US20050004558A1 - Flexible vascular inducing implants - Google Patents

Abstract

Implants and associated delivery systems for promoting angiogenesis in ischemic tissue are provided. The implants may be delivered percutaneously, thoracically or surgically and are particularly well suited for implantation into the myocardium of the heart. The implants are configured to be flexible so that they compress and expand with corresponding movement of the surrounding tissue into which they are implanted. The flow of blood into the implant and pooling of the blood in and around the implant leads to thrombosis and fibrin growth, a healing process that leads to angiogenesis in the tissue surrounding the implant. Additionally, the implants may contain an angiogenic substance or a thrombus of blood, preloaded or injected after implantation to aid in initiating angiogenesis.

Description

RELATED APPLICATION
• This application is a divisional of application Ser. No. 09/164,163 filed Sep. 30, 1998.
FIELD OF THE INVENTION
• This invention relates to methods and devices for inducing angiogenesis in ischemic tissue.
BACKGROUND OF THE INVENTION
• Tissue becomes ischemic when it is deprived of adequate blood flow. Ischemia causes pain in the area of the affected tissue and, in the case of muscle tissue, can interrupt muscular function. Left untreated, ischemic tissue can become infarcted and permanently non-functioning. Ischemia can be caused by a blockage in the vascular system that prohibits oxygenated blood from reaching the affected tissue area. However, ischemic tissue can be revived to function normally despite the deprivation of oxygenated blood because ischemic tissue can remain in a hibernating state, preserving its viability for some time. Restoring blood flow to the ischemic region serves to revive the ischemic tissue.
• Although ischemia can occur in various regions of the body, often tissue of the heart, the myocardium, is affected by ischemia due to coronary artery disease, occlusion of the coronary artery, which otherwise provides blood to the myocardium. Muscle tissue affected by ischemia can cause pain to the individual affected. Ischemia can be treated, if a tissue has remained viable despite the deprivation of oxygenated blood, by restoring blood flow to the affected tissue.
• Treatment of myocardial ischemia has been addressed by several techniques designed to restore blood supply to the affected region. Coronary artery bypass grafting CABG involves grafting a venous segment between the aorta and the coronary artery to bypass the occluded portion of the artery. Once blood flow is redirected to the portion of the coronary artery beyond the occlusion, the supply of oxygenated blood is restored to the area of ischemic tissue.
• Early researchers, more than thirty years ago, reported promising results for revascularizing the myocardium by piercing the muscle to create multiple channels for blood flow. Sen, P. K. et al., “Transmyocardial Acupuncture—A New Approach to Myocardial Revascularization”,Journal of Thoracic and Cardiovascular Surgery, Vol. 50, No. 2, August 1965, pp. 181-189. Although others have reported varying degrees of success with various methods of piercing the myocardium to restore blood flow to the muscle, many have faced common problems such as closure of the created channels. Various techniques of perforating the muscle tissue to avoid closure have been reported by researchers. These techniques include piercing with a solid sharp tip wire, hypodermic tube and physically stretching the channel after its formation. Reportedly, many of these methods still produced trauma and tearing of the tissue that ultimately led to closure of the channel.
• An alternative method of creating channels that potentially avoids the problem of closure involves the use of laser technology. Researchers have reported success in maintaining patent channels in the myocardium by forming the channels with the heat energy of a laser. Mirhoseini, M. et al., “Revascularization of the Heart by Laser”,Journal of Microsurgery, Vol. 2, No. 4, June 1981, pp. 253-260. The laser was said to form channels in the tissue were clean and made without tearing and trauma, suggesting that scarring does not occur and the channels are less likely to experience the closure that results from healing. U.S. Pat. No. 5,769,843 (Abela et al.) dicloses creating laser-made TMR channels utilizing a catheter based system. Abela also discloses a magnetic navigation system to guide the catheter to the desired position within the heart. Aita U.S. Pat. Nos. 5,380,316 and 5,389,096 disclose another approach to a catheter based system for TMR.
• Although there has been some published recognition of the desirability of performing transmyocardial revascularization (TMR) in a non-laser catheterization procedure, there does not appear to be evidence that such procedures have been put into practice. For example, U.S. Pat. No. 5,429,144 Wilk discloses inserting an expandable implant within a preformed channel created within the myocardium for the purposes of creating blood flow into the tissue from the left ventricle.
• Performing TMR by placing stents in the myocardium is also disclosed in U.S. Pat. No. 5,810,836 (Hussein et al.). The Hussein patent discloses several stent embodiments that are delivered through the epicardium of the heart, into the myocardium and positioned to be open to the left ventricle. The stents are intended to maintain an open channel in the myocardium through which blood enters from the ventricle and perfuses into the myocardium.
• Angiogenesis, the growth of new blood vessels in tissue, has been the subject of increased study in recent years. Such blood vessel growth to provide new supplies of oxygenated blood to a region of tissue has the potential to remedy a variety of tissue and muscular ailments, particularly ischemia. Primarily, study has focused on perfecting angiogenic factors such as human growth factors produced from genetic engineering techniques. It has been reported that injection of such a growth factor into myocardial tissue initiates angiogenesis at that site, which is exhibited by a new dense capillary network within the tissue. Schumacher et al., “Induction of Neo-Angiogenesis in Ischemic Myocardium by Human Growth Factors”,Circulation,1998; 97:645-650. The authors noted that such treatment could be an approach to management of diffused coronary heart disease after alternative methods of administration have been developed.
SUMMARY OF THE INVENTION
• The vascular inducing implants of the present invention provide a mechanism for initiating angiogenesis within ischemic tissue. The implants interact with the surrounding tissue in which they are implanted and the blood that is present in the tissue to initiate angiogenesis by various mechanisms.
• Primarily, it is expected that the implants will trigger angiogenesis in the ischemic tissue by interacting in one or more ways with the tissue to initiate an injury response. The body's response to tissue injury involves thrombosis formation at the site of the injury or irritation. Thrombosis leads to arterioles and fibrin growth which is believed to ultimately lead to new blood vessel growth to feed the new tissue with blood. The new blood vessels that develop in this region also serve to supply blood to the surrounding area of ischemic tissue that was previously deprived of oxygenated blood.
