Source: http://www.google.com/patents/US6902522?dq=5,987,610
Timestamp: 2014-07-14 01:50:52
Document Index: 412417967

Matched Legal Cases: ['art.\n1', 'art.\n2', 'art.\n3', 'art.\n5', 'art.\n6', 'art.\n7', 'art.\n8', 'art;\n12', 'art.\n18', 'art;\n3', 'art;\n4', 'art.\n19', 'art.\n20', 'art.\n22']

Patent US6902522 - Cardiac disease treatment and device - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA device for treating cardiac disease of a heart having an upper portion and a lower portion divided by an A�V groove, the device including a jacket adapted to be secured to the heart, and a delivery source for the delivery of one or more therapeutic agents to the surface of the heart. The jacket is...http://www.google.com/patents/US6902522?utm_source=gb-gplus-sharePatent US6902522 - Cardiac disease treatment and deviceAdvanced Patent SearchPublication numberUS6902522 B1Publication typeGrantApplication numberUS 09/591,754Publication dateJun 7, 2005Filing dateJun 12, 2000Priority dateJun 12, 2000Fee statusPaidAlso published asDE60133278D1, DE60133278T2, EP1289447A2, EP1289447B1, WO2001095832A2, WO2001095832A3Publication number09591754, 591754, US 6902522 B1, US 6902522B1, US-B1-6902522, US6902522 B1, US6902522B1InventorsRobert G. Walsh, Edward Shapland II J., Donald G. Rohrbaugh, F. Palme II DonaldOriginal AssigneeAcorn Cardiovascular, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (66), Non-Patent Citations (23), Referenced by (12), Classifications (8), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetCardiac disease treatment and deviceUS 6902522 B1Abstract A device for treating cardiac disease of a heart having an upper portion and a lower portion divided by an A�V groove, the device including a jacket adapted to be secured to the heart, and a delivery source for the delivery of one or more therapeutic agents to the surface of the heart. The jacket is fabricated from a flexible material defining a volume between an upper and a lower end, the jacket being adapted to be adjusted on the heart to snugly conform to an external geometry of the heart and assume a maximum adjusted volume for the jacket to constrain expansion of the heart beyond the maximum adjusted volume during diastole and permit substantially unimpeded contraction of the heart during systole. As a result of the flexible material, the jacket allows unimpeded diastolic filling of the heart. Also described is a method for treating cardiac disease including surgically accessing the heart, applying the treatment device of the invention, securing the treatment device to the heart, and surgically closing access to the heart while leaving the treatment device on the heart.
1. A device for treating cardiac disease of a heart having an upper portion and a lower portion divided by an A-V groove, the device comprising:
a. a jacket of flexible material defining a volume between an upper end and a lower end, the jacket adapted to be secured to the heart and adapted to be adjusted on the heart to snugly conform to an external geometry of the heart and permit substantially unimpeded contraction of the heart during systole while maintaining contact with said heart throughout a cardiac cycle;
b. a delivery source in association with the jacket for placement therewith on the heart and for the delivery of one or more therapeutic agents to a target surface of the heart following placement of the jacket on the heart;
c. said delivery source provided directly on said jacket and positioned on said jacket to oppose an exterior surface of said heart
d. said delivery source adapted for passive delivery of said therapeutic agents to said heart.
2. The device according to claim 1 wherein the flexible material is sufficiently flexible to gather excess amounts of the material following placement of the jacket over the heart to snugly conform the material to an external geometry of the heart.
3. The device according to claim 1 wherein the flexible material is selected from polytetrafluoroethylene, expanded polytetrafluoroethylene, polypropylene, polyester and stainless steel.
4. The device according to claim 1 wherein the jacket surrounds the lower portion of the heart.
5. The device according to claim 1 wherein the jacket surrounds the upper portion of the heart.
6. The device according to claim 1 wherein the device provides localized delivery of one or more therapeutic agents to a target area on the surface of the heart.
7. The device according to claim 1 wherein the device provides bi-directional delivery of one or more therapeutic agents to the surface of the heart and an area surrounding the heart.
8. The device according to claim 1 wherein the one or more therapeutic agents comprise one or more pharmacological agents.
