Balloon catheter devices with folded balloons

Catheter devices having an expandable balloon for delivering a therapeutic agent to a body site. The balloon has one or more folds which serve as a reservoir for containing the therapeutic agent. The fold may have any of various configurations to hold the therapeutic agent. In some cases, the balloon comprises one or more lobes that forms the fold(s). The therapeutic agent may be provided in various ways. For example, the therapeutic agent may be contained in packets that rupture upon expansion of the balloon, or as a plurality of discrete bulk masses, or sealed within compartments.

TECHNICAL FIELD

The present invention relates to medical devices, more particularly, to catheter devices.

BACKGROUND

Catheters are used in a wide variety of minimally-invasive or percutaneous medical procedures. Balloon catheters having drug coatings may be used to treat diseased portions of blood vessels. Typically, the balloon is inserted through a peripheral blood vessel and then guided via a catheter through the vascular system to the target intravascular site. However, as the balloon travels through the vascular system, the flow of blood may wash away some of the drug coating. In addition, the control of the timing, location, and/or duration of the drug release can be an issue. Therefore, there is a need for improved catheter-based devices for drug delivery to an intravascular site.

SUMMARY

In one embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter, the balloon having a main body and at least one lobe that forms a fold, wherein the fold opens upon expansion of the balloon; and a therapeutic agent disposed within the fold, wherein opening of the fold upon expansion of the balloon promotes the release of the therapeutic agent.

In another embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter, the balloon comprising at least one lobe forming a fold of the balloon, wherein the fold opens upon expansion of the balloon; and a packet disposed within the fold, the packet containing a therapeutic agent and having a first attachment site where the packet is attached to the lobe and a second attachment site where the packet is attached to an adjacent surface of the balloon.

In another embodiment, the present invention provides a medical device comprising: a catheter; a balloon mounted on the catheter, the balloon having a plurality of folds that open upon expansion of the balloon; and a plurality of discrete bulk masses of therapeutic agent disposed within the folds, wherein the bulk masses of therapeutic agent are released upon opening of the folds.

DETAILED DESCRIPTION

Catheter devices of the present invention use an expandable balloon for delivering a therapeutic agent to a target site in the body. The balloon is designed to be insertable in the body via a catheter. The therapeutic agent can be associated with the balloon in any of various ways, as further described below. Any of various mechanisms conventionally used for the delivery, actuation, or expansion (e.g., by inflation) of balloon catheter devices may be used in the present invention. The balloon catheter may be designed similar to those that have been known in the art, including but not limited to angioplasty catheters, stent delivery catheters, inflation catheters, and/or perfusion catheters. The catheter devices of the present invention may be used in conjunction with other drug delivery devices, such as stents.

The balloon has one or more folds which serve as reservoirs for containing a therapeutic agent. The folds may be oriented in any of various ways on the balloon, including, for example, longitudinally, radially, circumferentially, or helically. The folds may be made by any of the methods known in the art, including but not limited to methods described in U.S. Pat. No. 5,342,307 (Enteneuer et al.), 5,147,302 (Enteneuer et al.), 5,458,572 (Campbell et al.), 5,954,740 (Ravenscroft et al.), 6,013,055 (Bampos et al.), 7,128,868 (Eidenschink), or 7,306,616 (Eidenschink et al.), 2004/0215227 (McMorrow et al.), which are all incorporated by reference herein.

The folds may have any of various configurations to hold the therapeutic agent. For example, the folds may be in the form of pockets, grooves, dimples, or wells. The folds are not limited to structures formed by the bending, creasing, or pleating of the balloon wall. Folds may also be formed as voids within the balloon wall itself (e.g., as grooves, channels, or trenches), which may be made during extrusion or by etching, stamping, laser ablation, or heat ablation of the balloon.