• The presence of the implants in the tissue, alone, may trigger a foreign body response leading to endothelialization and fibrin growth around the implant. However, the implants of the present invention are specially configured to interact with the surrounding tissue to induce angiogenesis by a variety of mechanisms.
• Implant embodiments of the invention serve to initiate angiogenesis by providing a chamber or interior into which blood may enter and collect leading to thrombosis. The implants are configured to have a wall defining an interior, with at least one opening in the wall to permit passage of blood into and from the interior. The material and structure of the implants permits them to be flexible such that the implant compresses when the surrounding tissue contracts and the implant returns to an uncompressed configuration when the surrounding tissue relaxes. Cyclical compression and expansion of the implant in concert with the motion of the surrounding tissue creates a pumping action, drawing blood into the implant interior when expanded, then expelling the blood when the implant is compressed. One of the openings of the implant may include a check valve to control the flow of blood from the implant interior. Blood that enters the interior of the implant and remains, evenly temporarily, tends to coagulate and thrombose. Over time, continued pooling of the blood in the interior will cause thrombosis and fibrin growth throughout the interior of the implant and into the surrounding tissue. New blood vessels will grow to serve the new growth with oxygenated blood, the process of angiogenesis.
• Some embodiments are configured to have a high degree of flexibility such that they collapse completely under the compressive force of surrounding tissue in contraction. The highly flexible implants are configured to return to their uncompressed, volume defining shape when the surrounding tissue relaxes. The reduction of the volume defined by the interior to practically zero provides significant volume change providing pronounced pumping action to maximize blood exchange through the interior. Thrombosis can occur naturally in the highly flexible embodiments despite the increased blood flow through the interior. However, the highly flexible embodiments are also well suited to pump out into surrounding tissue substances pre-installed within their interior.
• Implant embodiments may further be prepared to initiate angiogenesis by having a thrombus of blood associated with them at the time of their implantation or inserted in the interior immediately following implantation. The thrombus of blood may be taken from the patient prior to the implant procedure and is believed to help initiate the tissue's healing response which leads to angiogenesis.
• Alternatively or in addition to a thrombus of blood, the implant devices may be preloaded with an angiogenic substance in a variety of ways to aid the process of angiogenesis in embodiments having a defined chamber or interior, the substance may be placed within the interior prior to implantation or injected after the implantation of the device. The substance may be fluid or solid. The blood flow into and interacting with the interior of the device will serve to distribute the substance through the surrounding tissue area because blood entering the device mixes with and then carries away the substance as it leaves the device. Viscosity of the substance and opening size through which it passes, determine the time-release rate of the substance.
• Substances may be associated with the device, not only by being carried within their interiors, but also by application of a coating to the device. Alternatively, the substance may be dispersed in the composition of the device material. Alternatively, the implant may be fabricated entirely of the angiogenic substance. Recognizing that there are many ways to attach an angiogenic substance or drug to a device, the methods listed above are provided merely as examples and are not intended to limit the scope of the invention. Regardless of the method of association, the implants of the present invention interact with the surrounding blood and tissue to distribute the angiogenic substance into the ischemic tissue.
• Additionally, each implant embodiment serves to provide a constant source of irritation and injury to the tissue in which it is implanted, thereby initiating the healing process in that tissue that is believed to lead to angiogenesis. As tissue surrounding the implant moves, such as the contraction and relaxation of muscle tissue, some friction and abrasion from the implant occurs, which injures the tissue. The injury caused by the outside surfaces of the implants to the surrounding tissue does not substantially destroy the tissue, but is sufficient to instigate an injury response and healing which leads to angiogenesis.
• Structurally, the implant devices may be configured in a variety of shapes to carry out the objectives outlined above for initiating angiogenesis. Additionally, varying degrees of flexibility are acceptable for carrying out the implant function. By way of example, the implant device may comprise a capsule or tubular shaped device formed from a flexible material such as a polymer or superelastic metal alloy and having at least one opening to the device interior to permit blood to enter and exit.
• One or more implants of the present invention may be applied to an area of ischemic tissue. By way of example, the implants may define a width of approximately 2 mm and a length corresponding to somewhat less than the thickness of the tissue into which it is implanted. It is anticipated that implants having a 2 mm wide profile would serve an area of ischemic tissue of approximately one square centimeter to adequately promote angiogenesis throughout the surrounding region of tissue yet avoid altering the movement of the tissue due to a high density of foreign objects within a small region.
• The devices may be delivered to the intended tissue location percutaneously and transluminally, thoracically or surgically by a cut down method. In the case of implants placed within myocardial tissue of the heart, delivery systems are disclosed for percutaneously accessing the left ventricle of the heart and penetrating and delivering the implant into the myocardium.
• It is an object of the present invention to provide a method of promoting angiogenesis within ischemic tissue.
• It is another object of the present invention to provide a method of promoting angiogenesis by implanting a device within ischemic tissue.
• It is another object of the present invention to provide a process of promoting angiogenesis within ischemic myocardial tissue of the heart.
• It is another object of the invention to provide an implant suitable for implantation within tissue of the human body.
• It is another objective of the present invention to provide an implant delivery system that is safe and simple to use while minimizing trauma to the patient.
• It is another object of the invention to provide an implant that will irritate tissue that surrounds the implant to initiate a healing response that leads to angiogenesis.
