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EP2007404A2 - Méthodes et systèmes de traitement de lésions du tissu cardiaque - Google Patents

Méthodes et systèmes de traitement de lésions du tissu cardiaque

Info

Publication number
EP2007404A2
EP2007404A2 EP07756277A EP07756277A EP2007404A2 EP 2007404 A2 EP2007404 A2 EP 2007404A2 EP 07756277 A EP07756277 A EP 07756277A EP 07756277 A EP07756277 A EP 07756277A EP 2007404 A2 EP2007404 A2 EP 2007404A2
Authority
EP
European Patent Office
Prior art keywords
tissue
platelet
cardiac tissue
composition
cardiac
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07756277A
Other languages
German (de)
English (en)
Inventor
Asha Nayak
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medtronic Vascular Inc
Original Assignee
Medtronic Vascular Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/426,211 external-priority patent/US20070042016A1/en
Application filed by Medtronic Vascular Inc filed Critical Medtronic Vascular Inc
Publication of EP2007404A2 publication Critical patent/EP2007404A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/19—Platelets; Megacaryocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/19—Syringes having more than one chamber, e.g. including a manifold coupling two parallelly aligned syringes through separate channels to a common discharge assembly
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • A61N1/303—Constructional details
    • A61N1/306—Arrangements where at least part of the apparatus is introduced into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/325—Applying electric currents by contact electrodes alternating or intermittent currents for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body

Definitions

  • the present invention relates generally to systems and methods for treating injured cardiac tissue. Specifically, the present invention discloses compositions, systems and methods for inducing regeneration in the injured tissue.
  • the human heart wall consists of an inner layer of simple squamous epithelium, referred to as the endocardium, overlying a variably thick heart muscle or myocardium and is enveloped within a multi-layer tissue structure referred to as the pericardium.
  • the innermost layer of the pericardium referred to as the visceral pericardium or epicardium, covers the myocardium.
  • the epicardium reflects outward at the origin of the aortic arch to form an outer tissue layer, referred to as the parietal pericardium, which is spaced from and forms an enclosed sac extending around the visceral pericardium of the ventricles and atria.
  • pericardium An outermost layer of the pericardium, referred to as the fibrous pericardium, attaches the parietal pericardium to the sternum, the great vessels and the diaphragm so that the heart is confined within the middle mediastinum.
  • the visceral pericardium and parietal pericardium lie in close contact with each other and are separated only by a thin layer of a serous pericardial fluid that enables friction free movement of the heart within the sac.
  • the space between the visceral and parietal pericardia is referred to as the pericardial space.
  • the visceral pericardium is usually referred to as the epicardium, and epicardium will be used hereafter.
  • the parietal pericardium is usually referred to as the pericardium, and pericardium will be used hereafter in reference to parietal pericardium.
  • Heart disease including myocardial infarction (Ml)
  • Ml myocardial infarction
  • a variety of heart diseases can progress to heart failure by a common mechanism called remodeling. With remodeling, cardiac function progressively deteriorates, often leading to clinical heart failure and associated symptoms. Heart disease can in turn impair other physiological systems.
  • Ml myocardial infarction
  • Myocardial infarction can result in an acute depression in ventricular function and expansion of the infarcted tissue under stress. This triggers a cascading sequence of myocellular events known as remodeling.
  • ischemic cardiomyopathy is the leading cause of heart failure in the United States. It is the objective of the present invention to improve vascular supply to patients who have or are at high-risk of developing cardiac disease (such as cardiac ischemia). Acutely or chronically diseased cardiac tissue would benefit from increased blood supply. Studies have shown that even in the adult, normal repair mechanisms are elicited (e.g. those involving the recruitment of endogenous regenerative cells) following cardiac injury. Inadequate blood supply limits the survival of such cells and may prevent healing. Blood supply is required to bring necessary oxygen, nutrients, and blood components (cells, chemokines, etc.) to the injured region and to clear metabolic products. A treatment that improves blood supply to such a region is very likely to benefit the patient by facilitating greater recovery.
  • cardiac disease such as cardiac ischemia
  • Cardiac tissue can be acutely or chronically ischemic. Severe ischemia resulting in cardiac cell death is referred to as infarction. Acute or chronic recovery may be improved by increasing vascular supply to or around the affected injured region.
  • a stenosed or blocked coronary artery is one example of heart disease.
  • a completely or substantially blocked coronary artery can cause immediate, intermediate term, and/or long-term adverse effects.
  • a myocardial infarction can occur when a coronary artery becomes occluded and can no longer supply blood to the myocardial tissue, thereby resulting in myocardial cell death.
  • the myocardial tissue that is no longer receiving adequate blood flow dies and is eventually replaced by scar tissue.
  • infarcted heart tissue In addition to immediate hemodynamic effects, the infarcted heart tissue and undergoes three major processes: infarct expansion, infarct extension, and chamber remodeling. These factors individually and in combination contribute to the eventual dysfunction observed in the cardiac tissue remote from the site of the infarction
  • Infarct expansion is a fixed, permanent, disproportionate regional thinning and dilatation of tissue within the infarct zone. Infarct expansion occurs early after a myocardial infarction. The mechanism is slippage of the tissue layers.