As the balloon is expanded (e.g., by inflation), the folds are made to open such that the therapeutic agent is exposed and allowed to be released. For example, referring to the embodiment shown inFIGS. 1A-1C, a catheter device10comprises a balloon14mounted on an elongate shaft12. Balloon14has a folded groove16extending in a helical fashion around the circumference of balloon14. As shown in the enlarged, cross-section view inFIG. 1B, when balloon14is in a deflated state, the edges17of folded groove16cooperate to form a compartment19holding a therapeutic agent18. The edges17may touch or be close together and may be held together by, for example, an adhesive, biodegradable or bioerodable sutures or stitching, or some other means by which the edges may be held closely together or touching during balloon delivery but which will allow the edges to separate upon balloon expansion. The width, pitch, pitch angle, and depth of folded groove16on balloon14will vary depending upon the particular application.

In operation, balloon14is inserted into the body via a catheter. Because therapeutic agent18is contained within folded groove16, therapeutic agent18is protected while balloon14is being guided to the target site. As shown inFIG. 1C, at the target site, balloon14is inflated, causing folded groove16to widen and causing edges17of folded groove16to separate, thus exposing therapeutic agent18for release at the target site.

In another example, referring to the embodiment shown inFIGS. 2A and 2B, a catheter device20comprises a balloon24mounted on an elongate shaft22. Balloon24has a plurality of folded grooves26extending in a radial fashion around the circumference of balloon24. When balloon24is in a deflated state, the edges27of grooves26cooperate to form compartments holding therapeutic agent18. The edges27may touch or be close together and may be held together as described above. The cross-section of a groove26may be similar to that shown inFIG. 1B. The number, width, pitch, and depth of folded grooves26on balloon24will vary depending upon the particular application.

In operation, balloon24is inserted into the body via a catheter. Because therapeutic agent18is contained within folded groove26, therapeutic agent18is protected while balloon24is being guided to the target site. As shown inFIG. 2B, at the target site, balloon24is inflated, causing groove26to widen and causing edges27of folded groove26to separate, thus exposing therapeutic agent18for release at the target site.

In certain embodiments of the invention, the configuration of the balloon and the therapeutic agent reservoirs can be controlled such as to allow release of the therapeutic agent only at the desired time. For example, the device may be designed such that a certain pressure within the balloon is required for the folds to open and release the therapeutic agent. In this way, the therapeutic agent can be held in the folds while the device is delivered through the blood vessel to the target site. Then, at the target site, the balloon is inflated, and when the balloon reaches the pressure and/or diameter at which the folds are designed to open, the therapeutic agent will be released. In this way, for example, the therapeutic agent release can be controlled such that it is released only if the balloon is in contact with or in close proximity to the vessel wall. This helps to prevent loss of the therapeutic agent during catheter placement and balloon inflation. Also, because deflation of the balloon can, in some instances, stop or substantially reduce therapeutic agent release, certain embodiments of the invention can control the duration of release after the initial release of therapeutic agent.

In certain embodiments, the balloon comprises one or more lobes (e.g., a wing, a bi-fold wing, a T-wing, or a cuff) that forms the one or more folds. For example, referring to the embodiment shown inFIGS. 3A and 3B, a catheter device30comprises a balloon34mounted on an elongate shaft32. Balloon34comprises a cylindrical main body31, which is coated with a therapeutic agent18, and two circumferential cuff portions36. When the balloon is in an unexpanded state, cuff portions36assume a low profile to allow insertion of the balloon into a catheter and/or blood vessel. The interior37of cuff portions36are in communication with the inflation chamber35of main body31. As shown inFIG. 3A, when balloon34is in a deflated state, cuff portions36are folded over balloon34such that cuff portions36cover therapeutic agent18. In certain embodiments, only the surfaces of balloon34that are covered by cuff portions36when in a deflated state are coated with the therapeutic agent.

In operation, balloon34is inserted into a blood vessel via a catheter. Because cuff portions36cover therapeutic agent18, therapeutic agent18is protected while balloon34is being guided to the target site. At the target site, as shown inFIG. 3B, balloon34is inflated, causing cuff portions36to extend outward in a radial direction, thus exposing therapeutic agent18for release at the target site. In an example embodiment, when the cuff portions36are fully extended radially, each cuff portion has a length of between about ¼ of the entire length of balloon34to ½ of the entire length of balloon34. Also, by extending in a radial direction, cuff portions36can also abut against the vessel wall38and seal the space between cuff portions36. In this way, therapeutic agent18can be applied to vessel wall38while reducing the amount of therapeutic agent18washed away downstream by the flow of blood.