• It is another object of the invention to provide an implant that is configured to have associated with it an angiogenic substance that promotes angiogenesis within tissue surrounding the implant.
• It is another object of the invention to provide an implant configured to interact with blood present in the tissue into which the implant is inserted.
• It is another object of the invention to provide an implant that defines an interior into which blood can enter and thrombose.
• It is another object of the invention to provide an implant to which a thrombus of blood or an angiogenic substance can be inserted before or after the implant has been inserted into tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
• The foregoing and other objects and advantages of the invention will be appreciated more fully from the following further description thereof, with reference to the accompanying diagrammatic drawings wherein:
• FIG. 1 is a sectional illustration of the flexible implant configured as a capsule and having a check valve;
• FIG. 1B is a cross-sectional diagram of the flexible implant configured as a capsule;
• FIG. 2A is a cross-sectional figure of a highly flexible implant configured as a capsule;
• FIG. 2B is a cross-sectional diagram of a highly flexible implant configured as a capsule in a compressed configuration;
• FIG. 2C is a cross-sectional figure of a highly flexible implant configured as a capsule in an uncompressed configuration;
• FIG. 3A is a cut-away illustration of a percutaneous delivery device delivering an implant configured as a capsule to a tissue location;
• FIG. 3B is a partial cut-away view of a delivery device penetrating the tissue location and delivering an implant configured as a capsule;
• FIG. 4 is a sectional illustration of the left ventricle of a human heart having several implants placed within the myocardium;
• FIGS. 5A-5D illustrate the steps of percutaneously delivering several implants to an area of ischemic myocardial tissue in the left ventricle;
• FIG. 6A is a side view of a flexible implant configured as a flexible tube;
• FIG. 6B is a side view of the flexible tube implant compressed by the tissue that surrounds it;
• FIG. 6C is a side view of the flexible tube implant in an uncompressed, expanded configuration;
• FIG. 7A is a side view illustration of the flexible tube implant being delivered to an intended tissue location on a delivery system;
• FIG. 7B is a side view of a delivered implant within tissue and the withdrawing delivery device;
• FIG. 8A is a perspective view of a porous tube flexible implant;
• FIG. 8B presents a sectional view of the porous tube flexible implant;
• FIG. 8C presents an end view of the porous tube flexible implant;
• FIG. 8D is a side view of the porous tube flexible implant being delivered to an intended tissue location on a corresponding delivery system;
• FIG. 8E is a side view of a porous flexible implant delivered into tissue and the withdrawing delivery system.
• FIG. 9A is a side view of a flexible tube embodiment being delivered into an intended tissue location on its associated delivery system;
• FIG. 9B is a side view of the flexible tube implant implanted within tissue and the withdrawing delivery system;
DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS
• FIGS. 1A and 1B show one embodiment of the implant device comprising acapsule10. The capsule embodiment has anexterior surface12, avolume defining interior14 with aninside surface16. Thewall18 of the capsule may be somewhat flexible to permit flexure with the movement and compressive forces of thesurrounding tissue4 into which it is implanted. However, the wall should be fabricated to provide sufficient structural support to resist complete collapse of the capsule when it flexes.
• Blood flow, represented byarrows20, is intended to enter and exit the implant as part of the function of the device. As shown inFIG. 1B,blood20 from the surroundingtissue4 enters the interior14 of theimplant10 through anopening22. There may be severaladditional openings22 to increase the amount of blood that can be exchanged through the device. Movement of the surroundingmyocardial tissue4 with the pumping of the heart flexes thecapsule10 and promotes blood interchange with the interior14. When implanted in muscle tissue, such as myocardial tissue of the heart, contraction of the muscle tissue compresses thecapsule10, reducing the volume ofinterior14, causing blood to be ejected throughopenings22. Relaxing of the surrounding muscle relieves pressure on the capsule, permitting it to expand resiliently back to a non-compressed configuration in which the interior volume is maximized and ready to receive blood flow. The cyclical pumping of the heart and associated expansion and contraction of the myocardium provide a mechanism for exchanging blood through thecapsule10. Additionally, the capsule may be provided with an opening having acheck valve26 as shown inFIG. 1A. The check valve can be formed in thewall18 of the capsule by forming at least oneflap28 that opens inwardly under fluid pressure from the exterior but does not open outwardly from the pressure of fluid within the interior14. The check valve allows blood flow into the interior of the capsule but prevents flow back out of the valve to provide additional flow control.
• While in theinterior14 of the implant, the trapped blood pools and tends to coagulate. The coagulated blood forms a thrombus that is believed to provide a mechanism for triggering angiogenesis. As the bolus of blood thromboses, fibrin and arterioles are formed. New blood vessels emerge in the new tissue growth to provide blood flow to the ischemic region. The new blood vessels, not only serve the site of new tissue formed by fibrin growth induced by the presence of the implant, but will also extend to surrounding areas of the myocardium.
• Alternatively or in addition to relying on pooling of blood in and around the implant, a thrombus of blood, previously removed from the patient's body may be inserted into the interior of the implant prior to implantation to help initiate the process of angiogenesis. The thrombus may be loaded into the capsule through a hypodermic needle and syringe inserted through anopening20. The pre-loaded thrombus of blood permits the implant to initiate the angiogenesis process at a more advanced stage.
• Alternatively or in addition to providing a thrombus of blood in theinterior14 of the implant, the blood may contact and mix with anangiogenic substance24 previously placed in theinterior14 of the device. The angiogenic substance may be applied to a thrombus that is preloaded into the interior of the implant or may be loaded independently into the interior. The angiogenic substance may be delivered into the capsule with a hypodermic needle and syringe through anopening20. In the case of a solid angiogenic substance,blood flow20 entering the interior14 would gradually erode the substance and carry it to the surroundingmyocardial tissue4 as part of the interchange of the blood with the device to provide a time released effect. The angiogenic substance may also be a fluid to mix more readily with blood flow and also to leech directly from the implant throughopenings22. The angiogenic substance continuously mixes with and is carried by the blood into the surroundingmyocardial tissue4 in a controlled quantity dictated by the size of theimplant openings22 and the viscosity of thesubstance24. By altering theopening22 size and fluid substance viscosity, the flow rate of the substance into the surrounding tissue can be tailored. Angiogenic substances also may be associated with the implant either by coating the surfaces of the implant or by intermingling molecules of the substance through the pores of a porous material that is used to form the wall of the implant or of a porous material that is adhered to the surface of the implant.