  • Infarct extension is additional myocardial necrosis following myocardial infarction. Infarct extension results in an increase in total mass of infarcted tissue and the additional infarcted tissue may also undergo infarct expansion. Infarct extension occurs days after a myocardial infarction. The mechanism for infarct extension appears to be an imbalance in the blood supply to the peri-infarct tissue versus the increased oxygen demands on the tissue.
  • Remodeling is usually the progressive enlargement of the ventricle accompanied by a depression of ventricular function. Myocyte function in the cardiac tissue remote from the initial myocardial infarction becomes depressed. Remodeling occurs weeks to years after myocardial infarction. Such remodeling usually occurs on the left side of the heart. Where remodeling does occur on the right side of the heart, it can generally be linked to remodeling (or some other negative event) on the left side of the heart. Remodeling can occur independently in the right heart, albeit less often than the left. There are many potential mechanisms for remodeling, but it is generally believed that the high stress on peri-infarct tissue plays an important role. Due to variety of factors such as altered geometry, wall stresses are much higher than normal in the cardiac tissue surrounding the infarction.
  • Ischemic heart disease can be acute or chronic. Mild disease results in inadequate blood supply during increased demand (e.g. during exertion). Severe disease results in inadequate blood supply even at rest. Both conditions would benefit from increased blood supply, as this would be expected to result in positive clinical sequellae. This may include any or all of increased exertional capacity, reduced symptoms, increased organ blood perfusion, improved cardiac output, and/or improved cardiac contractility.
  • Newer approaches include more aggressive efforts to restore patency to occluded vessels. This is accomplished through thrombolytic therapy or angioplasty and stents. Reopening the occluded artery (i.e. revascularization) within hours of initial occlusion can decrease tissue death, and thereby decrease the total magnitude of infarct expansion, extension, and thereby limit the stimulus for remodeling.
  • Re-establishing blood flow may be accomplished through stimulation of angiogenesis in which the body generates or expands blood supply to a particular region.
  • Prior methods for re-establishing blood flow and rehabilitating the heart frequently involved invasive surgery such as bypass surgery or angioplasty.
  • Other methods have used lasers to bore holes through the infarctions and ischemic zones to promote blood flow. These surgeries are complicated and dangerous. Therefore, a need exists for a safer less-invasive method for reestablishing blood flow.
  • the direct or selective delivery of agents to cardiac tissue is often preferred over the systemic delivery of such agents for several reasons.
  • One mode of delivering medical agents to cardiac tissue is by epicardial, direct injection into cardiac tissue during an open chest procedure.
  • Another approach taken to delivery medical agents into cardiac tissue has been an intravascular approach.
  • Catheters may be advanced through the vasculature and into the heart to inject materials into cardiac tissue from within the heart.
  • Another approach is deliver materials into cardiac wall from within the chamber of the heart, an endocardial approach.
  • additional therapies being developed for treating injured cardiac tissue include the injection of cells and/or other biologic agents into ischemic cardiac tissue or placement of cells and/or agents onto the ischemic tissue.
  • One therapy for treating infarcted cardiac tissue includes the delivery of cells that are capable of maturing into actively contracting cardiac muscle cells or regenerating cardiac tissue.
  • the present invention provides methods and compositions for inducing neovascularization and treating cardiac tissue by administering a platelet composition and a cellular therapy. Induction of neovascularization in the injured cardiac tissue prior to implantation of a cell preparation increases the survival, incorporation and maintenance of the implanted cells in the injured tissue.
  • a method for treating cardiac tissue comprising providing a platelet composition into a treatment site in the cardiac tissue wherein the composition induces neovascularization of the cardiac tissue; and injecting a cell preparation into the re-vascularized cardiac tissue.
  • the cardiac tissue is injured tissue or healthy tissue in an injured heart.
  • the method causes the regeneration of said cardiac tissue.
  • the target cardiac tissue is healthy tissue in an un-injured heart.
  • the platelet composition is selected from the group consisting of platelet gel, platelet rich plasma and platelet poor plasma.
  • the platelet composition is autologous.
  • the platelet gel is formed from platelet poor plasma or platelet rich plasma and an activating agent.
  • the activating agent is thrombin.
  • the thrombin is selected from the group consisting of recombinant thrombin, human thrombin, animal thrombin, engineered thrombin and autologous thrombin.
  • the platelet gel comprises platelet rich plasma or platelet poor plasma and thrombin at a ratio of between about 5:1 and about 25:1. In another embodiment, the ratio of platelet rich plasma or platelet poor plasma to thrombin is about 10:1.
  • the platelet composition comprises platelet rich plasma.
  • the platelet composition is delivered to the treatment site and forms a solid or a gel within said cardiac tissue at the treatment site.
  • the platelet composition further comprises a structural material selected from the group consisting of collagen, biocompatible polymers, alginates, synthetic/natural compounds, fibrinogen, silk-elastin polymers, hydrogels, and dental composite material.
  • the structural material forms a solid or a gel as a result of physical or chemical cross-linking or activation, wherein the activation is selected from the group consisting of enzymatic, chemical, thermal or light activation of said composition.
  • the platelet composition further comprises a bioactive agent.
  • the bioactive agent is selected from the group consisting of pharmaceutically active compounds, hormones, growth factors, enzymes, DNA, RNA, siRNA, viruses, proteins, lipids, polymers, hyaluronic acid, antibodies, antibiotics, anti-inflammatory agents, anti-sense nucleotides and transforming nucleic acids, and combinations thereof.
