|Publication number||US20050096731 A1|
|Application number||US 10/913,304|
|Publication date||May 5, 2005|
|Filing date||Aug 6, 2004|
|Priority date||Jul 11, 2002|
|Also published as||US8623066, US20080138378|
|Publication number||10913304, 913304, US 2005/0096731 A1, US 2005/096731 A1, US 20050096731 A1, US 20050096731A1, US 2005096731 A1, US 2005096731A1, US-A1-20050096731, US-A1-2005096731, US2005/0096731A1, US2005/096731A1, US20050096731 A1, US20050096731A1, US2005096731 A1, US2005096731A1|
|Inventors||Kareen Looi, Gary Owens|
|Original Assignee||Kareen Looi, Owens Gary K.|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (16), Referenced by (15), Classifications (35), Legal Events (4)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This application claims the benefit and priority of U.S. Provisional Patent Application No. 60/494,045 (Attorney Docket 021258-001700US), filed Aug. 7, 2003, the full disclosure of which is hereby incorporated by reference for all purposes.
This application is also a continuation in part of PCT Patent Application No. PCT/US03/21754 (Attorney Docket 021764-000920PC) filed on Jul. 11, 2003 which claims the benefit and priority of U.S. Provisional Patent Application No. 60/395,180 (Attorney Docket 021258-000900US) filed Jul. 11, 2002, and U.S. Provisional Patent Application No. 60/421,404 (Attorney Docket 021258-000910US) filed Oct. 24, 2002, the full disclosures of which are hereby incorporated by reference for all purposes.
This application is also a continuation in part of PCT Patent Application No. PCT/US03/21611 (Attorney Docket 021764-000720PC) filed on Jul. 11, 2003 which claims the benefit and priority of U.S. Provisional Patent Application No. 60/395,180 (Attorney Docket 021258-000900US) filed Jul. 11, 2002, U.S. Provisional Patent Application No. 60/421,404 (Attorney Docket 021258-000910US) filed Oct. 24, 2002, U.S. Provisional Patent Application No. 60/421,350 (Attorney Docket 021258-000700US) filed Oct. 24, 2002, and U.S. Provisional Patent Application No. 60/428,803 filed Nov. 25, 2002, the full disclosures of which are hereby incorporated by reference for all purposes.
This invention was made with government support under grant number R21 HL071976-01 (G. K. Owens, PI) entitled “Derivation of Smooth Muscle Lineages from Stem Cells,” awarded by the National Institutes of Health. The government may have certain rights in the invention.
The present invention relates to apparatuses, systems and methods of treating a patient. Particularly, the present invention relates to treating medical conditions using cell therapy via body lumens. In some instances, the present invention relates to treating a blood vessel, such as in the treatment of heart disease and aneurysms.
1. Heart Disease
Heart disease continues to be a leading cause of death in the United States. The mechanism of this disease is often progressive narrowing of coronary arteries by atherosclerotic plaque which can lead to acute myocardial infarction and disabling angina. Techniques to treat coronary atherosclerosis include percutaneous transluminal coronary angioplasty, (or PTCA, commonly referred to as balloon angioplasty), atherectomy, and coronary stenting. In each of these treatments, compression of the plaque and expansion of the coronary artery, or removal of the atherosclerotic plaque, often restores lumen patency. In stenting, a stent, such as a metal or wire cage-like structure, is expanded and deployed against the plaque.
Despite the overall initial success of these procedures, many patients undergoing these therapeutic procedures to clear blocked coronary arteries will suffer restenosis (re-blockage) at some point after the initial procedure. Such restenosis may be a manifestation of the general wound healing response or may be due to a variety of other factors.
Thus, it would be desired to provide devices, systems and methods which would provide therapeutic benefits to injured or diseased tissue. Such benefits may include reduction of the incidence of restenosis, particularly in blood vessels treated for atherosclerosis. However such benefits may be applicable to any body lumen which suffers from occlusion and possible restenosis. In addition, such benefits may include a reduction in any initial injury induced by intervention, such as by stenting. At least some of these objectives will be met by the embodiments of the present invention.