9. The device according to claim 1 wherein the one or more therapeutic agents comprise cellular material.
10. The device according to claim 9 wherein the cellular material comprises myocytes.
11. A device for treating cardiac disease of a heart having an upper portion and a lower portion divided by an A�V groove, the device comprising:
a. a jacket of flexible, elastic material defining a volume between an upper end and a lower end, the jacket adapted to be secured to the heart and adapted to be adjusted on the heart to snugly conform to an external geometry of the heart and permit substantially unimpeded contraction of the heart during systole while maintaining contact with said heart throughout a cardiac cycle; and
b. a delivery source comprising a coating on the jacket for the delivery of one or more therapeutic agents to a target surface of the heart following placement of the jacket on the heart,
c. said delivery source provided directly on said jacket and positioned on said jacket to oppose an exterior surface of said heart;
12. The device according to claim 11 wherein the coating comprises a matrix material and the therapeutic agent.
13. The device according to claim 12 wherein the matrix material is biodegradable.
14. The device according to claim 1 wherein the delivery source comprises a separable element from the jacket.
15. The device according to claim 14 wherein the separable element is a bladder or a patch.
16. The device according to claim 14 wherein the separable element is a bioadhesive.
17. The device according to claim 1 wherein the jacket actively assists in delivery of the therapeutic agent to the surface of the heart.
18. A method for treating cardiac disease of a heart having an upper portion and a lower portion divided by an A�V groove, the method comprising:
a. surgically accessing the heart;
b. applying a treatment device on the heart, the device comprising:
1) a jacket of flexible, elastic material defining a volume between an upper end and a lower end, the jacket adapted to be secured to the heart and adapted to be adjusted on the heart to snugly conform to an external geometry of the heart and permit substantially unimpeded contraction of the heart during systole while maintaining contact with said heart throughout a cardiac cycle; and
2) a delivery source in association with the jacket for placement therewith on the heart and for the delivery of one or more therapeutic agents to a target surface of the heart following placement of the jacket on the heart;
3) said delivery source provided directly on said jacket and positioned on said jacket to oppose an epicardial surface of said heart;
4) said delivery source adapted for passive delivery of said therapeutic agents to said heart;
c. securing the treatment device to the heart; and
d. surgically closing access to the heart while leaving the treatment device on the heart.
19. The method according to claim 18 wherein the jacket actively assists in delivery of the one or more therapeutic agents to the surface of the heart.
20. A method for providing controlled and sustained administration of one or more therapeutic agents effective in treating cardiac disease, the method comprising surgically implanting a sustained therapeutic agent delivery system at a desired location on the heart, the therapeutic agent delivery system comprising:
21. The method according to claim 20 wherein the jacket actively assists in delivery of the therapeutic agent to the surface of the heart.
22. The device of claim 1, wherein said jacket comprises a knit material and said delivery source occupies the interstitial spaces between the knit materials.
23. The device of claim 22, wherein said delivery source comprises a biodegradable space fill material that comprises a biologically active compatible polymer, a biodegradable polymer matrix, or a combination thereof that contains the therapeutic agent.
24. The device of claim 1, wherein the jacket material serves as a scaffold onto which a matrix material comprising the therapeutic agent is attached.
25. The device of claim 24, wherein said jacket material is a knit material.
FIELD OF THE INVENTION The present invention relates a device and method for treatment of cardiac disease and related cardiac complications. In particular, the present invention relates to a device for treating cardiac disease that includes a jacket that is adapted to be secured to the heart, and a delivery source for the delivery of a therapeutic agent to the surface of the heart.
BACKGROUND OF THE INVENTION Chronic or congestive heart disease is a progressive and debilitating illness. The disease is characterized by a progressive enlargement of the heart. Often, heart failure develops as a consequence of coronary artherosclerosis and myocardial infarction. After an infarction, the irreversibly injured myocardium is gradually replaced with fibrous scar tissue, since myocytes have limited ability to proliferate, and lost myocytes cannot regenerate. As myocytes are replaced with fibroblasts and collagen, changes in the mechanics of the heart lead to progressive onset of congestive heart failure.