  • the platelet composition is provided to the injured cardiac tissue between about 1 hour and about 1 year after injury occurs to the cardiac tissue.
  • either of the platelet composition or the cell preparation is provided by injection at approximately 1 to 20 sites.
  • the injections are provided sequentially.
  • the injections are provided approximately simultaneously.
  • the injection comprises a total injection volume up to 15 mL.
  • the injection comprises an injection volume up to 1100 microliters per injection.
  • the platelet composition or said cell preparation is injected into said cardiac tissue at an angle orthogonal or oblique to the tissue surface.
  • the cell preparation is provided to the cardiac tissue between about 1 hour and about 1 year after injury occurs to the cardiac tissue. In another embodiment, the cell preparation is provided to the cardiac tissue between about 1 hour and about 1 year after administration of the platelet composition. In another embodiment, the cell preparation is provided to the cardiac tissue after neovascularization is initiated in the injured cardiac tissue. In another embodiment, the platelet composition and the cell preparation are provided to the cardiac tissue approximately simultaneously.
  • the treatment site in the cardiac tissue is selected from the group consisting of sub-endocardial, sub-epicardial and intra-myocardial sites.
  • the platelet composition or cell preparation is injected into the cardiac tissue at a depth midway through the thickness of the myocardium.
  • the method further comprises a delivery device adapted to deliver the platelet composition or cell preparation into the injured cardiac tissue.
  • the delivery device is an injection catheter selected from the group consisting of an endocardial injection catheter, a transvascular injection catheter and an epicardial injection catheter.
  • the treatment site is selected from the group consisting of the injured area, the peri-injury area and the healthy tissue surrounding the injured area.
  • the platelet composition and cell preparation are injected into the same treatment site.
  • the platelet composition and cell preparation are injected into different treatment sites.
  • the cell preparation is injected adjacent to the site of injection of the platelet gel composition.
  • a method for treating cardiac tissue comprising providing a platelet composition into a treatment site in cardiac tissue; and recruiting blood vessel forming cells from tissues or blood to the treatment site and wherein the cardiac tissue is revascularized by said blood vessel forming cells.
  • the platelet composition further comprises molecules which attract blood vessel forming cells to the treatment site.
  • the molecules are selected from the group consisting of growth factors, growth factor receptors and chemoattractants.
  • a system for regeneration of cardiac tissue comprising a platelet composition; a cell preparation; and a least one delivery device for introducing the platelet composition into the cardiac tissue; wherein the platelet composition induces revascularization of the cardiac tissue such that regeneration of the cardiac tissue by the cell preparation is facilitated.
  • FIG. 1 is a drawing of a normal, healthy heart.
  • FIG. 2 is a drawing of a heart with a region of injured myocardium.
  • FIG. 3 is an enlarged view of the injured myocardium depicted in FIG. 2.
  • FIG. 4 is a cross-sectional depiction of the heart shown in FIG. 1.
  • FIG. 5 is a cross-sectional depiction of a heart showing a region of injured and remodeled cardiac tissue on the wall of the left ventricle.
  • Eligible injured cardiac tissue can be of different thicknesses and geometries. One example is shown with a mildly thinned and dilated (aneurismal) wall.
  • FIG. 6 depicts a needle being used to deliver a composition to the cardiac wall according to an embodiment of the current invention
  • FIG. 10 schematically depicts a detailed view of delivery of a composition into cardiac tissue according to another embodiment of the present invention.
  • FIG. 11 schematically depicts the migration of a composition within the myocardial tissue after delivery according to an embodiment of the present invention.
  • FIG. 12 schematically depicts an epicardial approach to delivery of compositions to cardiac tissue according to the teachings of the present invention.
  • FIG. 13A-B schematically depicts an endocardial approach to delivery of compositions to cardiac tissue according to the teachings of the present invention.
  • FIG. 13A depicts an anterograde endocardial approach through the venous system and
  • FIG. 13B depicts a retrograde endocardial approach through the arterial system.
  • FIG. 15 depicts a flow diagram of the system of the present invention.
  • FIG. 16 depicts a photomicrograph of infarcted myocardium eight weeks after injection with autologous platelet gel (platelet rich plasma and bovine thrombin at 10:1 ratio) one hour after infarction according to the teachings of the present invention.
  • platelet gel platelet rich plasma and bovine thrombin at 10:1 ratio
  • Many blood vessels are observed within a region of infarcted tissue (arrow C). These vessels are carrying red blood cells (arrow B).
  • angiogenesis refers to a physiologic process involving the growth of new blood vessels from pre-existing blood vessels.
  • Bioactive agent includes therapeutic agents and drugs and includes pharmaceutically active compounds, hormones, growth factors, enzymes, DNA, RNA, siRNA, viruses, proteins, lipids, polymers, hyaluronic acid, antibodies, antibiotics, anti-inflammatory agents, anti-sense nucleotides and transforming nucleic acids, inhibitors of compounds implicated in remodeling (e.g., inhibitors of angiotensin II, angiotensin converting enzyme, atrial natriuretic peptide, aldosterone, renin, norepinephrine, epinephrine, endothelin, etc.) and combinations thereof.
  • remodeling e.g., inhibitors of angiotensin II, angiotensin converting enzyme, atrial natriuretic peptide, aldosterone, renin, norepinephrine, epinephrine, endothelin, etc.
  • Chamber remodeling refers to remodeling of the atria or ventricles.