In another example, referring to the embodiment shown inFIGS. 4A-4C, a catheter device comprises a balloon60, which has a plurality of inflatable bi-fold wings62and an inflatable central body64. When the balloon is in an unexpanded state, bi-fold wings62assume a low profile to allow insertion of the balloon into a catheter and/or blood vessel. The interior66of bi-fold wings62are in communication with the inflation chamber65of central body64. As shown inFIG. 4A, when balloon60is in a deflated state, a therapeutic agent18is sandwiched between the folds of bi-fold wings62. Also, when balloon60is in a deflated state, bi-fold wings62circumferentially wrap around central body64.

In operation, balloon60is inserted into the body via a catheter. Because therapeutic agent18is sandwiched between the folds of bi-fold wings62, therapeutic agent18is protected while balloon60is being guided to the target site. At the target site, as shown inFIG. 4B, balloon60is inflated, causing bi-fold wings62to extend outward. As shown inFIG. 4C, with further inflation, balloon60assumes a more cylindrical shape, in which therapeutic agent18is exposed on the outer surface of balloon60to facilitate application of therapeutic agent18to the body tissue.

In another example, referring to the embodiment shown inFIGS. 5A-5C, a catheter device comprises a balloon90, which has a plurality of inflatable T-wings92and an inflatable central body94. The interior96of T-wings92are in communication with the inflation chamber95of central body94. As shown inFIG. 5B, when balloon90is in a deflated state, a therapeutic agent18coats the inside surfaces of T-wings92(i.e., the undersides99and stems98of T-wings92).

In operation, balloon90is inserted into a patient's body via a catheter. Because therapeutic agent18is located on a non-exposed surface of balloon90, therapeutic agent18is protected while balloon90is being guided to the target site. As balloon90is inflated, T-wings92assume a less distinctive shape. As shown inFIG. 5C, as balloon90is inflated, T-wings92expand outward such that balloon90assumes a more cylindrical shape, in which therapeutic agent18is exposed on the outer surface of balloon90to facilitate application of therapeutic agent18to the body tissue.

In some cases, one or more packets containing the therapeutic agent may be disposed within the folds that are created by the lobes of the balloon. The packet is attached to two or more sites on the surface of the balloon at two or more different sites on the packet. As the balloon is expanded, the balloon applies a pulling force on the packet, causing the packet to rupture and allow release of the therapeutic agent.

The walls of the packet may or may not be distinct from the walls of the balloon. In some cases, at least a portion of the packet shares the same wall as the balloon. In some cases, the packet may be manufactured separately from the balloon and then attached to the balloon. In such cases, the walls of the packet may be distinct from the walls of the balloon. The packet may have various three-dimensional shapes suitable for fitting within the folds of the balloon, including rectangular cuboid, cylindrical, spheroid, or ellipsoid shapes. The packet may or may not have an elongate shape. The packet may or may not be completely sealed.

The packet has a tensile rupture strength, which is the amount of stretching force required to rupture the packet. To allow the packet to rupture upon expansion of the balloon, the strength of the attachment between the packet and the balloon will exceed the tensile rupture strength of the packet. The tensile rupture strength of the packet and/or the stretching force applied to the packet may be varied to create a design such that the packets rupture upon expansion of the balloon. For example, adjustments can be made to various parameters, such as the structural, geometric, and/or material characteristics of the packet; the spatial geometry of the attachment sites on the packet; the structural, geometric, and/or material characteristics of the balloon; and the dynamic geometry of the balloon as it expands. For example, the tensile rupture strength of the packet may be reduced by making the packet with thinner walls. In some cases, the packet may be made with a soft and pliable polymeric material to prevent premature rupture of the packet. For example, the packet may be made of polyurethane, especially when the balloon is also made of polyurethane.

The packet may contain a single therapeutic agent or a mixture of different therapeutic agents. In cases where the balloon has a plurality of packets, different packets may contain different therapeutic agents. The therapeutic agent may be provided in any suitable formulation or dosage form, such as capsules or nanoparticles (e.g., albumin-bound paclitaxel, sold as Abraxane® (Astra-Zeneca)). The packet may further contain an excipient material to facilitate delivery of the therapeutic agent. For example, the packet may contain a viscous material for adhering the therapeutic agent to the tissue. Examples of viscous materials which may be suitable for use include bioabsorbable waxes, pastes, binders (e.g., polyvinyl pyrrolidone), plasticizers, gels, proteins (e.g., albumin, fibrinogen, or gelatin), fats, or biodegradable polymers (e.g., glycerol, polylactic acid, or polyglycolic acid).

