Prolonged, scaffold-mediated delivery of angiogenic compounds

Abstract

Devices, systems, and methods are provided for delivery of angiogenic compounds. A resorbable intravascular device is loaded with a high concentration of an angiogenic stimulant formulated for prolonged, intraluminal delivery directly downstream to ischemic target tissue. The device facilitates intravascular delivery of angiogenic moieties directly to ischemic tissue at sufficient dose and duration to safely and effectively treat cardiovascular disease. The scaffolds are loaded with angiogenic compounds such as proteins formulated within a biopolymer coating which controls downstream elution to ischemic tissue for prolonged periods. Once exhausted, the resorbable scaffold dissolves, leaving no permanent device within the patient.

Description

PROLONGED, SCAFFOLD-MEDIATED DELIVERY OF ANGIOGENIC COMPOUNDSCROSS REFERENCES TO RELATED APPLICATION

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 720711, entitled “PROLONGED, SCAFFOLD-MEDIATED DELIVERY OF ANGIOGENIC COMPOUNDS”, filed on November 14, 2024, the full disclosure of the above referenced application is incorporated herein by reference.FIELD OF THE INVENTION

[0002] The present application pertains generally to the field of medical devices. More specifically, the present application pertains to the design and manufacture of intravascular stents intended to treat occlusive vascular disease.BACKGROUND

[0003] Cardiovascular disease is a tremendous burden on global health. Inclusive of coronary heart disease, heart failure, stroke, hypertension and peripheral arterial occlusive disease, the prevalence of cardiovascular disease in adults is a staggering 49%. It is the leading cause of suffering and death worldwide. After steady and sustained increases in life expectancy over the past century, the prevalence and severity of cardiovascular disease has, for the first time in recorded history, caused the average lifespan of human beings living in developed nations to decrease.

[0004] The common pathophysiologic pathway for cardiovascular disease is atherosclerosis. Atherosclerosis is a degenerative disease; it is the process by which arteries age. As such, it is an inevitability of the human condition and anyone who lives long enough will get atherosclerosis. In youth, arteries are vibrant, dynamic, elastic organs. There is a high prevalence of elastin, a 60 kDA structural protein containing large proportions of glycine and proline. Human tissues rich in elastin include the aorta and major blood vessels (28-32% dry mass), the lungs (3-7%), elastic ligaments (50%), tendons (4%), and skin (2-3%). Elastin is a complex, functional protein. Its soluble form, tropoelastin, is formed through transcription of the ELN gene, translation in the rough endoplasmic reticulum, complexation with elastin-binding protein (EBP) and transport and secretion from the cell surface (elastogenesis). Within the extracellular matrix, tropoelastin monomers form multimers through aggregation of their hydrophobic domains. Under the modification of lysyl oxidase (LOX), tropoelastin aggregates undergo extensive cross-linking and eventually form functional, mature elastic fibers which provide a supple, flexible arterial scaffold capable of deformation and motion.-1- Attorney Docket No. EFML-01200WO

[0005] The human body’s elastin content is formed in embryogenesis; adults cannot make more elastin. Fortunately, the fibers have a long lifespan (up to 70 years) but, being a complex structural protein, the stretching of arterial elastin fibers with each contraction of the left ventricle inevitably leads to its fatigue: the crosslinks break, the protein denatures, and the fibers no longer function. Damaged or degenerated elastin fibers cannot be repaired; they

[0006] are replaced by collagen and proteoglycan, neither of which can facilitate motion. The result is that the arterial wall remains intact but no longer moves. It becomes a stiff, rigid conduit; still faithfully transmitting blood but no longer participating in the dynamics of pulsatility.

[0007] The phenomenon of arterial aging through elastin degradation is easily demonstrated. Older arteries exhibit a significantly reduced elastin content on quantitative assay and histologic examination with elastin staining reveals poor overall content, a disorganized structure and replacement with inert extracellular matrix. The effects are evident clinically, as well. Aged arteries insonated with continuous wave Doppler ultrasound exhibit reduced amplitude and attenuated pulsatility of the waveform (despite maintenance of blood pressure). This is because the rigid conduit no longer transmits the pulse wave reflected back from the arterioles. The usually triphasic waveform (that includes a component of flow reversal) becomes dampened and sluggish. Indeed, carotid pulse wave analysis is a popular method for evaluating arterial stiffness and stratifying cardiovascular risk.

