This invention relates to systems and methods for treating muscle ischemia.
BACKGROUND OF THE INVENTION
To function normally, muscle tissue requires adequate circulatory perfusion. With increases in muscle work, there is an increased demand for blood flow. When arterial inflow is compromised by peripheral vascular disease, this demand cannot be met. The resultant muscle ischemia leads to a syndrome of muscle pain termed claudication. Lower extremities are most commonly affected with peripheral vascular disease and concomitant claudication. Symptoms may abate with sufficient rest, but may then resume with further exertion. Claudication thus can be debilitating. If there is sufficient ongoing muscle ischemia, pain symptoms do not abate with cessation of exertion; the patient then experiences extremity pain at rest. As vascular disease advances, with progressive decrease in arterial inflow, circulation becomes inadequate to support tissue metabolism even at rest. At this point, frank tissue death ensues, including muscle necrosis. Pharmacological treatment offers only minimal palliation of this inexorable process. Surgical intervention through successful arterial revascularization is required before the onset of tissue death if lower extremity amputation is to be avoided.
Acute vascular compromise can also result in tissue necrosis. Embolic phenomena or traumatic injury may occlude major arteries, causing acute ischemia. Emergent surgical intervention is required to prevent catastrophic tissue loss distal to the occlusion. Acute muscle ischemia also occurs following non-vascular trauma. The most common instance of this type of ischemic insult is found in compartment syndromes of the extremities. Compartment syndrome takes place when an injured muscle begins to swell but is restricted in its expansion by some type of local or circumferential compression. Compression may be applied externally, for example by a cylindrical cast or a dressing that is tightly applied, or compression may be applied internally by the fascia covering the muscles within an extremity compartment. The result of a compartment syndrome is some degree of ischemic damage to the muscle, culminating in frank muscle necrosis if the ischemia persists long enough. Treatment of compartment syndromes requires relief of external circumferential compression and release of anatomical compression through surgery. Release of the confining anatomic structures may entail longitudinal incisions in both the skin and the muscular fascia. Even after adequate compartment release, the local ischemia and its sequelae must resolve over time as the compartment pressures and the intravascular perfusion pressures reach a more physiological equilibrium. During this period, further tissue damage may occur, with subsequent functional effects. No specific therapeutic interventions exist to decrease the extent of ischemic damage to muscle tissue following restoration of effective circulation. One example of the outcome of extensive muscle necrosis is Volkmann's ischemic contracture, a condition that results from the death of the forearm flexor wad muscles following a forearm compartment syndrome: a patient afflicted with Volkmann's ischemic contracture positions the wrist and fingers in a permanently flexed position due to the contracture of the damaged muscle mass, and the patient loses the ability either to flex or to extend the wrist or the fingers.
Muscle ischemia, when it occurs in the muscle of the myocardium, leads to similar symptoms of muscle pain and local muscle death and dysfunction. Myocardial ischemia is well-known to lead to angina pectoris and myocardial infarction, disorders that can be debilitating and life-threatening. The American Heart Association estimates that these disorders afflict more than six million people (American Heart Association, Heart and Stroke Facts, 1994 Statistical Supplement (Dallas: American Heart Association, 1994)). All these conditions entail a mismatch between coronary blood inflow and myocardial oxygen demand. Medical therapies have been developed to alter the demand side of this equation, reducing cardiac preload, afterload, heart rate and contractility. In addition, thrombolytic therapies are available in the setting of acute myocardial infarction to effect restoration of interrupted local blood flow. However, despite the medical interventions that have evolved to treat or palliate the consequences of ischemic heart disease, morbidity and mortality remain substantial.