  • Remodeling refers to a series of events (which may include changes in gene expression, molecular, cellular and interstitial changes) that result in changes in size, shape and function of cardiac tissue following stress or injury. Remodeling may occur after myocardial infarction (Ml), pressure overload (e.g., aortic stenosis, hypertension), volume overload (e.g., valvular regurgitation), inflammatory heart disease (e.g., myocarditis), or in idiopathic cases (e.g., idiopathic dilated cardiomyopathy). Remodeling is often pathologic, resulting in progressively worsening cardiac function and ultimately a failing heart. Pathologic remodeling as described above will be referred to as remodeling in this disclosure.
  • Cardiac tissue injury refers to any area of abnormal tissue in the heart caused by a disease, disorder or injury and includes damage to the epicardium, endocardium, and/ or myocardium.
  • Non-limiting examples of causes of cardiac tissue injury include acute or chronic stress (systemic hypertension, pulmonary hypertension, valve dysfunction, etc.), coronary artery disease, ischemia or infarction, inflammatory disease and cardiomyopathies.
  • Cardiac tissue injury most often involves injury to the myocardium and therefore, for the purposes of this disclosure, myocardial injury is equivalent to cardiac tissue injury.
  • Injured cardiac tissue includes tissue that is ischemic, infarcted or otherwise focally or diffusely diseased.
  • composition refers to an injectate, substance or a combination of substances which can be delivered into a tissue and are used interchangeably herein.
  • exemplary compositions include, but are not limited to, platelet gel, autologous platelet gel, platelet rich plasma, and platelet poor plasma, with and without addition of bioactive agents, structural materials, etc.
  • Delivery refers to providing a composition to a treatment site in an injured tissue through any method appropriate to deliver the functional composition to the treatment site.
  • Non-limiting examples of delivery methods include direct injection at the treatment site, direct topical application at the treatment site, percutaneous delivery for injection, percutaneous delivery for topical application, and other delivery methods well known to persons of ordinary skill in the art.
  • injury area refers to the injured tissue.
  • the "peri-injury area” refers to the tissue immediately adjacent to the injured tissue. That is, the tissue at the junction between the injured tissue and the normal tissue.
  • injured tissue refers to tissue injured by trauma, ischemic tissue, infarcted tissue or tissue damaged by any means which results in interruption of normal blood flow to the tissue.
  • injured tissue includes tissue undergoing any of the changes described under “cardiac tissue injury.”
  • Neovascularization refers to the formation of functional vascular networks that may be perfused by blood or blood components. Neovascularization includes angiogenesis, budding angiogenesis, intussuceptive angiogenesis, sprouting angiogenesis, therapeutic angiogenesis and vasculogenesis.
  • Percutaneous refers to any penetration through the skin of the patient, whether in the form of a small cut, incision, hole, cannula, tubular access sleeve or port or the like. A percutaneous penetration may be made in an interstitial space between the ribs of the patient or it may be made elsewhere, such as the groin area of a patient.
  • Structural support As used herein, the term “structural support” refers to mechanical reinforcement providing resistance against the stresses and maladaptive processes of remodeling.
  • Vasculogenesis refers to blood vessels formation by de novo production of endothelial cells, a process that occurs during development and also in adulthood (e.g. after trauma or after cardiac injury).
  • the present invention provides methods and compositions for inducing neovascularization and treating cardiac tissue by administering a platelet composition followed after a period of time by cellular therapy. Induction of neovascularization in the injured cardiac tissue prior to implantation of a cell preparation increases the survival, incorporation and maintenance of the implanted cells in the injured tissue.
  • methods are provided for inducing angiogenesis in cardiac tissue by injecting a platelet composition directly into the injured or surrounding heart tissue and, subsequently, providing cellular therapy to promote regeneration of the injured tissue.
  • Neovascularization refers to the development of new blood vessels from endothelial precursor cells by any means, such as by vasculogenesis, angiogenesis, or the formation of new blood vessels from endothelial precursor cells that link to existing blood vessels.
  • Angiogenesis is the process by which new blood vessels grow from the endothelium of existing blood vessels in a developed animal. Endothelial precursor cells circulate in the blood and selectively migrate, or "home,” to sites of active neovascularization (see U.S. Pat. No. 5,980,887, lsner et al., the contents of which are incorporated herein by reference in their entirety).
  • a method comprising providing a platelet composition to a treatment site in cardiac tissue wherein the composition induces neovascularization of the cardiac tissue, injecting a cell preparation into the neovascularized cardiac tissue and wherein the cell preparation causes regeneration of said cardiac tissue.
  • FIGS. 1 and 4 there can be seen depictions of a normal heart 10.
  • the cross-sectional view in FIG. 4 shows the right ventricle 44 and the left ventricle 42 of a normal heart that has not undergone chamber remodeling.
  • FIG. 2 depicts a heart 20 having an ischemic or infarcted region 24, and a peri-infarct region 26 that is surrounded by healthy non-ischemic myocardium 28.
  • an infarction occurs, the cardiac tissue that is no longer receiving adequate blood flow dies and is replaced with scar tissue.
  • a cascade of events cause the walls to thin, dilate, and ultimately fail.
  • Inadequate blood flow in injured tissue prevents healing, in which endogenous cells and mechanisms may lead otherwise to repopulation and repair of the injured tissue.
  • FIG. 3 is an enlarged view of the area bordered by dotted lines in FIG. 2.