An aneurysm is the focal abnormal dilation of a blood vessel. The complications which arise from aneurysms can include rupture, embolization, fistularisation and symptoms related to pressure on surrounding structures. Aneurysms are commonly found in the abdominal aorta, being that part of the aorta which extends from the diaphragm to the point at which the aorta bifurcates into the common iliac arteries. These abdominal aortic aneurysms typically occur between the point at which the renal arteries branch from the aorta and the bifurcation of the aorta. When left untreated, an abdominal aortic aneurysm may eventually cause rupture of the aorta with ensuing fatal hemorrhaging in a very short time. High mortality associated with the rupture has led to the development of transabdominal surgical repair of abdominal aortic aneurysms.
A clinical approach to aneurysm repair which is less invasive than conventional transabdominal surgery is known as endovascular grafting. Endovascular grafting typically involves the transluminal placement of a prosthetic arterial graft within the lumen of the artery. The graft may be attached to the internal surface of an arterial wall by means of attachment devices (often similar to expandable stents), one above the aneurysm and a second below the aneurysm. Such attachment devices permit fixation of a graft to the internal surface of an arterial wall without sewing.
It would be desirable, to provide devices, systems and methods that improve the treatment of aneurysms, such as improving fixation of the graft, increased resistance to graft migration and leakage and/or improvements in the characteristics of the surrounding tissue once in place. At least some of these objectives will be met by the embodiments of the present invention.
3. Use of Cell-Based Therapies
Methods have been developed for using pluripotent stem cells for therapeutic applications, including the delivery of therapeutic genes. Pluripotent stem cells appear to have the ability to differentiate into a number of different cell types, including neurons, cardiomyocytes, skeletal muscle, smooth muscle and pancreatic beta cells, to name a few, that are involved in the pathogenesis of many human diseases, such as atherosclerosis, diabetes, hypertension and various others. However, current methods have limitations which preclude the successful use of such pluripotent stem cells in treating various medical conditions.
To begin, a stem cell per se exhibits almost no target tissue selectivity. As such, if stem cells are simply introduced to target tissues by current methods, such as intravenously or by direct injection, a safety concern is the risk that the cells will differentiate into a non-target cell type and disrupt the normal functions in the target tissues. At worst, this may result in tumorigenesis and/or patient mortality. A possible solution is to use stem cells which have been triggered to becoming the target cell type, i.e. progenitor cell types such as smooth muscle progenitor cells. Since these stem-cell derived progenitor cells have started onto the differentiation pathway sufficiently to be “committed” to becoming the desired cell type, there is reduced risk of tumorigenesis or differentiation into an undesired cell type. The drawback to this approach (i.e. the use of progenitor cells) is that the engraftment efficiency is usually inversely related to the extent of cell differentiation. Thus, while the use of stem-cell-derived progenitor cells may reduce or eliminate safety concerns, the fact that the progenitor cells are further down the differentiation pathway as compared to pluripotent stem cells means that their engraftment efficiency is reduced, and this will in turn reduce the likelihood of a clinical benefit.
Alternatively, differentiated somatic cells have been used for cell-based therapies. However, these applications have also been limited by the lack of methods to provide efficient engraftment as described above.
Thus, it would be desirable to provide devices, systems and methods that will deliver therapeutic cells directly to the target site, such that regardless of the extent to which these cells have differentiated, their engraftment into the target site will be significantly improved. At least some of these objectives will be met by the embodiments of the present invention.
4. Immune Issues Related to Use of Non-Autologous Cells
Interest has developed in using non-autologous cells for cell-based therapies, particularly non-autologous embryonic stem cells. Embryonic stem cells may have properties, such as pluripotentiality and infinite replicative life span, that are not obtainable with autologous somatic stem cells. In addition, various non-human cells may be used in the treatment of human diseases, for example, porcine pancreatic beta cells for treatment of diabetes. However, non-autologous and non-human cells are attacked by the patient's immune system, thus limiting their long term efficacy and viability.