In cases of life-threatening ischemia, or in cases that have been refractory to medical management, more invasive intervention is required. Available modalities include surgery and percutaneous transluminal coronary angioplasty (PTCA), both designed to improve the supply side of the inflow/demand equation. The predominant surgical procedure, since its introduction by Favaloro in 1967, (R. Favaloro, “Saphenous vein autograft replacement of severe segmental coronary artery occlusion: Operative technique,” Ann. Thor. Surg. 5:334, 1968) is the coronary artery bypass graft (CABG) operation. Coronary artery bypass grafts, using the patient's native veins or arteries, are conduits that bring blood from vessels proximal to a coronary vascular obstruction to the distal coronary artery. This procedure is long and technically complicated, with a prolonged convalescence and an extensive list of potential complications (S. Mehta and W. Pae, “Complications of cardiac surgery,” pp. 369-402 in Cardiac Surgery in the Adult, ed. L E Edmunds (New York: McGraw-Hill, 1997)). The operation usually requires cardiopulmonary bypass, with its own set of risks. Surgical access is through a thoracotomy or, more commonly, a median sternotomy; both access routes are associated with post-operative pain, atelectasis and wound healing problems.
Today, several hundred thousand CABG procedures are performed annually. Survival benefit has been described in patients with higher risk disease, and relief of symptoms occurs in 80-90% of patients for whom medical management had proven inadequate (Yusef et al., “Effect of coronary artery bypass graft surgery on survival: Overview of ten-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialist Collaboration,” Lancet 344:1449, 1994). However, these effects are not permanent. Recurrence of angina following CABG surgery occurs in 3-20% of patients, and 31% will require repeat surgical or interventional cardiologic revascularization by year twelve (Weintraub et al., “Frequency of repeat coronary bypass or coronary angioplasty after coronary artery bypass surgery using saphenous vein grafts,” Am. J. Cardiol. 73:103, 1994).
Before the CABG operation became accepted, various other methods were attempted to improve arterial inflow. Pedicle grafts of muscle and omentum were employed in the 1930's by Beck and O'Shaughnessy (C. Beck, “The development of a new blood supply to the heart by operation,” Ann. Surg. 102:801, 1935; L. O'Shaughnessy, “An experimental method of providing a collateral circulation to the heart,” Br. J. Surg. 23:665, 1935). In the early 1940's, Vineberg developed the technique for implanting a distally ligated internal mammary artery with its side branches not ligated into a bluntly created tunnel in the myocardium (A. Vineberg, “Coronary anastomosis by internal mammary implantation,” Can. Med. Assoc. J. 78:871, 1958), with clinical application beginning in 1950. Murray et al. used the internal mammary artery experimentally as a pedicled bypass in 1954 (Murray et al., “Anastomosis of a systemic artery to the coronary,” Can. Med. Assoc. J. 71:594. 1954). By the 1960's, experimenters were working on the techniques that matured into present-day aortocoronary bypass and segmental coronary artery bypass (Johnson et al., “Extended treatment of severe coronary artery disease,” Ann. Surg. 170:460, 1969).
The technique for percutaneous transluminal angioplasty was introduced in the early 1970's by Gruentzig, initially for work in the peripheral vasculature. By 1978, he had applied this technique to the coronary arteries (A. Gruentzig, “Transluminal dilatation of coronary artery stenosis,” Lancet 1:263, 1978). Although this procedure avoids the drawbacks of coronary artery surgery, it is limited by its own risks of abrupt vessel closure, incomplete revascularization at the time of the procedure, and restenosis. A restenosis rate of 30% is the average reported in the literature (M. Bevans and E. Mclimore, “Intracoronary stents: a new approach to coronary artery dilatation,” J. Cardiovascular Nursing 7:34, 1992). Studies show that all arteries undergoing any type of intervention—balloon angioplasty, atherectomy, stent placement or laser balloon angioplasty—show similar restenosis rates at 6 months (Kuntz et al., “Novel approach to the analysis of restenosis after the use of three new coronary devices,” J. Am. Coll. Cardiol. 19:1493, 1992). Other new technologies are undergoing evaluation for treatment of coronary artery disease, including various types of stents with different characteristics, low speed rotators, transluminal extraction catheters, laser angioplasty and adjunctive therapies. As yet, the problems of acute complications and restenosis remain unsolved.
