Abstract:
A method and implantable device for treating anoxic tissue. A substrate supporting an angiogenesis factor in an amount for treating anoxic tissue is implanted so as to promote revascularization of the tissue. The substrate is a physiologically compatible polymer and may have different configurations such as a fiber, a filament, a microsphere, a needle or a pin. The implantable device may be transported through a catheter or implanted directly in the anoxic tissue. The anoxic tissue may be heart, eye, brain, brain stem, spinal cord, bone and combinations of tissues.

Description:
BACKGROUND OF THE INVENTION 
     Angiogenesis is the process of inducing new blood vessels. Angiogenesis-producing factors are signals that serve as stimuli to cause angiogenesis. The result of angiogenesis is neovascularization to initiate a blood supply to a tissue or to revascularize ischemic tissue. Neovascularization or revascularization by angiogenesis-producing factors includes recanalization whereby hollow capillary tubes form to support a blood supply. 
     Angiogenesis is also the process whereby a tissue responds to a tumor by inciting growth of new blood vessels toward the tumor. Beside tumors, substances that may induce angiogenesis include proteolytic enzymes, growth factors, and chemicals such as EDTA. 
     Proteolytic enzymes are secreted by tumor cells or destroyed cells in the process of cytolysis. These enzymes induce cell movement toward their chemical stimuli in the process of chemokinesis. Chemicals such as EDTA can cause instability of a cell membrane and similarly trigger cell movement. It has been also shown that growth factors, such as fibroblast growth factor (FGF), transforming growth factor (TGF), nerve growth factor (NGF), and so on, play a role in regulating proliferation of endothelial cells. Regardless of the pathogenesis of angiogenesis, the process is accompanied by proliferation of endothelial cells from initially normal vessels toward the stimulus. 
     Folkman in 1971 proposed the concept of anti-angiogenesis. Anti-angiogenesis involves inhibiting new blood vessel formation in order to either prevent growth of a tumor or control growth of metastatic tumors. Much work has been done in this area to identify and test anti-angiogenesis agents. Examples of such agents include anti-inflammatory or suppressive factors (inhibitors) that prevent endothelial cell proliferation, and inhibitors of proteolytic enzymes such as plasminogen activator inhibitors. Such inhibitors can prevent the breakdown of the protein matrix and maintain the integrity of endothelial cells, thereby preventing their migration. Efforts in this area have been concentrated in attempting to treat tumors by preventing neovascularization. 
     Although in the last two decades there have been attempts to revascularize an ischemic area of myocardial tissue using laser energy, these attempts have been only partially successful. This is due to laser-induced channels closing by themselves, as well as to the unpredictable rate of revascularization of these channels. Similarly, in central retinal vein thrombosis, attempts have been made to rupture small retinal veins with laser energy applied in a transpupillary direction, thus also rupturing Bruch&#39;s membrane in the hope of creating a channel from the retina to the choroidal circulation. These techniques have met with only minimal success; less than a 30% success rate has been achieved with this method to create new channels. Additionally, revascularization of the retina cannot occur in patients who have central vein occlusion or other diseases which create capillary occlusion in the retina or any other organ, such as the brain. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to a method and device for treating anoxic tissue. A physiologically compatible device supports an angiogenesis factor in an amount for treating an anoxic tissue. The device is implanted in the anoxic tissue so as to induce revascularization of the tissue. 
     The invention is also directed to a method of making an angiogenesis-inducing implant, comprising supporting an angiogenesis factor on a physiologically compatible substrate for retaining the factor, to form an implantable device. 
     The invention also describes methods and materials used to successfully induce neovascularization in an ischemic tissue, in an attempt to reestablish function of these tissues. In particular embodiments, the devices and methods of the invention may be used to revascularize anoxic heart and eye tissue. 
     Until now, no attempt has been made to in fact use angiogenesis-stimulating factors to revascularize ischemic tissue. One example where angiogenesis-stimulating factors may be used is in a damaged heart muscle where closure of one or more coronary arteries has resulted in a myocardial infarction. Such closure leads to either acute myocardial infarction or to a gradual cardiomyopathy, with its predominant symptom of angina pectoris. Another example where angiogenesis-stimulating factors may be used is in anoxic tissue in the eye. Central retinal artery occlusion in the eye causes immediate discontinuation of blood supply to the retina. If this condition is not treated within a short period of time, or if the vessels are not reopened by themselves, pushing microemboli in the peripheral branches, complete loss of sight occurs. Another example is central vein occlusion that results from thrombosis of the central retinal vein. Lack of blood flow in the central retinal vein produces congestion, with subsequent breakdown of the capillary network and hemorrhage in the retinal tissue. Lack of oxygen and nutrients, carried by blood, produces ischemic processes in the retina and may result in the loss of sight. 