Thus, it would be desirable to provide devices, systems and methods that allow the delivery of non-autologous cells to a desired tissue site while simultaneously isolating them from the patient's immune system. This would reduce or prevent any immunologic rejection of the cells. At least some of these objectives will be met by the embodiments of the present invention.
The present invention provides devices, systems and methods for the localized delivery of cells which provide a therapeutic benefit. The cells may include but are not limited to autologous stem cells. Localized delivery is achieved with the use of a stent-like expandable body seeded with cells which is positioned within a body lumen. The expandable body is expanded to contact at least a portion of the inner walls of the body lumen and the cells and/or cellular products are delivered to the surrounding tissue. The therapeutic benefit provided is dependent on the type of cells used and the features of the expandable body, to name a few.
In a first aspect of the present invention, the expandable body may take the form of any of a variety of stents used for placement within body lumens, such as blood vessels. For example, the expandable body may comprise a conventional stent used to treat coronary occlusions, such as described by U.S. Pat. Nos. 6,540,775, 6,113,621, and 4,776,337, each of which is incorporated by reference herein for all purposes. Or, the expandable body may comprise a conventional stent graft used to treat aneurysms, particularly abdominal aortic aneurysms, such as described by U.S. Pat. Nos. 5,824,039 and 5,693,084, each of which is incorporated by reference herein for all purposes.
In other embodiments, the expandable body comprises a device such as provided by Reed et al. (U.S. Pat. No. 6,197,013), incorporated by reference herein for all purposes. The Reed et al. devices include arrays of micromechanical probes present on the surface of the devices which penetrate the body lumen wall and allow for efficient transport of therapeutic agents, such as cells, into the wall. In the specific example of blood vessels, delivery can be effected directly to at least the medial layer of the vessel wall.
In still other embodiments, the expandable body comprises a device having deployable microstructures, such as provided by U.S. Provisional Patent Application No. 60/395,180 (Attorney Docket 021258-000900US), U.S. Provisional Patent Application No. 60/421,404 (Attorney Docket 021258-000910US), and PCT Application No. PCT/US03/21754 (Attorney Docket 021764-000920PC), the full disclosures of which are hereby incorporated by reference for all purposes. The microstructures are formed in or attached to the expandable body in a low profile fashion suitable for atraumatic introduction to the body lumen with the use of a catheter or other suitable device. Each microstructure has an end which is attached to the expandable body and a free end. Once the apparatus is positioned within the body lumen in a desired location, the body is expanded and the microstructures deployed to a position wherein the free ends project radially outwardly. The free ends of the deployed microstructures then penetrate the lumen wall by continued expansion of the body. Additionally, a therapeutic agent, such as cells, may be delivered to the lumen wall by the microstructures. When the expandable body comprises a stent, the mechanism may be left in place, the microstructures providing anchoring and sealing against the lumen wall.
In yet other embodiments, the expandable body comprises any of the devices for treating aneurysms described in U.S. Provisional Patent Application No. 60/421,350 (Attorney Docket 021258-000700US), U.S. Provisional Patent Application No. 60/428,803 and PCT Application No. PCT/US03/21611 (Attorney Docket 021764-000720PC), the full disclosures of which are hereby incorporated by reference for all purposes. These devices include a tube which is held in place within the vasculature by at least one expandable body having at least one microstructure. The microstructures are attached to the expandable body in a low profile fashion suitable for atraumatic introduction to the vasculature with the use of a catheter or other suitable device. Each microstructure has an end which is attached to the expandable body and a free end. Once the apparatus is positioned within the vasculature in the desired location, the microstructures are deployed so that the free ends project radially outwardly. The free ends of the deployed microstructures then penetrate the blood vessel wall by continued expansion of the body, holding the tube in place.