SUMMARY OF THE INVENTION The present invention provides a device and method for treating cardiac disease and related cardiac complications. According to the invention, the device comprises a jacket that is adapted to be secured to the heart, and a delivery source for the delivery of a therapeutic agent to the surface of the heart. Preferably, the device provides sustained, controlled release of one or more therapeutic agents while in intimate, non-shifting contact with the heart. In a preferred embodiment, application of the therapeutic agent can be localized so that the therapeutic agent is only delivered to one or more selected target areas of the heart and/or target areas surrounding the heart.
In one embodiment, a device for treating cardiac disease comprises a jacket of flexible material that is secured to the heart and conforms to an external geometry of the heart, and a delivery source for the delivery of a therapeutic agent to the surface of the heart. Preferably, the jacket is adapted to be adjusted on the heart to snugly conform to an external geometry of the heart and assume a maximum adjusted volume for the jacket to constrain expansion of the heart beyond the maximum adjusted volume during diastole and permit substantially unimpeded contraction of the heart during systole. In one aspect, the therapeutic agent comprises one or more pharmacological agents, cellular material, or a combination thereof.
In another embodiment, methods for treating cardiac disease and related cardiac complications are described, the method comprising surgically accessing the heart; applying a treatment device on the heart, the device comprising a jacket of flexible material that is secured to the heart and conforms to an external geometry of the heart, and a delivery source for the delivery of a therapeutic agent to the surface of the heart; securing the treatment device to the heart; and surgically closing access to the heart while leaving the treatment device on the heart.
In yet another embodiment, the invention provides a method for providing controlled and sustained administration of a therapeutic agent effective in treating cardiac disease and related cardiac complications, the method comprising surgically implanting a sustained therapeutic agent delivery system of the invention at a desired location on the heart.
FIG. 10 is a schematic cross sectional view of an embodiment of a cardiac reinforcement device according to the invention, including a separable element.
DETAILED DESCRIPTION The present invention provides devices and methods for treatment of cardiac conditions such as cardiomyopathy, valvular insufficiency, arrhythmias, and other cardiac complications. Generally, the invention is directed to a jacket that is secured to the heart and constrains expansion of the heart during diastole to a predetermined limit, and a delivery source for the delivery of a therapeutic agent to the surface of the heart.
Due to the compound curves of the upper and lower portions UP′, LP′, the upper and lower portions UP′, LP′ meet at a circumferential groove commonly referred to as the A�V groove AVG′. Extending away from the upper portion UP′ are a plurality of major blood vessels communicating with the chambers RA′, RV′, LA′, LV′. For ease of illustration, only the superior vena cava SVC′ and a left pulmonary vein LPV′ are shown as being representative.
The valves are secured, in part, to the myocardium MYO′ in a region of the lower portion LP′ adjacent the A�V groove AVG′ and referred to as the valvular annulus VA′. The valves TV′ and MV′ open and close through the beating cycle of the heart H.
Comparing FIGS. 1 and 2 (showing hearts H′ and H during systole), the lower portion LP of the diseased heart H has lost the tapered conical shape of the lower portion LP′ of the healthy heart H′. Instead, the lower portion LP of the diseased heart H bulges outwardly between the apex A and the A�V groove AVG. So deformed, the diseased heart H during systole (FIG. 2) resembles the healthy heart H′ during diastole (FIG. 1A). During diastole (FIG. 2A), the deformation is even more extreme.
The device of the present invention comprises a jacket adapted to be secured to the heart and a delivery source for delivery of one or more therapeutic agents to the heart. In general, a jacket of the invention is configured to surround the myocardium MYO. As used herein, �surround� means that the jacket provides reduced expansion of the heart wall at end diastole by applying constraining surfaces at least at diametrically opposing aspects of the heart. In some preferred embodiments disclosed herein, the diametrically opposed surfaces are interconnected, for example, by a continuous material that can substantially encircle the external surface of the heart. The jacket is also preferably fabricated from a flexible material to allow unrestricted filling of the heart during diastole.
With reference now to FIGS. 3, 3A, 4 and 4A, the device of the present invention is shown as a jacket 10 of flexible biologically compatible material. As used herein, �biologically compatible material� means material that is not biologically adverse such that the material will not cause adverse effects to surrounding tissues, such as rejection, infection, inflammation, and the like. Such material can be a biostable material such as a biostable polymer, or a biodegradable material as discussed in more detail below.
