeneration of viable tissue.
  • [0020]
    In another embodiment, a different multi-component treatment of the infarct zone introduces a scaffold system that provides a matrix to facilitate cell growth and inhibit the remodeling event post-MI. In addition the treatment includes a perfluorinated compound that enhances the re-oxygenation of the tissue.
  • [0021]
    In another embodiment, a solution is delivered to a site in a ventricle. The solution contains an agent(s) capable of precipitating at a region for reinforcement of that region. Another solution contains one or more agents that are delivered to a region in a ventricle and remain in that region while the supporting solution dissipates into surrounding tissue.
  • [0022]
    In one embodiment, the treatments proposed may occur at any time after an infarction. In another embodiment, the treatments proposed may occur within seven weeks of an MI event (or prior to myocyte replacement). In another embodiment, the treatments proposed may occur within two weeks of an MI event.
  • [0023]
    In any of these or other embodiments the gel-forming agent comprises aloe-derived pectin.
  • [0024]
    In a further embodiment, a kit is disclosed. One example of such a kit is a kit including an injectable composition having the property of forming a gel once introduced to the treatment area. The gel may be formed due to one or more environmental changes or alternatively a response to one or more internal components. In these or other embodiments the gel-forming agent comprises aloe-derived pectin.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • [0025]
    The methods and compositions are illustrated by way of example, and not limitation, in the figure of the accompanying drawings in which:
  • [0026]
    FIG. 1A illustrates a longitudinally sectioned healthy artery and blood flow therein.
  • [0027]
    FIG. 1B illustrates a longitudinally sectioned damaged artery due to a tear or a spasm.
  • [0028]
    FIG. 1C illustrates a longitudinally sectioned occluded artery due to fat and cholesterol build up.
  • [0029]
    FIG. 2A illustrates plaque build up in an artery that may result restriction of blood and oxygen flow to the heart.
  • [0030]
    FIG. 2B illustrates the damage to the heart as a result of the plague build-up in an artery that lead to an MI.
  • [0031]
    FIG. 3A illustrates a normal artery.
  • [0032]
    FIG. 3B illustrates an artery with arteriosclerosis (50 percent blockage) that may lead to an MI.
  • [0033]
    FIG. 3C illustrates normal myocardium.
  • [0034]
    FIG. 3D illustrates an example of myocardium of an early acute myocardial infarction.
  • [0035]
    FIG. 3E illustrates an example of myocardium of an early myocardial infarction whereby a myocardium demonstrates increasing loss of cross striations.
  • [0036]
    FIG. 3F illustrates an example of myocardium of an acute myocardial infarction and the loss of striations and the nuclei.
  • [0037]
    FIG. 3G illustrates an example of myocardium of an acute myocardial infarction resulting in neutrophilic infiltration and necrosis.
  • [0038]
    FIG. 3H illustrates an example of the myocardium of an acute myocardial infarction approximately one week after a myocardial infarction occurred. The capillaries, fibroblasts and macrophages fill with haemosiderin.
  • [0039]
    FIG. 3I illustrates an example of the myocardium a couple of weeks after a myocardial infarction. A lot of collagen has been deposited at the site of damage.
  • [0040]
    FIG. 3J illustrates myocardium several weeks after a myocardial infarction. Many surviving myocytes appear hypertrophic and their nuclei are dark in color. Interstitial fibrosis is also observed.
  • [0041]
    FIG. 4 illustrates various ways to restructure remodeling of the infarct region via retention and recruitment of fibroblasts and delivering a swellable reinforcing material and/or introduce additional tropoelastin to the infarct region.
  • [0042]
    FIGS. 5A-5E illustrate the introduction of a pro-fibroblastic agent to an infarct zone and the formation of structural scaffolding.
  • [0043]
    FIG. 6 illustrates a multi-component method for structural reinforcing an infarct region.
  • [0044]
    FIG. 7 illustrates a multi-component method for structural reinforcing an infarct region and/or facilitating oxygenation of an infarct region.
  • [0045]
    FIG. 8 illustrates a general structure of the first and of the second component of FIG. 7.
  • [0046]
    FIGS. 9A-9F illustrate introduction and action of the multi-component method for structural reinforcement to an infarct region, for example, FIG. 6 and/or FIG. 7.
  • [0047]
    FIG. 10 illustrates an ester bond formed by at least two of the components of embodiments illustrated in FIG. 7 and FIG. 8.
  • [0048]
    FIGS. 11A-11F illustrate introduction of structural reinforcement in the form of swellable microparticles to an infarct zone.
  • [0049]
    FIG. 12 illustrates a flowchart of the several possible structural reinforcing agents that may be introduced to an infarct region.
  • [0050]
    FIG. 13 illustrates an expansion of FIG. 12 (1240) disclosing possible dual component systems.
  • [0051]
    FIG. 14 illustrates introduction and action of the methods illustrated in the flowchart of FIG. 13 in an infarct region.
  • [0052]
    FIG. 15 illustrates two possible methods to structurally reinforce an infarct zone by bulking up a region.
  • [0053]
    FIG. 16 illustrates examples of bulking agents that may structurally reinforce an infarct region.
  • [0054]
    FIG. 17 illustrates stabilizing the collagen in an infarct zone by cross-linking.
  • [0055]
    FIG. 18 illustrates various agents that may cross-link the collagen in an infarct region.
  • [0056]
    FIG. 19 illustrates various embodiments to clot the blood in an infarct region post MI.
  • [0057]
    FIG. 20 illustrates various methods to reinforce an infarct region using light sensitive components.
  • [0058]
    FIGS. 21A-21E illustrate a cross-sectional view of introduction of an embodiment using a photo-polymerizable component of FIG. 20 to an infarct region.
  • [0059]
    FIG. 22A illustrates a longitudinal view of a catheter device that has a light source and at least one component lumen.
  • [0060]
    FIG. 22B illustrates a cross-sectional view of a catheter device that has a light source and at least one component lumen.
  • [0061]
    FIG. 23 illustrates one example of a multi-component method to reinforce the infarct region and/or re-oxygenate the infarct region.
  • [0062]
    FIG. 24A illustrates a longitudinal view of a catheter device that has two delivery ports and a control mechanism to deliver one component prior the second component.
  • [0063]
    FIG. 24B illustrates a front view of the distal end of a catheter device with two delivery ports.
  • [0064]
    FIG. 24C illustrates the distal end of a catheter device where one delivery port may be extended while the second port may be confined to the housing of the catheter.
  • [0065]
    FIGS. 25A-25D illustrate the introduction of two separate components into an infarct region of the ventricle and formation of a structural reinforcing composition at the infarct region using a catheter with retractable dual delivery ports.
  • [0066]
    FIG. 26 illustrates the introduction of one component through a vein and the second through an artery using the catheter with retractable dual delivery ports.
  • DEFINITIONS
  • [0067]
    “a container”—a receptacle, such as a carton, can, vial, tube, bottle, or jar, in which material is held or carried.
  • [0068]
    “cardiomyocyte-like”—a cell(s) capable of converting to a cardiomyocyte(s) or a cell or components capable of functioning like a cardiomyocyte.
  • [0069]
    “polymer-forming”—any agent or agents capable of forming a gelatinous material either alone or in combination.
  • [0070]
    “delivery device”—an apparatus or system capable of depositing a solution, powder, concentrate, a single reagent and/or multiple reagents.
  • [0071]
    “pro-fibroblastic” agent—one or more compounds capable of retaining, inducing proliferation of and/or recruiting fibroblasts cells.
  • [0072]
    “compliance”—the ability of a blood vessel or a cardiac chamber to change its volume in response to changes in pressure has important physiological implications. In physical terms, the relationship between a change in volume (ΔV) and a change in pressure (ΔP) is termed compliance (C), where C=ΔV/ΔP. Compliance, therefore, is related to the ease by which a given change in pressure causes a change in volume. In biological tissues, the relationship between ΔV and ΔP is not linear. Compliance is the slope of the line relating volume and pressure that decreases at higher volumes and pressures. Another way to view this is that the “stiffness” of the chamber or vessel wall increases at higher volumes and pressures. Changes in compliance have important physiological effects in cardiac chambers and blood vessels.
  • DETAILED DESCRIPTION
  • [0073]
    In the following section, several embodiments of, for example, processes, compositions, devices and methods are described in order to thoroughly detail various embodiments. It will be obvious though, to one skilled in the art that practicing the various embodiments does not require the employment of all or even some of the specific details outlined herein. In some cases, well known methods or components have not been included in the description in order to prevent unnecessarily masking various embodiments.
  • [0074]
    Methods and compositions to treat a ventricle after a myocardial infarction (MI) are disclosed. In one embodiment, the infarct region or the area of the ventricle containing the infarct injury may be treated alone or in combination with other treatments. One benefit to such treatment is that the region of injury may be targeted with little or no affect on the outlying healthy heart tissue. In addition, another benefit of such treatment is that the treatment may prevent the loss of functionality of a region of injury due to the normal remodeling and scar forming procedure to mend an infarct region. Another benefit may be that the treatment may increase the compliance of the ventricle. Still another benefit is the reduction in thinning of a ventricular wall of an infarct zone. In the following description, structural reinforcement of the infarct region of the ventricle is described. Since most myocardial infarctions occur in the left ventricle most descriptions will be directed towards left ventricle repair. But, it is appreciated that treatment of the right ventricle may be achieved in a similar manner.
  • [0075]
    If the remodeling of the infarct region could be modified prior to scar formation and ultimate thinning of the ventricular wall, functional tissue may be rescued. The inhibition of scar formation and guided regeneration of viable cells would lead to increased wall strength and decreased collagen deposition, instead of thinning and hypertrophied myocytes. Further, decreasing the probability of wall thinning and fortifying the influx of structural components such as fibroblasts might be beneficial and preferred over the current treatment of an MI, namely continual exposure to systemic drugs to treat the symptoms and not the disease. Another benefit may be that any one of the treatments herein may result in an increase in compliance of the ventricle. Thus, any one or more combinations of these treatments may provide a potential for healing the infarct region and prevention of further complications.
  • [0076]
    In other embodiments, a kit (e.g., a pre-manufactured package) is disclosed. A suitable kit includes at least one agent and a lumen to house the agent. The agent has a property that may increase the modulus (tensile strength, “stiffness”) of elasticity of the infarct region, increase compliance of the ventricle and/or prevent or reduce thinning caused by remodeling. The kit may be suitable, in one example, in the methods described.
  • Mapping of the Heart
  • [0077]
    In each of the methods described herein, it is appreciated that specific areas of the heart may be targeted for application of any of the incorporated methods, thus there are techniques previously described that may be used for targeting the infarct region. One example of targeting a specific region such as an infarct zone uses a technique known as mapping the heart (U.S. Pat. No. 6,447,504). The data are acquired by using one or more catheters that are advanced into the heart. These catheters usually have electrical and location sensors in their distal tips. Some of the catheters have multiple electrodes on a three-dimensional structure and others have multiple electrodes distributed over a surface area. One example of the later catheter may be a sensor electrode distributed on a series of circumferences of the distal end portion, lying in planes spaced from each other. These techniques provide methods to characterize the condition of the heart in some situations using electrical potentials in the heart tissue as well as using electromechanical mapping, ultrasonic mapping to map the viable and the non-viable regions of the heart for example the left ventricle and the infarct zone. In addition, the ultrasound waves may be used to determine the thickness of the heart tissue in the vicinity of the probe for example, sensing the characteristic of the heart tissue by analyzing the ultrasound signals to determine the depth of the channels. Another method known as viability mapping (for example Spect, MRI, PET) may also be used. Viability mapping may be used to identify areas of the heart that are ischemic but still viable as well as area that have lost their viability due to infarction. These maps are based on electrophysiological data that indicate the flow of activation signals through the heart tissue. In addition, the data may be biomedical and/or mechanical data for example, variations in the thickness of the heart wall between systolic and diastolic stages of the heart cycle. The data that is used to analyze the heart by mapping may also be a combination of electro-physiological and biomedical data in order to more accurately locate and target the infarct region. In absence of viability mapping devices, it is appreciated that the location of the infarction may be also assessed through LV angiography or echo, where location of the akinetic or hypokinetic region may be identified.
  • Delivery Systems
  • [0078]
    Any one or more catheters may be used to deliver the any one or multiple components of the embodiments to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart for example an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,102,926; 6,120,520; 6,251,104; 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardiac drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor. The apparatus may include, for example, a catheter body capable of traversing a blood vessel and a dilatable balloon assembly coupled to the catheter body comprising a balloon having a proximal wall. A needle may be disposed within the catheter body and includes a lumen having dimensions suitable for a needle to be advanced therethrough. The needle body includes an end coupled to the proximal wall of the balloon. The apparatus also includes an imaging body disposed within the catheter body and including a lumen having a dimension suitable for a portion of an imaging device to be advanced therethrough. The apparatus may further include a portion of an imaging device disposed within the imaging body adapted to generate imaging signal of the infarct region within the ventricle. The apparatus may be suitable for accurately introducing a treatment agent at a desired treatment site.
  • [0079]
    In another embodiment, a needle catheter used to deliver the agent to the ventricle for example, the infarct region, may be configured to include a feedback sensor for mapping the penetration depth and location of the needle insertion. The use of a feedback sensor provides the advantage of accurately targeting the injection location. Depending on the type of agent administered, the target location for delivering the agent may vary. For example, one agent may require multiple small injections within an infarct region where no two injections penetrate the same site.
  • [0080]
    In other embodiments, the catheter assembly may include a maneuverable instrument. This catheter assembly includes a flexible assembly. The catheter assembly may be deflectable and includes a first catheter, a second catheter, and a third catheter. The second catheter fits coaxially within the first catheter. At least one of the first catheter and the second catheter include a deflectable portion to allow deflection of that catheter from a first position to a second position, and the other of the first catheter and second catheter includes a portion which is pre-shaped (e.g., an angled portion formed by two segments of the angled portion). The third catheter has a sheath and a medical instrument positioned within the sheath. The third catheter fits coaxially within the second catheter. In another embodiment, a stabilizer, such as a donut-shaped balloon, is coupled to a distal portion of the third catheter. Each catheter is free to move longitudinally and radially relative to the other catheters. The catheter assembly may be used but not limited to the local delivery of bioagents, such as cells used for cell therapy, one or more growth factors for fibroblast retention, or vectors containing genes for gene therapy, to the left ventricle. In one embodiment, the catheter assembly described may be used in delivering cell therapy for heart failure or to treat one or more portions of the heart that are ischemic. The catheter assembly uses coaxially telescoping catheters at least one or more being deflectable, to position a medical instrument at different target locations within a body organ such as the left ventricle. The catheter assembly may be flexible enough to bend according to the contours of the body organ. The catheter assembly may be flexible in that the catheter assembly may achieve a set angle according to what the medical procedure requires. The catheter assembly will not only allow some flexibility in angle changes, the catheter assembly moves in a three coordinate system allowing an operator greater control over the catheter assembly's movement portion of the second catheter, allowing for the distal tip of the third catheter to be selectively and controllably placed at a multitude of positions. It will be appreciated that the deflectable portion may alternatively be on the second catheter and the preshaped portion may be on the first catheter.
  • [0081]
    In a further embodiment, an apparatus is disclosed. In one embodiment, the apparatus includes a first annular member having a first lumen disposed about a length of the first annular member, and a second annular member coupled to the first annular member having a second lumen disposed about a length of the second annular member, wherein collectively the first annular member and the second annular member have a diameter suitable for placement at a treatment site within a mammalian body. Representatively, distal ends of the first annular member and the second annular member are positioned with respect to one another to allow a combining of treatment agents introduced through each of the first annular member and the second annular member to allow a combining of treatment agents at the treatment site. Such an apparatus is particularly suitable for delivering a multi-component gel material (e.g., individual components through respective annular members that form a bioerodable gel within an infarct region of a ventricle).
  • [0082]
    In the embodiments described herein, a substance delivery device and a method for delivering a substance are disclosed. The delivery device and method described are particularly suitable, but not limited to, local drug delivery in which a treatment agent composition (possibly including multiple treatment agents and/or a sustained-release composition) is introduced via needle delivery to a treatment site within a mammalian host. A kit of a treatment agent composition is also described. One suitable application for a delivery device is that of a catheter device, including a needle delivery system. Suitable therapies include, but are not limited to, delivery of drugs for the treatment of arterial restenosis, therapeutic angiogenesis, or cancer treatment drugs/agents.
  • [0083]
    In other embodiments, larger doses of treatment agent may be considered for example about 2 mL to about 250 mL that may require any one or more of the delivery devices such as intra-venous retro infusion, intra-arterial infusion and needle catheter systems (INVIGOR available from Abbott Vascular, Santa Clara, U.S.A.) as well as subxyphoid approaches.