It may be appreciated that the expandable body may take the form of any device which is expandable within a body lumen to provide localized delivery of cells and/or cellular products to the body lumen. Various body lumens are found in but are not limited to the vascular system, the pulmonary system, the gastro-intestinal tract, the urinary tract and the reproductive system.
It may be further appreciated that the surface of the expandable body may be porous to allow for a greater retention of therapeutic agents, cells or other substances that may have direct or indirect therapeutic benefits, such as matrix components, growth factors and/or combinations thereof. These substances may promote wound healing or tissue/organ regeneration or repair by augmenting the function of the patient's existing cells or tissues. Some embodiments of such a porous surface are obtained by means of a de-alloying method, preferred embodiments of which have been described in U.S. Provisional Patent Application No. 60/426,106 filed on Nov. 30, 2002, incorporated herein by reference for all purposes. In other embodiments, the porous surface provides controlled release over time of substances that regulate the activity or properties of the cells contained on the device or in proximity to the device. For example, the porous surface may provide controlled release of TGFβ1, a substance known to increase matrix production by smooth muscle cells as well as many other cell types. Such controlled release may be useful in the repair of aneurysms where it is desirable to have cells produce large quantities of extracellular matrix components. In still other embodiments, the porous surface is used to deliver agents that control the activity of a therapeutic gene contained with cells seeded thereon. Such control is achieved by influencing the activity of the therapeutic gene (e.g. through an activation mechanism) or the activity of a promoter-enhancer used to drive expression of the therapeutic gene (e.g. by inclusion of tetracycline or similar responsive elements within the promoter driving the therapeutic gene and inclusion of the inducing agent for that response element in the porous surface).
In a second aspect of the present invention, the cells seeded on the expandable body may be comprised of any cells which provide a therapeutic benefit to the body lumen. Examples of such cells include endothelial cells, pancreatic beta cells, myofibroblasts, cardiac myocytes, skeletal muscle satellite cells, smooth muscle cells, dendritic cells, epithelial cells, multi-potential somatic stem cells and derivatives thereof, embryonic stem cells and derivatives thereof, neuronal cells, glial cells, hepatocytes, and various endocrine cells (e.g. thyroid, parathyroid, adrenal cortex), to name a few.
In some embodiments, genetically modified cells are used to over-express a therapeutic gene. In preferred embodiments, genetically modified smooth muscle cells (SMC) are used. This is because a large number of major human diseases, including coronary artery disease, hypertension, and asthma are associated with abnormal function of SMCs. In addition, SMC dysfunction also contributes to numerous other human health problems including vascular aneurysms, and reproductive, bladder and gastrointestinal disorders. Therefore, a therapeutic effect can be achieved by delivering SMCs which have been genetically modified to over express a therapeutic agent, thereby reducing or eliminating the physiological consequences caused by SMC dysfunction.
Although the present invention relates to the use of a plurality of cell types and sources, one preferred embodiment uses genetically modified stem cells or cells derived therefrom. Stem cells exhibit a virtually infinite replicative lifespan which is beneficial for carrying out genetic engineering methods. Such a lifespan is also beneficial for being able to generate sufficient numbers of cells for clinical applications. This is particularly useful since a patient's own stem cells may often be available in very limited supply, at least without major surgery or patient risk. In contrast, use of somatic differentiated cell populations are limited in that these cells can only undergo a relatively small number of population doublings before senescing.
One preferred embodiment of the present invention is to employ stem cell derived smooth muscle progenitor cells produced using methods described in WO 02/074925, incorporated herein by reference for all purposes. These smooth muscle progenitor cells have been isolated and purified by transforming a population of pluripotent somatic or embryonic stem cells with a DNA construct comprising a smooth muscle specific promoter operably linked to a selectable marker gene.