For example, referring to the embodiment shown inFIGS. 6A and 6B(transverse cross-section views), a catheter device comprises an elongate balloon100mounted on an elongate shaft102. Balloon100has a plurality of lobes104that form one or more folds. Disposed within the folds of balloon100are elongate strip-shaped packets106that hold a therapeutic agent108. Strip-shaped packets106are oriented parallel to the longitudinal axis of elongate balloon100. Packets106are adhered between a lobe104and an adjacent surface of the balloon100or between adjacent lobes104of balloon100. As shown here, packets106face the balloon surface at its “top” face103and “bottom” face105, which are the sites at which packet106is adhered to the balloon surface.

In operation, balloon100is inserted into the body via a catheter. Because packets106of therapeutic agent are contained within the folds created by lobes104, the therapeutic agent is protected while balloon100is being guided to the target site. As shown inFIG. 6B, upon inflation of balloon100, lobes106expand outward and open the folds. This expansion of lobes106pull apart packet106at its attachment sites causing packets106to rupture. As shown inFIG. 6B, rupture of packets106(leavings its remnants107) allows the release of therapeutic agent108.

FIG. 7shows one manner by which balloon100inFIG. 6Amay be made. With balloon100in an uninflated state, lobes104are unfolded to expose their sides. An adhesive is applied onto the “top” and “bottom” faces of packets106. Packets106are adhered onto one side of lobes104. Lobes104are then folded over such that the other side of each packet106is adhered to an adjacent surface of balloon100.

The packets may be designed in such a way to facilitate their rupture. For example,FIG. 8shows a rectangular-cuboid shaped packet120containing a therapeutic agent128. Packet120has a top face122, a bottom face124, and lateral faces126. The wall of packet120is thicker at the top face122and bottom face124, which are the sites of attachment to the balloon, and thinner at the lateral faces126. Thus, when top face122is pulled apart from bottom face124as the balloon is inflated, packet120will preferentially rupture at the lateral walls126.

In the embodiment shown inFIG. 6A, the attachment sites are on substantially opposite faces of packet106, with the attachment sites being pulled apart in opposite directions when balloon100is inflated. However, the attachment sites do not necessarily have to be located on opposite faces or be pulled apart in opposite directions, so long as the forces pulling upon the attachment sites are sufficient to rupture the packets. In some cases, the balloon and/or packets may be designed such that the attachment sites are pulled apart at an angle in the range of 60-180° as the balloon is inflated. To illustrate,FIG. 9shows an ovoid-shaped packet110containing a therapeutic agent111. Packet110is attached to lobes116of a balloon at attachment sites112and114. Arrows118and119represent the direction vector in which lobes116will pull on packet110as the balloon is inflated. In some embodiments, the angle θ between these two vectors is in the range of 60-180°, but other angles are also possible.

The use of packets as described herein allows for the containment of the therapeutic agent during manufacturing and/or delivery of the medical device into a blood vessel. Thus, the therapeutic agent is protected from the environment and from early release until the device is at the target site and the balloon is inflated. Also, the use of packets as well as the use of therapeutic agent reservoirs as described above can allow for the use of therapeutic agents (or formulation mixtures thereof) that could not otherwise be used because of lack of adherence to the balloon.

Also, the packets can be designed to protect the therapeutic agent in cases where the device is subjected to a sterilization process. For example, the packets can be sealed or have walls that are thicker or made of a less permeable material to make the packets in-penetrable to the sterilization process. As such, a wider range of sterilizations processes for the device can be made available, even some that may otherwise be harmful to an openly exposed therapeutic agent. For example, if it is desirable to use ethylene oxide to sterilize the device but the therapeutic agent is sensitive to ethylene oxide, the packets could be designed to be impermeable to ethylene oxide to protect the therapeutic agent contained inside. Furthermore, in cases where a vascular stent is crimped onto the balloon, the packets can be designed to withstand the forces that are applied during crimping of the stent onto the balloon.