  • [0084]
    Various apparatuses (devices) and methods described herein can be used as a stand-alone injection needle/catheter during a surgical procedure such as an open heart surgery (e.g., Coronary Bypass Graft (CABG)) procedure in which areas of the heart may be treated with, for example, growth factors, for affecting therapeutic angiogenesis, or incorporated into a catheter-based system to access locations that are commonly used in percutaneous transluminal coronary artery (PTCA) procedures. The apparatuses and methods may similarly be used in other surgical procedures such as cancer-related procedures (e.g., brain, abdomen, or colon cancer procedures or surgeries). Additionally, various apparatuses and methods described herein can be used in conjunction with various catheter-related or endoscopy procedures that generally require minimal invasiveness to deliver a specific drug or growth factor into tissue.
  • [0085]
    One concern of introducing any treatment agent composition, whether adjacent a blood vessel to affect therapeutic angiogenesis, adjacent to a tumor to inhibit tumor growth, or to induce or stimulate collagen growth in endoscopic procedures, is that the composition remains (at least partially) at the treatment site for a desired treatment duration (or a portion of the treatment duration). In this manner, an accurate amount may be placed at a treatment site with reduced concern that the treatment agent will disperse, perhaps with serious consequences. In one embodiment, a composition and technique for retaining a treatment agent at a treatment site (injection site) is described. In one embodiment, a treatment agent and a bioerodable gel or non-bioerodable gel or particle may be introduced at a treatment site (e.g., an injection site). The gel or particle(s) may be introduced prior to, after, or simultaneously with the treatment agent. In one embodiment, the gel or particle(s) acts to retain the treatment agent at the treatment site by, representatively, sealing the treatment site or sealing the treatment agent at the treatment site. The use of a gel or particle(s) with a treatment agent can reduce the amount of treatment agent backflow from the injection site as well as reduce the load requirement of the treatment agent at the treatment site. For example, a bioerodable product such as a gel or particle may decrease the local pressure thereby further resulting in backflow reduction. A non-bioerodable product may also decrease the local pressure to reduce the backflow in a more permanent fashion and at the same time may also lead to an increase in compliance.
  • [0086]
    Using the above-mentioned techniques, an imaging modality may be added such as a contrast-assisted fluorescent scope that permits a cardiologist to observe the placement of the catheter tip or other instrument within the heart chamber. The contrast-assisted fluoroscopy utilizes a contrast agent that may be injected into heart chamber and then the area viewed under examination by a scope, thus the topography of the region is more easily observed and may be more easily treated (U.S. Pat. Nos. 6,385,476 and 6,368,285). Suitable imaging techniques include, but are not limited to, ultrasonic imaging, optical imaging, and magnetic resonance imaging, for example, Echo, ECG, SPECT, MRI, Angiogram. Therefore, mapping of the heart is one technique that may be used in combination with the techniques proposed in the following embodiments. In one embodiment, an echo angiograph may be performed to confirm the occurrence and the location of the infarct region. In another embodiment, a CAT scan may be performed to confirm an MI has occurred and to confirm the location of the infarct region. In another embodiment an EKG may be performed to identify the occurrence and location of an infarct.
  • [0087]
    In another embodiment, a method may include introducing a treatment agent in a sustained release composition. The preferred period for sustained release of one or more agents is for a period of one to twelve weeks, preferably two to eight weeks. Methods for local delivery of sustained release agents include but are not limited to percutaneous devices for example intra-ventricular (coronary) or intravascular (coronary and peripheral) devices.
  • Fibroblast Retention and Recruiting Agents Agents
  • [0088]
    FIG. 4 describes one embodiment of a method to treat an infarct region of a left ventricle. This is an illustrative diagram only and any of the treatments may be used in parallel (e.g., at the same time) or sequentially or in any treatment combination. According to the method illustrated in FIG. 4, a myocardial infarction may be detected by an imaging process for example magnetic resonance imaging, optical imaging or ultrasonic imaging for example Echo ECG, spect, MRI, angiogram 410. Next, the area of the left ventricle is reinforced 410 by retention or recruitment of surrounding fibroblasts cells 420. In FIG. 4 one option to encourage the fibroblast occupancy of the infarct zone includes the use of swellable material 430 delivered to the infarct zone. Another method, summarized in FIG. 4 (440) to encourage the occupancy of fibroblasts to the infarct zone includes the delivery of tropo-elastin to the site. It has been demonstrated that injections of fibroblasts into a scar region may improve the structural integrity of a terminally injured heart in a rabbit model. See Hutcheson, K. A., et al., Comparison of Benefits on Myocardial Performance of Cellular Cardiomyoplasty with Skeletal Myoblasts and Fibroblasts, Cell Transplant, May-June 2000, pp. 359-368, 9(3). Since the fibroblasts naturally infiltrate the scar during the healing process, it would be beneficial to attract these cells in larger numbers, or to induce their proliferation in the infarct region such that fibroblasts are encouraged to remain in the region for a prolonged period or permanently remain in the region. In addition, a further benefit of retaining fibroblasts in an infarct region may be to convert the fibroblast phenotype such as influencing the conversion from non-contractile cell to a muscular cell. The conversion is promoted in the presence of growth factors for example TGF-β1 (transforming growth factor beta 1). Therefore, the infarct region may be treated with agents that encourage fibroblast retention and recruitment. Suitable treatment agents that may modify or recruit fibroblasts include but are not limited to, Angiotensin II, fibroblast growth factor (FGF basic and acidic), insulin growth factor (IGF), TGF-β in any of its isoforms, vascular endothelial growth factor (VEGF) in any of its isoforms, tumor necrosis factor-alpha (TGF-α), platelet-derived growth factor-BB (PDGF-BB), angiogenin, angiopoietin-1, Del-1, follistatin, granulocyte colony-stimulating factor (G-CSF), pleiotrophin (PTN), proliferin, transforming growth factor-alpha (TGF-(α), vascular permeability factor (VPF), and LIH (leukemia inhibitory factor) genes that encode these proteins, transfected cells carrying the genes of these proteins, small molecules and pro-proteins that also contain these recruiting properties.
  • [0089]
    In one embodiment, basic fibroblast growth factor may be introduced to the infarct region by at least one of the methods described. In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 50 μl.
  • [0090]
    In alternate embodiments, the treatment volume may be larger (e.g., intravenous pressure perfusion (IV) route). These volumes may range from about 2 ml to about 250 ml. Alternatively, these volumes may range from about 2 ml to about 100 ml. In other embodiments, these volumes may range from about 2 ml to about 30 ml.
  • Sequence of Treatment
  • [0091]
    FIG. 4 illustrates a flow chart of a process for treating MI by retaining and recruiting fibroblasts. FIGS. 5A-5E illustrate the introduction and action of fibroblast retention and recruitment. Detection of acute myocardial necrosis may be performed using an ECG (electrocardio-cardiogram) or by a more modern technology. For example, one technology such as 99mTechnetium-pyrophosphate or 111In-antimyosin antibody imaging has recently been approved by the Food and Drug Administration. With both these two tracers, results are obtained only 24-48 hours after acute infarction and therefore, the clinical utility of these techniques have been limited. There is another new agent called 99mTc-glucurate that produces results within an hour after acute myocardial infarction. See Iskandrian, A. S., et al., Nuclear Cardiac Imaging: Principles and Applications, 1996, 2nd Ed. Once the MI is detected the exact location of the infarct may be identified using a magnetic resonance imaging then the ventricle infarct region may be treated by reinforcement 501. An agent 520 (for example, tropoelastin) is introduced to the infarct region 510. One way the agent may be introduced to the area is percutaneously, with the use of a catheter. A distal end of the catheter is advanced to the infarct zone 530, 540, or 550 and the agent 520 is released. Then the fibroblasts 560 are recruited to the site or retained 570. FIG. 5E illustrates the fibroblast reinforcement of the infarct area.
  • Description of Several Possible Treatment Agent(s) and Deliveries
  • [0092]
    Tropoelastin
  • [0093]
    FIGS. 5A-5E describe the combination of promoting fibroblast retention and migration into the infarct region with the addition of, for example, tropoelastin 520. Elastin is a highly pliable extracellular protein. In vivo, it is usually in a cross-linked insoluble state. A linear uncross-linked soluble precursor is available that is referred to as tropoelastin. Tropoelastin 520 can be made by recombinant methods and is commercially available. Tropoelastin is an approximately 70-kDa protein consisting of alternating hydrophobic regions, responsible for elasticity, and cross-linking domains. Additionally, it ends with a hydrophilic carboxy-terminal sequence containing its only two cysteine-residues. Tropoelastin is a protein that is prominent in the skin of an infant and as one matures less and less of this protein is made. Tropoelastin is sometimes used as an important marker of some heart conditions such as MI since it is released into the bloodstream following heart injury. The production of recombinant tropoelastin in bacterial systems has greatly simplified the availability of tropoelastin. In addition, it provides a valuable means for obtaining human tropoelastin. Purification from human aortas was greatly simplified compared with tissue extraction methods but relatively low yields were obtained. The purification from the aortas posed the potential for degradation of the polypeptide. Recently, human tropoelastin cDNA has also been expressed in bacteria as a fusion with influenza NS1 protein. See Indik, Z., et al., Production of Recombinant Human Tropoelastin: Characterization and Demonstration of Immunologic and Chemotactic Activity, Arch. Biochem. Biophys., July 1990, pp. 80-86, 280(1). This isoform of tropoelastin, containing exon 26A and the signal peptide, was the first form of human tropoelastin to be obtained for study. In view of tropoelastin's extreme amino acid usage, a synthetic human tropoelastin gene has been constructed containing codons designed to optimize expression in E. coli. See Martin, S. L., et al., Total Synthesis and Expression in Escherichia coli of a Gene Encoding Human Tropoelastin, Gene, Mar. 10, 1995, pp. 154-166, 154(2). This synthetic gene is expressed at high levels in soluble form both as a fusion with glutathione S-transferase and directly, as the mature polypeptide. Alternatively, a simplified purification scheme using alcohol dissolution and eliminating the need for cyanogen bromide (CNBr) treatment resulted in significantly higher yields. Therefore, purified or genetically engineered tropoelastin is available. Recombinant forms of tropoelastin have proved to be viable alternatives to tissue-derived tropoelastin. Recombinant tropoelastin reacts with elastin antibodies, is a chemotactic agent, demonstrates coacervation ability and has the some similar characteristics to naturally occurring tropoelastin (i.e., circular dichroism).
  • [0094]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to about 50 μl.
  • Microparticles and Growth Factors Delivery
  • [0095]
    One embodiment of a composition suitable for the described method includes the use of a bioerodable microparticle harboring one or more of the aforementioned growth factors. The bioerodable microparticle may consist of a bioerodable polymer such as poly (lactide-co-glycolide). The composition of the bioerodable polymer is controlled to release the growth factor over a period of 1-2 weeks. It was previously demonstrated that biodegradable microparticles for example, poly (lactide-co-glycolide) were capable of controlled release of an oligonucleotide. These microparticles were prepared by the multiple emulsion-solvent evaporation technique. In order to increase the uptake of the oligonucleotide into the microparticles it was accompanied by polyethylenimine (PEI). The PEI also tended to make the microparticles more porous thus facilitating the delivery of the oligonucleotide out of the particles. See De Rosa, et al., Biodegradable Microparticles for the Controlled Delivery of Oligonucleotides, Int J. Pharm., Aug. 21, 2002, pp. 225-228, 242(1-2). In one preferred embodiment of a composition, the bioerodable microparticle may be a PLGA polymer 50:50 with carboxylic acid end groups. PLGA is a base polymer often used for controlled release of drugs and medical implant materials (i.e., anti-cancer drugs such as anti-prostate cancer agents). Two common delivery forms for controlled release include a microcapsule and a microparticle (e.g., a microsphere). The polymer and the agent are combined and usually heated to form the microparticle prior to delivery to the site of interest (Mitsui Chemicals, Inc). As the microparticles erode 560, a porous network of the microparticle composition is formed 570 in the infarct region resulting in a matrix with a controlled pore size 580. As the porous network is formed at least one angiogenic and/or pro-fibroblastic factor may be released encouraging the in-growth of new capillaries. One embodiment, the bioerodable polymer harbors the growth factor TGF-β1. In one embodiment, the PLGA polymer 50:50 with carboxylic acid end groups harbors TGF-β1 for slow release. It is preferred that each microparticle may release at least 20 percent of its contents and more preferably around 90 percent of its contents. In one embodiment, the microparticle harboring at least one angiogenic and/or pro-fibroblastic agent will degrade slowly over time releasing the factor or release the factor immediately upon contact with the infarct area in order to rapidly recruit fibroblasts to the site. In another embodiment, the microparticles may be a combination of controlled-release microparticles and immediate release microparticles. A preferred rate of deposition of the delivered factor will vary depending on the condition of the subject undergoing treatment.
  • [0096]
    Another embodiment of a composition suitable for the described method includes the use of non-bioerodable microparticles that may harbor one or more of the aforementioned growth factors. The growth factors may be released from the microparticle by controlled-release or rapid release. The microparticles may be placed directly in the infarct region. By directly placing the particles in the infarct region, they may also provide bulk for the region for reinforcement. The non-bioerodable microparticle may consist of a non-bioerodable polymer such as an acrylic based microsphere, for example, a tris acryl microsphere (provided by Biosphere Medical). In one embodiment, non-bioerodable microparticles may be used alone or in combination with an agent to increase compliance of a ventricle. In another embodiment, non-bioerodable microparticles may be used alone or in combination with an agent to recruit fibroblasts and/or stimulate fibroblast proliferation. In addition, non-bioerodable microparticles may be used to increase compliance and recruit fibroblasts to an infarct region of a ventricle.
  • [0097]
    In one embodiment, the treatment agent compositions suitable for reinforcement of the infarct zone are rendered resistant to phagocytosis by inhibiting opsonin protein absorption to the composition of the particles. In this regard, treatment agent compositions including sustained release carriers include particles having an average diameter up to about 10 microns. In other situations, the particle size may range from about 1 mm to about 200 mm. The larger size particles may be considered in certain cases to avoid macrophage frustration and to avoid chronic inflammation in the treatment site. When needed, the particle size of up to 200 mm may be considered and may be introduced via an intraventricular catheter or retrograde venous catheter for any of the embodiments herein to avoid chronic inflammation due to macrophage influx into the treatment site.
  • [0098]
    One method of inhibiting opsonization and subsequent rapid phagocytosis of treatment agents is to form a composition comprising a treatment agent disposed with a carrier for example a sustained release carrier and to coat the carrier with an opsonin inhibitor. One suitable opsonin-inhibitor includes polyethylene glycol (PEG) that creates a brush-like steric barrier to opsonization. PEG may alternatively be blended into the polymer constituting the carrier, or incorporated into the molecular architecture of the polymer constituting the carrier, as a copolymer, to render the carrier resistant to phagocytosis. Examples of preparing the opsonin-inhibited microparticles include the following.
  • [0099]
    For the encapsulation polymers, a blend of a polyalkylene glycol such as polyethylene glycol (PEG), polypropylene 1,2-glycol or polypropylene 1,3-glycol is co-dissolved with an encapsulating polymer in a common organic solvent during the carrier forming process. The percentage of PEG in the PEG/encapsulating polymer blend is between five percent and 60 percent by weight. Other hydrophilic polymers such as polyvinyl pyrolidone, polyvinyl alcohol, or polyoxyethylene-polyoxypropylene copolymers can be used in place of polyalkylene glycols, although polyalkylene glycols and more specifically, polyethylene glycol is generally preferred.
  • [0100]
    Alternatively, a diblock or triblock copolymer of an encapsulating polymer such as poly (L-lactide), poly (D,L-lactide), or poly (lactide-co-glycolide) with a polyalkylene glycol may be prepared. Diblocks can be prepared by: (i) reacting the encapsulating polymer with a monomethoxy polyakylene glycol such as PEG with one protected hydroxyl group and one group capable of reacting with the encapsulating polymer, (ii) by polymerizing the encapsulating polymer onto the monomethoxy polyalkylene glycol, such as PEG, with one protected group and one group capable of reacting with the encapsulating polymer; or (iii) by reacting the encapsulating polymer with a polyalkylene glycol such as PEG with amino functional termination. Triblocks can be prepared as described above using branched polyalkylene glycols with protection of groups that are not to react. Opsonization resistant carriers (microparticles/nanoparticles) can also be prepared using the techniques described above to form sustained-release carriers (microparticles/nanoparticles) with these copolymers.