A major limitation in using these stem cell derived smooth muscle progenitor cells with conventional delivery methods is that the conventional delivery methods do not provide effective engraftment of the cells into the desired tissue site while at the same time reducing or eliminating the risks of delivery to non-target sites. As mentioned, the engraftment potential is highest for undifferentiated cells, however undifferentiated cells pose the greatest risk for tumorigenesis or other undesired side effects. Therefore, a balance between these risks and benefits is desired. Such a balance may be achieved by the use of expandable bodies having micromechanical probes, such as provided by Reed et al. (U.S. Pat. No. 6,197,013), or expandable bodies having deployable microstructures as described above. In this preferred embodiment, the cells are seeded onto the expandable body and delivered directly to specific locations, particularly within the wall of a body lumen. The cells are mechanically embedded into and/or held against the wall of the body lumen which improves engraftment of the cells into the target tissue. This process may be further aided by use of the porous coating to deliver agents that promote engraftment as well as other desired properties of the cells.
In preferred embodiments, genetically modified autologous SMC, adult or embryonic stem cell derived SMC or SMC progenitor cells isolated from the patient's own somatic stem cells are used. In some embodiments, SMC progenitor cells as described in PCT/US02/08402, incorporated herein for all purposes, may be used. Any of these cells may be modified to over-express a possible therapeutic gene, such as endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS). Nitric oxide (NO) has many actions that could be beneficial to the vascular system, particularly following vascular injury. These include inhibition of platelet deposition and leukocyte adherence, inhibition of vascular smooth muscle cell proliferation and migration, inhibition of endothelial cell apoptosis, stimulation of endothelial cell growth, and vasodilation. Furthermore, inadequate NO production at sites of injury has been shown to contribute to vascular occlusive diseases including atherosclerosis and restenosis following angioplasty, endarterectomy, cardiac bypass surgery, or peripheral vascular bypass surgery. Local delivery of NO to a particular site may be achieved through transfer of an NOS gene, such as eNOS, iNOS, or NNOS, to the site by incorporation into the cells of the cell-seeded expandable body of the present invention. By delivering NOS gene expressing cells to a specific site, NO will be produced at that site without systemic effects. In addition, a porous surface on the expandable body, as described previously, may be used to release co-factors that are known to enhance the biological activity of NOS/NO.
Alternative genes that might be expressed to confer a therapeutic benefit include TGFβ1, which has anti-inflammatory properties and which also has been shown to inhibit SMC growth, promote differentiation, and enhance production of extracellular matrix components. Other possibilities include cytokines IL-4, IL-10 or IL-13 whose anti-inflammatory properties may promote wound repair or regeneration and/or reduced restenosis.
It may be appreciated that genetic modification such as described above may be applied to cells other than SMCs, and these cells may also be used with the cell-seeded expandable body of the present invention. In addition, the methods provided in WO 02/074925, exemplified for the isolation of SMC and smooth muscle progenitor cells, are readily adaptable to the production of any desired cell type by replacing the SMC specific/selective promoter/enhancer of the reporter gene construct with an appropriate promoter regulatory element that is selective/specific for the cell type of interest. Examples include the use of promoter/enhancers specific for cardiac myocytes, endothelial cells and neurons. As an example, cells used in the present invention may be comprised of progenitor cells derived by a method comprising the steps of providing a population of cells comprising totipotent or pluripotent cells, transfecting the population of cells with a nucleic acid sequence comprising a smooth muscle cell specific promoter/enhancer operably linked to a marker, inducing the population of cells to become smooth muscle cells and identifying the smooth muscle progenitor cells based on the expression of the marker.
In other embodiments, cells which have not been genetically modified to over-express a possible therapeutic gene, referred to herein as “unmodified cells”, are used. Such cells may be used to augment tissue repair and regeneration. For example, when unmodified autologous SMC, stem cell derived SMC or SMC progenitor cells are used, proliferation of the SMCs and/or associated production of extracellular matrix components including collagen and elastin can rebuild blood vessels. The blood vessels may have been damaged due to traumatic injury, such as by an accident, major reconstructive surgery, or repair of a congenital vascular defect. The SMCs can also be used to rebuild blood vessels which suffer from aneurysms, a progressive vascular abnormality associated with degeneration and dissection of the blood vessel wall and SMC hypocellularity. They may be caused by many factors including extensive atherosclerotic disease, a congenital vascular defect, or mutations in genes important for determining the tensile strength of blood vessels, such as in the case of Marfan's Syndrome which is the result of mutations in the fibrillin gene. In addition, a porous surface on the expandable body may be employed to deliver agents that enhance the desired properties of the unmodified cells. For example, TGFβ1 may be used since it is known to dramatically enhance matrix production, and/or PDGF BB may be used to promote proliferation of progenitor cells provided on the device as well as recruitment of resident cells that could aid in the repair process.