The number of lobes and packets may vary, with possibly multiple packets per lobe. Also, the shape of the lobes can vary. For example, the lobes may be configured like the cuffs or wings shown inFIGS. 3A,3B,4A,4B,5A, and5B, with the packets being adhered in the places where the therapeutic agent is shown in these figures.

In certain embodiments, the therapeutic agent is provided as a plurality of bulk masses that are disposed within the folds. The bulk masses of therapeutic agent are discrete, i.e., distinct and detached from each other. The bulk masses of therapeutic agent may have any of various three-dimensional shapes suitable for fitting within the folds of the balloon, including rectangular cuboid, cylindrical, spheroid, or ellipsoid shapes. For example, the bulk masses of therapeutic agent may have an elongate shape in the form of rods, ribbons, strips, or fibers. The balloon may have from 10 to 1000 individual bulk masses of therapeutic agent disposed thereon, but other quantities are also possible depending upon the particular application.

The bulk masses of therapeutic agent may be thicker than the typical thickness of conventional drug coatings on balloons. For example, the bulk masses may have a thickness in the range of 10-150 μm, and in some cases, in the range of 25-100 μm, but larger or smaller thicknesses are also possible. The length of each bulk mass may be as small as 0.25 mm or smaller, and may range up to the entire length of the balloon (e.g., 8 mm for coronary artery balloons or 200 mm for peripheral artery balloons) or longer. In cases where paclitaxel is the therapeutic agent, each bulk mass may contain, for example, from 0.1 to 100 μg of paclitaxel.

For example, referring to the embodiment shown inFIG. 10, a bulk mass of therapeutic agent has the shape of a rod150. Referring to the embodiment shown inFIG. 11A(transverse cross-section view), the wall152of an elongate balloon is creased into folds154that extend longitudinally along the length of the balloon. Folds154contain the rods150of therapeutic agent. The folds may have edges similar to those described above with respect toFIG. 1B.

In operation, the balloon is inserted into the body via a catheter. Because rods150of therapeutic agent are contained within folds154, rods150are protected while the balloon is being guided to the target site. As shown inFIG. 11B, when the balloon is delivered to the target site and inflated, folds154open such that rods150are released from the balloon.

The bulk mass of therapeutic agent may be formed in any suitable way known in the art. For example, rods150may be made by preparing a liquid formulation of the therapeutic agent in a solvent. The liquid formulation of therapeutic agent is then applied into folds154of the balloon (e.g., by spraying or dip coating). The liquid formulation is then dried such that the solid residue of therapeutic agent is cast into the shape of fold154(i.e., as a rod shape). The shaping may be aided by crystallization of the therapeutic agent as it is dried. Also, shaping may be aided by adding other materials, such as binders, plasticizers, polymeric materials, metallic materials, or radiocontrast agents into the liquid formulation. Alternatively, rods150may be made separately and then inserted into folds154of the balloon. The bulk masses may be, for example, polymeric, organic, and/or metal, and may be biostable, bioresorbable, bioerodable, or biodegradable. In some embodiments, the rods150of therapeutic agent may be localized to particular segments of the balloon. This feature may be useful in avoiding delivery of the therapeutic agent to segments of an artery containing calcified lesions. In some cases, the bulk masses may be implantable in the target tissue (e.g., blood vessel wall).

In certain embodiments, the edges of a fold may come together to form a sealed compartment for containing the therapeutic agent. For example, referring to the embodiment shown inFIGS. 12A-12E, a catheter device comprises a balloon134mounted on an elongate shaft132. In its interior, balloon134has an inflation chamber136, and on its exterior, balloon134has a plurality of longitudinal folds140. As seen inFIGS. 12B and 12C, the edges144of folds140meet to create a compartment148for containing a therapeutic agent18. Furthermore, the edges144of folds140can each have an adhesive strip146that are mutually aligned with each other. The edges144of folds140can be joined together by contact between adhesive strips146such that therapeutic agent18is sealed within compartment148.