The jacket of the invention can be provided in any suitable size and shape for application to the heart. In one embodiment for example, the jacket 10 is provided in a conical shape. As used herein, �conical� refers to a shape of the jacket wherein the diameter of the jacket decreases from the upper end 12, 12′ towards the lower end 14, 14′, to approximate the ellipsoid shape of the heart. In one embodiment, the size of the jacket 10 is predetermined, such that the jacket is fabricated in a conical shape prior to application to the heart. Alternatively, the shape of the jacket is adjusted at the time of placement of the device on the heart.
Since enlargement of the lower portion LP is most troublesome, in a preferred embodiment, the jacket 10 is sized so that the upper end 12 can reside in the A�V groove AVG. Where it is desired to constrain enlargement of the upper portion UP, the jacket 10 may be extended to cover the upper portion UP.
Sizing the jacket 10 for the upper end 12 to terminate at the A�V groove AVG may be desirable for a number of reasons. First, the groove AVG is a readily identifiable anatomical feature to assist a surgeon in placing the jacket 10. By placing the upper end 12 in the A�V groove AVG, the surgeon is assured the jacket 10 will provide sufficient constraint at the valvular annulus VA. The A�V groove AVG and the major vessels act as natural stops for placement of the jacket 10 while assuring coverage of the valvular annulus VA. Using such features as natural stops is particularly beneficial in minimally invasive surgeries where a surgeon's vision may be obscured or limited.
In the embodiment of FIGS. 3 and 3A, the lower end 14 is closed and the length L is sized for the apex A of the heart H to be received within the lower end 14 when the upper end 12 is placed at the A�V groove AVG. In the embodiment of FIGS. 4 and 4A, the lower end 14�is open and the length L� is sized for the apex A of the heart H to protrude beyond the lower end 14′ when the upper end 12′ is placed at the A�V groove AVG. The length L′ is sized so that the lower end 14′ extends beyond the lower ventricular extremities LE such that in both of jackets 10, 10′, the myocardium MYO surrounding the ventricles RV, LV is in direct opposition to material of the jacket 10, 10′. Such placement is desirable for the jacket 10, 10′ to present a constraint against enlargement of the ventricular walls of the heart H.
In another embodiment, the jacket is secured to the heart using a suitable bioadhesive. The bioadhesive can be used in connection with a jacket alone, or in combination with one or more therapeutic agents and/or a nonadherent material. As used herein, a �bioadhesive� means a material that adheres an element to a biological tissue, or two biological tissues to each other. Preferably, the bioadhesive is fabricated from a material that is biologically compatible and allows secure attachment to a tissue. According to the present invention, preferred bioadhesives attach the jacket 10 to the heart in a sufficient non-shifting manner and for a sufficient amount of time to allow the desired effects. The bioadhesive preferably secures the jacket sufficiently to avoid dislocation of the jacket as a result of the heart's natural movement. Preferred bioadhesives are thus somewhat flexible to accommodate movement of the heart or surrounding tissue.
Preferred bioadhesives are fabricated from such materials as polyethylene glycol, fibrin, cyanoacrylate, or material comprising a combination of bovine serum albumin (BSA) and gluteraldehyde. Suitable polyethylene glycol-based materials are provided by Focal, Inc., under the product name Focal Seal�, and Cohesion Technologies, Inc. under the product name CoSeal�. Examples of fibrin-based materials are provided by Haemacure Corporation under the product name Hemaseel�. Suitable material based in combining bovine serum albumin and gluteraldehyde are provided by Cryolife International, Inc. Examples of cyanoacrylate-based materials are provided by Johnson & Johnson under product name Dermabond�. Other suitable bioadhesives known in the art could be substituted for the above materials, given the description herein.
The jacket 10 is constructed from a knit, biocompatible material. The knit 18 is illustrated in FIG. 6. Preferably, the knit is a so-called �Atlas knit� well known in the fabric industry. The Atlas knit is described in Paling, Warp Knitting Technology, p. 111, Columbine Press (Publishers) Ltd., Buxton, Great Britain (1970).