When the cell-seeded expandable bodies of the present invention are used to treat an aneurysm, the expandable bodies anchor a tube or graft to the vessel walls surrounding an aneurysm. SMCs may be delivered to the vessel walls to increase anchorage of the tube and reduce migration of the tube along the blood vessel. Such migration could lead to leakage, exposure of the aneurysm and damage to the blood vessel, to name a few. In addition, the improved anchorage may also prevent apparent migration of the apparatus which occurs when the aneurysmal sac grows in size and as such encroaches upon the ends of the apparatus. This results in a reduction of the distance between the terminus of the apparatus and the aneurysm which is the same effect as migration. Thus, the SMCs help maintain intimate contact between the apparatus and the vessel wall and prevent aneurysmal sac growth. The SMCs can also be delivered to the blood vessel lumen, the blood vessel walls and/or the outer surface of the blood vessel to encourage tissue regrowth or extra-cellular matrix formation. The SMCs may also be delivered to the aneurysmal sac. This may allow for tissue regrowth within the sac, strengthening the tissue within the aneurysmal walls. In addition, as noted above, a porous surface on the device may be employed to deliver agents to enhance the repair or regenerative process.
SMCs may also be employed in reconstructive surgery of the gastrointestinal tract, urinary tract, or other tissues in which SMC are a predominant cell type. Other cell types may also be used to rebuild other types of tissues. For example, autologous stem cell derived cell types may be used to enhance wound healing, bone repair, musculo-skeletal repair following traumatic injury or disease, tissue engineering, and replacement of degenerative or senescent cells, to name a few.
It may be appreciated that any combination of the above described cell types and expandable body types may be used. However, for clarity of description, cells will mainly be described and illustrated as generic “cells” representing any of the described cell types. In addition, the expandable bodies will mainly be described and illustrated as comprising a device having deployable microstructures. However, this is not intended to limit the scope of the invention as the features provided may apply to any of the expandable body types.
Together, the microstructures 14 and the expandable body 12 form the cylindrical structure surrounding the longitudinal axis 20.
As illustrated in
Cell Seeding of Expandable Body
The expandable body 12 is seeded with the desired cells by any suitable method. Typically the cells are mixed with whole blood or tissue culture media and incubated with the expandable body 12. The incubation time will be sufficient to provide desired cell retention upon the body 12. In some embodiments, the incubation time will be sufficient to generate a confluent monolayer of cells on the surfaces of the expandable body 12. Various methods of cellular application may be used, including rotating the expandable body 12 about cell-rich seeding suspensions, application of an external vacuum or use of surface electrocharging to improve seeding efficiency, adhesion strength and uniformity. In addition, the expandable body 12 may be coated with a substance or substrate prior to seeding to improve ultimate seeding efficiency. The substances may comprise polymer substrates, biocompatible proteins, growth factors, extracellular matrix components, or a combination of these.