• As mentioned above the tissue healing process, including thrombosis and fibrin growth, is believed to induce the growth of new blood vessels in the healing tissue which extend through surrounding tissue. The implants of the present invention may be configured to further trigger a healing response in surroundingmyocardial tissue4 by having anouter surface12 that is configured to irritate the tissue as it contacts the surface. Thesurface12 may be roughened, characterized by small projections that abrade the surrounding myocardial tissue as it continuously moves against the surface of the implant. Thus the implant provides a mechanism for triggering ongoing injury and healing of the myocardium that ultimately leads to new blood vessel growth to supply blood to the injured areas.
• Thecapsule10 may be any shape capable of defining a chamber or interior. The example shown inFIGS. 1A and 1B are depicted as somewhat spherical shell; however, this shape is intended merely to be illustrative of the inventive concept and is not intended to limit the scope of the invention to an implant having any particular shape. Thecapsule10 may be formed from any material having the requisite strength, when configured in the chosen shape, to resist substantial compression by contractingtissue4 that will surround the implant. The implant may be formed from a stainless steel or from a polymer and may be made to be bioabsorbable. In a preferred embodiment, the capsule is formed from a high density polymer and is formed by a molding process suitable of making hollow vessels such as blow molding or spin molding. Alternatively the capsule may molded in two halves that are later fused together.Openings22 may be formed after the capsule is formed by piercing, punching, drilling or laser energy.
• In another embodiment shown inFIGS. 2A-2C, thecapsule10 may be configured to be highly flexible so that it is easily fully compressed by the surroundingmyocardial tissue4 during periods of contraction. As the myocardial tissue relaxes, thecapsule10 returns to its uncompressed, volume defining configuration. The device shown inFIGS. 2A-2C also has at least oneopening22 to permit blood flow into and from the interior of thecapsule14 permittingblood flow20 to freely enter the interior14 of the capsule from surroundingmyocardial tissue4.FIG. 2A represents the capsule in its unstressed, uncompressed state.FIG. 2B represents the capsule in a collapsed state under the compressive forces of the surroundingmyocardial tissue4 in contraction, the collapsing volume forcing blood flow out of the interior14 of the capsule.FIG. 2C represents the capsule once again returning to an uncompressed configuration when the surroundingmyocardial tissue4 relaxes during the cardiac cycle. The capsule repeatedly collapses and expands coinciding with the contraction and relaxing of themyocardial tissue4. The flexible capsule does not resist the external forces applied by the surrounding myocardium. The capsule collapses completely upon itself and expands again to define a maximum volume with an interior14 that is filled withblood flow20. The large volume change repeatedly experienced when the capsule expands and compresses provides a pumping action to move the blood into and from the capsule.
• As with the less flexible capsule embodiment described above, the flexible capsule uses blood flow into the interior14 to initiate mechanisms for angiogenesis.Blood flow20 entering thecapsule10 throughopenings22 while the capsule is in its uncompressed form has an opportunity to thrombose, a process which is believed to lead to angiogenesis as discussed above. Theflexible capsule10 may be preloaded with a thrombus of blood previously obtained from the patient or with anangiogenic substance24, which can leach out from the implant to promote angiogenesis in surrounding tissue. The greater volume change provided by the flexible capsule implant between its compressed configuration and uncompressed configuration, provides substantial pumping action, making this embodiment particularly well suited for pumping a preloaded angiogenic substance into the surrounding tissue. As discussed above in connection with the less flexible capsule embodiment, a fluid angiogenic substance may be disposed within theinterior14 of the capsule and pumped out after implantation by the motion of the capsule and flow of blood through the interior causing the substance to exit theopenings22 of the capsule. Substance viscosity and opening size may be tailored to provide a specified release rate of the substance into the surrounding tissue.
• As mentioned above, several of the implant devices may be placed within an area of ischemic tissue to promote angiogenesis over a broad area that is ischemic. In the case of ischemic myocardial tissue, multiple implants should be spaced sufficiently so that the aggregate effect of the presence of foreign bodies within the tissue does not adversely alter the muscle's flexibility and function. Implants on the order of 2 mm in diameter are believed to serve an ischemic area of about 1 square cm adequately without having an adverse effect on muscular function.
• Although the depth level of the implants within the myocardium is not crucial, it is believed that placing the implants closer to theendocardial surface6 will yield the best results. The rationale for this theory is based on observations that the myocardial muscle closer to the endocardial surface appears more active in creating the pumping movement along the myocardial layer than does the myocardial area closer to the epicardium. Placing the implants in an area higher muscle activity is believed to lead to a more pronounced angiogenic response to the presence of the implants. Though it is acceptable, it is not essential that a portion of the implant be exposed to the left ventricle. The entire implant may be submerged within the myocardium, interacting with the blood that is present within the tissue. For a myocardium having a thickness of 10 mm, implants having a length on the order of 5-8 mm should be suitable to carry out the objects of the invention.
• Access to ischemic tissue sites within a patient to deliver an implant may be accomplished percutaneously, surgically by a cut-down method or thoracically. However, the less invasive and traumatic percutaneous approach of delivering the implants is generally preferred. A percutaneous delivery device for delivering the capsule embodiments to the myocardium of the heart is shown inFIGS. 3A and 3B.FIG. 4 shows a diagrammatically sectional view of aleft ventricle2 of ahuman heart1. Each of the implant embodiments described herein may be delivered percutaneously through adelivery catheter36, shown inFIGS. 5A-5D, as will be described in detail below. It is noted that, throughout the description of the implant embodiments and their associated delivery systems, “proximal” refers to the direction along the delivery path leading external of the patient and “distal” refers to the direction leading internal to the patient.