For ease of illustration, fabric 18 is schematically shown in FIG. 7 with the axis of the strands 21 a, 21 b only being shown. The strands 21 a, 21 b are interwoven with the axes Xa and Xb defining a diamond-shaped open cell 23 having diagonal axes Am. In a preferred embodiment, the axes Am are 5 mm in length when the fabric 18 is at rest and not stretched. The fabric 18 can stretch in response to a force. For any given force, the fabric 18 stretches most when the force is applied parallel to the diagonal axes Am. The fabric 18 stretches least when the force is applied parallel to the strand axes Xa and Xb. The jacket 10 is constructed for the material of the knit to be directionally aligned for a diagonal axis Am to be parallel to the heart's longitudinal axis AA�BB.
A large open area for cells 23 is desirable to minimize the amount of surface area of the heart H in contact with the material of the jacket 10 (thereby reducing fibrosis). However, if the cell area 23 is too large, localized aneurysm can form. Also, a strand 21 a, 21 b can overlay a coronary vessel with sufficient force to partially block the vessel. A smaller cell size increases the number of strands thereby decreasing the restricting force per strand. In a preferred embodiment, the cell area CA of cells in a particular row directly correlates with a cross-sectional circumferential dimension of the heart that the row of cells surrounds relative to other cross-sectional circumferential dimensions. That is, the greater the cross-sectional circumferential dimension, the greater the area of the cells in the row of cells directly overlying that cross-sectional circumferential dimension. By �correlating� cell area with cross-sectional circumferential dimension of the heart, the cell area is determined as a function of the cross-sectional circumferential dimension of the heart. The cell area is determined so that when the weave material is applied to the heart or is shaped into a jacket and applied to the heart, each cell can widen sufficiently to provide desirable cardiac constraint. Thus, the cell area will be smaller for cells in a row applied over a region of the heart that has a smaller cross-sectional circumferential dimension than the cell area of cells in a row applied over a region of the heart having a larger cross-sectional circumferential dimension. The appropriate maximum cell area may be, for example, 1 to 100 mm2, typically 3 to 9 mm2. The maximum cell area is the area of a cell 23 after the material of the jacket 10 is fully stretched and adjusted to the maximum adjusted volume on the heart H as previously described.
In one embodiment, a non-adherent material is provided in connection with the jacket 10 of the invention, to prevent unwanted fibrosis as a result of the presence of the jacket on the surface of the heart. As used herein, �non-adherent material� means a material that is biocompatible and does not adhere to surfaces of organs, such as the epicardial surface of the heart. The material can be preformed in a manner similar to the jacket of the invention, as described above. In one embodiment, the non-adherent material is fabricated as part of the jacket of the invention. Alternatively, the non-adherent material is fabricated as a separate element of the invention, and is positioned between the jacket of the invention and the epicardial surface of the heart. The non-adherent material facilitates removal of the jacket, which can become difficult when the jacket has been in place on the heart for a long period of time.
In another embodiment, the non-adherent material is placed on the outer surface of the jacket; that is, the surface of the jacket facing away from the heart. In this embodiment, the non-adherent material prevents unwanted fibrosis of surrounding tissues. Alternatively, the non-adherent material can be configured to be a hydrogel material that fills interstitial spaces of the jacket. It will be apparent to one of skill in the art that the non-adherent material can be configured to prevent undesirable fibrosis or other damage to any target tissue.
Alternatively, the non-adherent material is placed at strategic base-to-apex locations to allow relief of constriction. In one embodiment shown in FIG. 9, the non-adherent material 32 forms ribs 34 that course from base to apex of the heart. Preferably, the ribs are provided a finite distance apart along the device. This embodiment is desirable should the jacket cause constriction of the heart. The ribs allow the surgeon to score the jacket at the rib sites in the event a patient develops a constrictive or restrictive pattern as a result of the jacket. Relief of constriction is desirable in certain patients. For example, constrictive physiology may occur in some patients as a result of the presence of the jacket and pressure of the heart during diastole. This may in turn require removal of the jacket.