  • [0101]
    A second way to inhibit opsonization is the biomimetic approach. For example, the external region of cell membrane, known as the “glycocalyx,” is dominated by glycoslylated molecules that prevent non-specific adhesion of other molecules and cells. Surfactant polymers consisting of a flexible poly (vinyl amine) backbone randomly-dextran and alkanoyl (hexanoyl or lauroyl) side chains which constrain the polymer backbone to lie parallel to the substrate. Hydrated dextran side chains protrude into the aqueous phase, creating a glycocalyx-like monolayer coating that suppresses plasma protein deposition on the foreign body surface. To mimic glycocalyx, glycocalyx-like molecules can be coated on the carriers (e.g., nanoparticles or microparticles) or blended into a polymer constituting the carrier to render the treatment agent resistant to phagocytosis. An alternate biomimetic approach is to coat the carrier with, or blend in, phosphorylcholine or a synthetic mimetic of phosphatidylcholine, into the polymer constituting the carrier.
  • [0102]
    For catheter delivery, a carrier comprising a treatment agent (e.g., the composition in the form of a nanoparticle or microparticle) may be suspended in a fluid for delivery through the needle, at a concentration of about one percent to about 20 percent weight by volume. In one embodiment, the loading of the treatment agent in a carrier is about 0.5 percent to about 30 percent by weight of the composition. Co-encapsulated with protein or small molecule treatment agents could be stabilizers that prolong the biological half-life of the treatment agent in the carrier upon injection into tissue. Stabilizers may also be added to impart stability to the treatment agent during encapsulation. Hydrophilic polymers such as PEG or biomimetic brush-like dextran structures or phosphorylcholine are either coated on the surface or the carrier, grafted on the surface of the carrier, blended into the polymer constituting the carrier, or incorporated into the molecular architecture of the polymer constituting the carrier, so the carrier is resistant to phagocytosis upon injection into the target tissue location.
  • [0103]
    Any one or more catheters may be used to deliver the any one or multiple components of the embodiments to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart, for example, an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardiac drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor.
  • Angiogenesis
  • [0104]
    After an MI, the infarct tissue as well as the border zone and the remote zone begin to remodel. The scar tissue forms in the infarct region as the granulation is replaced with collagen, causing the scar to thin out and stretch. The perfusion in this region is typically 10% of the healthy zone, decreasing the number of active capillaries. Increasing the number of capillaries may lead to an increase in compliance of the ventricle due to filling up with blood. Other benefits of increasing blood flow to the infarcted region include providing a route for circulating stem cells to seed and proliferate in the infarct region. Angiogenesis may also lead to increased oxygenation for the surviving cellular islets within the infarct region, or to prime the infarct region for subsequent cell transplantation for myocardial regeneration. In the border zone, surviving cells would also benefit from an increase in blood supply through an angiogenesis process. In the remote zone, where cardiac cells tend to hypertrophy and become surrounded wit some interstitial fibrosis, the ability of cells to receive oxygen and therefore function to full capacity are also compromised; thus, angiogenesis would be beneficial in these regions as well. In one embodiment, angiogenesis will be stimulated in ay region of the heart—infarct, border or remote—through delivery of agiogenesis-stimulating factors. Examples of these factors include but are not limited to isoforms of VEGF (e.g., VEGF121), FGF (e.g., b-FGF), Del 1, HIF 1-alpha (hypoxia inducing factor), PR39, MCP-1 (monocyte chemotractant protein), Nicotine, PDGF (platelet derived growth factor), IGF (Insulin Growth Factor), TGF alpha (Transforming Growth Factor), HGF (Hepatocyte growth factor), estrogens, Follistatin, Proliferin, Prostaglandin E1, E2, TNF-alpha (tumor necrosis factor), Il-8 (Interleukin 8), Hemotopoietic growth factors, erythropoietin, G-CSF (granulocyte colony-stimulating factors), PD-ECGF (platelet-derived endothelial growth factor), Angiogenin. In other embodiments, these factors may be provided in a sustained release formulation as an independent factor or in combination with other factors or appropriate gene vectors with any of the gel or microparticle components described in this application.
  • Microparticles and Angiogenic and Pro-Fibroblastic Agents
  • [0105]
    The microparticles may be prepared as microparticles harboring anangiogenic and/or pro-fibroblastic agent. On the other hand, the microparicles may be prepared and then the angiogenic and/or pro-fibroblastic agent introduced into the microparticle, for example, by diffusion prior to introduction to the infarct region. In the later example. the microparicles might also be coated with the factor and upon introduction to the infarct region the factor immediately recruits fibroblasts to the area. Additionally, the microparticle-factor composition might consist of any combination of the above-mentioned treatments. In other embodiments, it may be necessary to add at least one pharmaceutically acceptable inhibitor to the microparticles that prevents decomposition of the angiogenic or pro-fibroblastic agent.
  • Microparticle Components
  • [0106]
    FIG. 4 describes a method to structurally reinforce the infarct region. This method may be combined with any of the methods describing introducing angiogenic and/or fibroblast-recruiting agents, for example growth factors, to the infarct region to retain and/or promote fibroblast migration to this zone. Microparticles capable of taking up fluid will be introduced to the infarct region. Examples of these microparticles include swellable non-biological or synthetic biological particles. The microparticles are introduced to the infarct zone and become trapped in the tissue. The microparticles tend to immediately start to swell. The swollen microparticles remain lodged in the tissue and provide reinforcement to the ventricular wall and add thickness to the thinning infarct region.
  • [0107]
    The dimensions of the infarct zone may determine the size range of the microparticles and the number of microparticles introduced to the infarct region. This will insure that the optimum post-hydrated microparticle mass is achieved. An embodiment relates to microparticles that are about 200 microns or less in diameter. In another embodiment the microparticles may be about 20 microns or less in diameter. In a preferred embodiment, the particle size may be about 5-10 microns in diameter. Particles of about 20 microns or less may also include an opsonization inhibitor (previously discussed). The swellable microparticles may be a range of sizes introduced to the infarct region. In one embodiment, the swellable non-biological material may be a hydrogel microsphere material. These microparticles are available commercially (A.P. Pharma or BioSphere Medical). These microparticles are resistant to non-specific absorption and are bio-stable.
  • [0108]
    In other embodiments, hydrogels may be used as a treatment for a myocardial infarction. Examples of hydrogel materials are high molecular weight polyacrylamide or high molecular weight polyvinylpyrrolidone (PVP). Typically, the monomer supplied in these products contains di-functional monomers such as di-vinyl benzene, ethylene glycol dimethylacrylate or bis-acrylamide acetate resulting in the formation of a cross-linked network resistant to dissolution in an aqueous environment or to stimulate controlled magnitude angiogenic response. These components may be used to generate microspheres. Alternatively the di-functional polymers may be used to synthesize a hydrogel microsphere.
  • [0109]
    In one embodiment of the invention the first component of a biosynthetic polymeric gel may be (acrylamidomethyl) cellulose acetate propionate and the second component may be a dithiol functional polyethylene glycol polymer (such as sold by Shearwater Polymers). In another embodiment, the first component of a biosynthetic polymeric gel may be (acrylamidomethyl) cellulose acetate propionate and the second component may be a reduced peptide sequence. In a further embodiment, the reduced peptide sequence could be biologically derived such as the amino acid sequence, glycine-cysteine-tyrosine-lysine-asparagine-ginine-aspartic acid-cysteine-glycine. A dual bore needle system may deliver both components separately one at a time or simultaneously to an infarct zone. The thiol-group(s) of the thiol-containing component may undergo nucleophilic addition to the acrylamide functional group of the first component. This forms the elastomeric structural reinforcing gel.
  • [0110]
    In other embodiments, the delivery of a nonbiologic or synthetic gel may be combined with angiogenic and/or fibroblast recruiting agents utilizing microparticles capable of releasing the agents at a rate optimal for fibroblast retention and migration in the infarct region.
  • [0111]
    In one embodiment, tropoelastin suspended in a solution, such as saline, is introduced to the infarct region for structural reinforcement of the ventricular wall. Another embodiment includes the introduction of tropoelastin suspended in saline in the presence of copper ions. Another embodiment includes the introduction of tropoelastin in the presence of a converting enzyme. Another embodiment includes the introduction of tropoelastin in the presence of lysyl oxidase. Once introduced to the infarct zone, the solution forms elastin by cross-linking via a lysine residue oxidation. The cross-linked elastin remains in the infarct region to fortify the tissue and enhance the modulus (wall strength/elongation=modulus) of elasticity.
  • Methods for Introduction and Action
  • [0112]
    FIGS. 5A-5E illustrate the introduction and action of pro-fibroblastic agents to the infarct region to recruit fibroblast cell growth. The pro-fibroblastic agent may be introduced to the site 500 by a minimally invasive procedure 510. The solution may be injected in the infarct zone during an open chest procedure 520. The introduction of the pro-fibroblastic agent(s) includes one of the following procedures: sub-xiphoid and percutaneously 530. The mode of introduction of the pro-fibroblastic agent(s) by a percutaneous injection includes one of the following consisting of an intraventricular (coronary) catheter, a transvascular needle catheter, IC infusion and retrograde venous perfusion. One percutaneous route for a catheter is via a femoral artery traversing through and then across the aortic arch into the left ventricle. Imaging techniques can guide the catheter to the infarct region. The infarct region for example may be distinguished from healthy tissue using MRI techniques. A catheter having imported the MRI data may then be guided directly to the infarct region. Once the agent 540 is distributed through out the infarct region 510, the fibroblasts 560 may be attracted to the area by chemotactic responses. The fibroblast cells that infiltrate the area may proliferate in the area. Once the fibroblasts proliferate they form a reinforcing mass to the region and strengthen the damaged site 510. The fibroblast in this aspect of the present invention may act as a structural reinforcing agent in the infarct zone 570. These cells add bulk to the area and replace the degraded myocytes that normally lead to a thinning of the infarct regional wall. In turn, the viable fibroblast cells release factors that may recruit other cells into the area for further reinforcement of the infarct zone.
  • [0113]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to about 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to about 50 μl. If an agent is introduced via an IV or an IC route the volumes may range from about 1 ml to about 500 ml.
  • [0114]
    Any one or more catheters may be used to deliver the any one or multiple components of the embodiments to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart for example an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardial drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor.
  • Multiple Component Systems for Infarct Reconstruction Component One
  • [0115]
    To prevent heart failure, it has been proposed that cardiomyocytes can be directly introduced into the infarct region to restore cardiac function cells of various origins, including embryonic and adult stem cells. The viability of tissue engineering for a myocardial infarct zone requires that oxygen and nutrient supplies are readily available, as well as a mode for removal of waste products from cell metabolism. The cells in these areas also need a supporting structure for adherence. The bioerodable gel with angiogenic and/or fibroblast recruiting agents previously discussed provides this later supporting structure. In the literature, it is known that the introduction of scaffolding with a bore size of less than 10 microns leads to a tightly fibrotic encapsulated scaffold with poor capillary in-growth. On the other hand, as demonstrated in FIG. 6 and 9, if the scaffolding pore diameter is around 20 microns, cellular encapsulation of the scaffold system is well perfused with capillary in-growth leading to fibrotic poor cellular rich region. One embodiment includes scaffolding that is introduced to the infarct zone 610, 910 and acts as a mechanical reinforcement. The force is distributed more evenly 990 at the infarct region and ventricular remodeling is prevented.
  • [0116]
    In one embodiment, separate components are included to provide a network such as described above. One example is described in FIG. 6. A multi-component composition includes the first component including the previously illustrated bioerodable matrix or scaffolding 630, 990. In this particular composition, the matrix (first component) provides a porous scaffolding to enhance capillary in-growth. The microparticles of the first component may be approximately 20 microns. In another embodiment, the first component of the composition may be introduced by a minimally invasive procedure 960; for example, the first component of the composition may be introduced percutaneously. A distal end of the catheter is advanced to the infarct zone 910 and the bioerodable microparticles 920 are released. In a further embodiment, the first component of the composition may be introduced via an intra-ventricular needle device 930 to the infarct region. In a further embodiment, an intra-ventricular needle device including introducing multiple injections to the infarct region may introduce the first component of the composition. The first component may serve in one aspect as a domain to promote cell growth. In addition, porosity may be controlled that leads to capillary in-growth. The first component 920 may be a bioerodable microparticle with growth factor and angiogenic potential. The factor or other agent may release over a 1-2 week period. One embodiment may be that the first component includes PLGA 50:50 (previously described) with carboxylic acid end groups. An example of capillary in-growth to the domain provided by the first component may be facilitated by the release of angiogenic factors 980. One embodiment includes microparticles containing angiogenic factors 980 that release rapidly after introduction to the infarct region. This tends to result in a rapid angiogenic response.
  • [0117]
    Biomaterials have been employed to conduct and accelerate otherwise naturally occurring phenomena, such as tissue regeneration in wound healing in an otherwise healthy subject; to induce cellular responses that might not normally be present, such as healing in a diseased subject or the generation of a new vascular bed to receive a subsequent cell transplant; and to block natural phenomena, such as the immune rejection of cell transplants from other species or the transmission of growth factor signals that stimulate scar formation in certain situations.
  • Component Two
  • [0118]
    A second component 640 of the multi component composition according to the method may be an acrylate agent that is biocompatible. A second component serves in one aspect to disperse the first component in order to form a more uniform scaffold over the entire infarct zone and may include border zone as well. It may be an oligomeric, di- (or multi-) functional acrylate agent 930 based on a component that is biocompatible. An embodiment of the two-component composition may include a second component 930 comprising the following group di-acryloyl polyethylene glycol, tetra-acryloyl polyethylene glycol (PEG) or (acrylamidomethyl) cellulose acetate propionate. In order to dissolve the acrylamide functional cellulose component ethanol or a biocompatible is required. The second component 930 disperses the microparticles 970/990 acting as a suspending media. It is known that PEG-coated microparticles 990 are less inflammatory and are seen not to elicit a fibrotic response. Thus, it in one aspect may serve as an anti-opsonization agent. Thus, they serve as a camouflage from the immune system for introduction of the microparticles to the infarct region. One embodiment includes the injection of both the growth factor containing microparticles and the scaffold-forming matrix (acryloyl functional macromer) using a dual bore needle. FIG. 9D illustrates the final formation of the scaffold gel 915. The introduction of the two solutions simultaneously creates the near instantaneous (around 10 seconds) formation of the gel with a microparticle network embedded within the scaffold gel 915. As the microparticles 925 decompose, growth factors are released promoting the capillary formation within the matrix. In addition, cells begin to grow in the infarct area 935. These cells release proteases that may result in the decomposition of the scaffolding ultimately creating additional area for cellular in-growth. In addition, the cells secrete their own extracellular matrix, the polymer degrades and the resulting tissue may eventually become a completely natural environment. The decomposition products may be cleared from the area by the renal system since capillary re-growth may occur.
  • Component Three
  • [0119]
    Another component of a multi component composition and method is illustrated in 650 and 905. A third component includes one of the following: thiol-containing peptide or a di- or multi-functional biocompatible such as dithio-PEG. An example of a thiol-containing peptide 905 may be polycysteine oligomers. An example of this is a protected form of a polycysteine oligomer, Poly-S-CBZ-L-cysteine or Poly-S-benzyl-L-cysteine (Sigma Chemical P0263 and P7639 respectively). These agents can be de-protected using standard organic chemistry protocols. See Berger, et al., Poly-L-cysteine, J. Am. Chem. Soc., Sep. 5, 1956, pp. 4483-4488, 78. The preparation of these thiol-containing agents is well known. See Zervas, L., et al., On Cysteine and Cystine Peptides. II. S-Acylcysteines in Peptide Synthesis, J. Am. Chem. Soc., May 5, 1963, pp. 1337-1341, 85(9). Additional agents that may function as the third component of a multi-component composition may be naturally occurring peptides. In one embodiment, the third component of the multi-component scaffolding may be one of the following consisting of Poly-S-CBZ-L-cysteine and Poly-S-benzyl-L-cysteine. In another embodiment of a multi-component composition, the third component of the multi-component scaffolding may be a naturally occurring peptide. In a further embodiment of a multi-component composition the third component of a multi-component scaffolding may be the naturally occurring peptide glycine-cysteine-tyrosine-lysine-asparagine-arginine-aspartic acid-cysteine-glycine peptide sequence. The third component preferably contains at least two thiol groups. FIGS. 9A-9F illustrate the introduction of the three components to the infarct region to treat an MI. One embodiment may be the introduction of the first component and the second component 920/930 through a dual bore needle and then the introduction of a thiol-containing third component 905 through a second needle. FIG. 9D illustrates a schematic of the final structure 915 that subsequently recruits fibroblast growth 935 and capillary 945 in-growth into the infarct region. The thiol-containing component 905 may be used to decrease the rate of decomposition of the scaffold and control release of the fibroblast recruiting components of the microparticles.