To increase the ability of the cells 5 to be seeded on the microstructures 14, the structural material of the expandable body 12 may have a porous surface. This may allow any substances which are used to more highly bond with the expandable body 12. This may in turn increase the retention of the cells 5. In one embodiment pores are created by anodizing the metal forming the apparatus or coating the metal with a material which is then anodized. Anodization produces a high density of small, vertically oriented pores, of which the size and configuration can be controlled by varying the anodization current, temperature and solution concentration. If the pores are of sufficient size in relation to the cells 5, the cells 5 may seed within the pores themselves allowing even greater retention. In other embodiments, a porous coating is created by depositing a precursor alloy onto the expandable body followed by a de-alloying procedure. The de-alloying procedure chemically or electrochemically removes one or more components of the precursor alloy leaving behind a nanoporous matrix. Embodiments of such a method have been described in U.S. Provisional Patent Application No. 60/426,106 filed on Nov. 30, 2002, incorporated herein by reference for all purposes.
In these and other embodiments, the porous surface may comprise a controlled release porous coating which provides time dependent release of various substances. When the coating comprises a nanoporous metallic coating, the coating may have a morphology that provides the controlled time dependent release of various substances. One or more substances may be used to regulate the activity or properties of the cells on the expandable body or in proximity to the expandable body. For example, the substances may promote cell adherence and/or cell growth. An example of such a substance is a member of the TGFβ family, such as TGFβ1 which is known to dramatically increase matrix production by smooth muscle cells as well as other cell types. Release of TGFβ1 in a controlled manner is useful in the repair of aneurysms where it is desirable to have cells produce large quantities of extracellular matrix components. Other substances may augment growth of endothelial cells and/or smooth muscle cells. Example substances include VEGF, bFGF, PLGF, and PDGF. Or, one or more substances may be used to control the activity of a therapeutic gene (e.g. through an activation mechanism) or the activity of a promoter-enhancer used to drive expression of the therapeutic gene (e.g. by inclusion of tetracycline or similar responsive elements within the promoter driving the therapeutic gene and inclusion of the inducing substance for that response element in the porous coating).
Alternatively, as illustrated in
As mentioned, each microstructure 14 has an attached end 30, attached to the body 12, and a free end 32, both in the deployed and undeployed positions. In preferred embodiments, each microstructure has a directional axis 40, such as shown in
Generally, the expandable body 12 comprises a series of interconnected solid sections having spaces therebetween. The solid sections form the structure of the expandable body 12 and form the microstructures 14. In most embodiments, each microstructure has at least a first support and a second support and a free end, the first and second supports being affixed to associate first and second adjacent portions of the radially expandable body. Expansion of the expandable body effects relative movement between the associated first and second portions of the expandable body. For example, the relative movement of the associated first and second portions of the expandable body may comprise circumferential movement of the first portion relative to the second portion when the expandable body expands radially. Although this relative movement may be in any direction, typically the relative movement comprises moving the associated first and second portions apart. Often the circumferential movement pulls the affixed ends of the first and second supports apart, which in turn moves the free end. Thus, such relative movement deploys the microstructures from an undeployed position along the expandable body to a deployed position with the free end projecting radially outwardly from the longitudinal axis. A variety of embodiments are provided to illustrate these aspects of the present invention.
The free ends 32 of the microstructures 14 depicted in
It may be appreciated that although the free end 32 is illustrated to have a pointed shape, the free ends 32 may have any desired shape, including the shapes illustrated in
It may be appreciated that the expandable body 12 of
The free ends 32 of the microstructures 14 depicted in
Embodiments for Repairing Aneurysms
As mentioned previously, the cell-seeded expandable bodies of the present invention may be used to anchor a tube or graft to the vessel walls surrounding an aneurysm. The cells are seeded on the expandable bodies as described above. The cells may then be delivered to the vessel walls to increase anchorage of the tube. The cells can also be delivered to the blood vessel lumen, the blood vessel walls and/or the outer surface of the blood vessel to encourage tissue regrowth or extra-cellular matrix formation. Or the cells may be delivered to the aneurysmal sac. This may allow for tissue regrowth within the sac, strengthening the tissue within the aneurysmal walls. Typically, smooth muscle cells will be used for such application.