  • FIGS. 2 and 3 depict an area of myocardium 24 that has undergone some kind of ischemic insult such as an Ml or other injury. If necrosis has occurred, that portion of myocardium that has experienced necrosis will be totally infarcted.
  • the area immediately surrounding the ischemic/infarcted area 26 is known as the peri-infarct area and is surrounded by healthy myocardium 28.
  • the peri-infarct area 26 may have experienced some level of ischemic activity but the blood supply has not yet been interrupted to the same extent as that of the ischemic/infarcted area 24.
  • FIG. 5 is a cross sectional view of the heart shown in FIG. 2.
  • FIG. 5 shows a right ventricle 54 and a left ventricle 52 having an area 50 of a left ventricle that has undergone remodeling. As can be seen in the figure, the heart walls are thinner in the expanded area 50.
  • a limited amount of remodeling can be beneficial for the patient and occurs mainly in two contexts.
  • the first is termed "physiologic remodeling" which occurs in some high-performance athletes as an adaptive response to above-normal demands on the heart.
  • the compensatory changes in cardiac geometry and function in the physiologically remodeled heart render it better able to perform in a high-performance environment.
  • the second context is during the earliest stages of post-injury remodeling.
  • the initial phase of this remodeling can actually be adaptive and protective. If to a limited degree, some cellular rearrangement within the cardiac wall and increased chamber volume, can preserve or even augment cardiac output. These changes can be beneficial.
  • endogenous repair mechanisms are not able to restore cardiac tissue or function. Endogenous cells have been demonstrated to "home” to injured tissue, even in the adult heart, but blood flow limitations may prevent them from taking residence and promoting healing.
  • Measures to assess cardiac remodeling include cardiac size, cardiac shape, cardiac mass, ejection fraction, end-diastolic and end-systolic volumes, and peak force of contraction.
  • Left ventricular volume (especially left ventricular end systolic volume) is the best predictor of mortality in humans after myocardial infarction.
  • compositions which provide angiotensin-converting-enzyme inhibition (e.g., captopril, enalapril) and beta-adrenergic blockade (e.g., carvedilol, metoprolol, propranolol, timolol) have been shown to slow certain parameters of cardiac remodeling.
  • These therapies are intended to reduce the body's remodeling response to injurious or mechanically stressful stimuli and have been shown in clinical trials to reduce mortality and morbidity in myocardial infarction and heart failure patients.
  • Other therapies such as anti-hypertensive agents, have been used to reduce chronic loads placed on the heart which can trigger or worsen pathologic remodeling.
  • remodeling remains at best, a process that is partially treatable.
  • none of these agents induce neovascularization in the injured tissue as a means of preventing further cardiac damage or restoring cardiac tissue or function.
  • embodiments of the present invention address cardiac injury and remodeling by injecting a composition into the cardiac wall to induce neovascularization and thus prevent remodeling.
  • the injected composition may occupy some of the interstitial space between the cells of an area of the cardiac wall and provide structural reinforcement of the tissue in addition to inducing neovascularization.
  • the present invention contemplates providing neovascularization to any cardiac wall site and includes both the atria and ventricles.
  • the injected platelet composition may be a substance that can provide some level of structural support as well as the desired neovascularization in the tissue. Substances that can provide both structural reinforcement of the tissue and stimulate neovascularization are included in the platelet compositions disclosed herein.
  • the term "platelet gel" refers to platelet compositions which are administered with an activating agent and may provide both structural reinforcement of the tissue and biological therapy such as neovascularization.
  • the platelet composition can refer to platelet rich or platelet poor plasma that is administered without an activating agent. Platelet compositions such as platelet rich and platelet poor plasma can additionally be activated by tissue thrombin in situ to provide both structural support and neovascularization.
  • Exemplary, non-limiting platelet compositions include platelet gel, autologous platelet gel, platelet rich plasma, and platelet poor plasma.
  • Cell retention into target tissue has posed a significant challenge to cell-based technologies currently being developed. If delivered approximately simultaneously with cells, platelet compositions providing structural support will further act to increase tissue retention of delivered cells.
  • compositions of the present invention can be administered with other compositions capable of providing structural support including, but not limited to, collagen, cyanoacrylate, adhesives that cure with injection into tissue, liquids that solidify or gel after injection into tissue, suture material, agar, gelatin, light-activated dental composite, other dental composites, silk-elastin polymers, Matrigel ® (BD Biosciences), hydrogels and other suitable biopolymers.
  • Such compositions can include single or multi-component compounds. These compositions can include agents that are delivered as a liquid and then gel or harden to a solid after delivery.
  • the hardening/gelling can be triggered by temperature, pH, proteins, or other environmental factors inherent in or created within the target tissue.
  • These platelet compositions can be injected separately or in combination with each other and/or platelet compositions. Additionally the compositions or combinations thereof can include other additives. Some of these compositions and/or additives are further described below.
  • the platelet compositions of the current invention can be fortified with a biocompatible liquid that solidifies and/or cross-links in situ to render a structurally supportive structure on delivery into the cardiac wall.
  • Other embodiments of the platelet composition of the current invention may include synthetic or naturally-occurring materials and/or non-degradable or biodegradable materials to provide strength, for example.
  • the structural material includes cyanoacrylate or silk- elastin protein polymers.
  • the platelet compositions of various embodiments of the current invention can include additives, such as fibrinogen, to increase the structural strength of the cardiac wall.