  • [0120]
    Any one or more catheters may be used to deliver the any one or multiple components of the embodiments to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart for example an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardiac drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor.
  • Multi Component System for Infarct Reconstruction and Infarct Reoxygenation
  • [0121]
    The progression of heart failure after an MI is a result of the remodeling of the heart after infarct. In the remodeling processes the heart becomes thinner and the diameter increases in response to a decrease in heart output, in an effort to maintain a continual cardiac output. This process of thinning results in an increase in the radius of the heart and the stresses on the heart increase.
  • [0122]
    It has been shown that perfluorocarbon compounds have a high affinity for gases, for example carbon dioxide and oxygen. The ability of perfluorocarbons to transport oxygen is approximately eighteen times greater than blood plasma in a comparable volume of each component. In addition, it was shown that the half-life for oxygenation/deoxygenation is approximately three and one half times faster for many perfluorinated compounds as compared to hemoglobin. Thus, perfluoro compounds may be used in tissues to aid in the reoxygenation of an affected region such as an infarct region. A few examples that demonstrate biocompatibility in a subject are identified in Table 1.
  • [0123]
    FIG. 7 illustrates the multi-component system in a flowchart. The myocardial infarction is located 720. Then, the components are delivered to the region via a minimally invasive procedure by methods previously described and/or by catheter delivery. It was previously disclosed that the addition of a thiol functionality (FIG. 6, component 3) in the presence of an electron deficient double bond, such as an acyloyl functionality (FIG. 6, component 2), can undergo a Michael addition reaction. Under basic conditions, the thiol functionality becomes hypernucleophilic and rapidly (<10 seconds) forms a bond with the acryloyl functionality (see FIG. 10). As illustrated in FIG. 6, a gel may be formed to prevent infarct expansion and/or bulking, thus preventing a remodeling of the heart that may lead to heart failure. FIG. 7 (730) illustrates the first component that includes a bioerodable gel and 740 illustrates the gel accompanied by a perfluorinated compound as the second component to enhance oxygenation of the tissue. The gel is formed by a three-component system. The first component includes a biocompatible polymer as previously described with a multifunctional spacer group 730. The second component 840 includes a difunctional or multifunctional perfluorinated molecule 810. The third component 750 includes a hetero-functional molecule with a reactive functionality on one side of the spacer group, and a cell binding peptide sequence, such as the peptide sequences previously described, on the terminal end. One example of a peptide sequence includes the RGD sequence. FIG. 8 illustrates in schematic form the reaction of the thiol component 800 and the acyloyl functional group 820 to form one compound 830 of the three-component system of FIG. 7. This three-component system may be introduced to the infarct region by similar minimally invasive methods as described for the methods of FIG. 6 that may be guided by mapping the heart prior to administration of an agent. Examples of this three-component system are discussed in the example section.
  • [0124]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 50 μl. IV and IC routes may be required which would involve larger treatment volumes (for example about 2 ml to about 250 ml).
  • [0125]
    FIG. 10 illustrates the ester bond formed between the second component (1000) and the third component (1010) of a multi-component composition of FIG. 6. This bond (1020) is necessary for delaying the degradation of the scaffolding and release of the active agents within the microparticles. This bond tends to resist degradation for approximately 2 months.
  • Swellable Agent Systems for Reinforcement
  • [0126]
    FIGS. 11A-11F illustrate the introduction of a swellable non-biologic material to structurally reinforce and/or bulk the infarct region. FIG. 11A illustrates the introduction of microparticles 1130 to an infarct region 1110. Microparticles 1130 are shown accumulated in a mass at the site of the left ventricle 1100 within the infarct zone. One method for introduction of the microparticles 1120 is percutaneously with the use of a catheter 1130. A distal end of the catheter is advanced to the infarct region 1110 and the microparticles 1130 are released. The microparticles become lodged in the infarct tissue 1140. FIG. 11B illustrates microparticles 1130 acquiring the necessary surrounding fluid 1150 to swell 1160/1170. One embodiment includes the use of microparticle beads capable of fluid uptake in the infarct region to structurally reinforce the region. The particles will range in size from approximately 5 to approximately 10 microns. The microparticles will be less than 10 microns so that the completely swollen particle becomes lodged in the site (1180) but is not too large to become an obstruction in the area. In addition, the swollen microparticles provide mechanical strength and thickness to the damaged area by replacing the dead and degraded myocardial cells.
  • Agents Hydrogels Spheres
  • [0127]
    Examples include hydrogel spheres composed of cross-linked polyacrylamide or cross-linked PVP. The monomeric form of these products will contain di-functional monomers such as di-vinyl benzene, ethylene glycol dimethylacrylate or bis acrylamido acetic acid. These agents form a cross-linked network that is resistant to dissolution in aqueous systems.
  • Commercial Products
  • [0128]
    Several commercial products are available that may be used such as microparticles obtained from A. P. Pharma or Biosphere Medical. These microparticles resist non-specific protein absorption and have bio-stable backbone linkages. These microparticles are not bioerodable or bioabsorbable. FIG. 11E illustrates the microparticles dispersed in the infarct region taking up the surrounding fluid and swelling until they become lodged in the region (FIG. 11F).
  • Structural Reinforcement Compositions and Materials
  • [0129]
    FIG. 12 illustrates several possible methods to reinforce the ventricular wall of the infarct region of an MI subject. Restraining the infarct zone by suturing an epicardial polymer mesh was previously demonstrated. See Kelley, S. T., et al., Restraining Infarct Expansion Preserves Left Ventricular Geometry and Function After Acute Anteroapical Infarction, Circ., 1999, pp. 135-142, 99. Due to the nature of this technique suturing the mesh directly into the tissue was necessary. This may cause further damage. This procedure requires invasive surgery. In addition, the polymer mesh does not degrade over time and this may also be a problem. By injecting a reinforcing agent directly into the affected area by minimally invasive procedures, this avoids the intrusive suturing protocol. The solution may be injected in the infarct zone during an open chest procedure. In one embodiment, the introduction of the reinforcing solution comprises the following procedures consisting of sub-xiphoid and percutaneously. In another embodiment, the mode of introduction of the reinforcing solution by a percutaneous injection comprises one of the following consisting of an intraventricular catheter, a transvascular needle catheter and retrograde venous perfusion.
  • Single Component Systems
  • [0130]
    FIG. 12 (1210/1220/1230) illustrates the identification and reinforcement of the MI region prior to intervention by a reinforcing agent. FIG. 12 (1210) describes the use of a single component injected into the infarct region. This example constitutes a single pseudoplastic or thixotropic material capable of forming a gel-like reinforcement to the infarct region wall. Several examples of these materials exist. In one embodiment, the structural reinforcing agent includes one of the following consisting of hyaluronic acid, bovine collagen, high-molecular weight ultra-pure polyacrylamide and polyvinyl pyrrolidone.
  • [0131]
    In one specific embodiment of the present invention, the single component for structural reinforcement comprises bovine collagen dispersed with PMMA (polymethyl methylacrylate) beads. These beads may be manufactured under the trade name of ARTECOLL (Rofil Medical International, Breda, The Netherlands). PMMA is one of several cross-linked or highly insoluble microparticles. PMMA was discovered in the early 1900's and was used initially in dental prosthesis. Recently, it has been used in bone replacement of the jaw and hip. In addition, it has been used for artificial eye lenses, pacemakers and dentures. ARTECOLL™ has principally been used in filling folds and wrinkles of the face, augmenting lips, adjusting an irregular nose.
  • [0132]
    Possibly one of the most important features of the insoluble microparticles is the surface of the microparticles must be smooth to induce collagen deposition. A rough surface promotes macrophage activity while discouraging collagen deposition. The methods incorporate the use of smooth surface particles. The components may act as a substrate for endogenous collagen deposition. As the reinforcing gel degrades, the highly stable and smooth microparticles may be exposed to the fibroblast cell population occupying the site. This triggers the production of collagen to replace the decomposing gel. Therefore, the infarct zone may be reinforced by the collagen replacement of the temporary gel. In one embodiment, the dispersing material includes one of the following group of microparticle materials consisting of PMMA (polymethyl methylacrylate), P(MMA-co BMA) (polymethyl methylacrylate-co butyl methylacrylate), carbon microparticles (Durasphere), polystyrene, cross-linked acrylic hydrogels and PLGA. In another embodiment, the cross-linked acrylic hydrogel may include the following HEMA (2-hydroxyethyl methacrylate), AA (acrylic acid), AMPS (acrylamido-methyl-propane sulfonate), acrylamide, N,N,di-methyl acrylamide, diacetone acrylamide, styrene sulfonate, and di- or tri-functional monomers. The di or tri-functional monomers may be EGDMA (ethylene glycol di-methacrylate) and DVB (di-vinyl benzene). In addition, the use of highly crystalline (and hydrolysis resistant) PLGA microparticles may outlast the carrier gel and also provide a useful substrate for collagen deposition.
  • [0133]
    Another single solution introduced to the infarct zone may be hyaluronic acid dissolved in sodium salt in water. This is a manufactured gel sold as a dermal augmentation gel (RESTYLANE™). Hyaluronic acid hydrogel has also been used in the past for control of delivery of therapeutic agents in wound sites (Luo, Y. et al. Cross-linked hyaluronic acid hydrogel films: new biomaterials for drug delivery” Journal of Controlled Release (2000) 69:169-184). Other possible single introduced components include bovine collagen (ZYDERM™ or ZYPLAST™), another dermal augmentation gel developed by Collagen Corp. The high molecular weight, ultrapure polyacrylamide in water may be FORMACRYL™ or BIOFORM™ other dermal augmentation gels. The bovine collagen may be dispersed by the PMMA product ARTECOLL™. ARTECOLL™ is best known for its success as a biocompatible dermal augmentation gel for reconstruction. RESOPLAST™ (Rofil Medical International, Breda, The Netherlands) may also be used as a single component gel.
  • [0134]
    FIG. 12 (1220) illustrates another method to reinforce the infarct zone of the ventricle using a single component system. This example utilizes the introduction of a single component that forms a gel after reacting with an endogenous component. One such component may be tropoelastin (detailed previously). Elastin is the insoluble, elastic protein of high tensile strength found in connective tissue of the large arteries, trachea, bronchi and ligaments. Rarely seen endogenously as tropoelastin (the uncross-linked form), it rapidly cross-links to lysine residues in a process of oxidative deamination by the enzyme lysyl oxidase when introduced in vivo. As stated previously, tropoelastin is available commercially as a recombinant bacterial product. When heated in water tropoelastin forms a coacervate and this may be injected into the infarct region where lysyl oxidase induces lysine cross-linking by the oxidative deamination process. In one embodiment, tropoelastin may be introduced to the infarct region. In another embodiment, tropoelastin may be introduced to the infarct region after the introduction of the highly insoluble microparticles described above. Another reactive single-component may be cyanoacrylate adhesive. This is a widely used plastics binding agent. In one embodiment the cyanoacrylate may be octyl cyanoacrylate. The octyl cyanoacrylate may be the manufactured product called Dermabond™ (Johnson and Johnson). This product was recently approved for use as a tissue adhesive for wound closure. Octyl cyanoacrylate may be introduced to the infarct region as a liquid. Once it contacts the infarct region, it solidifies due to its exposure to moisture. In another embodiment, the octyl cyanoacrylate may be introduced to the infarct region after the introduction of the highly insoluble, stable microparticles described above.
  • [0135]
    In another embodiment, a reactive single component includes a component that is temperature sensitive. This is illustrated in FIG. 12 (1230). One example of this type of component is a component that may be a liquid at room temperature, and, once exposed to a temperature approximately equal to body temperature, the component gels. A more specific component includes introducing block co-polymers of silk protein-like sub units and elastin-like sub units. An example of the block co-polymer synthetic protein may be ProLastin (PPTI, Protein Polymer Technologies). These components gel due to non-covalent interactions (hydrogen bonding and crystallization of silk-like subunits) at elevated temperatures for example approximately equal to body temperature. With these components, no lysine residues are present, so cross-linking due to endogenous lysyl oxidase does not occur. The formation of the gel via a change in temperature may be adjusted using additives. These additives include but are not limited to sodium chloride, Diglyme (Diethylene Glycol Dimethyl Ether; 2-Methoxyethyl Ether; Bis(2-Methoxy Ethyl Ether), and ethanol.
  • [0136]
    Many thermal reversible materials may be used for reinforcement of the myocardial tissue. Generally, thermal reversible components at temperatures of approximately 37 degrees Celsius ad below are liquid or soft gel. When the temperature shifts to 37 degrees Celsius or above, the thermal reversible components tend to harden. In one embodiment, the temperature sensitive structural reinforcing component may be Triblock poly(lactide-co-glycolide)-polyethylene glycol copolymer. This is commercially available (REGEL™ Macromed, Utah). In another embodiment, the temperature sensitive structural reinforcing component may include the following consisting of poly(N-isopropylacrylamide) and copolymers of polyacrylic acid and poly(N-isopropylacrylamide). Another temperature sensitive structural reinforcing component commercially available is PLURONICS™ (aqueous solutions of PEO-PPO-PEO (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymers BASF, N. J.) (Huang, K. et al. “Synthesis and Characterization of Self-Assembling Block copolymers Containing Bioadhesive End Groups” Biomacromolecules 2002, 3, 397-406). Another embodiment includes combining two or more of the single components in order to structurally reinforce the infarct region. For example, silk-elastin, collagen and Laminin may be used as a one-part system. The silk-elastin would likely form in situ cross-links due to the silk blocks.
  • [0137]
    In another embodiment, a reactive single component includes a component that is pH sensitive. The component remains in a liquid state if it is sufficiently protonated preventing gelation. In another embodiment, the component is initially maintained at a low pH for example pH 3.0 and later introduced to the treatment area which results in gelation of the component due to the physiological pH of the environment. One example of this is discussed in Example 3. Several possible cationic agents may be, but are not limited to, one of the following cationic agents that remain protonated at low pH, poly(allyl amine), DEAE-Dextran, ethoxylated Poly(ethylenimine), and Poly(lysine). Other examples may one of, but are not limited to, the following anionic agents: dextran sulfate, carboxymethyl dextran, carboxymethylcellulose, polystyrene sulfanate and chrondroitin sulfate.
  • [0138]
    Additionally, any of these microparticle components may be accompanied by one or more contrast agent and/or suitable agent(s) for treatment of the region. The contrast agent or treatment agent may be conjugated to or dissolved into the structural component prior to introduction to the infarct area. The agents that may accompany the reinforcing component(s) may include, but are not limited to, angiogenic agents, ACE inhibitors, angiotensin receptor blockers, SRCA (sercoplasmic reticulum calcium pump) pump increasing agents, phospholamban inhibitors and anti-apoptotic drugs. These agents may be in the form of small molecules, peptides, proteins or gene products. The small molecules may be optionally conjugated to a component of the solution, dispersed in solution, or dissolved in solution to improve the adhesion of the reinforcing components to the tissue. One embodiment is to conjugate a peptide with a conserved region that mediates adhesion processes. A conserved region of a peptide may be a sequence of amino acids having a special function of identification that has been conserved in a protein family over time. Another embodiment includes the use of a specific peptide conjugate with a conserved RGD (arginine(R)-glycine(G)-asparagine(D)) motif in the presence of the reinforcing component. In further embodiments, the RGD motif peptide may include the following: von Willebrand factor, osteopontin, fibronectin, fibrinogen, vitronectin, laminin and collagen. One embodiment seeks to minimize thinning during remodeling of the infarct region. Thus, bulking and reinforcing the infarct region post-MI may preserve the geometry of the ventricle.
  • [0139]
    Any one or more catheters may be used to deliver the any one or multiple components of the embodiments to the infarct region area. Several catheters have been designed in order to precisely deliver agents to a damaged region within the heart for example an infarct region. Several of these catheters have been described (U.S. Pat. Nos. 6,309,370; 6,432,119; 6,485,481). The delivery device may include an apparatus for intracardiac drug administration, including a sensor for positioning within the heart, a delivery device to administer the desired agent and amount at the site of the position sensor.