     Other advantages and embodiments will be understood with reference to the drawings and following detailed description. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1A is a device in the form of a single pin to be situated in the eye. 
     FIG. 1B is a device in the form of a fork-like pin to be situated in the eye. 
     FIG. 1C is a device in the form of a fork-like pin with arrowheads to be situated in the eye. 
     FIG. 1D is a device in the form of a microsphere to be situated in the heart. 
     FIG. 1E is one embodiment of the device shown in FIG. 1B showing a fiber coating on the fork-like pin to be situated in the eye. 
     FIG. 2 is a schematic longitudinal cross section of part of the human eye. 
     FIG. 3 is a fragmentary cross section of the circled area  3  of FIG. 2 showing a pin implanted along a vessel. 
     FIG. 4 is a fragmentary cross section of the circled area  4  of FIG. 2 showing an eye wall. 
     FIG. 4A is the section of the eye wall shown in FIG. 4 with a pin implanted from the interior. 
     FIG. 4B is a section of the eye wall shown in FIG. 4 with a pin implanted from the exterior. 
     FIG. 5 is a schematic longitudinal cross section of the human heart. 
     FIG. 5A is a fragmentary cross section of the heart shown in FIG. 1 showing one embodiment of the device in the form of pins implanted from inside a wall of the heart. 
     FIG. 5B is a section of the heart shown in FIG. 5 showing one embodiment of the device in the form of pins implanted from outside a wall of the heart. 
     FIG. 5C is a section of the heart shown in FIG. 5 showing another embodiment of the device in the form of microspheres placed in a wall of the heart. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     As shown in FIGS. 1A-E the devices  10  of the present invention are physiologically compatible substrates  11  supporting angiogenesis-producing factors  12 . The devices  10  may take various forms. As shown in FIG. 1A, the device  10  may be a single pin  13 . The pin  13  may have a length of about 20 to about 4000 microns and a diameter of about 20 to about 1000 microns when used in organs such as heart and eye, but may extend up to many centimeters when implanted in larger organs and tissues, such as large bones. As shown in FIG. 1B, the device  10  may have a fork-like shape  14  with a head section  16  and two prongs  18 . In one embodiment, the length of each prong is about 20 to about 5000 microns and the diameter is about 50 to about 1000 microns for use in organs such as heart and eye, but may be enlarged depending upon the size of the organ or tissue. In another embodiment, as shown in FIG. 1C, the device  10  has a substantially fork-like shape  14  with the head of the fork  16  extending between the prongs  18  and terminating in a complete arrowhead  20 , and with each prong  18  of the fork  14  terminating in a one-sided arrowhead  22 . In still another embodiment, as shown in FIG. 1D, the device  10  may be in the form of a microsphere  23 , ranging in size from about 0.1 micron to about 3 microns. Other forms of the device are also possible, such as a ring form. As shown in FIG. 1E, any configuration of the device  10  may contain a coating  24  of fibers  26 . The fibers  26  may be synthetic or natural fibers, such as silk, nylon, porous silicone, or other material. 
     The devices  10  support the angiogenesis-producing factors  12  by providing substrates  11 , preferably biocompatible polymers, for retaining the factors  12 . In one embodiment, the devices may be permeable. The devices may be manufactured of proteins, polyesters, polyamides, polyvinyl alcohol, polyolefins, polyanhydrides, or polycarboxylic acids. For example, proteins such as silk, hydroxyapatite, cross-linked or non-cross-linked collagen, cross-linked or non-cross-linked fibrin, catgut and mixtures of these proteins can be used. Polyesters such as polyethylene terephthalate, polycaprolactone, and mixtures of these polyesters can also be used. Similarly, a polyamide such as nylon or a polyvinyl alcohol may be used. Polyanhydrides such as poly(fatty acid dimer), poly(sebacic acid), and their copolymers of poly(fatty acid dimer-sebacic acid), and copolymers of bis(carboxyphenoxy)propane-sebacic acid may be used. Polycarboxylic acids such as polylactic acid, polyglycolic acid and mixtures of these may be used. 
     Polymeric substrates  11  configured into fibers or filaments and supporting angiogenesis-producing factors  12  can enhance the process of endothelial cell migration. One example of such a configuration is a polymeric device  10  containing silk and angiogenesis-producing factors  12 . The polymeric device  10  can also be made of hydroxyapatite which subsequently can enhance neovascularization and ossification as needed; for example, in the bone or after evisceration in the eye. 
     The angiogenesis-producing factors  12  used in the present invention may be produced from proteolytic enzymes, cellular extracts, or destroyed cells. Other angiogenesis-producing factors  12  that may be used include fibrin growth factor (FGF), nerve growth factor (NGF), transforming growth factor (TGF), tumor necrosis factor (TNF), tissue plasminogen activator (TPA), urokinase, streptokinase, toxins, platelet factor  4  (PF 4 ), suramin, ornithine decarboxylase, interleukins (IL), SPARC platelet activating factors (PAF), prostaglandins, phorbols, lipopolysaccharides, and thrombin. 