  • the fibrinogen can be autologous, allogeneic, recombinant, human, engineered, or purified from animal sources.
  • At least one embodiment includes elastin to increase the elasticity of the treated cardiac wall.
  • the compositions may be delivered as a liquid (without cross-linking or solidifying components) such that the key soluble factors are trapped in the target tissue (physically or by binding to sites in the tissue) without providing an inherent structural component.
  • the compositions may be delivered with one or more structural materials to provide additional structural support to the tissue.
  • the present invention may be practiced using substances containing synthetic biodegradable materials that provide strength for a specified time interval after delivery, and then resorb.
  • Such materials include genetically-engineered or modified compounds such as collagen or fibrin.
  • Naturally-occurring materials such as, but not limited to, cartilage, bone or bone components, gelatin, collagen, glycosaminoglycans, starches, polysaccharides, or any other material that provide strength for a specified time interval after delivery, and then resorbs, may also be used.
  • Other embodiments of the present invention may include a combination of any of a variety of compounds that can create the desired local effect of tissue bulking.
  • Components that cause local edema, thickening of the tissue, structural reinforcement of the tissue, or any other effect that prevents remodeling are included in this invention.
  • Such compounds include ground-up suture material to create edema and hydrogels for structural reinforcement of the tissue. These materials may be added to PRP or PRP + thrombin.
  • biodegradable micro-particles between 50-100 ⁇ m in size (at the widest point of the particle), such that they are small enough for needle injection but too large to fit into capillaries and venules, may be added to the platelet composition.
  • the micro-particles may be impregnated with a drug that elutes as the particles degrade.
  • micro-particles alone are delivered to the cardiac tissue by injection into the coronary sinus. Based on their size characteristics, they are expected to lodge in the tissue and provide structural reinforcement of the tissue.
  • the micro-particles used may have a glass transition temperature (Tg) > 37 0 C, so they would gel over days after insertion. The injected micro-particles would provide "mass" and volume for immediate structural reinforcement of the tissue, but soften to gel to become a single member over time.
  • Embodiments of the platelet compositions of the present invention may include polymers that can covalently bind directly to one or more proteins located on the surface of one or more cell types so as to retain the polymers at the local site of injection.
  • polymers that can covalently bind to the primary amine groups (-NH 3 ) of proteins may be used.
  • the cell used in the cell preparation of the present invention includes cells that proliferate and engraft into the myocardium of the patient and a physiologic carrier solution.
  • the cells may be derived from a single individual or multiple individuals and may be of the same species or a different species than the recipient. In one embodiment, the cells are autologous.
  • Suitable physiologic carrier solutions include solvents or dispersing mediums including, for example, water, ethanol, polyols (such as, but not limited to, glycerol, polyethylene glycol and propylene glycol) and mixtures thereof.
  • solvents or dispersing mediums including, for example, water, ethanol, polyols (such as, but not limited to, glycerol, polyethylene glycol and propylene glycol) and mixtures thereof.
  • the platelet composition after injection at a treatment site, attracts blood vessel-forming cells to the treatment site, and wherein the blood vessel-forming cells induce the neovascularization of the cardiac tissue.
  • the platelet composition further comprises molecules which attract blood vessel-forming cells to the treatment site. Non-limiting examples of such molecules include growth factors, growth factor receptors and chemoattractants.
  • either or both of the platelet composition and cell preparation can include one or more bioactive agents to induce healing or regeneration of damaged cardiac tissue.
  • bioactive agents include, but are not limited to, pharmaceutically active compounds, hormones, growth factors, enzymes, DNA, RNA, siRNA, viruses, proteins, lipids, polymers, hyaluronic acid, pro-inflammatory molecules, antibodies, antibiotics, anti-inflammatory agents, anti-sense nucleotides and transforming nucleic acids or combinations thereof.
  • the cells may naturally secrete one or more biologically active molecules or they may be genetically engineered to secrete a therapeutically effective amount of one or more biologically active proteins.
  • Suitable biologically active proteins include, but are not limited to, growth factors and cytokines.
  • the secretion may be controlled by the presence of an inducible promoter or the secretion may be constitutive.
  • any composition is injected into a heart having a region of injured tissue, to induce neovascularization or to provide structural reinforcement of the tissue to the cardiac wall, the location and extent of the injured region is identified.
  • Multiple technologies and approaches are available for the clinician to identify and assess normal, injured-non-viable, and injured-viable cardiac tissue. These include, but are not limited to, visual inspection during open chest surgical procedures, localized blood flow determinations, local electrical and structural activity, nuclear cardiology, echocardiography, echocardiographic stress test, coronary angiography, magnetic resonance imaging (MRI), computerized tomography (CT) scans, and ventriculography.
  • the platelet compositions are prepared using the Medtronic Magellan ® Platelet Separator.
  • Anticoagulated whole blood is prepared by combining an anticoagulant with whole blood freshly removed from the subject.
  • the Magellan ® device is used to then extract platelet rich plasma (PRP) and platelet poor plastma (PPP) from the sample of anticoagulated whole blood.
  • Platelet gel is prepared by combining the resulting PRP or PPP with an activator.
  • the activator is bovine thrombin which has been reconstituted to 1000 Units/milliliter in 10% calcium chloride solution.
  • PRP is combined in an approximately 10:1 ratio with bovine thrombin.