  • Dual Component Systems
  • [0140]
    FIG. 12 (1240) illustrates the use of dual component systems for the formation of structural reinforcing gels for application to the infarct region. Initially, the infarct region is identified (1300) by imaging methods previously discussed. FIG. 13 (1330/1340/1350/1360/1370/1380/1390) illustrates a flowchart further describing dual component systems to form a structural reinforcing gel in the infarct region 1320. In one example 1330, two components are combined at the infarct zone at around physiological pH. Component one is a principally anionic solution and the second component is principally a cationic solution at approximately physiological pH. When the two components are mixed together at the infarct zone, a gel forms rapidly and irreversibly. In one embodiment, a dual component system may comprise poly (acrylic acid) as a first component and poly (allyl amine) as a second component as illustrated in FIG. 13 (1330). In another embodiment, a dual component system may comprise poly (acrylic acid) as a first component and poly (allyl amine) as a second component that may be delivered by a catheter with dual injection lumens. Other dual component systems to form a structural reinforcing gel in the infarct region may include elastin as a first component and lysyl oxidase as a second component 1340; sodium alginate as a first component and an aqueous solution of calcium chloride as a second component 1350, and tropoelastin and collagen as a first component and cross-linker lysyl dehydrogenase as a second component and laminin 1395 may be added to this combination later. The composition of each component will depend on the mechanical property of the final cross-linked system. Other substances that can replace the lysyl dehydrogenase or complement its cross-linking ability might be used such as glutaraldehyde, and/or photoactivatable crosslinkers, for example, blue dye used to cross-link. Additionally, these dual component systems may be combined with other individual system utilizing commercial products such as AVITENE™ (Microfibrillar Collagen Hemostat), SUGICEL™, (absorbable haemostat, Johnson & Johnson), GELFOAM™, FLOSEAL™ (Baxter, matrix hemostatic sealant with a granular physical structure and thrombin), FOCAL SEAL™ (Focal, Inc.) or FIBRIN SEAL™ (FS). FLOSEAL™ is a gel constituting collagen derived particles and topical thrombin capable of being injected. It has been approved for uses including vascular sealing. Several other possible cationic agents may be, but are not limited to, one of the following cationic agents that remain protonated at low pH: poly(allyl amine), DEAE-Dextran, ethoxylated Poly(ethylenimine), and Poly(lysine). Other examples may be one of, but are not limited to, the following anionic agents: dextran sulfate, carboxymethyl dextran, carboxymethylcellulose, polystyrene sulfanate and chrondroitin sulfate. In a preferred embodiment, the first material may be DEAE Dextran and the second material may be polystyrenesulfonate.
  • [0141]
    FIG. 13 (1370) illustrates the use of another dual component system, DOPA (3,4-dihydroxyphenyl-L-alanine), a principle component responsible for muscle adhesive proteins, capable of forming a hydrogel in conducive conditions. Specifically, a component known as star block DOPA-block-PEG undergoes cross-linking in situ forming the hydrogel after an oxidation process converts the DOPA to O-quinone. This process forms a stable in situ hydrogel. Other examples are represented as dual components in FIG. 13 (1370/1380). FIG. 13 (1380) includes the use of an acrylate macromer solution and a dithiol solution injected into the infarct region for structural reinforcement. These components when mixed at the infarct site undergo a cross-linking reaction leading to the formation of a hydrogel. A specific embodiment may comprise the use of PEG triacrylate as the first component and PEG thiol as the second component introduced to the infarct zone via a dual lumen needle system discussed previously. In FIG. 13 (1390), a glue-like component system may be employed. One embodiment may include the use of GRF glue that is made up of gelatin, resorcinol and formaldehyde (GRF) as a structural reinforcing agent introduced to the infarct zone. To accomplish this, a two-part system may be used to induce cross-linking upon admixture of the components at the infarct zone. In other embodiments, the following structural reinforcing components may be added along with GRF: cross-linking agents such as polyglutamic acid, polylysine and WSC (water-soluble carbodimides).
  • [0142]
    FIG. 14 illustrates the introduction and action of a single component or dual components to the infarct region for structural reinforcement. FIG. 14 illustrates the identification of the infarct region 1410 of the ventricle 1400 by methods previously described and subsequent multi-injection of the separate components to the site of damage 1420. In a dual component system, the two components 1430/1440 contact each other at the site and form reinforcing structural scaffold 1430/1440. In FIG. 15B, a single pseudoplastic or thixotropic agent is introduced to the area in multiple injections 1450 and structurally reinforces the wall 1460. These agents are introduced in final form and require no additional agents. FIG. 14 illustrates the addition of at least one agent 1430/1440/1450/1480 by multiple injections each at a different site 1405/1415 that requires an endogenous component or a temperature change 1460/1490 to convert to a structural reinforcing form 1450/1470/1495. The structural reinforcing agent(s) is localized to the infarct region via minimally invasive procedures discussed previously.
  • [0143]
    In addition, biocompatible viscosifiers, for example, type 1 gels may be added in combination with any of the single or multiple component systems illustrated. For example, hyaluronic acid or PVP may be used to increase the resistance of the active formula from natural degradation once introduced to the infarct zone. In one embodiment the viscosity of the treatment agent may be about 0-100 centipoise. In other embodiments, the viscosity of the treatment agent may be about 0-50 centipoise. In a preferred embodiment, the viscosity of the treatment agent may be about 25-40 centipoise. In a preferred embodiment, the viscosity of the treatment agent may be about 35 centipoise.
  • [0144]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 50 μl. IV and IC routes may be required which would involve larger treatment volumes (for example about 2 ml to about 250 ml).
  • [0145]
    Biocompatible dyes may be added to any single or combination components of any of the described embodiments to trace the components in the infarct region in any procedure. Other dyes may be added for experimental purposes to trace the deposition of any agent for example in a rat heart. Some examples of these dyes include but are not limited to Sudan Red B, Fat Brown RR, Eosin Y and Toluidine blue.
  • [0146]
    On the other hand, tissue adhesive components may also be added in combination with any of the single or dual component systems illustrated in FIGS. 12, 13 and 14. For example, Laminin-5, polyacrylic acid, Chitosan and water-soluble chitosan may be used to increase the tissue retention of the active formulation. Laminin-5 is a basement membrane extracellular matrix macromolecule that provides an attachment substrate for both adhesion and migration in a wide variety of cell types, including epithelial cells, fibroblasts, neurons and leukocytes. Chitosan is the only natural positive ion polysaccharide obtained from deacetylated chitin. It possesses decomposability, good membrane forming state, biocompatibility, anti-fungal and anti-tumor function. Chitosan has excellent viscosity, compressibility and fluidity.
  • [0147]
    Another two component system is based on a pectin material and could be referred to as a pseudo-one-component system because it gels on exposure to bodily fluids (such as intercellular fluid). This system uses pectin as the gelling material or component. In some embodiments this system uses aloe-derived-pectin as the first component for the gelling material or component. Alternatively, if an aloe-derived pectin embodiment using bodily fluids for gelation was not uniform or consistent, gelation could arise from separately, but simultaneously, providing an additional ion solution. This solution could be delivered through the catheter sheath or a second needle.
  • [0148]
    Many naturally derived polysaccharides provoke pro-inflammatory responses of various degrees, e.g. alginate, especially in easily sensitized animals such as pigs. Aloe-derived pectin of appropriate purity will show a more benign response and could in some cases demonstrate a pro-healing effect. Pectin has long been used in the food industry and the FDA classifies it as generally regarded as safe. A specific example of such aloe-derived pectin is known by the trade name GelSite (manufactured by GelSite). This aloe-derived pectin is biodegradable and animal studies have shown it to be well tolerated. Aloe-derived-pectin, in-situ-gelling, drug delivery systems are based on high-molecular-weight pectins extracted and purified from aloe plants. Chemically, the aloe-derived pectin polymer is an alpha-1-4-linked polygalacturonic acid with a molecular weight of 38040 kDa. This water soluble polymer has in situ gelling properties. The aloe-derived-pectin drug delivery system (polymer concentration ≧0.25%, w/v) transforms from a liquid into a gel upon contact with body fluid and provide one or more days to one-week of delivery period. Unlike other in situ gelling systems, the gelation of aloe-derived-pectin system is not pH or temperature dependent. The aloe-derived-pectin polymer is sensitive to calcium and can form a calcium gel. The aloe-derived-pectin polymer can bind and stabilize heparin-binding growth factors. This polymer gel may provide myocardial reinforcement or regeneration, and can aid cell retention in cardiomyoplasty. Since it binds growth factors or other cytokines, it could be useful as a controlled release medium for delivering such factors or cytokines directly to tissue such as cardiac or vascular tissue. It can be used as a single-component gel by dissolving it in water. The solution would gel upon contact with the myocardium: intercellular fluid would provide enough ions for gelation. This material would have a low osmolarity, low enough to cause distress in the delivered cells if used for cell therapy applications (such as delivering cells to tissue). But using 2-component delivery through a dual needle, one component containing cells in phosphate-buffered saline, and the other containing aloe-derived-pectin in sterile water, would allow the system to function in cell therapy applications. If an embodiment using aloe-derived pectin with gelation from intercellular fluid was not uniform or consistent, ions of low concentration could be added to the cell solution (at low concentration to prevent cell death) or in a separate third component, which could be delivered through the catheter sheath or a second inner needle. For cell therapy, an alternate approach would be to dissolve an aloe-derived-pectin polymer into an ammonium chloride or sucrose solution of physiological osmolarity and disperse the cells into it. Sucrose and ammonium chloride are cytocompatible and neither will cause gelation of the pectin. The advantage of this approach is that delivery could be accomplished using a single lumen or single needle device.
  • [0149]
    Aloe-derived pectin molecular weight and polymer concentration can be modified for the appropriate gel modulus and degradation rate appropriate for the therapy. Aloe-derived pectin can also be blended with other biomaterial gels such as those based on natural materials like fibrinogen, alginate, chitosan, collagen, gelatin, and hyaluronan or synthetics such as those based on poly(ethylene glycol) or poly(vinyl alcohol) in order to produce gels of desired mechanical, biological and degradative properties. For example blending with another ionotropic gel such as sodium alginate may serve to reduce the inflammatory response seen with implantation of alginate alone. As a by-product and additional benefit of this therapy, any aloe inadvertently dispersed into the circulation could act as a drag reducer and improve perfusion. Pectins derived from aloe species other than the aloe-derived-pectin system may also be utilized in any of the above embodiments as desired by one of ordinary skill in the art.
  • Single Components Suspended in a Delivery Medium
  • [0150]
    FIG. 15 illustrates flowcharts describing other methods to prevent the remodeling and ultimate thinning of the infarct region. As with several of the previously discussed methods, these methods provide a bulking or structural reinforcing agent to the infarct region. In FIG. 15 (1510), an agent comprising microparticles in solution (a dispersion) is introduced to the infarct region after identification of the infarct region as described previously. The microparticles may be a predetermined range of about 1 to about 200 microns. In one embodiment, the microparticles may be 20 microns or less. In a preferred embodiment, the microparticles may be 10 microns or less. The microparticle size delivered to an infarct region may be determined by the delivery method used. For example, an intraventricular catheter may be used to deliver particles up to 200 microns that may avoid the risk of an embolism. One suspending solution for the microparticles may be water. On the other hand, the suspending solution may also be a solvent, for example, dimethylsulfoxide (DMSO) or ethanol adjuvants. In one embodiment, a suspending solution along with the microparticles may be introduced as a dispersion to an infarct region and the microparticles remain in the region as the solution dissipates into the surrounding tissue. Thus, the microparticles provide a structural reinforcing bulk to the region. This may result in reduction of stress to the post infarct myocardium. It may also serve as a substrate for additional site for collagen deposition. In one embodiment, the dispersion (detailed above) may be injected into the infarct zone during an open chest procedure via a minimally invasive procedure. In another embodiment, the minimally invasive procedure includes at least one of subxiphoid and percutaneously. In another embodiment, the percutaneous introduction into the infarct zone may include one of intra-ventricular needle, transvascular catheter and retrograde venous perfusion.
  • [0151]
    FIG. 15 (1520) illustrates a flow chart of an additional method similar to FIG. 15 (1510) except that the microparticles precipitate out of the solution (the dispersion). In FIG. 15 (1520), an agent including microparticles in solution (a dispersion) is introduced to the infarct region. The microparticles may be a predetermined size of 0 to 200 microns. In a preferred embodiment, the microparticles are 10 microns or less. In one embodiment, the suspending solution along with the microparticles may be introduced to the infarct region and the microparticles precipitate out of the dispersion in the region. Thus, the microparticles provide a structural reinforcing bulk to the region. This may result in reduction of stress to the post infarct myocardium. It may also serve as a substrate for additional site for collagen deposition. In one embodiment, the dispersion (detailed above) may be injected in to the infarct zone during an open chest procedure via a minimally invasive procedure. In another embodiment, a minimally invasive procedure including sub-xiphoid and percutaneously methods may be employed. In another embodiment, a percutaneous introduction into the infarct zone may include one of an intra-ventricular needle, transvascular needle catheter and retrograde venous perfusion.
  • [0152]
    Several examples of the microparticles of FIG. 15 (1510) and (1520) are illustrated in FIG. 16. FIG. 16 (1610) illustrates the viscous liquid sucrose acetate isobutyrate (SAIB). SAIB is water-insoluble. SAIB may be dissolved in a solvent or a combination of solvents for example, ethanol, dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol, triacetin, 2-pyrrolidone, N-methyl pyrrolidone, propylene carbonate or glycofurol. These solvents decrease the viscosity of SAIB in order to facilitate the introduction of this agent through a needle or lumen. In one embodiment, SAIB may be introduced accompanied by a solvent to the infarct region and the solvent dissipates at the site leaving behind the viscous SAIB in the region.
  • [0153]
    Other biocompatible polymer systems may be introduced to an infarct zone (FIG. 16, 1620). Some of these agents are not only biocompatible but also substantially water-insoluble similar to SAIB. Solvents or mixtures of solvents may be used to dissolve the polymer in order to facilitate introduction to the infarct zone. In one embodiment, a biocompatible water-insoluble polymer may include the following consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyalkylene oxates, polyamides, polyurethanes, polyesteramides, polydioxanones, polyhydroxyvalerates, polyacetals, polyketals, polycarbonates, polyorthoesters, polyphosphazenes, polyhydroxybutyrates, polyalkylene succinates, and poly(amino acids). Any one of these insoluble polymers may be dissolved in solvents, for example, Diglyme, dimethyl isosorbide, N-methyl-2-pyrrolidone, 2-pyrrolidone, glycerol, propylene glycol, ethanol, tetraglycol, diethyl succinate, solketal, ethyl acetate, ethyl lactate, ethyl butyrate, dibutyl malonate, tributyl citrate, tri-n-hexyl acetylcitrate, dietyl glutarate, diethyl malonate, triethyl citrate, triacetin, tributyrin, diethyl carbonate, propylene carbonate acetone, methyl ethyl ketone, dimethyl sulfoxide dimethyl sulfone, tetrahydrofuran, capralactum, N,N-diethyl-m-toluamide, 1-dodecylazacycloheptan-2-one, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and glycerol formal to form an injectible polymer solution. The dispersion may be introduced into the infarct region of the heart wherein the solvent may dissipate and the polymer may precipitate out of the dispersion to structurally reinforce the infarct regional wall. In one embodiment, the disclosed polymers may be used in any combination as co-polymers of two or more polymers introduced to the infarct region.
  • [0154]
    FIG. 16 (1630) illustrates a flowchart describing the use of a vinyl polymer and acrylate biocompatible polymer system. Once injected into an infarct zone, the vinyl polymer/acrylate agent contacts water and the polymer precipitates thus reinforcing the surrounding tissue of the infarct region. In one embodiment, the vinyl polymer/acrylate agent includes the following such as polyvinyl butyral, PBMA-HEMA, PEMA-HEMA, PMMA-HEMA and other acrylate copolymers that dissolve in ethanol, acetone and I-PA. In another embodiment, the vinyl polymerlacrylate agent introduced to the infarct region may be EVAL™ that has a solid phase or melt phase forming process. EVAL™ Resins have a high crystalline structure. Thermoforming grades of EVAL™ resins have monoclinic crystalline structure while most polyolefins have either a hexagonal or orthorhombic type structure. This characteristic provides flexibility within its thermoforming capabilities. In another embodiment, the vinyl polymer/acrylate agent introduced to the infarct region may be BUTVAR™ (polyvinyl butyral). In one embodiment, the agent may be P(BMA co-MMA) (Aldrich Chem.) in Diglyme. In another embodiment, the agent may be EVAL™, a co-polymer of ethylene and vinyl alcohol (EVAL Co. of America, Houston, Tex.) in dimethyl acetamide. In another embodiment, the polymer may be PLGA poly(lactide co-glycolide) (Birmingham Polymers, Birmingham, Ala.) in Diglyme.