     Polymeric devices  10  coated with angiogenesis factors  12  induce neovascular tissue to form and to move from a normal unaffected area of the tissue toward an ischemic area. FIG. 2 shows a human eye  28  which may become anoxic in a particular area due to lack of blood supply through a blood vessel  29  such as the retinal artery  30  or retinal vein  32 . As shown in FIG. 3, for revascularization in the case of central vein thrombosis of the eye  28 , a regular pars plana vectrectomy is performed with incisions  33  made along a vessel  29 . The vitreous is removed by a vitrector under direct visualization. The small branches of the central retinal vein  32  are isolated, and small incisions  33  are made adjacent to them to free them from the surrounding structure. The implanted devices  10  depress the branches of the retinal vein  32 , forcing the branches down into the choroid tissue  34  where they are held by the force exerted by the solid polymer substrate  11  portion of the device  10 . The choroidal vessels  36 , in turn, penetrate and migrate into this structure and simultaneously create new channels from the choroid tissue  34  into the branches of the retinal vein  32 . FIG. 4A shows the device  10  depressing a key vessel  29 ,  30 ,  32  into the choroid tissue  34 , where the device  10  is implanted from the inside. FIG. 4B shows the device  10  after implantation from the outside. Similarly, in an anoxic area of the retina  38 , multiple devices  10  coated with angiogenesis-producing factors  12  may be implanted through the retina  38  in the choroid  34  to induce migration and recanalization of the retina  38 . 
     Implanting the devices  10  can be performed not only transvitrially, but also from outside the eye  28  through the sclera  40  to create neovascularization at the desired site. Furthermore, in early cases of central retinal artery  30  occlusion or branch retinal artery occlusion, recanalization may be achieved using the methods and devices  10  of the invention. 
     As shown in FIG. 5, a human heart  42  having areas of anoxia in the right ventricle  44  and left ventricle  46  may be treated by the methods and devices  10  of the present invention. To administer the devices  10  to the anoxic ventricular  44 , 46  areas of the heart  42 , the devices  10  may be transported to the heart  42  by a catheter  48 . 
     The catheter  48  is inserted through any accessible venous structure lying in the subcutaneous tissue, such as the anticubital vein or femoral vein. The catheter  48  is advanced toward the vena cava  49  and is subsequently brought through the right atrium  50  and into the right ventricle  44  of the heart  42 . Similarly, if a catheter  48  is moved through the arterial system, such as the femoral artery or anticubital artery, the catheter  48  is brought through the aorta  51  to the left atrium  52  to gain access to the left ventricle  46 . These techniques are routinely used to either perform angiography or for balloon angioplasty, such as when a coronary artery is reached via the aorta  51 . In one embodiment of the present invention, a laser  54  is connected to a catheter  48  to either unblock the coronary artery or to create small channels in the myocardium  56  from inside the heart  42  in the process of recanalization. 
     The devices  10  may be injected into the heart  42  by force, or may be mechanically implanted into the heart  42 . The devices  10  may be configured into a needle-like or pin-like shape for easier penetration, or may be configured as a fiber, filament, or microsphere  23 . As shown in FIG. 5A, the device  10  in the form of a pin  13  can be implanted from inside the wall of the heart  42 , that is, into the myocardium  56 . As shown in FIG. 5B, the device  10  in the form of a pin  13  may also be implanted from outside the heart  42  into the wall of the myocardium  56 . As shown in FIG. 5C, the device  10 , in the form of a microsphere  23 , may be placed in the myocardium  56  either from inside or outside the heart  42 . 
     Depending on the anoxic area and extent of the anoxic process in a tissue, the devices  10  may be placed at regular intervals to enhance vascularization of the entire ischemic area. The devices  10  may be implanted as close as a few millimeters or as far as a few centimeters from each other, depending on the need for vascularization. The process can be repeated, if desired, through a small incision made in the chest wall. The devices  10 , and methods of using the devices  10  disclosed in the present invention, can also be used in other parts of the body where vascular occlusion has occurred or is threatening to occur. Such occlusion may be the result of, for example, closure of the main vessels thereby affecting the brain, brain stem, or spinal cord. The methods and devices  10  of the present invention may also find use after a spinal cord injury. Revascularization and recanalization may also have some application in the extremities where major vessels may be impaired, for example, as a result of arteriosclerosis, an inflammatory process, or trauma. 
     Other variations or embodiments of this invention will become apparent to one of ordinary skill in the art in view of the above drawings and description, and the forgoing embodiments are not to be construed as limiting the scope of this invention.