• To access the left ventricle of the heart percutaneously, a guide catheter (not shown) is first navigated through the patient's vessels to reach theleft ventricle2 of theheart1. A barb tipped guidewire34 may then be inserted through the guide catheter and into the ventricle where it pierces themyocardium4 and becomes anchored within the tissue. After anchoring the guidewire, asteerable delivery catheter36 may be advanced over the guidewire to become positioned within the ventricle for delivery of the implants. To facilitate delivery of multiple implants, the guidewire lumen of thedelivery catheter36 may be eccentrically located on thecatheter36. Therefore, when the catheter is rotated about the guidewire, the center of the catheter will rotate through a circular path as demonstrated inFIGS. 5C and 5D, to encompass a broader delivery area with one guidewire placement. The outside diameter of the delivery catheter is preferably less than 0.100 inch. Additionally, the delivery catheter may be provided with steering capability by means of a pull wire extending the length of the catheter and attached at its distal end such that pulling on the wire from the proximal end causes the distal tip of the catheter to be deflected. Therefore, the steering capability provides a broader range of delivery area with a single catheterization. A detailed description of the construction of a delivery catheter for reaching multiple sites within the left ventricle is described in U.S. patent application Ser. No. 09/073,118 filed May 5, 1998, the entire disclosure of which is herein incorporated by reference.
• Acapsule delivery catheter40 suitable for percutaneously delivering thecapsule implants10 into the myocardium is shown inFIG. 3A. First, thesteerable delivery catheter36 is navigated into theleft ventricle2 as shown inFIGS. 5A-5D (which represent adelivery catheter36 of a general type accessing theleft ventricle2, applicable to all implant and delivery embodiments herein described). Thecapsule delivery catheter40 is inserted through thesteerable delivery catheter36. Thecapsule delivery catheter40 shown inFIGS. 3A and 3B slidably receives aninner push tube44 with acapsule carrier42 at its distal end. The inner push tube is slidable within thecatheter tube40 and is withdrawn inside the outer tube during delivery to the myocardial site throughout the steerable catheter. After reaching the myocardial site, the inner push tube is moved distally with respect to thecatheter tube40 to extend the capsule carrier past the distal tip of the catheter prior to advancement into the tissue.
• Thecapsule carrier42 is shaped to have aconcave cradle50 suitable for pushing thecapsule10 through the lumen41 of the capsule catheter during delivery. Extending distally past thecradle50 on the capsule carrier is a piercingdistal tip48 that pierces theendocardium6 at the selected site as theinner push tube44 is moved distally. As shown inFIG. 3B, continued distal movement of thepush tube44 causes the capsule carrier to penetrate the myocardium through the penetration site initiated by the piercingtip48. Only the endocardial surface presents any measurable resistance to penetration, and once it is penetrated by the piercingtip48, continued penetration into themyocardium4 presents little additional resistance. Therefore, thecapsule carrier42 with acapsule10 nested within thecradle50 can penetrate into themyocardium4 with little resistance or interference with thecapsule10. Once thecradle portion50 of thecapsule carrier42 has penetrated the endocardial surface, apush wire52, slidable within thepush tube44 andcapsule carrier42, is moved distally through cradle port51 to push thecapsule10 from thecradle area50 so that it becomes implanted within themyocardium40. After implantation, thepush wire52 and pushtube44 withcapsule carrier42 are withdrawn proximally into thecatheter tube40 so that thesteerable delivery catheter36 may be withdrawn from the ventricle. The piercingtip48 of thecapsule carrier42 should be sheathed within thecatheter tube40 during entry and withdrawal so as not to inadvertently pierce other areas of tissue.
• The catheters and push tube described above may be fabricated from conventional materials known in the art of catheter manufacture. Thepush wire52 also may be fabricated from conventional materials known in the guidewire art: stainless steel or a plastic material. Thecapsule carrier42 may be fabricated from a rigid polymer or stainless steel and joined to the distal end of thepush tube44 by any conventional means of bonding. Thecradle area50 should be configured to nest and hold the capsule during delivery to permit passage of thepush wire52 through cradle port51 so that the capsule can be pushed from the cradle into the myocardium. By way of example, thecradle50 may have a concave, dish-like shape if intended to hold a spherical shaped capsule as has been described.
• Another flexible implant embodiment is shown inFIGS. 6A-6C. Aflexible tube60 is provided that is configured for significant longitudinal compression and expansion as shown inFIGS. 6B and 6C under the force of the cyclical contraction and relaxation of muscle tissue into which it is implanted, such as that of the myocardium. As with the flexible capsule embodiment discussed above, theflexible tube embodiment60 initiates angiogenesis in part by its interaction with blood flow into and from the device as well as its dynamic movement within the myocardial tissue while implanted. Thetube embodiment60 is comprised of aflexible sleeve62 of a thin flexible polymer material such as polyimide. The sleeve defines an interior66 and has anouter surface68 andinner surface69. Aflexible coil spring64 shown in phantom inFIG. 6A may reside within the interior66 against theinner surface69 to support thesleeve62 in an open, tubular configuration. While providing radial support, the also coil permits longitudinal compression of the sleeve shown inFIG. 6B and helps to provide resilience to the sleeve so that it may recover to an elongated tubular shape when the surrounding tissue relaxes as is shown inFIG. 6C.
• When the surrounding tissue is in a relaxed state, theflexible tube60 maintains an uncompressed tubular shape that permits blood to enter the interior66 throughend openings70 andside openings72 of thesleeve62. Blood within theinterior66 of theflexible tube60 will tend to thrombose which leads to angiogenesis as described above in connection with the capsule embodiments. Additionally, as with the capsule embodiments, a thrombus of blood and/or angiogenic substance may be loaded into theflexible tube implant60 to interact withblood flow20 to further enhance the process of angiogenesis. Substances may be placed within theinterior66 of thetube60 prior to implantation or after the tube has been implanted into the myocardium by inserting the substance through anopening70. Alternatively, a coating containing an angiogenic substance may be applied onto thesleeve62 or a substance may be embedded within the structure of the sleeve material. Compression of the flexible tube as shown inFIG. 6B causesblood flow20 along with angiogenic substances to be ejected outward throughopening70 and72 into the surroundingtissue4.