The non-adherent material is fabricated from any suitable material that provides the desired properties. In one embodiment, the non-adherent material is fabricated from the same material used to fabricate the jacket 10, for example, polyesters, PTFE, polypropylene, polyurethane, silicone, and the like. In yet another embodiment, the non-adherent material is fabricated from a different material than the jacket 10. Another example of suitable non-adherent material is available commercially under the brand name GORE-TEX�. In yet another embodiment, the non-adherent material is fabricated from a hydrogel, as described herein. The non-adherent material can be flexible or rigid, depending upon the desired application. Given the present teaching, one of skill in the art can select a suitable non-adherent material.
The non-adherent material is provided, in one embodiment, as a separate element of the device. For example, the non-adherent material can be provided as a separate lining that is placed between the jacket and the surface of the heart, or on the outside surface of the jacket, facing away from the heart. In yet another embodiment, the non-adherent material of the invention is provided as a coating on the jacket of the device.
The jacket 10, including the knit construction, freely permits longitudinal and circumferential contraction of the heart H (necessary for heart function). Unlike a solid wrap (such as a muscle wrap in a cardiomyoplasty procedure), the fabric 18 does not impede cardiac contraction. Further, the jacket permits unrestricted diastolic filling of the heart. The jacket prevents overstressing or stretching of the ventricle at the end of diastole. After fitting, the jacket 10 is inelastic to prevent further heart enlargement while permitting unrestricted inward movement of the ventricular walls. The open cell structure permits access to coronary vessels for bypass procedures subsequent to placement of the jacket 10. Also, in cardiomyoplasty, the latissimus dorsi muscle has a variable and large thickness (ranging from about 1 mm to 1 cm). In contrast, the material of the jacket 10 is uniformly thin (less than 1 mm thick). The thin wall construction thus reduces the risk of fibrosis and minimizes interference with cardiac contractile function.
The jacket described above is used in connection with a delivery source for the delivery of a therapeutic agent to the surface of the heart. As used herein, a �therapeutic agent� is an agent that assists in the treatment, cure, relief or prevention of disease or disorders of the heart or surrounding tissue. Therapeutic agents function by affecting the structure or function of the tissue treated, to have the desired effect.
The present invention provides a device and method for localized, targeted delivery of a therapeutic agent to a target area of the heart and/or of surrounding tissues. As used herein, �target,� �target area� and �target tissue� refer to a selected site of the heart, or of tissues surrounding the heart, intended to be treated using the present invention. As contemplated in the present invention, the target tissue can comprise any desired area to be treated with a method or device of the invention, including, for example, a specific area of the heart (such as an area of ischemia or necrosis, or one or more diseased or damaged arteries), the entire surface of the heart, or selected tissues surrounding the heart (such as the lung or pericardium). Further, after delivery to the surface of the target tissue, such as the heart, the therapeutic agent can penetrate the tissue surface and thereby act below the surface of the tissue.
As contemplated by the present invention, anti-arrhythmic drugs are compounds that act to inhibit arrhythmia (that is, abnormal cardiac rhythm) and stabilize normal sinus rhythm to the heart. Examples of anti-arrhythmic drugs include those classified as type I (such as lidocaine, procainamide, encainide, flecainide), type II (for example, β-adrenergic blocking agents such as norepinephrine, epinephrine, isoproterenol, propanolol, dobutamine), and type III (such as ibutilide and solatol), as well as quinidine, phenyloin, angiotensin converting enzyme (ACE) inhibitors, nitroglycerin, hydralazine, captopril, and calcium channel blockers such as verapanil, nifedipine, and diltiazem.
Alternatively, the therapeutic agent of the present invention comprises one or more anti-inflammatory or anti-fibrotic agents. Such anti-inflammatory or anti-fibrotic agents are agents that inhibit scar formation associated with aberrant fibrosis and prevent formation of epicardial fibrosis, which could interfere with diffusion of other agents from the device of the present invention to the target tissue and could increase resistance to electric current flow, thus requiring a pacemaker to deliver more voltage. Examples of suitable anti-inflammatory or anti-fibrotic agents include steroids, such as dexamethasone and the like, and lathrogenic agents such as penicillamine, n-acetyl-cysteine, α-aminopropionitrile, and the like.