In operation, balloon134is inserted into a patient's body via a catheter. Because therapeutic agent18is sealed within compartments148, therapeutic agent18is protected as balloon134is being guided to the target site. At the target site, balloon134is inflated, causing adhesive strips146to pull apart. As shown inFIGS. 12D and 12E, as balloon134continues to expand, adhesive strips146detach such that edges144open, allowing therapeutic agent18to be released from compartment148. In an alternate embodiment, the edges144of folds140can be sealed by other means, such as laser welding, heat setting, or by other holding means such as biodegradable or bioerodable sutures or stitching.

Folds containing the therapeutic agent may be formed in various ways. One way of making folds in the balloon is shown with reference toFIGS. 13A-13C, which show transverse cross-sections of a balloon (having a balloon wall252). Referring toFIG. 13A, a therapeutic agent18(either free or formulated with a carrier material) is deposited on the surface250of the balloon as stripes that are oriented substantially longitudinally along the balloon. Referring toFIG. 13B, the areas between the stripes of therapeutic agent18is coated with a hydrophobic layer254formed of a hydrophobic material (e.g., hydrophobic polymers, such as styrene-isobutylene-styrene (SIBS) block copolymers or styrene-ethylene/butylene-styrene (SEBS) block copolymers). Referring toFIG. 13C, the balloon is folded around the stripes of therapeutic agent18to create folds256which contain the stripes of therapeutic agent18. The edges258of folds256meet such that therapeutic agent18is sealed within folds256. The hydrophobic material can help retard fluid penetration to slow or prevent the release of therapeutic agent until the desired time.

Therapeutic agent18may be released from folds256upon inflation of the balloon at the target site, which causes the edges258of folds256to pull apart, allowing the release of therapeutic agent18. Alternatively, the edges258of folds256do not pull apart and therapeutic agent18is released by diffusion through hydrophobic layer254.

In certain embodiments, the balloon is designed such that the folds open when the balloon reaches a certain pressure or a certain expanded diameter, such as when the balloon is close to abutting against the wall of a blood vessel (i.e., the internal diameter of the blood vessel). In certain embodiments, when the balloon is inflated and as the folds open, the folds form a protruding structure that projects outwardly from the main body of the balloon.

Medical devices of the present invention may also include a vascular stent mounted on the balloon. The vascular stent may be any of those known in the art, including those with or without coatings that elute a therapeutic agent. The stent may also be biostable, bioerodable, or biodegradable.

The balloons of the present invention may also be coated with a low-molecular weight carbohydrate, such as mannitol. The carbohydrate may be a separate coating or be blended with the therapeutic agent. The balloons of the present invention may also be coated with a radiocontrast agent (ionic or non-ionic), such as iopromide. The contrast agent may be a separate coating or be blended with the therapeutic agent.

The therapeutic agent used in the present invention may be any pharmaceutically-acceptable agent such as a drug, a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells. Example drugs include anti-proliferative agents or anti-restenosis agents such as paclitaxel, sirolimus (rapamycin), tacrolimus, everolimus, and zotarolimus.

Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.

Non-limiting examples of proteins include serca-2 protein, monocyte chemoattractant proteins (MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (VGR-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homodimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bcl-2 family factors and Akt kinase; serca 2 gene; and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factors α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin-like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase and combinations thereof and other agents useful for interfering with cell proliferation.

Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.

Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered. Non-limiting examples of cells include side population (SP) cells, lineage negative (Lin−) cells including Lin−CD34−, Lin−CD34+, Lin−cKit+, mesenchymal stem cells including mesenchymal stem cells with 5-aza, cord blood cells, cardiac or other tissue derived stem cells, whole bone marrow, bone marrow mononuclear cells, endothelial progenitor cells, skeletal myoblasts or satellite cells, muscle derived cells, go cells, endothelial cells, adult cardiomyocytes, fibroblasts, smooth muscle cells, adult cardiac fibroblasts+5-aza, genetically modified cells, tissue engineered grafts, MyoD scar fibroblasts, pacing cells, embryonic stem cell clones, embryonic stem cells, fetal or neonatal cells, immunologically masked cells, and teratoma derived cells. Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.

The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the present invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention. Modifications of the disclosed embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art and such modifications are within the scope of the present invention.