  • [0155]
    Other components may act as a substrate for endogenous collagen deposition and protect the precipitated or remaining microparticles described in FIG. 16 from erosion. As the reinforcing gel degrades, the highly stable and smooth microparticles may be exposed to the fibroblast cell population occupying the site. This triggers the production of collagen to replace the decomposing gel. Therefore, the infarct zone may be reinforced by the collagen replacement of the temporary gel. The dispersed material includes the following group of microparticle materials: PMMA, P(MMA-co BMA), carbon microparticles (Durasphere), polystyrene, cross-linked acrylic hydrogels and PLGA. In another embodiment, the cross-linked acrylic hydrogel may include the following: HEMA, AA, AMPS, acrylamide, N,N,di-methyl acrylamide, diacetone acrylamide, styrene sulfonate, and di or tri functional monomers. The di or tri-functional monomers may be EGDMA and DVB. Another example of durable microparticles includes pyrolytic carbon-coated microparticles. One example of pyrolytic carbon-coated microparticles was originally produced for urinary incontinence (Carbon Medical Technologies) and trisacryl gelatin microparticles for use as embolization particles (Biosphere). In addition, the use of highly crystalline (and hydrolysis resistant) PLGA microparticles may outlast the carrier gel and also provide a useful substrate for collagen deposition.
  • [0156]
    One or more contrast agents 1540 and/or suitable treatment agent(s) 1550 may accompany the previously detailed components as a treatment of the infarct region. The contrast agent or treatment agent may be conjugated to or dissolved into the structural component prior to introduction to the infarct area. The contrast agents may be used for detection in X-ray or MR analysis. The agents that may accompany the reinforcing component(s) may include, but are not limited, to angiogenic agents, ACE inhibitors, angiotensin receptor blockers, SRCA pump (sarcoplasmic reticulum calcium pump) increasing agents, phospholamban inhibitors and antiapoptotic drugs. These agents may be in the form of small molecules, peptides, proteins or gene products. The small molecules may be optionally conjugated to a component of the solution, dispersed in solution, or dissolved in solution to improve the adhesion of the reinforcing components to the tissue. One embodiment is to conjugate a peptide with a conserved region that mediates adhesion processes. Another embodiment includes the use of a specific peptide conjugate with a RGD (arginine-glycine-asparagine) motif in the presence of the reinforcing component. In further embodiments, the RGD motif peptide may include von Willebrand factor, osteopontin, fibronectin, fibrinogen, vitronectin, laminin and collagen.
  • [0157]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 50 μl.
  • Collagen Cross-Linking Agents for Structural Reinforcement
  • [0158]
    FIG. 17 illustrates a flowchart describing a method to structurally reinforce the infarct region of the ventricle 1710. As previously mentioned, thinning is a key factor in the cascade of events following remodeling of the infarct region. One factor contributing to the thinning is collagen degradation by MMPs (matrixmetalloproteinases) and collagen helix slippage due to hemodynamic stress. The collagen slippage generates infarct scar expansion that leads to additional remodeling and remote zone hypertrophy. Previous inventions to prevent collagen slippage include a suturing procedure. See Kelley, S. T., et al., Restraining Infarct Expansion Preserves Left Ventricular Geometry and Function After Acute Anteroapical Infarction, Circ., 1999, pp. 135-142, 99. This involves directly suturing a epicardial polymer mesh to the region. According to one embodiment, agents will be introduced to the region by a minimally invasive procedure to prevent collagen slippage. An agent or dispersion will be introduced in one embodiment by multiple injections to the infarct zone then the agent will react with the collagen scar directly to cross-link it. This results in prevention of slippage and strength to the regional wall. In one embodiment, the agent (detailed above) may be injected into the infarct zone during an open chest procedure via a minimally invasive procedure. In another embodiment, the minimally invasive procedure may include sub-xiphoid and percutaneously methods. In another embodiment, the percutaneous introduction into the infarct zone may comprise one of intra-ventricular needle, transvascular needle catheter and retrograde venous perfusion.
  • [0159]
    A contrast agent or treatment agent may be conjugated to or dissolved into the structural component prior to introduction to the infarct area, such as those described previously.
  • [0160]
    Several possible cross-linking agents are illustrated in FIG. 18 to illustrate the possible agents of 1720 to prevent collagen slippage 1730. The agent injected into the infarct region may be polyfunctional (either hetero or homopolymer). Another important feature of the cross-linking agent is the ability of the agent to cross-link to the side groups of the amino acids of the collagen (type I and III). In one embodiment, the agent is soluble in a biocompatible water miscible solvent that is capable of being drawn out of the dispersion by aqueous fluid present in the myocardium. This enables the cross-linking agent the ability to precipitate out into the infarct region minimizing migration of the cross-linking agent out of the area. In another embodiment, the biocompatible solvent used in the presence of the cross-linking agent may be the following: Diglyme and dimethyl isosorbide. Collagen is made up of a large number of lysine and hydroxyproline residues that carry reactive side groups of primary amines and hydroxyl groups respectively. In the following examples, the cross-linking agents react with at least one of these side groups. FIG. 18 (1810) illustrates a flowchart describing a method using polyepoxy functional resins for cross-linking the collagen. In one embodiment a polyepoxyl functional resin may be introduced to the infarct region. In another embodiment, the polyepoxy functional resin may comprise the following: Bisphenol A epoxies (Shell 828), Epoxy-Novolak resins (Ciba 1138 and 1139, Dow 431), homopolymers of glycidyl methacrylate (GMA) or copolymers of GMA with other acrylates. In another embodiment, the polyepoxy functional resins may include a multifunctional epoxide. In another embodiment, the polyepoxy functional resins may include an acrylate. The later resins, multifunctional epoxides and acrylate, are based on a cubic silicone with eight epoxide or acrylate functionalities (silsesquioxanes). In another embodiment, the polyepoxy functional resins may include a tetra-functional epoxide silicone. In another embodiment, the polyepoxy functional resins may include di-functional epoxide silicone.
  • [0161]
    FIG. 18 (1820) illustrates a flowchart describing the use of polyisocyanates as the cross-lining agent. In one embodiment, the cross-linking agent used to link the collagen may comprise a polyisocyanate. In another, the polyisocyanate may include the following: the biuret of hexamethylene di-isocyanate and isocyanurate of hexamethylene di-isocyanate. Both of these products are manufactured commercially under the name DESMODUR N 100 and DESMODUR 3300 respectively (commercially available from Bayer). FIG. 18 (1830) illustrates a flowchart describing the use of aromatic halogenated compounds as a possible collagen cross-linking agent. In one embodiment, the agent used to cross-link the collagen to prevent slippage and structurally reinforce the infarct region may include a halogenated compound. In another embodiment, the halogen compound used to cross-link the collagen may include 1,5-difluoro-2,4-dinitrobenzene (DFNB).
  • [0162]
    Polyhydroxyl aromatics (resorcinol groups) such as vegetable tannins have been used to cross-link collagen for processing animal hides into leather. FIG. 18 illustrates a flowchart describing the use of these resorcinol groups for collagen cross-linking. Solvent soluble resorcinol-formaldehyde resins contain numerous resorcinol groups. A methylene bridge and/or an ether bridge connect the resorcinol groups. RESORCINOL™ is capable of cross-linking collagen but one problem is that it is corrosive and water miscible in its monomeric form. In one embodiment, the cross-linking agent to secure the collagen and structurally reinforce the infarct region may be a resorcinol-formaldehyde resin.
  • [0163]
    FIG. 18 (1850) illustrates a flowchart describing the use of agents that terminate in an acrylate group as a potential cross-linking agent to prevent collagen slippage in the infarct region and structurally reinforce the ventricular wall. These acrylate-terminating agents react with the primary amine groups of the collagen and form a stabilizing cross-link. In one embodiment, the cross-linking agent may be an acrylate-terminating agent. In another embodiment, the acrylate-terminating agent used to cross-link the collagen may include one of the following water-insoluble agents urethane-acrylates and epoxy-acrylates. These compounds are commercially available (Cognis Corp, Ohio, U.S.A.). Another example of a cross-linking agent is illustrated in the flowchart of FIG. 18 (1860). Lysyl oxidase discussed earlier may be use alone or in combination with other agents to cross-link the collagen for prevention of slippage and as a structural reinforcing agent in the infarct region. Lysyl oxidase is an enzyme that oxidatively deaminates lysine side groups and forms reactive aldehyde groups capable of forming strong cross-linking bonds with the collagen. In one embodiment, lysyl oxidase may be introduced to the infarct region to cross-link the existing collagen for prevention of slippage.
  • [0164]
    In the final flowchart example of FIG. 18 (1870) illustrates a flowchart describing the use of microparticles to cross-link and stabilize the collagen in the infarct region. One example includes the use of surfactant free styrene latex particles in narrow size distributions that also contain the following functional surface groups comprising chloromethyl, epoxy and aldehyde. The aldehyde surface groups may be tightly packed therefore borohydride reduction would not be necessary for a stable linkage. Chloromethyl groups react with primary and secondary amines thus forming a stable cross-link. Other possible functional reacting groups may include succinimidyl ester, benzotriazole carbonate and p-nitrophenyl carbonate. Other possible functional groups may be used. In one embodiment, the size limitation of the microparticles may include submicron to single digit micron size. This size range prevents the microparticles that may back-wash out of the site from causing an embolic hazard. In other embodiments, the cross-linking agent may be a functionalized surfactant free styrene latex microparticle. Several examples exist of these styrene microparticles. Examples of commercially available functional stryrene microparticles are manufactured by Interfacial Dynamics Corporation and Magsphere.
  • [0165]
    Additionally, any one of these agents illustrated in FIGS. 17 and 18 may be accompanied by one or more contrast agent 1740 and/or suitable agent(s) 1750 for treatment of the region. The contrast agent or treatment agent may be conjugated to or dissolved into the structural component prior to introduction to the infarct area. The agents that may accompany the reinforcing component(s) may include, but are not limited, to angiogenic agents, ACE inhibitors, angiotensin receptor blockers, SRCA pump increasing agents, phospholamban inhibitors and anti-apoptotic drugs. These agents may be in the form of small molecules, peptides, proteins or gene products. The small molecules may be optionally conjugated to a component of the solution, dispersed in solution, or dissolved in solution to improve the adhesion of the reinforcing components to the tissue. One embodiment is to conjugate a peptide with a conserved region that mediates adhesion processes. Another embodiment includes the use of a specific peptide conjugate with a RGD (arginine-glycine-asparagine) motif in the presence of the reinforcing component. In further embodiments, the RGD motif peptide comprises the following: von Willebrand factor, osteopontin, fibronectin, fibrinogen, vitronectin, laminin and collagen.
  • Prevention of Myocardial Edema and “Cementing” of the Infarct Region
  • [0166]
    FIG. 19 illustrates flowcharts describing the introduction of clotting factors immediately after an MI 1900. One of the initial responses of the process post-MI is myocardial edema. The edema is composed of extravasated blood evident within a few hours after infarction. This is followed by its dissolution within the next few hours. The process that occurs immediately post-MI is that the infarct regional wall thickens and then it thins. The present invention illustrated in FIG. 19 introduces one or more clotting factors to the region thereby “cementing” the now clotted blood to reinforce the wall and thicken the wall 1910. FIG. 19 (1920/1930) illustrates one method to clot the blood using a dual solution technique. In one embodiment, the first solution includes calcium chloride and thrombin 1920 and the second solution 1930 includes fibrinogen and transexamic acid. Transexamic acid is an anti-fibrinolytic agent. The introduction of these two solutions to the infarct region sequentially result in localized clotting of the blood that forms a structural reinforcing mass 1940 within the region preventing thinning of the infarct site. In another embodiment, intra-venous pressure perfusion may be used to deliver the clot inducing solutions to the infarct zone. This prevents the possibility of the clot releasing into the arterial circulation. FIG. 19 (1950) illustrates a flowchart describing the use of shear-activated platelet fraction to induce localized clotting. This platelet fraction may be isolated from the MI subject's own blood or another source. FIG. 19 (1960) illustrates a flowchart of other initiators of the clotting cascade. These factors encompass factors that are termed intrinsic and extrinsic factors. Intrinsic factors initiate clotting in the absence of injury. Extrinsic factors initiate clotting that is caused by injury. In one embodiment, the clotting factor used to cease myocardial edema and reinforce the ventricular wall at the infarct zone may comprise the following: von Willebrand Factor (vWF), High Molecular Weight Kininogen (HMWK), Fibrinogen, Prothrombin, and Tissue Factors III-X. In another embodiment of the present invention, any combination of the clotting factors mentioned previously may be used that may provide increased tensile strength the infarct regional wall.
  • Matrix Metalloproteinase Inhibitors Use in the Infarct Region
  • [0167]
    After an MI injury occurs macrophages tend to infiltrate the infarct region. The macrophages release matrix metalloproteinases (MMPs). As members of a zinc-containing endoproteinase family, the MMPs have structural similarities but each enzyme has a different substrate specificity, produced by different cells and additionally have different inducibilities. These enzymes cause destruction in the infarct zone. One important structural component destroyed by MMPs is the extracellular matrix (ECM). The ECM is a complex structural entity surrounding and supporting cells that are found within mammalian tissues. The ECM is often referred to as the connective tissue. The ECM is composed of 3 major classes of biomolecules: structural proteins, for example, collagen and elastin; specialized proteins, for example, fibrillin, fibronectin, and laminin; and proteoglycans. These are composed of a protein core to which is attached long chains of repeating disaccharide units termed of glycosaminoglycans (GAGs) forming extremely complex high molecular weight components of the ECM. Collagen is the principal component of the ECM and MMP induce ECM degradation and affect collagen deposition. Inhibitors of MMP(s) exist 1970 and some of these inhibitors are tissue specific. It was previously demonstrated that acute pharmacological inhibition of MMPs or, in some cases, a deficiency in MMP-9, that the left ventricle dilatation is attenuated in the infarct heart of a mouse. See Creemers, E., et al., Matrix Metalloproteinase Inhibition After MI: A New Approach to Prevent Hear Failure? Circ., 2001, pp. 201-210, 89. The inhibitors of MMPs are referred to as tissue inhibitors of metalloproteinases (TIMPPs). Synthetic forms of MMPIs also exist, for example, BB-94, AG3340, Ro32-355b and GM 6001. It was previously shown that MMPIs reduce the remodeling in the left ventricle by reducing wall thinning. These experiments were performed on rabbits. In addition, this study also demonstrated that MMPI increases rather than decreases neovascularization in the subendocardium. See Lindsey, M. L., et al., Selective Matrix Metalloproteinase Inhibitors Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction, Circ., Feb. 12, 2002, pp. 753-758, 105(6). In one embodiment, MMPIs may be introduced to the infarct region to delay the remodeling process by reducing the migration of fibroblasts and deposition of collagen and prevent ECM degradation, reduce leukocyte influx and also reduce wall stress. In one embodiment, the MMPIs may include the following: o TIMP-1, TIMP-2, TIMP-3 and TIMP-4, which can be introduced to the infarct region in combination with the introduction of any of the described structural reinforcing agents. In another embodiment, naturally occurring inhibitors of MMPs may be increased by exogenous administration of recombinant TIMPs. In another embodiment, the MMPI comprises a synthetically derived MMPI introduced to the infarct region in combination with the introduction of any of the described structural reinforcing agents. The introduction of MMPIs to the infarct zone may be accomplished by several different methods. It is critical that the introduction of these MMPI agents be accomplished by a minimally invasive technique. In one embodiment, MMPI agents will be introduced to the region by a minimally invasive procedure to prevent ECM degradation. An agent or dispersion will be introduced, in one embodiment, by multiple injections to the infarct region. This results in prevention of ECM degradation and increased strength to the regional wall. In one embodiment, the MMPI agent may be injected into the infarct zone during an open chest procedure via a minimally invasive procedure. In another, the minimally invasive procedure may include one of sub-xiphoid and percutaneous methods. In another embodiment, the percutaneous introduction into the infarct zone may include one of intra-ventricular needle, transvascular needle catheter and retrograde venous perfusion. In addition, the MMPI agents may be introduced via suspension or sustained release formula, for example, introduced in microparticles detailed in the three-component system of FIG. 6. In one embodiment, the introduction of MMPIs may follow any of the cross-linking events that prevent collagen slippage. In another embodiment, the cross-linking agent may be cleared from the targeted infarct area prior to introducing the MMPI(s).
  • [0168]
    After an MI, the myocardium may be significantly affected resulting in a percentage of the tissue being akinetic or dyskinetic. This often occurs when the MI is caused by an occluded left anterior descending artery. Moderate infarct where 20 to 40 percent of the tissue is affected decreased cardiac output occurs resulting in the activation of the neurohormonal system (via a RAAS (renin-angiotensin-aldosterone) system). Thus, the neurohormonal activation causes an increase in blood pressure resulting in further stress to the myocardium. The induced necrosis results in an inflammatory response that clears the site of the necrotic tissue and ultimately leads to thinning of the myocardium. The cycle continues with an increase in stress on the myocardium and may result ultimately in heart failure.