Alternatively, the therapeutic agent can be provided in the form of a therapeutic gene that functions to assist in the treatment, cure, relief or prevention of disease or disorders of the heart or surrounding tissue. As used herein, a �therapeutic gene� is a segment of nucleic acid that specifies a particular protein or polypeptide chain that, when expressed, provides a therapeutic effect. Many such therapeutic genes are known in the art to provide beneficial effects in the treatment of cardiac disease or disorders. For example, suitable therapeutic genes function to prevent restenosis, promote angiogenesis, modulate pathways of electrical conductance to control cardiac arrhythmias, enhance the wound healing process (for example, using such growth factors as TGF-β), or express thrombolytic agents such as tissue plasminogen activator (TPA) or urokinase.
Suitable pharmacological agents can be surface-acting or can penetrate the myocardium. For example, small molecule compounds are capable of penetrating the myocardium to act beneath the surface of the heart. Examples of small molecule compounds that are capable of penetrating the MYO include anti-arrhythmic agents, lathrogenic agents such as penicillamine, N-acetyl-L-cysteine, and 3-aminoproprionitrile fumarate, and the like.
When the therapeutic agent comprises a pharmacological agent, the agent can be provided with any suitable carrier diluent, filler, binder or other excipient, depending upon the composition of the delivery source and the dosage desired, for delivery of the agent to the target tissue. By �carrier� is meant a pharmaceutically acceptable carrier that is conventionally used in the art to facilitate the storage, administration, and/or healing effect of the agent. A carrier may also reduce any undesirable side effects of the agent. A suitable carrier should be stable, i.e., incapable of reacting with other ingredients of the formulation. It should not produce local adverse effects in recipients at the dosages and concentrations employed for treatment. Such carriers are generally known in the art. See Remington's Pharmaceutical Sciences, 16th edition, Olso, A. ed. (1980).
The implanted cellular material may include culture media. Those of skill in the art are familiar with cell culture media. Examples of commercial available media include Ham's F10 (Sigma), Minimal Essential Medium (�MEM�, sigma), RPMI-1640 (Sigma), and Dulbecco's Modified Eagle's Medium (�DMEM�, Sigma). The media may be supplemented as necessary with hormone and/or other growth factors, salts, buffers, nuclosides, antibiotics and trace elements (inorganic compounds usually present at final concentrations in the micromolar range). Alternately, the delivery source may allow nutrients to diffuse into the cavity to support the live cell culture.
In one embodiment of the invention, the implanted cells can be genetically engineered transformed cells. As used herein, the term �transformed cells� refers to cells in which an extrinsic DNA or gene construct has been introduced such that the DNA is replicable, either as an extrachromosomal element or by chromosomal integration. Transformation of the cells is accomplished using standard techniques known to those of skill in the art and is described, for example, by Sambrook et al., Molecular Cloning: A Laboratory Manual, New York, Cold Spring Harbor Laboratory Press (1989).
In one embodiment, cellular material is selected from smooth muscle cells, endothelial cells, mesenchymal stem cells, and fibroblasts and is introduced into the cardiac environment using transdifferentiation. Transdifferentiation is a procedure such as that described by Kessler et all, that involves the conversion of a committed, differentiated, or specialized cell to another differentiated cell type with a distinctly different phenotype (See Myoblast Cell Grafting Into Heart Muscle: Cellular Biology and Potential Applications, P. D. Kessler et al., Annu. Rev. Physiol. 1999, 61:219�42). In the present invention, smooth muscle cells, endothelial cells, mesenchymal stem cells, and/or fibroblasts from a donor can be provided in connection with the delivery source (e.g., the cells can be seeded onto the surface of the delivery source, as discussed in more detail below), to provide a source of cellular material for transdifferentiation.