• As mentioned above in connection with the capsule embodiment, movement of the implant in the myocardium during the cardiac cycle also tends to initiate angiogenesis by irritating or slightly injuring the tissue. Theflexible tube60 forms a plurality ofpleats74 when it is compressed longitudinally as shown inFIG. 6B. As thetube60 flexes during the cardiac cycle, the cyclical formation ofpleats74 created by the collapse ofsleeve62 project outward into surroundingtissue4 when the muscle tissue is in contraction. As themuscle tissue4 relaxes, the tube returns to its uncompressed form drawing up slack in thesleeve62 to withdrawpleats74. The repeated formation and retraction of each pleat will irritate a small area of surrounding tissue. The plurality of pleats, therefore, provide a plurality of nucleation sites where angiogenesis can be initiated with a single implant.
• A percutaneous delivery device for implanting the flexible tube into myocardial tissue of the heart is shown inFIGS. 7A and 7B. Thedelivery device80 is comprised of a catheter that is percutaneously deliverable to the heart through a guide catheter and asteerable catheter36 that is advanceable to the intended myocardial implant location through the left ventricle as shown inFIGS. 5A-5D. Within thesteerable delivery catheter36 is slidable, the flexible tubeimplant delivery system80 shown inFIGS. 7A and 7B. Thedelivery device catheter80 has atubular push shaft82 having joined at its distal end aproximal crinkle tube84, which is joined at its distal end to adistal crinkle tube86 of a smaller diameter than theproximal crinkle tube84. Slidable within thepush tube82 is a piercingwire88 having a sharpeneddistal tip90 that is suitable for piercing theendocardium6 to implant the device. Thedistal crinkle tube86 is attached at its distal end to the distal end of thepush wire88. The crinkle tubes are formed from a thin flexible material that will collapse into a random pattern of pleated folds when placed under an axial compressive load. A suitable material for the crinkle tubes is polyethylene or polyethylene terephthalate. As the crinkle tubes collapse, the pleats of the wall serve to increase the overall profile of the tube. When collapsed within thetubular implant60, thepleats92 of the crinkle tubes contact theinside surface69 of the tube to hold it during delivery into the myocardium.
• Theproximal crinkle tube84, having a larger diameter than the distal crinkle tube presents a larger profile when collapsed into pleated form. The larger diameter crinkle tube is intended to collapse to a profile that is larger than the diameter of thetubular implant60 so that during delivery the crinkle tube will butt against the proximal end of the tubular implant to provide a pushing force as it is inserted into themyocardial tissue4.
• The crinkle tubes are compressed and expanded by moving thepush wire88 longitudinally with respect to thepush tube82. The distal end of thedistal crinkle tube86 is heat bonded to the distal end of thepush wire88. Theproximal end94 of thedistal crinkle tube86 is bonded to thedistal end90 of thepush wire88 and theproximal end96 of the distal crinkle tube is bonded to thedistal end98 of theproximal crinkle tube84. Theproximal end98 of theproximal crinkle tube84 is bonded to thedistal end100 of thepush tube82. The crinkle tubes are collapsed to their larger profile by pulling thepush wire88 proximally and pushing thepush tube82 distally, drawing their distal ends together, to apply an axial compressive load upon both crinkle tubes simultaneously, collapsing them. The crinkle tubes return to their reduced profile by pulling them taut which is accomplished by moving the push wire distally and the push tube proximally.
• Using thedelivery system60, a tubular implant is placed over thedistal crinkle tube86 while the tubes are in a taut low profile configuration. The push tube and pull wire are moved relative to each other to compress both crinkle tubes simultaneously causing the pleats of thedistal crinkle tube86 to engage theinside surface69 of the tubular implant. Thepleats92 of theproximal crinkle tube84 bunch up proximal to thetubular implant60 and present a profile that is larger than the diameter of the tube to provide a backstop to prevent proximal movement of the implant on the delivery system during implantation into thetissue4. Thedistal crinkle tube86 also serves to hold thetubular implant60 in place on the delivery device during implantation by virtue of the frictional engagement created between thepleats92 of the crinkle tube and the interior surface of theimplant69. Alternatively, as is described below with regards to other implant embodiments, the delivery device may comprise a single, distal crinkle tube that engages the interior of the implant to locate the implant on the delivery catheter.
• With the crinkle tubes in their compressed configuration, tubular implant secured over the distal crinkle tube, thedelivery device80 is advanced distally to the intended location on theendocardial surface6. Both apush tube82 andpush wire88 are advanced distally in unison to pierce theendocardium6 with the sharpdistal tip90 of thepush wire88 as shown inFIG. 7A. Further distal advancement of thepush wire88 and pushtube82 serves to insert thetubular implant60 into thetissue4. As mentioned above in relation to the capsule implant embodiment, the implants may be placed anywhere within the myocardium, either embedded to some depth within the tissue or placed such that the proximal end of the implant meets theendocardial surface6 and is open to theleft ventricle2. After theimplant60 has been placed in the myocardium, thepush tube82 is pulled proximally, while maintaining thepush wire88 in position to pull thecrinkle tubes84 and86 taut, releasing them from theinterior surface69 of the implant. Thedelivery device80 may then be withdrawn from the myocardium leaving the implant in place. After delivery of the implant, a substance, such as a thrombus of blood or angiogenic substance, may be inserted into the interior66 of the implant. Such a substance may be delivered through a lumen of thedelivery catheter80,push tube82 or push wire88 (if fabricated from hypodermic tubing) into the distalopen end70 of the device. Fluid pressure applied from the proximal end of the shaft would cause the substance to be delivered and ejected through a distal opening, possibly formed in the sharpenedtip90 directly into the interior66.
• Another flexible implant embodiment which is formed from a porous material is shown inFIGS. 8A-8E. Aporous implant91 is shown in a tubular configuration, but may be any shape that is implantable in tissue. Preferably, the shape of theporous implant91 defines an interior93 into whichblood flow20 may enter from the surroundingtissue4. The porous material comprising theimplant91 may be a relatively stiff foam material such as expanded polyethylene or any aerated polymer. The outside diameter of the porous implant may be on the order of 2 mm and it may be of length somewhat less than the thickness of tissue into which it is implanted.