It may be appreciated that any number of microstructures 14 may be present and may be arranged in a variety of patterns along the entire length of the body 12 or along any subportion. For example,
Referring now to
When the expandable body 12 is positioned within the tube 2, expansion of the body 12 and deployment of the microstructures 14 occurs within the tube 2 so that further expansion penetrates the microstructures 14 through the tube wall 8, as illustrated in
The present invention may be particularly suitable for repair of abdominal aortic aneurysms. An abdominal aortic aneurysm is a sac caused by an abnormal dilation of the wall of the aorta, a major artery of the body, as it passes through the abdomen. The abdomen is that portion of the body which lies between the thorax and the pelvis. It contains a cavity, known as the abdominal cavity, separated by the diaphragm from the thoracic cavity and lined with a serous membrane, the peritoneum. The aorta is the main trunk, or artery, from which the systemic arterial system proceeds. It arises from the left ventricle of the heart, passes upward, bends over and passes down through the thorax and through the abdomen to about the level of the fourth lumbar vertebra, where it divides into the two common iliac arteries at a bifurcation.
To treat abdominal aortic aneurysms, the apparatus 10 is shaped to be disposed at least partially within the aneurysm. In particular, the tube 2 is shaped to fit the aortic geometry. For example,
Delivery of Cells from Expandable Body
Positioning of the apparatus of the present invention is typically performed via standard catheterization techniques. These methods are well known to cardiac physicians and are described in detail in many standard references. Examples of such positioning will be provided in relation to the vascular system, however, such example is not intended to limit the scope of the invention. In brief, percutaneous access of the femoral or brachial arteries is obtained with standard needles, guide wires, sheaths, and catheters. After engagement of the coronary arteries with a hollow guiding catheter, a wire is passed across the coronary stenosis where the apparatus is to be deployed. The apparatus is then passed over this wire, using standard coronary interventional techniques, to the site where therapy is to be delivered.
The apparatus is then delivered and expanded to force the microstructures 14 through the tissue so the microstructure tips reach within the vessel wall, as shown in
As mentioned previously, the present invention may be utilized for any sort of treatment which involves delivery of a therapeutic agent and/or anchoring of a device. The devices could be introduced into various body lumens, such as those found in the vascular system, the pulmonary system, the gastro-intestinal tract, the urinary tract and the reproductive tract, to name a few. The function of the microstructures includes but is not limited to facilitating delivery of a therapeutic agent, such as cells, securing the device in place and providing a mechanical seal to the lumen wall.
Although the invention has been described in detail in the foregoing embodiments for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be described by the following claims.
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|U.S. Classification||623/1.16, 623/1.42, 623/1.36, 623/1.41, 435/402|
|International Classification||A61L31/00, A61F2/90, A61L31/08, A61L31/14, A61F2/06, C12N5/08, A61F2/00, A61F2/04|
|Cooperative Classification||A61F2/848, A61L2400/12, A61F2002/91575, A61F2/915, A61L31/088, A61F2002/075, A61F2/0077, A61F2/91, A61L31/005, A61F2002/91533, A61L31/146, A61F2/07, A61F2220/0033, A61F2/90, A61F2220/0016, A61F2230/0013|
|European Classification||A61F2/91, A61F2/07, A61F2/915, A61L31/14H, A61L31/08B6, A61L31/00F|
|Jan 3, 2005||AS||Assignment|
Owner name: UNIVERSITY OF VIRGINIA, VIRGINIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:OWENS, GARY K.;REEL/FRAME:015506/0499
Effective date: 20050103
|Jan 5, 2005||AS||Assignment|
Owner name: UNIVERSITY OF VIRGINIA PATENT FOUNDATION, VIRGINIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:UNIVERSITY OF VIRGINIA;REEL/FRAME:015516/0932
Effective date: 20050104
|Feb 17, 2005||AS||Assignment|
Owner name: SETAGON, INC., VIRGINIA
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LOOI, KAREEN;REEL/FRAME:015695/0965
Effective date: 20041228
|Jun 2, 2008||AS||Assignment|
Owner name: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF
Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF VIRGINIA;REEL/FRAME:021031/0295
Effective date: 20050112