  • the platelet gel composition is made using a PRP to thrombin ratio of about 10:1.
  • Another embodiment uses a PRP to thrombin ratio of about 11 :1.
  • Other embodiments of the present invention have ratios of PRP to thrombin of about 5:1 to about 25:1.
  • the ratio of PRP to thrombin is about 7:1 to about 20:1.
  • the ratio of PRP to thrombin is about 9:1 to about 15:1.
  • the ration of PRP to thrombin is about 10:1 to about 12:1.
  • no thrombin is included and PRP is injected into the cardiac tissue alone.
  • Other embodiments of the present invention include multiple components of the composition in ratios needed to achieve or optimize the desired effect.
  • the PRP and thrombin When the PRP and thrombin are injected such that they mix to form platelet gel in the cardiac tissue (see description of delivery devices below) they will gel in the tissue.
  • Several embodiments of the present invention provide accelerated gel times.
  • the gelling time in situ can be accelerated by applying local heat to the injection site via a delivery catheter or other instrument, increasing the thrombin concentration, or combining the PRP and thrombin in a mixing chamber and injecting the mixture into the cardiac tissue after the mixture has begun gelling.
  • This description also applies for other multi-component compositions, where the components gel, cross-link and/or polymerize after being mixed together.
  • the PRP contains a high concentration of platelets that can aggregate during gelling, as well as release cytokines, growth factors or enzymes following activation.
  • Some of the many factors released by the platelets and the white blood cells that constitute the PRP include platelet-derived growth factor (PDGF), platelet-derived epidermal growth factor (PDEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF- ⁇ ) and platelet-derived angiogenesis growth factor (PDAF).
  • PDGF platelet-derived growth factor
  • PEGF platelet-derived epidermal growth factor
  • FGF fibroblast growth factor
  • TGF- ⁇ transforming growth factor-beta
  • PDAF platelet-derived angiogenesis growth factor
  • the clinician can access and begin injecting the cardiac wall with the platelet composition.
  • the platelet composition comprises PRP and thrombin.
  • the platelet composition comprises PRP alone.
  • the platelet composition comprises PPP and thrombin.
  • the platelet composition comprises PPP alone.
  • the components of the platelet composition may be derived from humans, and/or animals, and/or recombinant sources. The components may also be artificially produced.
  • the components for platelet composition can be categorized as autologous, or non-autologous, and the non-autologous components can be further categorized as described above (i.e., animal, recombinant, engineered, allogeneic human, etc.).
  • Autologous platelet gel refers to a composition made from autologous PRP or autologous PPP and an autologous or non- autologous activator.
  • either or both of the platelet compositions and the cell prepraration of the present invention can include a contrast agent for detection by X- rays, magnetic resonance imaging (MRI) or ultrasound.
  • MRI magnetic resonance imaging
  • Suitable contrast agents are known to persons of ordinary skill in the art and include, but are not limited to, radiopaque agents, echogenic agents and paramagnetic agents.
  • a contrast agent may be used in the composition of some embodiments for visual confirmation of injection success.
  • contrast agents include, but are not limited to, X-ray contrast (e.g., IsoVue or other contrast agents having a high X-ray attenuation coefficient), MRI contrast (e.g., gadolinium or other contrast agents detectable as signal or signal-void by MRI) 1 and ultrasound contrast (echogenic or echo-opaque compounds).
  • X-ray contrast e.g., IsoVue or other contrast agents having a high X-ray attenuation coefficient
  • MRI contrast e.g., gadolinium or other contrast agents detectable as signal or signal-void by MRI
  • ultrasound contrast echogenic or echo-opaque compounds
  • Controlled injections were possible with or without a cardiac stabilization device, and it was possible to make the injections without exogenous cardiac pacing. Injections were made both orthogonally and obliquely to the cardiac surface at intervals of 0.5 to 2.5 cm. A plurality of injections can be made per heart without safety problems.
  • the total injectate volume can be as high as 15.0 ml_, and the volume of individual injections can be as high as 1100 ⁇ l per injection site.
  • autologous platelet gel administration following cardiac injury partially or fully reverses detrimental acute effects of infarction on the ejection fraction (EF), and can augment EF towards or above pre-infarct levels.
  • EF ejection fraction
  • autologous platelet gel administration following myocardial injury into ischemic tissue stimulated neovascularization in the injured tissue (FIG. 16-17). This vascularization was not observed in infarcted animals not receiving platelet gel therapy. All or a subset of the components of platelet gel (PRP or PPP components with or without thrombin) may be used to generate such an effect.
  • a clinician may use one of a variety of access techniques. These include surgical (sternotomy, thoracotomy, mini- thoracotomy, sub-xiphoid) approaches and percutaneous (transvascular and endocardial) approaches. Once access has been obtained, the composition(s) may be delivered via epicardial, endocardial, or transvascular approaches.
  • the platelet composition(s) may be delivered to the cardiac wall tissue in one or more locations. This includes intra-myocardial, sub-endocardial, and/or sub-epicardial administration.
  • the platelet composition is delivered more than one week after the injury, including up to months or years after injury. Other times for injecting platelet compositions into cardiac tissue are also contemplated, including prior to any injurious event, and immediately upon finding an area of injured cardiac tissue (for preventing additional remodeling in older injuries).
  • platelet compositions can be injected into the cardiac tissue years after an injurious event.