In addition to the technical difficulties that beset surgical and cardiological interventions are their anatomical constraints: all these technologies are limited to macroscopic lesions in the larger coronary arteries. Although these interventions increase proximal arterial inflow when successful, this may not benefit myocardial tissue if there is extensive distal or small vessel disease. Furthermore, none of these techniques addresses the problem of ischemia at the tissue level which may result from uncorrected multivessel macro-disease, from uncorrected small vessel disease or from disease progression after successful revascularization.
To circumvent these anatomical constraints, techniques have been described to allow blood to enter the myocardium transmurally, directly from the ventricular cavity. Early techniques have focused on the placement of conduits from the ventricle into the myocardial wall (Goldman et al., “Experimental method of producing a collateral circulation to the heart directly from the left ventricle,” J. Thor. Surg. 31:364, 1956; Massimo et al., “Myocardial revascularization by a new method of carrying blood directly from the left ventricular cavity into the coronary circulation,” J. Thor. Surg. 34:257, 1957). More recently, techniques have been proposed that create channels into the myocardium, providing a supply of blood extravascularly (Mirhoseini et al., “Revascularization of the heart by laser,” J. Microsurg. 2:253, 1981). None of these techniques directly connects with the local vascular system, depending instead on intramural diffusion into the myocardial sinusoids to supply tissue needs. None of these techniques, therefore, provides a method for small vessel or microvessel arterial revascularization within the myocardium.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the invention to improve vascular inflow to ischemic muscle tissue. Revascularization at the level of the microcirculation would serve to complement or supplement existing macrovascular techniques (e.g., peripheral vascular bypass, CABG and PTCA) for increasing arterial inflow.
It is a further object of the invention to stimulate angiogenesis within muscle tissue.
It is yet another object of the invention to improve the balance between muscle tissue oxygen supply and oxygen demand by improving small vessel circulation and microcirculation through stimulation of local intramuscular angiogenesis.
Other objects of the invention will, in part, be set forth below and, in part, be obvious to one of ordinary skill in the art given the following description.
The invention includes, inter alia, methods for treating muscle ischemia. In one embodiment, the invention described herein can be understood as methods for stimulating angiogenesis within muscle tissue. According to this practice, the method includes accessing the muscle with a delivery system, penetrating the muscle and using the delivery system so as to enclose within the muscle at least one body formed of a biocompatible material and dimensionally adapted for being enclosed within the muscle. A delivery system can include any system adapted for accessing a muscle. The delivery system, in one embodiment, can include a catheter. Access to the muscle can take place by guiding a catheter delivery system through the patient's vascular system. Once the muscle has been accessed, it can be penetrated. The delivery system then operates to enclose within the muscle at least one body formed of a biocompatible material and dimensionally adapted for being enclosed within the muscle.
The method can include stimulating angiogenesis by enclosing within the muscle a body that is of an appropriate size and shape to be implanted within the designated muscle. The delivery system can operate to enclose the body in the muscle by substantially sealing the body within the muscle. In one embodiment, penetrating the muscle can include driving the distal portion of the delivery system into the muscle. Penetrating the muscle can include driving the biocompatible body into the muscle. The delivery system is adapted for enclosing at least one biocompatible body within the muscle. Alternatively, the delivery system can be adapted for implanting a plurality of bodies in muscle tissue. In one embodiment, the delivery system is adapted for delivering into the muscle an agent for promoting angiogenesis. An agent capable of promoting angiogenesis can include any substance whose biological effects include stimulating the growth and development of blood vessels.
Angiogenesis, as the term is used herein, is understood to be those processes of forming or developing blood vessels in a tissue. It is understood that angiogenesis is promoted through contact of the surfaces of said body with the muscle tissue. Accordingly, a body can be any three dimensional structure with surfaces that contact the muscle tissue. It is desirable that the body described herein be made of materials compatible with the tissues of the human body, so that the materials do not incite toxic reactions. The term biocompatible, as used herein, refers to any material that does not incite toxic reactions. In one embodiment, the materials used for the implantable device can be conducive to thrombus formation. In this embodiment, the implantable device can have the effect of keeping patent a space within the muscle tissue surrounding the device so that blood pooling can take place adjacent to the device. However, any method conducive to thrombus formation can be used. Furthermore, any agent capable of promoting angiogenesis can be delivered into the muscle.