• The porous material provides flexibility to the implant, permitting it to be compressed with contractions of the surrounding tissue and permitted to expand to an uncompressed configuration when the tissue relaxes. As with the previous embodiments, it is expected that, once implanted in the ischemictissue blood flow20 will enter theends95 of the implant while it is in its uncompressed configuration, as shown inFIG. 8B. Blood will then be forced out of the interior93 of the implant when it is compressed by the surroundingtissue4 in contraction. The inflow and outflow of the blood created by the cyclic compression and expansion of the flexible device encourages blood collection and thrombus formation within theinterior93 of the device which can lead to angiogenesis as described above in connection with the previous flexible implant embodiments. Additionally, the porous material from which the implant is formed, such as the open cell structure of foam, will encourage blood pooling leading to fibrin and tissue ingrowth throughout the implant structure while it is implanted in theischemic tissue4. Eachopen cell101 of the foam material provides a protective cavity into which blood flow can recede after entering the device.
• Not only does theinterior93 of the implant provide a location for holding an angiogenic substance, but the entire open cell structure of the implant provides a network of small spaces defined by the open cells, which may hold a liquid or solid substance that can leach out from the implant or become mixed with blood entering the interior93, which serves to carry the substance into the surroundingmyocardial tissue4 asblood flow20 exits the implant. The network of open spaces defined by the foam material also provides numerous friction contact points that will irritate surrounding tissue with relative movement of the implant with respect to the tissue. It is expected that the numerous irritation points will result in numerous nucleation points where angiogenesis will begin.
• Theporous implant91 may be delivered to the intended tissue location by the methods described above. Specifically, as shown inFIG. 8D, theimplant91 may be delivered percutaneously, navigated to the intended location, such as the myocardium, over the distal end of adelivery catheter104 as is shown inFIG. 8D. A generally tubular shaped porous implant may be delivered over adelivery catheter104 comprised of acrinkle tube110 that is configured to buckle under a compressive load, formingmultiple folds114 along its length, each of a greater diameter than the crinkle tube exhibited in a non-folded configuration. The increased diameter folds114 engage theinterior surface99 of the porous tube to locate it on thecatheter104.
• Theproximal end116 of the crinkle tube is mounted to distal end of thepush tube106 and theproximal end118 of the crinkle tube is bonded to the piercingdistal end112 ofpush wire108 that is slidable within thepush tube106. Compressive force is applied by moving thepush tube106 distally while drawing thepush wire108 proximally, bringing their distal ends together to collapse thecrinkle tube110. With theimplant91 positioned over the crinkle tube in the collapsed configuration, thefolds114 of the crinkle tube hold the implant, not only by engaging theinside surface99 of the implant, but also by bunching and creating a stop at theproximal end116 of thecrinkle tube110 against which the implant can rest during insertion into themyocardium4. In this configuration, thedelivery catheter104 is moved distally so that the piercingtip112 of thepush wire108 penetrates theendocardial surface6 of themyocardium4.
• As described above, the implant may be inserted so that itsproximal end120 is flush with theendocardial surface6 or so that theimplant91 is completely within themyocardium4 and not open to the left ventricle as is shown inFIG. 8E. Although the implant may be placed at any depth within the myocardium, it is believed that greater muscle activity and blood flow occurs in the myocardium near the endocardial surface than occurs near the epicardial surface. Therefore, the opportunity for triggering angiogenesis with the implant appears to be increased if the implant is placed closer to the endocardial surface. After implantation, tension is applied to thecrinkle tube110 to release the implant from thedelivery catheter104. As shown inFIG. 8D when thecrinkle tube110 is in tension, folds114 are removed and the overall diameter of the crinkle tube is reduced so as to disengage from theinterior93 of theimplant91. Thecrinkle tube110 is pulled taut by moving thepush wire108 in a distal direction while moving thepush tube106 in a proximal direction. Thetaut crinkle tube110 can then be withdrawn easily and theentire delivery catheter104 is removed in a proximal direction from theimplant90 left within themyocardium4.
• Another flexible implant embodiment is shown on its associated delivery device inFIGS. 9A and 9B. Theimplant130 is intended to compress and expand to a reduced degree with the contraction and relaxation of the surrounding tissue in which it is implanted. The implant is intended to have inherent resiliency so that it returns to an open configuration under its own strength when surrounding tissue is relaxed. In this manner, theflexible tube130 is more resilient than theflexible tube embodiment60 described above, which requires a spring within its interior to help it return to its open configuration. Theresilient tube implant130 is similar to thecapsule embodiments10 in that it can resiliently return to a uncompressed configuration defining an interior132. Like the capsule embodiments, theresilient implant130 may be molded from a polymer material, such as PVC for added rigidity, or from a low density polymer to provide more flexibility when surrounding muscle tissue is contracted. In addition to endopenings134, the implant may be provided withside openings136 to permitblood flow20 into the implant while it is in an open configuration and out of the implant when it is compressed by surroundingmuscle tissue4. Theresilient implant130 may be formed into a tubular shape similar to the porous and flexible implants illustrated above. Configured as a tube, the implant may be delivered percutaneously to a location within themyocardium4 by adelivery catheter104 having acrinkle tube110 that engages the interior of the implant during delivery as was discussed above with regards to the previous embodiment.
• From the foregoing, it will be appreciated that the invention provides an implant and delivery system for promoting angiogenesis within ischemic, viable tissue. The invention is particularly advantageous in promoting angiogenesis within ischemic myocardial tissue of the heart. The implants are simple and readily insertable into the intended tissue location with a minimum of steps. The delivery systems are simple to operate to implant the devices quickly.
• It should be understood, however, that the foregoing description of the invention is intended merely to be illustrative thereof and that other modifications, embodiments and equivalents may be apparent to those skilled in the art without departing from its spirit.