  • the platelet composition is injected into the cardiac tissue from about 1 hour to about 2 years after an injurious event.
  • the platelet composition is injected into the cardiac tissue from about 6 hours to about 1 year after an injurious event.
  • Target Tissue Injections were performed in the left ventricle (LV, at its base, mid-position, and apex) and right ventricle (RV, at its base, mid-position, and apex). Injections into the LV were targeted to a 5 mm depth. Injections into the RV were targeted to a 3 mm depth.
  • Results Hemostasis after APG injections was excellent. Specifically, multiple left ventricular injections of up to 1000 ⁇ l/each of APG (PRP:thrombin at 10:1 ) into healthy porcine myocardium were feasible and clinically safe. No adverse events were observed for up to 3 days of follow-up. Multiple right ventricular injections of up to 200 ⁇ il/each of APG (PRP:thrombin at 10:1 ) into healthy porcine myocardium were feasible and clinically safe. No adverse events were observed over a 2 hour follow-up period.
  • APG injection into myocardium demonstrated a protective effect against arrhythmia.
  • injection of 5600 ⁇ l of APG in divided left ventricle (LV) injections rendered the heart relatively resistant to fatal arrhythmia caused by an intravascular dose of potassium chloride (KCI).
  • KCI potassium chloride
  • Platelet gel can be formed from PRP alone without the addition of exogenous thrombin. Platelet rich plasma injected into myocardium alone (without thrombin) surprisingly gels in situ. The present inventor has formulated the non-binding hypothesis that tissue thrombin may be present in sufficient quantities to trigger this gelling reaction. Therefore, PRP may be used to create APG within the tissue when injected alone into myocardium in vivo.
  • APG injection also had a beneficial effect on post-MI EF, as it was restored from 62.1 % to 70.3% of the pre-MI level.
  • APG delivery resulted in an EF that was 111.1 % of pre-MI levels. That is, in this animal, EF was 45% at baseline, 35% immediately post-infarction, and 50% following administration of APG.
  • APG administration following cardiac injury can partially or fully reverse detrimental acute effects of infarction on EF, and in some situations may augment EF to above pre-infarct levels.
  • the injected compositions can be visualized by intra-operative ECHO (echocardiography), which can be used to confirm adequate needle placement and retention.
  • ECHO echocardiography
  • the ECHO can be used as a separate device or can be included within the delivery system (e.g. similar to intravascular ultrasound [IVUS]).
  • Such a device may have at least one sensor include, but not limited to, a pressure sensor, a color detector, an oxygen sensor, a carbon dioxide sensor or a lumen to express backflowing blood under pressure that generates a unique signal when the delivery system is positioned such that its target is in a blood space. Once alerted, the user can re-position the device before delivering the composition.
  • the system of the current invention comprises identification of the injured area of cardiac tissue and the treatment site, accessing the treatment site with a delivery device, injecting the composition at one or more locations at the treatment site in the cardiac tissue and removing the delivery device from the patient.

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Abstract

La présente invention concerne des méthodes et des systèmes de traitement du tissu cardiaque par administration d'une composition de plaquettes induisant une néovascularisation dans le tissu cardiaque puis d'une préparation de cellules induisant une régénération dans le tissu revascularisé. La composition de plaquettes peut également contenir des matières structurelles et/ou des agents bioactifs.
EP07756277A 2006-03-23 2007-01-03 Méthodes et systèmes de traitement de lésions du tissu cardiaque Withdrawn EP2007404A2 (fr)

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US74368606P 2006-03-23 2006-03-23
US11/426,211 US20070042016A1 (en) 2005-06-23 2006-06-23 Methods and Systems for Treating Injured Cardiac Tissue
US11/426,219 US20070014784A1 (en) 2005-06-23 2006-06-23 Methods and Systems for Treating Injured Cardiac Tissue
PCT/US2007/060060 WO2007112136A2 (fr) 2006-03-23 2007-01-03 Méthodes et systèmes de traitement de lésions du tissu cardiaque

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US6811777B2 (en) 2002-04-13 2004-11-02 Allan Mishra Compositions and minimally invasive methods for treating incomplete connective tissue repair
US8057426B2 (en) 2007-01-03 2011-11-15 Medtronic Vascular, Inc. Devices and methods for injection of multiple-component therapies
US20100112081A1 (en) 2008-10-07 2010-05-06 Bioparadox, Llc Use of platelet rich plasma composition in the treatment of cardiac conduction abnormalities
JP2012505239A (ja) * 2008-10-09 2012-03-01 バイオパラドックス，リミテッド ライアビリティー カンパニー 心臓治療用の多血小板血漿製剤
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US20140356893A1 (en) 2013-06-04 2014-12-04 Allan Mishra Compositions and methods for using platelet-rich plasma for drug discovery, cell nuclear reprogramming, proliferation or differentiation

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US7628780B2 (en) * 2001-01-13 2009-12-08 Medtronic, Inc. Devices and methods for interstitial injection of biologic agents into tissue
US7740623B2 (en) * 2001-01-13 2010-06-22 Medtronic, Inc. Devices and methods for interstitial injection of biologic agents into tissue
US20030007957A1 (en) * 2001-07-03 2003-01-09 Calvin Britton Novel wound healing composition not containing bovine-derived activating reagents
US20040197319A1 (en) * 2003-03-24 2004-10-07 Paul Harch Wound healing composition derived from low platelet concentration plasma

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