The term implant may be used to refer to certain embodiments of these devices, although this term is not intended to limit the scope of the descriptions that follow. Biocompatible materials can be made biostable or biodegradable, bioactive or inert, depending upon the selected composition. Biocompatible materials can include bioartificial polymeric materials, formed as a hybrid or composite of synthetic and biological polymers that thereby overcomes the lack of biocompatibility associated with certain synthetic polymers and enhances the mechanical properties of natural polymers. Biocompatible materials can include hydrogels, which are materials comprising water-swollen polymer networks. Conventional hydrogels change little in swelling with environmental conditions while stimuli-responsive hydrogels may swell or deswell, depending on changes in environment such as temperature, pH, ionic strength, electric field, chemical or biological agents, mechanical stress or radiation. Hydrogels may be biostable or biodegradable. Hydrogels can be combined with other biocompatible materials to make implants. Further descriptions of exemplary types of bodies are presented herein. Other embodiments and materials for manufacture will be apparent to those ordinarily skilled in the art.
One practice of these methods involves stimulating angiogenesis within the myocardium, although it is understood that these methods are not thereby limited but rather can be applied to any muscle tissue. According to this practice, the method can include the steps of accessing the myocardium, penetrating the myocardial wall of the heart, and releasing within the myocardial wall a device that stimulates angiogenesis. Myocardial access can be via a transepicardial or a transendocardial route. Access can be provided intraoperatively or transvenously. In one practice, the physician uses the transvenous, transendocardial route for access and, under fluoroscopic control, manipulates a catheter to the intended site for device implantation. In one practice of this method, penetration of the myocardium can be accomplished by the device that is to be implanted. In an alternative method, penetration can be accomplished by a catheter-directed mechanism that serves as a guidewire over which the device is implanted. Other methods for delivering the device into the myocardium will be apparent to those of ordinary skill in the art.
According to one method, the device implanted in the tissues of a muscle has been deformed before its insertion and dynamically tends to revert to its pre-deformation shape after it is implanted. Deformation can occur by the application of deforming stresses. Deforming stresses are those forces that alter the shape of a body, commonly by compression or extension. The native configuration of a body is the shape in which it exists in the absence of these deforming stresses. Dimensions that have been altered can vary in size or in shape. The implantable devices as described herein may be made of resilient or flexible materials. A flexible device can be characterized by its ability to be deformed. A device deformed prior to insertion can revert towards its pre-deformation shape after implantation. Alternatively, a device may be susceptible to deformation after implantation, either from the action of the contracting and relaxing muscle, as exemplified by the beating heart or from reaction to body heat, upon application of an activating agent, or by any other suitable means. Representative materials include metallics and plastics. Metallic materials include stainless steel, MP35N, Nitinol™, Elgiloy, and Titanium, materials with sufficient resilience to be employed to form flexible bodies. Plastic materials include polymers, for example silicone.
According to another method, the device implanted in the myocardium is made of a heat responsive material. A material that changes its shape in response to heat is termed a heat responsive material. In one embodiment, the implantable body changes its shape in response to intramuscular heat. Intramuscular heat can include that heat intrinsic to the muscle or that heat obtained from a source external to the muscle that is conveyed into the muscle's interior. Some heat responsive materials will return to a pre-selected shape in response to a change in thermal condition. These materials are termed thermal shape memory materials, an example of which is Nitinol™.