  • Structural Reinforcement of the Infarct Zone by Inducible Gel Systems
  • [0169]
    FIG. 20 illustrates a flowchart describing the introduction of photo-polymerizable hydrogels to the infarct region 2000 for structural reinforcement of the infarct zone. Hydrogels have been used before in tissue engineering applications. These gels are biocompatible and do not cause thrombosis or tissue damage. These hydrogels may be photo-polymerized in vivo and in vitro in the presence of ultraviolet (UV) or visible light depending on the photo initiation system. Photo-polymerizing materials may be spatially and temporally controlled by the polymerization rate. These hydrogels have very fast curing rates. A monomer or macromer form of the hydrogel may be introduced to the infarct zone for augmentation with a photoinitiator. Examples of these hydrogel materials include PEG acrylate derivatives, PEG methacrylate derivatives or modified polysaccharides.
  • [0170]
    Visible light 2030/2160 may be used to initiate interfacial photopolymerization of a polyoxyethylene glycol (PEG)-co-poly(alpha-hydroxy acid) copolymer 2100 based on PEG 8000 macromonomer in the presence of an initiator, for example, Quanticare QTX. Initiator 2-hydroxy-3-[3,4,dimethyl-9-oxo-9H-thioxanthen-2-yloxy]N,N,N-trimethyl-1-propanium chloride photo-initiator may be obtained as Quantacure QTX. This is a specific water-soluble photoinitiator that absorbs ultraviolet and/or visible radiation and forms an excited state that may subsequently react with electron-donating sites and may produce free radicals. This technology has been used to demonstrate adherence to porcine aortic tissue, resulting in a hydrogel barrier that conformed to the region of introduction. The resulting matrix was optimized in vitro and resulted in the formation of a 5-100 microns thick barrier. See Lyman, M. D., et al., Characterization of the Formation of Interfacially Photopolymerized Thin Hydrogels in Contact with Arterial Tissue, Biomaterials, February 1996, pp. 359-364, 17(3). Scaffolding 2040/2130 may be directed to only the desired area of the ventricle using minimally invasive procedures discussed previously. The structural reinforcement could remain in place until it is cleared or degraded 2050/2170.
  • [0171]
    One embodiment includes introduction to the infarct zone of benzoin derivatives, hydroxalkylphenones, benziketals and acetophenone derivatives or similar compounds. These photoinitiators form radicals upon exposure to UV light by either photocleavage or by hydrogen abstraction to initiate the reaction see FIGS. 21A-21E. The source of the UV or visible light may be supplied by means of a catheter 2160, for example, a fiber optic tip catheter or lead on a catheter illustrated in FIG. 21C, or, transdermally. FIGS. 22A-22B illustrate a catheter assembly that may be used to deliver a light-sensitive material. The catheter 2210 is designed to provide a delivery device with at least one lumen for one or more agent(s) 2230 and a light source 2220 for modification of the delivered agent. The catheter controller 2240 may house a switch 2250 for the light source 2220 and a controller for agent delivery 2260. In another embodiment, the photoinitiator Camphorquinone may be used. Camphorquinone has been used extensively in dental applications and has a λmax of 467 nanometers. For example, this agent can be activated by a GaN blue LED on the tip of a catheter. One embodiment includes the use of visible light at the end of the delivery catheter to induce the polymerization event in the presence of a light sensitive initiator. Another embodiment includes the use of the photoinitiator, Camphorquinone, that may facilitate the cross-linking of the hydrogel by a light on the tip of a catheter within the infarct region. Another embodiment includes the use of the photoinitiator, Quanticare QTX, that may facilitate the cross-linking of the hydrogel by a light on the tip of a catheter within the infarct region. Another embodiment includes the use of a catheter with a UVA light source to induce the polymerization event in the presence of a light sensitive initiator. Other initiators of polymerization in the visible group include water-soluble free radical initiator 2-hydroxy-3-[3,4,dimethyl-9-oxo-9H-thioxanthen-2-yloxy]N,N,N-trimethyl-1-propanium chloride. This cascade of events provides the necessary environment for initiation of polymerization of suitable vinyl monomers or pre-polymers in aqueous form within the infarct region. See Kinart, et al., Electrochemical Studies of 2-hydroxy-3-(3,4-dimetlyl-9-oxo-9H-thioxanthen-2-yloxy)N,N,N-trimethyl-1-propanium chloride, J. Electroanal. Chem., 1990, pp. 293-297, 294.
  • [0172]
    One possible method of introducing a photo-polymerizable agent to the infarct region is illustrated in FIGS. 21A-21E. In one embodiment, the photo-polymerizable material is introduced to the infarct region during an open chest procedure or via a minimally invasive procedure 2130. In another embodiment, the minimally invasive procedure includes sub-xiphoid and percutaneous methods. In another embodiment, the percutaneous introduction into the infarct zone may comprise one of the following: intra-ventricular needle, transvascular needle catheter and retrograde venous perfusion. A single bore needle catheter 2120 may be used to introduce the photo-polymerizable material into the infarct zone 2140. Once the agent is introduced to the region, several heartbeats clear the excess agent into the ventricle 2150, and this excess agent is cleared from the cardiac region. Once the excess material is cleared, the light source 2160 may be introduced to induce polymerization 2170. Thus, the structural reinforcement is confined to the local area of damage where tissue augmentation is required. As illustrated in FIG. 20, the scaffolding may be made up of a resistant material or a biodegradable material 2050. Some examples of biodegradable materials include PEG-co-poly (α-hydroxy acid) diacrylate macromers, derivatives of this material that vary the length and composition of the α-hydroxy acid segment in the co-polymer, poly(propylene fumarate-co-ethylene)glycol and hyaluronic acid derivatives. The degradation rates of the polymers may be varied according to the optimum length of time the material is required to remain in the infarct region. It has been shown that the degradation rates of theses gels can be modified by the appropriate choice of the oligo(α-hydroxy acid) from less than one day to as long as 4 months. See Sawhney, A. S., et al., Bioerodable Hydrogels Based on Photopolymerized Poly(ethylene glycol)-co-poly(a-hydroxy acid) Diacrylare Macromers, Macromolecules, 1993, pp. 581-587, 26. Any of these polymer chains may be formed in the presence of a photoinitiator, such as Quanticare QTX, and a light source.
  • [0173]
    FIGS. 21A-21E illustrate the process of introduction of a potential photopolymerizable material to the infarct zone. FIG. 21A and FIG. 21B illustrate the introduction of the material to the site 2100 and 2110. FIG. 21C illustrates the clearing of the excess material into the ventricle 2150. Then, in FIG. 21C the light source may be introduced via a catheter to polymerize the material 2160. The material remains in the site 2170 as structural reinforcement until at which time it degrades or not depending on the material used.
  • [0174]
    In one embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 1 ml. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 300 μl. In another embodiment, any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 100 μl. In a preferred embodiment, the any of the described agents may be introduced in one or more doses in a volume of about 1 μl to 50 μl.
  • [0175]
    FIG. 24A and FIG. 24B illustrate a catheter assembly that may be used to deliver a dual component composition. In FIG. 24A, component 1 (2410) and component 2 (2420) are housed 2430 in separate lumens of a delivery device. Delivery of the components is controlled by a handle 2470 at the base of the device. The handle 2470 is rotated to allow one needle to extend and then the other. Only one needle is engaged at a time. A cross-sectional view illustrated in FIG. 24B illustrates the first needle port 2450 and the second needle port 2460 and the central tendon 2480 that controls the needle extension. At the distal end 2490 of the device, FIG. 24C, the handle is turned and the needle extends while retracting the other needle. In one embodiment, this catheter device may be used to deliver components to the infarct region of a left ventricle intramyocardium. In another embodiment, this catheter device may be used to deliver a first component to the area and a second component after the excess first component is allowed some time to wash away.
  • [0176]
    FIGS. 25A-25D illustrate the introduction of dual components using the catheter device of FIG. 24 to an infarct region while avoiding the possibility of injecting the agents into the exact same site. The delivery device of FIG. 24 is used to deliver the components to the infarct region. The infarction is illustrated as a region between the endocardium and the epicardium. The device 2540 is advanced to this site and the first component is delivered by extending needle 2550 and the component 2560 is dispersed in the infarct area. Then this needle 2550 is retracted while the second needle 2570 is extended. The second component 2580 is dispersed. The delivery of the two components to the area is capable of forming a gel 2590.
  • [0177]
    FIG. 26 illustrates the delivery of the catheter device illustrated in FIGS. 24 and 25. Both of the components are delivered through a lumen of a catheter (for example a balloon catheter) 2630/2640 at the same time. For example, the first component 2650 may be delivered through a venous route 2610 and the second component 2660 may be delivered through an arterial route 2620. This procedure ensures the appropriate pressure balance to contain the components in the microcirculation. This avoids leakage to either the venous or arterial side. The driving pressure for the venous side is greater than 100 mm Hg (ΔP) 2670 is calculated to ensure the confinement of the component in capillary level) and the arterial side does not require an external pressure gradient. The arterial side may be accomplished by infusion. In one embodiment, the catheter may be used to deliver the first component through the venous tree followed by the second component through the arterial tree. This device may be used to deliver any of the component combination methods described in the embodiments detailed previously.
  • Ventricular Plugs
  • [0178]
    Another method for reinforcing the damaged wall of a ventricle may include introduction of a solid material to the damaged area. The solid material may be used to fill or bulk the region by introducing plugs of the solid material to the site and may increase the compliance of the ventricle. These materials may be made of organic or silicon-based polymers, biodegradable polymers, non-biodegradable polymers, engineered biomaterials and/or metals. In one embodiment. the plug may have barbs or pointed ends in order to lodge the material into the area and ensure it remains there. In other embodiments, the sealant or plug may add bulk to the thinning wall of an infarct post myocardial infarction. This may result in an increase in the modulus of elasticity of the damaged area. In other embodiments, the sealant or plug may invoke an inflammatory response to the infarct region. The inflammatory response will result in the increase in angiogenic response capable of causing recruitment and activation of fibroblasts that deposit additional collagen to bulk the thinning infarct region and increase the modulus of elasticity of this region. Still, other embodiments include the addition of a plug to the damaged region of a ventricle that may add strength to the wall and also cause an inflammatory response to the region.
  • [0179]
    In one embodiment, the plug supplied to the damaged region of the ventricle may include biocompatible organic components. In other embodiments, the plug supplied to the damaged region of the ventricle may include a biocompatible silicone-based polymer. In other embodiments, the plug supplied to the damaged region of the ventricle may include biocompatible biodegradable polymers for example PLGA, Poly(hydroxyvalerate) and poly ortho esters. In other embodiments, the plug supplied to the damaged region of the ventricle may include biocompatible non-biodegradable material, for example, polypropylene and PMMA. In still further embodiments, the plug supplied to the damaged region of the ventricle may include biocompatible metal compounds, for example, 316L, Co—Cr alloy, tantalum and titanium. Another advantage to using a plug directly implanted in the region of interest may be to add additional surface components to the plug such as side groups. These side groups may contain reactive side groups that react with exogenously supplied or endogenous collagen, for example, type I and type III collagen. Since collagen contains a significant number of lysine and hydroxyproline residues, these residues harbor primary amine and hydroxyl groups capable of reacting with other moieties. In one embodiment, the plug supplied to the damaged region of the ventricle may include surface aldehyde groups capable of reacting with the primary amines of lysine in collagen.
  • [0180]
    The size and the shape of the plugs may vary depending on the situation. For example, polymeric plugs mentioned previously may be machined, injection molded, extruded or solution cast. In one embodiment, the shape of the plug may be elongated and thin in order to facilitate delivery by a catheter device. These plugs may also possess a barb or side protrusion to prevent the plug from slipping out of the site once it is introduced to the damaged region of the ventricle. In other embodiments, the plug may be created in the shape similar to a screw or a helix. In one embodiment, the plug may be a polymeric material. In other embodiments, the plug may be a polymeric material with SS anchors for example, a plug with a stainless steel band with anchors for embedding the plug into the site of interest. The size of the plug may also vary. In one embodiment, the radial diameter of the plug may be from about 0.1 mm to about 5 mm. In other embodiments, the radial diameter of the plug may be about 0.2 mm to about 3 mm. In other embodiments, the length of the plug may be from about 1 mm to about 20 mm. In other embodiments, the length of the plug may be about 2 mm to about 12 mm. In addition to the size and shape of the plug, the number of plugs supplied to a region in the ventricle may also vary depending on the extent of damage and the condition of the subject. In one embodiment, the number of plugs supplied to the region may about 1 to about 200. In other embodiments, the number of plugs supplied to the region may be about 5 to about 50. In still further embodiments, the number of plugs supplied to the region may be about 2 to about 20.
  • [0181]
    In a preferred embodiment, the plug may be a processed biocompatible biomaterial. This biomaterial may be advantageous for recruiting cells to the damaged region for additional strength to the site. One example of a biomaterial includes porcine derived Small Intestine Submucosa, termed SIS. This engineered biomaterial may be supplied from DePuy Inc and the Cook Group. It is available in sterile sheets. SIS includes the complete small intestinal submucosa, including de-cellularized extracellular matrix (ECM) in a native configuration. It also includes important endogenous growth factors adhered to the matrix. SIS has previously been shown to recruit pluripotent bone marrow-derived stem cells that adhere to the SIS and induce healing. SIS has previously been used to repair rotator cuff injuries, diabetic foot ulcers and hip joints. SIS has been shown to re-absorb after a period of approximately 3 to 4 months. After re-absorption, the healed live tissue has replaced the matrix. In one embodiment, small disks of SIS may be supplied to a region in the ventricle for example an infarct region. The SIS disks may provide similar recruitment of cells into the damaged myocardium. These cells may then transform into viable muscle tissue and may form contractile myocytes.
  • [0182]
    There are several methods that may be used to introduce any of the plugs described. An optimum approach for introduction of the plugs may include, but is not limited to. introduction to the infarct region and/or the border zone of an infarct region during an open-heart procedure; or through a minimally invasive procedure for example sub-xiphoid or percutaneously for example with an intra-ventricular catheter or transvascular catheter (venous or arterial). One embodiment for introducing the plugs to the infarct region may include directly introducing the plugs to the site during an open-heart surgical procedure.
  • [0183]
    One or more contrast agents and/or suitable treatment agent(s) may accompany the previously detailed components. The contrast agent or treatment agent may be dispersed into, conjugated to, or dissolved into the plug component prior to introduction to the infarct area. The contrast agents may be used for detection in X-ray or MR analysis. The agents that may accompany the reinforcing component(s) may include, but are not limited, to angiogenic agents, ACE inhibitors, angiotensin receptor blockers, SRCA pump (sarcoplasmic reticulum calcium pump) increasing agents, phospholamban inhibitors and anti-apoptotic drugs. These agents may be in the form of small molecules, peptides, proteins or gene products. The agents may be optionally conjugated to a component of the resin mix that makes the plug, dispersed in the plug solution prior to forming the plug, or dissolved in the plug solution prior to forming the plug, or packed into machined pockets or reservoirs in the plug to elicit a biological effect (e.g., improve implant adhesion, recruit cells, promote healing). One embodiment is to conjugate a peptide with a conserved region that mediates adhesion processes. Another embodiment includes the use of a specific peptide conjugate with a RGD (arginine-glycine-asparagine) motif or the peptide receptor to RGD, such as DDM (aspartate-aspartate-methionine) in the presence of the reinforcing component. In further embodiments, the RGD motif peptide may include von Willebrand factor, osteopontin, fibronectin, fibrinogen, vitronectin, laminin and collagen.
  • [0184]
    In the foregoing specification, the embodiments have been described with reference to specific exemplary embodiments. It will, however, be evident that various modifications and changes may be made without departing from the broader spirit and scope of the invention as detailed in the appended claims. The specification and drawings are, accordingly, to be regarded in an illustrative rather than a restrictive sense.
  • EXAMPLES Prophetic Example 1
  • [0185]
    As a treatment for severe MI or heart failure, a 0.1% solution of GelSite aloe pectin is dissolved in 300 mOs/kg Ammonium Chloride. To this solution, one adds human mesenchymal stem cells (5M to 20M cells per ml) and disperses the cells gently using a pipettor or alternate method. This cell suspension is delivered to the border and infarct zones of the patient myocardium using an intramyocardial catheter such as the Maserati. Endogenous Calcium ions are present at a sufficient concentration within the tissue to gel the pectin and cause an enhancement of cells retained within the myocardium.
Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3804097 *14 Dec 197216 Apr 1974P RudieMethod of irrigating and treating an abcess
US4141973 *25 Oct 19778 Aug 1989 Title not available
US4794931 *28 Feb 19863 Jan 1989Cardiovascular Imaging Systems, Inc.Catheter apparatus, system and method for intravascular two-dimensional ultrasonography
US4818291 *10 Dec 19874 Apr 1989Ajinomoto Co., Inc.Silk-fibroin and human-fibrinogen adhesive composition
US5000185 *23 Dec 198819 Mar 1991Cardiovascular Imaging Systems, Inc.Method for intravascular two-dimensional ultrasonography and recanalization
US5092848 *5 Oct 19903 Mar 1992Deciutiis Vincent LIntravenous catheter with built-in cutting tip and method for making the same
US5100185 *14 May 199131 Mar 1992Kiekert Gmbh & Co.Motor-vehicle door latch
US5109859 *4 Oct 19895 May 1992Beth Israel Hospital AssociationUltrasound guided laser angioplasty
US5116317 *18 Jun 199126 May 1992Optimed Technologies, Inc.Angioplasty catheter with integral fiber optic assembly
US5202745 *2 Mar 199213 Apr 1993Hewlett-Packard CompanyPolarization independent optical coherence-domain reflectometry
US5203338 *14 Aug 199220 Apr 1993Cardiovascular Imaging Systems, Inc.Vascular catheter having low-profile distal end
US5291267 *22 Jan 19921 Mar 1994Hewlett-Packard CompanyOptical low-coherence reflectometry using optical amplification
US5306250 *2 Apr 199226 Apr 1994Indiana University FoundationMethod and apparatus for intravascular drug delivery
US5380292 *22 Dec 199310 Jan 1995Wilson-Cook Medical, Inc.Gastrointestinal needle mechanism
US5419777 *2 May 199430 May 1995Bavaria Medizin Technologie GmbhCatheter for injecting a fluid or medicine
US5485486 *23 Mar 199416 Jan 1996Qualcomm IncorporatedMethod and apparatus for controlling transmission power in a CDMA cellular mobile telephone system
US5499630 *22 Nov 199419 Mar 1996Kabushiki Kaisha ToshibaCatheter type ultrasound probe
US5516532 *5 Aug 199414 May 1996Children's Medical Center CorporationInjectable non-immunogenic cartilage and bone preparation
US5621610 *4 Jun 199615 Apr 1997Compaq Computer CorporationCollapsible computer keyboard structure with associated collapsible pointing stick
US5631011 *17 Jun 199220 May 1997Wadstroem; JonasTissue treatment composition comprising fibrin or fibrinogen and biodegradable and biocompatible polymer
US5722403 *28 Oct 19963 Mar 1998Ep Technologies, Inc.Systems and methods using a porous electrode for ablating and visualizing interior tissue regions
US5725551 *27 Apr 199510 Mar 1998Myers; GeneMethod and apparatus for arteriotomy closure
US5730732 *4 Dec 199624 Mar 1998Ethicon, Inc.Non-magnetic stainless steel surgical needle
US5740808 *28 Oct 199621 Apr 1998Ep Technologies, IncSystems and methods for guilding diagnostic or therapeutic devices in interior tissue regions
US5749915 *7 Jun 199512 May 1998Focal, Inc.Polymeric endoluminal paving process
US5874500 *18 Dec 199623 Feb 1999Cohesion Technologies, Inc.Crosslinked polymer compositions and methods for their use
US5879713 *23 Jan 19979 Mar 1999Focal, Inc.Targeted delivery via biodegradable polymers
US5900433 *23 Jun 19954 May 1999Cormedics Corp.Vascular treatment method and apparatus
US5906934 *14 Mar 199525 May 1999Morphogen Pharmaceuticals, Inc.Mesenchymal stem cells for cartilage repair
US6022540 *28 Aug 19988 Feb 2000Osiris Therapeutics, Inc.Ligands that modulate differentiation of mesenchymal stem cells
US6045565 *2 Nov 19984 Apr 2000Scimed Life Systems, Inc.Percutaneous myocardial revascularization growth factor mediums and method
US6050949 *8 Sep 199818 Apr 2000Scimed Life Systems, Inc.Catheher system having connectable distal and proximal portions
US6051071 *1 Dec 199518 Apr 2000Societe Nationale D'etude Et De Construction De Moteurs D'aviationDevice for extracting gas from an oven for chemical vapor deposition or infiltration in an installation for fabricating composite material parts
US6051648 *13 Jan 199918 Apr 2000Cohesion Technologies, Inc.Crosslinked polymer compositions and methods for their use
US6056744 *19 Feb 19982 May 2000Conway Stuart Medical, Inc.Sphincter treatment apparatus
US6175669 *30 Mar 199816 Jan 2001The Regents Of The Universtiy Of CaliforniaOptical coherence domain reflectometry guidewire
US6177407 *13 Aug 199923 Jan 2001University Of Southern CaliforniaMethods to increase blood flow to ischemic tissue
US6179809 *18 Sep 199830 Jan 2001Eclipse Surgical Technologies, Inc.Drug delivery catheter with tip alignment
US6183432 *13 Nov 19976 Feb 2001Lumend, Inc.Guidewire and catheter with rotating and reciprocating symmetrical or asymmetrical distal tip
US6183444 *16 May 19986 Feb 2001Microheart, Inc.Drug delivery module
US6187330 *28 Jan 199913 Feb 2001Scios Inc.Controlled release delivery of peptide or protein
US6190353 *11 Oct 199620 Feb 2001Transvascular, Inc.Methods and apparatus for bypassing arterial obstructions and/or performing other transvascular procedures
US6191144 *26 Jul 199920 Feb 2001Warner-Lambert CompanyMethod of using angiotensin converting enzyme inhibitor to stimulate angiogenesis
US6192271 *20 Apr 199920 Feb 2001Michael HaymanRadiotherapy stent
US6193763 *17 Dec 199827 Feb 2001Robert A. MackinApparatus and method for contemporaneous treatment and fluoroscopic mapping of body tissue
US6197324 *15 Jul 19986 Mar 2001C. R. Bard, Inc.System and methods for local delivery of an agent
US6201608 *13 Mar 199813 Mar 2001Optical Biopsy Technologies, Inc.Method and apparatus for measuring optical reflectivity and imaging through a scattering medium
US6206893 *8 Apr 199827 Mar 2001Perclose, Inc.Device and method for suturing of internal puncture sites
US6206914 *31 Aug 199827 Mar 2001Medtronic, Inc.Implantable system with drug-eluting cells for on-demand local drug delivery
US6207180 *14 Mar 200027 Mar 2001Thomas B. OttoboniIntravesical drug delivery
US6210392 *15 Jan 19993 Apr 2001Interventional Technologies, Inc.Method for treating a wall of a blood vessel
US6217527 *30 Sep 199817 Apr 2001Lumend, Inc.Methods and apparatus for crossing vascular occlusions
US6217554 *12 Feb 199917 Apr 2001Pharmaspec CorporationMethods and apparatus for delivering substances into extravascular tissue
US6221049 *27 Oct 199924 Apr 2001Lumend, Inc.Methods and apparatus for crossing vascular occlusions
US6334872 *7 Jul 19971 Jan 2002Organogenesis Inc.Method for treating diseased or damaged organs
US6338717 *20 Dec 199915 Jan 2002Asahi Kogaku Kogyo Kabushiki KaishaTip of ultrasonic endoscope
US6346098 *7 Mar 200012 Feb 2002The Board Of Trustees Of The Leland Stanford Junior UniversityMethods and kits for locally administering an active agent to an interstitial space of a host
US6346099 *12 Aug 200012 Feb 2002Biocardia, Inc.Catheter drug delivery system and method for use
US6346515 *18 Jun 199912 Feb 2002Colbar R & D Ltd.Collegan-based matrix
US6358247 *2 Mar 199919 Mar 2002Peter A. AltmanCardiac drug delivery system
US6358258 *14 Sep 199919 Mar 2002Abbott LaboratoriesDevice and method for performing end-to-side anastomosis
US6360129 *13 Dec 199919 Mar 2002Cardiac Pacemakers, Inc.Mannitol/hydrogel cap for tissue-insertable connections
US6368285 *18 Aug 20009 Apr 2002Biosense, Inc.Method and apparatus for mapping a chamber of a heart
US6371935 *20 Aug 199916 Apr 2002Cardeon CorporationAortic catheter with flow divider and methods for preventing cerebral embolization
US6371992 *19 Dec 199716 Apr 2002The Regents Of The University Of CaliforniaAcellular matrix grafts: preparation and use
US6379379 *13 Aug 199930 Apr 2002Scimed Life Systems, Inc.Stent with smooth ends
US6514217 *25 Apr 20004 Feb 2003Lumend, Inc.Methods and apparatus for treating vascular occlusions
US6544227 *28 Feb 20028 Apr 2003Scimed Life Systems, Inc.Immobilizing objects in the body
US6544230 *31 Mar 19998 Apr 2003Transvascular, Inc.Catheters, systems and methods for percutaneous in situ arterio-venous bypass
US6548081 *22 May 200115 Apr 2003Anika Therapeutics, Inc.Bioabsorbable composites of derivatized hyaluronic acid and other biodegradable, biocompatible polymers
US6554801 *26 Oct 200029 Apr 2003Advanced Cardiovascular Systems, Inc.Directional needle injection drug delivery device and method of use
US6682730 *29 Jan 200227 Jan 2004Genzyme CorporationTransplants for myocardial scars
US6689608 *26 Sep 200010 Feb 2004Massachusetts Institute Of TechnologyPorous biodegradable polymeric materials for cell transplantation
US6692466 *21 Dec 200017 Feb 2004Advanced Cardiovascular Systems, Inc.Drug delivery catheter with retractable needle
US6702744 *30 Nov 20019 Mar 2004Advanced Cardiovascular Systems, Inc.Agents that stimulate therapeutic angiogenesis and techniques and devices that enable their delivery
US6706034 *30 Dec 199916 Mar 2004Advanced Cardiovascular Systems, Inc.Process for agent retention in biological tissues
US6726677 *29 Mar 200027 Apr 2004Transvascular, Inc.Stabilized tissue penetrating catheters
US6726923 *16 Jan 200227 Apr 2004Vascular Therapies, LlcApparatus and methods for preventing or treating failure of hemodialysis vascular access and other vascular grafts
US6777000 *28 Feb 200117 Aug 2004Carrington Laboratories, Inc.In-situ gel formation of pectin
US6858229 *26 Apr 200022 Feb 2005California Institute Of TechnologyIn situ forming hydrogels
US6992172 *10 Nov 200031 Jan 2006Fibrogen, Inc.Recombinant gelatins
US7008411 *30 Sep 20027 Mar 2006Advanced Cardiovascular Systems, Inc.Method and apparatus for treating vulnerable plaque
US7035092 *19 Dec 200325 Apr 2006Apple Computer, Inc.Computer controlled display device
US7169127 *21 Feb 200230 Jan 2007Boston Scientific Scimed, Inc.Pressure apron direct injection catheter
US7361360 *26 Jul 200622 Apr 2008Lipid Sciences, Inc.Method of treating cancer cells to create a modified cancer cell that provokes an immunogenic response
US20020013408 *17 Aug 200131 Jan 2002Rhee Woonza M.Cross-linked polymer compositions and methods for their use
US20020042473 *15 Jun 200111 Apr 2002Trollsas Olof MikaelCompositions and systems for forming crosslinked biomaterials and associated methods of preparation and use
US20030023202 *26 Jul 200130 Jan 2003Nielson David H.Apparatus for delivering aerosolized fibrin endoscopically to a wound
US20030040712 *10 Oct 200227 Feb 2003Pinaki RaySubstance delivery apparatus and a method of delivering a therapeutic substance to an anatomical passageway
US20030050597 *12 Sep 200113 Mar 20033M Innovative Properties CompanyApparatus and methods for dispensing an adhesive tissue sealant
US20030078671 *24 Oct 200224 Apr 2003Lesniak Jeanne M.Prevention of myocardial infarction induced ventricular expansion and remodeling
US20040002650 *30 Nov 20011 Jan 2004Evgenia MandrusovAgents that stimulate therapeutic angiogenesis and techniques and devices that enable their delivery
US20040015048 *11 Jul 200322 Jan 2004American Medical SystemsImplantable article and method
US20050015048 *11 Mar 200420 Jan 2005Chiu Jessica G.Infusion treatment agents, catheters, filter devices, and occlusion devices, and use thereof
US20050031874 *17 Sep 200410 Feb 2005Michal Eugene T.Medical device having surface modification with superoxide dismutase mimic
US20050042254 *15 Jul 200424 Feb 2005Toby FreymanAligned scaffolds for improved myocardial regeneration
US20050064038 *11 Aug 200424 Mar 2005Dinh Thomas Q.Active agent delivery systems including a single layer of a miscible polymer blend, medical devices, and methods
US20050065281 *7 Nov 200224 Mar 2005Mathias LutolfSynthetic matrix for controlled cell ingrowth and tissue regeneration
US20050070844 *30 Sep 200331 Mar 2005Mina ChowDeflectable catheter assembly and method of making same
US20080025943 *31 Jul 200631 Jan 2008Eugene MichalModified two-component gelation systems, methods of use and methods of manufacture
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US867285725 Aug 201018 Mar 2014Bg Medicine, Inc.Galectin-3 and cardiac resynchronization therapy
US888279624 Aug 201211 Nov 2014Microvention, Inc.Three element coaxial vaso-occlusive device
US8968417 *25 Oct 20123 Mar 2015Institut Quimic De SarriaBioactive implant for myocardial regeneration and ventricular chamber restoration
US906699228 May 201330 Jun 2015Abbott Cardiovascular Systems Inc.Polymers for implantable devices exhibiting shape-memory effects
US911420024 Sep 201025 Aug 2015Microvention, Inc.Injectable hydrogel filaments for biomedical uses
US925922818 Jan 201316 Feb 2016Microvention, Inc.Embolization device constructed from expansile polymer
US925951510 Apr 200816 Feb 2016Abbott Cardiovascular Systems Inc.Implantable medical devices fabricated from polyurethanes with grafted radiopaque groups
US938127818 Mar 20155 Jul 2016Microvention, Inc.Embolic devices
US945196319 Jul 201227 Sep 2016Microvention, Inc.Embolization device constructed from expansile polymer
US945682318 Apr 20124 Oct 2016Terumo CorporationEmbolic devices
US948622121 May 20138 Nov 2016Microvision, Inc.Hydrogel filaments for biomedical uses
US97241037 Jan 20168 Aug 2017Microvention, Inc.Embolization device constructed from expansile polymer
US20090035350 *3 Aug 20075 Feb 2009John StankusPolymers for implantable devices exhibiting shape-memory effects
US20100143954 *29 Oct 200910 Jun 2010Bg Medicine, Inc.Galectin-3 Immunoassay
US20100261662 *9 Apr 201014 Oct 2010Endologix, Inc.Utilization of mural thrombus for local drug delivery into vascular tissue
US20110071583 *25 Aug 201024 Mar 2011Bg Medicine, Inc.Galectin-3 and Cardiac Resynchronization Therapy
US20110184455 *25 Oct 201028 Jul 2011Microvention, Inc.Embolization Device Constructed From Expansile Polymer
US20130116789 *25 Oct 20129 May 2013CreaspineBioactive implant for myocardial regeneration and ventricular chamber restoration
CN102791183A *25 Oct 201021 Nov 2012微排放器公司Embolization device constructed from expansile polymer
WO2011053555A1 *25 Oct 20105 May 2011Microvention, Inc.Embolization device constructed from expansile polymer
WO2012162531A1 *24 May 201229 Nov 2012Bg Medicine, Inc.Inhibitors of galectin-3 and methods of use thereof
Classifications
U.S. Classification604/511, 128/898, 604/522, 604/48, 604/500
International ClassificationA61M31/00, A61K41/00, A61K45/06, A61P9/04, A61K31/00, A61K31/78, A61P9/10, A61K47/48, A61P43/00, A61K31/728, A61K49/04, A61L24/04, A61K38/40, A61K31/79
Cooperative ClassificationA61K47/62, A61K47/60, A61N1/3625, A61L27/50, A61N1/36521, A61K49/0404, A61K31/00, A61K36/886, A61K31/728, A61L27/54, A61K47/02, A61L27/20, A61K9/0024, A61K41/0042, A61K31/79, A61L2430/20, A61K38/40, A61K45/06, A61L24/043, A61K47/34, A61K31/734, A61K31/732, A61K31/78
European ClassificationA61K47/34, A61K9/00M5D, A61K47/48K6P, A61K38/40, A61K31/00, A61K31/78, A61K45/06, A61K31/79, A61K31/728, A61K41/00R, A61L24/04M, A61K47/48R, A61K49/04B, A61K36/886