In one embodiment, the jacket material serves as a scaffold onto which the matrix material containing the therapeutic agent is attached. For example, contractile cells can be seeded or sodded into/onto the jacket in such a way that the jacket material serves as a scaffold for support of the cells. As described herein, the cells can be harvested from a patient culture and applied to the jacket material. Alternatively, mesenchymal cells can be harvested from another patient and applied to the jacket material. In either event, these cells can then be adapted to perform contractile work, much in the way that skeletal muscle is adapted to the requirements for contraction in association with cardiomyoplasty. Cells implanted on/in the jacket can be exposed to an oriented electric field in such a way that the cells orient into a contractile element. Optimally, the biocompatible material comprising the material of the jacket is itself designed and oriented in the proper direction(s) of muscle contraction (i.e., in line with muscle fibers of the heart). The cells contained on the device are then capable of being stimulated using an electronic pacemaker, synchronous with the heart. Approaches to replacing myocardial scar tissue with cardiac cells are discussed, for example, by Li et al., in Cell Therapy to Repair Broken Hearts, Can. J. Cardiol. 14, 5: 735�744 (1998).
In one embodiment, the delivery source is provided as a coating on, and/or impregnated into the material of, the jacket of the device. In this embodiment, the coating comprises a matrix material and one or more therapeutic agents. As used herein, the matrix material is a biologically and pharmacologically compatible and/or biodegradable material that can be adapted to include one or more therapeutic agents. Preferably, the matrix material is flexible and permeable to the therapeutic agent to provide a suitable source for controlled release of the agent. Examples of suitable matrix materials include and polymeric matrix materials and hydrogels.
Whether the coating is provided along the fiber strands only, or over both the fiber strands and open cells, the flexibility of the jacket is maintained. The directional expansion properties of the knit material allows the delivery source of the device to maintain intimate contact with the surface of the heart so that one or more therapeutic agents can be released directly to the surface of the heart and/or target tissue surrounding the heart. The coating itself is sufficiently flexible so that it does not fracture and fall or peel off from the material, but rather expands along with the jacket material. Further, because the jacket surrounds the heart and expands along with the heart during its natural movement, the delivery source is maintained in intimate contact with the surface of the heart for prolonged periods of time. The device is not loosened by natural movement of the heart, and therefore delivery of one or more therapeutic agents that is intimate and non-shifting can be provided for prolonged periods of time.
In another embodiment of the present invention, the delivery source is provided as an element that is separate from the jacket 10 of the device, herein referred to as a �separable element� 36. The separable element 36 can be provided in the form of a patch containing the therapeutic agent of interest, or a bladder containing the therapeutic agent. Suitable patches and bladders are known in the art. For example, see Epicardial Administration of Ibutilide from Polyurethane matrixes: Effects on Defibrillation Threshold and Electrophysiologic Parameters, Labhasetwar et al., J. Of Cardiovascular Pharm., 24:826�840 (1994), Sotalol Controlled-Release Systems for Arrhythmias: In Vitro Characterization, In Vivo Drug Disposition, and Electrophysiologic Effects, Labhasetwar et al., J. of Pharm. Sciences, 83: 156�164 (1994).
In this embodiment, an example of which is depicted in FIG. 10, the jacket provides an anchoring surface for the separable element 36 that presses the separable element 36 against the surface of the heart and maintains the separable element 36 in position on the heart H. According to the invention, the patch or bladder can be provided underneath the jacket 10, such that the separable element 36 is positioned between the jacket and the heart. The jacket presses the separable element 36 against the heart, without causing damage to the heart that would result from directly attaching the separable element 36 at the treatment site, by sutures, adhesives or the like. The separable element 36 can be attached to the jacket, for example, using sutures or bioadhesives, to maintain the position of the separable element 36 in relation to the jacket. Alternatively, the patch or bladder can be held in place simply by the pressure of the jacket against the heart. Because the jacket itself is maintained in non-shifting contact with the heart, the separable element 36 is also provided with a non-shifting position on the surface of the heart. For example, the use of the jacket to maintain the positioning of the separable element 36 avoids such undesirable effects as fibrosis, necrosis, and the like.
In a particular aspect, the invention provides a delivery source that can be either bi-directional or uni-directional. Bi-directional release of the therapeutic agent is desirable, for example, when preventing adhesion between the heart and surrounding tissues. For example, when the target tissue is the heart, the delivery source can be adapted to release the therapeutic agent towards the heart only. In one embodiment, this unidirectional release can be accomplished by providing a coating containing the therapeutic agent on the jacket facing the heart only. Alternatively, when the target tissue is the tissue surrounding the heart, the delivery device can be adapted to release the therapeutic agent away from the heart, and thus towards the target tissues.
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