In one embodiment, the systems and methods produce biological reactions for purposes of stimulating angiogenesis. The methods described herein include those methods of promoting angiogenesis by implanting in a muscle tissue a body formed of a biocompatible material that incites an inflammatory reaction within the tissue of the muscle. It is understood that inflammation can be incited by the implantation of substances that trigger the inflammatory cascade to stimulate angiogenesis. The inflammatory cascade can be triggered by those processes related to wound healing and tissue repair. In certain embodiments, the methods described herein further include the implantation of devices that can produce blood coagulation by biochemical stimulation, and thereby form thrombus. An example of a device that produces blood coagulation by biochemical stimulation is a device that includes substances that trigger the coagulation cascade such as thrombin. Such biochemical substances can be imbedded in the structural material of the device, or can be carried on or affixed to its surfaces.
In one embodiment, angiogenesis can be stimulated by inciting local healing reactions in the muscle tissue. These local healing reactions are understood to trigger the inflammatory cascade and stimulate angiogenesis. Mechanical stimulus for inflammation is produced by the presence of a rigid or flexible device within muscle tissue that provides resistance to normal muscle contraction and relaxation. Mechanical stimulus for inflammation is also produced by a flexible body introduced into the muscle in a deformed state that has the inherent tendency to return to its native configuration. Such a body, as it reverts to its native configuration following implantation, applies a force to the surrounding tissues and is understood to provide thereby a mechanical stimulus for triggering inflammation.
One embodiment of the systems and methods described herein can include a kit for promoting angiogenesis. In one embodiment, the kit can include a delivery system for accessing a muscle, an implantable body dimensionally adapted for being enclosed within the tissues of the muscle, and an implantation device to insert the implant within the muscle.
In one embodiment, the systems and methods described herein include apparatus for promoting angiogenesis. In one embodiment, this apparatus has at least one surface carrying a substance capable of promoting localized angiogenesis. As one embodiment, this apparatus can include an implant formed of a biocompatible material that has a drug releasing compound affixed to at least one of its surfaces. The surface carrying the substance capable of promoting localized angiogenesis can be coated with said substance or can be made of a material that comprises said substance. The substance capable of promoting localized angiogenesis can be a drug releasing compound. The term drug releasing compound as employed herein will be understood to include any substance that conveys a pharmacological or therapeutic agent. The drug releasing compound can include a pharmacological agent combined with an appropriate vehicle, or alternatively, the drug releasing compound may entirely consist of a pharmacological agent. One example of a drug releasing compound is the coagulation factor thrombin. In one embodiment, this apparatus can have at least one drug releasing compound affixed to the implantable device beneath a timed release coating. Alternatively, the drug releasing compound can be admixed with a timed release agent. In an alternate embodiment, the implantable device is entirely made of a drug releasing compound.
In yet another embodiment, the device is designed to contain an internal reservoir into which can be placed a drug releasing compound that is able to diffuse through the wall of the device. The reservoir can be constructed as an empty cavity within the device to be filled with a drug releasing compound. In this embodiment, the device is made of a material that is specifically permeable to the drug releasing compound within it, so that the contained drug can penetrate the device and contact the surrounding tissue. Alternatively, the drug releasing compound can be contained within the lumen of a spring, to be released between the spring coils as the heart contracts, or the compound can be formulated as a gel or resin that is deployed between the coils of the spring, to be released into the tissues with myocardial contraction.
In another embodiment, the implantable device includes a radiation source. A body made of a biocompatible material can be made to deliver localized amounts of radiation to surrounding tissues by incorporating a radiation source. The radiation source can be affixed to a surface of the implantable device. Alternatively, the radiation source can be carried within the implantable device. In yet another embodiment, the radiation source can be incorporated into the material employed to form the implantable device. When a bioceramic material such as glass is used to form the implanted device, radioactivity present within the implantable body will degrade the glass and dissolve it in time, resulting in biodegradation.
Not to be bound by theory, nonetheless it is understood that angiogenesis may be promoted by causing blood to pool in a localized area and the pooling of blood is understood to result in thrombus formation with the subsequent stimulation of angiogenesis. Accordingly, in one embodiment, the system described herein provides an implantable body that includes a surface that allows blood to pool. This surface may be on the external or the internal aspect of the device. In one embodiment, the surface of the device may provide at least one concave area in which blood can pool. The external face may have a projection that imbeds itself into the muscle tissue and prevents normal muscle contraction or relaxation. The action of the projection upon the muscle tissue during a cycle of muscle contraction and relaxation results in the creation of lacunae within the muscle that become filled with pooled blood.