Claims (11)

1. A method of promoting angiogenesis in ischemic tissue comprising the steps of:

providing at least one flexible implant having first and second configurations and configured to move between the first and second configurations under the influence of the movement of surrounding tissue and defining a volume, at least while in the first configuration, that is in fluid communication with the surrounding tissue;

implanting at least one implant in an area of ischemic tissue.

2. A method of promoting angiogenesis as defined inclaim 1 further comprising the step of associating an angiogenic substance with the implant prior to implantation.

3. A method of promoting angiogenesis as defined inclaim 1 further comprising the step of associating an angiogenic substance with the implant after implantation.

4. A method of promoting angiogenesis as defined inclaim 1 where the implant is delivered to an implant site percutaneously through a delivery catheter.

5. A method of promoting angiogenesis as defined inclaim 1 wherein the tissue is myocardial tissue of the heart and the implants are implanted in the myocardium.

6. A method as defined inclaim 5 wherein the implants are implanted entirely and only within the myocardium.

7. A method as defined inclaim 5 wherein one or more implants are implanted in the myocardium such that a portion of each implant is substantially flush with the endocardial surface.

8. A method as defined inclaim 7 wherein the implants are in fluid communication with the left ventricle.

9-13. (Canceled)

14. A method of promoting angiogenesis in the myocardium, comprising: generating thrombus in the myocardium to stimulate angiogenesis by placing at least one implant in the myocardium, wherein the implant is placed closer to the endocardium than to the epicardium.

15-18. (Canceled)

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