In one embodiment, the devices described herein include a flexible structure. Flexible materials may be arranged in a variety of shapes, including springs and bellows. The spring can comprise a regularly coiled filament of a metal or plastic material arranged in a tubular shape. In other embodiments the spring is arranged in alternative geometries, each of which provides a deformable resilient body. The term tubular will be understood to include any shape defined by a sidewall that includes at least two openings with a space extending therebetween, and wherein the sidewall can be generally cylindrical, rectangular, triangular or any other suitable shape. A bellows device is able to be compressed and to be expanded as it is acted upon by the myocardium. A bellows may enclose a cavity having drug-releasing compounds contained therein and optionally the bellows may include a port for releasing the compound from the cavity upon compression and expansion of the bellows spring. Blood pooling can take place within the lumen of the spring, thereby to stimulate angiogenesis. The spring may be close-wound, such that adjacent coils are in contact, or the spring may be open pitch with a space between adjacent coils.
In one embodiment, the biocompatible body comprises a heat responsive material. This term is understood to include thermal shape memory or superelastic materials. In an alternative embodiment, the biocompatible body comprises a rigid material. The implantable devices described herein can include rigid materials that are sufficiently stiff to prevent or reduce deformation of the implantable device. A rigid material can resist deforming stresses such as those produced by muscle contraction. Rigid materials can be bioabsorbable, subject to local degradation and resorption over time. Representative materials include metallics and plastics. Metallic materials include stainless steel, MP35N, Nitinol™, Elgiloy, and Titanium. Plastic materials include Teflon, polymethyl methacrylate (PMMA) and bioabsorbable materials such as Polyglycolide (PGA) and Lactide Polylactide (LPLA). Biocompatible materials conforming to these definitional parameters are well-known in the art of biomedical engineering and any suitable biomaterial, including polymers, metals, ceramics, carbons, processed collagen, chemically treated animal or human tissues, or bioabsorbable materials may be used.
In one embodiment, the apparatus can include a scaffold that supports tissue ingrowth. The scaffold can be a structural matrix of solid supporting elements that surround interstitial spaces. The interstitial spaces provide foramina for tissue ingrowth throughout the scaffold, and the supporting elements organize the arrangement of the tissue elements within the scaffold. Tissue growth factors deployed in the interstitial spaces or carried on or affixed to the supporting elements enhance tissue ingrowth and angiogenesis. Tissue growth factors are agents that act to initiate or accelerate the processes of tissue proliferation. Examples of tissue growth factors include Fibroblast growth factor (FGF) types I and II, and vascular endothelial growth factor (VEGF).
In one embodiment, the devices can be substantially solid scaffolding, with relatively small channels provided within this solid material to permit and organize tissue ingrowth. This embodiment can be configured to enclose a space within it into which tissue can grow. Apertures in the solid body are openings that permit tissues to grow into the interior cavity. The cavity may be entirely enclosed by solid walls on all sides, with apertures providing the route for tissue ingrowth. Alternatively, the device may be tubular in shape with at least one sidewall removed, so that the internal cavity is in communication with the milieu external to the device. In another embodiment, the scaffold can include channels extending through the biocompatible body to support tissue ingrowth.
Other aspects and embodiments of the invention will be apparent from the following description of certain illustrative embodiments.
The invention provides systems and methods for promoting angiogenesis in muscle tissue. These systems can be employed for treating ischemia caused by acute or chronic circulatory insufficiency, for example, arterial occlusions or compartment syndromes. For purposes of clarity, the system and methods of the invention will now be described with reference to treating ischemia within the myocardium. However, it will be understood that the system and methods of the invention are not to be restricted to application within the myocardium, but rather can be applied to any muscle of the body, and that these applications of the system and methods of the invention in muscle tissue will be apparent to those of ordinary skill in the art from the following description of the illustrated embodiments.