[0008] The net effect of the loss of elastin and the stiffening of the arterial wall is that blood flow slows down. The dynamic, multiphasic velocity profile of youth gives way to the stagnant, monophasic flow of the elderly. The result is an increase in residence time of circulating blood elements at the arterial wall. Arterial blood flow is often thought of as brisk and rapid (as any surgeon will attest). Of course, this is true in the centerline where velocity is maximal. However, the velocity profile of blood flow in human arteries is parabolic: it is rapid in the center but slows down markedly at the wall. In fact, the velocity of blood in the boundary layer (immediately adjacent to the wall) is quite slow and, in aged and stiff arteries, almost motionless. This allows circulating blood elements, such as monocytes and platelets, to interact with adhesion molecules expressed on the aging endothelial surface. The cells “stick” to the wall and penetrate into the media. In this unfamiliar environment, they attempt to phagocytize the degenerating extracellular matrix and become foam cells, bloated with intracellular debris and expressing cytokines which further disrupts the endothelium and accelerates the pathologic process. The result is the familiar “fatty streak” on the dorsal arterial wall: the progenitor of mature, occlusive atherosclerotic plaque.

[0009] The formation of occlusive, atherosclerotic plaque has become the bane of human existence. Plaque in the coronary arteries causes angina and myocardial infraction; in the cerebrovascular arteries causes transient ischemic attack and stroke; and in the peripheral arteries causes claudication, gangrene and amputation. Contemporary medical therapy for cardiovascular disease, including antiplatelet, antithrombotic, lipid-lowering and antihypertensive agents, reduces clinical events but exerts no effect on blood flow; ischemic tissue can only be treated by performing a surgical procedure (angioplasty, stenting, endarterectomy or bypass). Despite many decades of basic and clinical research, there is still no other way to improve blood flow in human beings.-2- Attorney Docket No. EFML-01200WO

[0010] The physiologic processes by which collateral arteries develop in response to ischemia are called angiogenesis and arteriogenesis. Angiogenesis is defined as the creation and proliferation of new blood vessels (FIG. 1). This process spouts entirely new vascular channels through the differentiation, proliferation and migration of endothelial cells (ECs) and their supporting elements. The developing arteries intussuscept into existing capillary networks providing entirely new routes for blood flow and tissue perfusion. The major stimulus for adult angiogenesis is ischemia which induces inflammatory cells and ECs to produce and secrete vascular endothelial graft factor (VEGF), a 121-206 amino acid signaling protein originally described in 1983 as vascular permeability factor (VPF). VEGF binds to tyrosine kinase receptors (VEGFRs) on the surface of ECs to stimulate proliferation (mTOR), migration and vasopermeability. A variety of other cytokines have additionally been implicated in this process including fibroblast growth factor (FGF), hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and hypoxia-inducible factor 1 (HIF-1).

[0011] Related to angiogenesis which creates new blood vessels, arteriogenesis is the process by which existing collateral channels enlarge in response to ischemia (FIG. 1). This phenomenon is easily appreciated angiographically in patients with vascular disease in whom large, serpiginous, collateral arteries can frequently be observed adjacent to chronic occlusions. A major stimulus for arteriogenesis is the increased flow and local shear stress exerted upon the small arterial branches that are proximal to a large-vessel obstruction. The ECs transduce these hemodynamic signals and respond with luminal enlargement and wall thinning to accommodate the increased flow. Other mediators that stimulate and regulate arteriogenesis include intercellular adhesion molecule (IC AM), C-C chemokine receptor 2 (CCR2) and stromal-derived factor 1 (SDF-1). The resultant arterial remodeling and collateralization serves to restore and maintain distal perfusion even when major, named arteries are chronically occluded by atherosclerosis.

[0012] Therapeutic angiogenesis is the idea that exogenous delivery of proteins known to stimulate blood vessel growth might provide effective treatment for the syndromes of chronic ischemia caused by atherosclerosis. This could potentially be accomplished through direct protein delivery (via intramuscular, intravenous or intraarterial injection), through delivery of proteins loaded onto intravascular delivery devices (such as angioplasty balloons or stents), through gene therapy by vectors that encode angiogenic genes (such as naked DNA, plasmids or modified retrovirus / adenovirus) or by infusing intact cells known to stimulate blood vessel growth (such as modified angiogenic ECs, smooth muscle cells, progenitor stem cells, mononuclear cells and / or fibroblasts). Virtually all of these strategies have been tested pre-clinically and found to yield positive findings. For instance, bFGF was injected into the ischemic hind limbs of rabbits and found dose-dependent enhancements in transcutaneous oxygen tension, capillaries / mm2, capillary :muscle fiber ratio, thigh muscle viability and protection against infarction. Additionally, a single intraarterial bolus of 500-1000 pg recombinant VEGF was infused into the ischemic hind limbs of rabbits and, after 20-40 days, found significant increases in capillary density angiographically and capillary / muscle fiber ratio histologically. Using this same model, naked DNA encoding an Hypoxia-inducible factor-1 hybrid transcription factor (HIF-la / VP16) was injected and showed significant improvements in calf blood pressure ratio, angiographic score, resting and maximal regional blood flow, and capillary density. Plasmids encoding human hepatocyte growth factor (HGF) were injected injected into ischemic rat and rabbit hind limbs and noted increased levels of protein along with -3- Attorney Docket No. EFML-01200WOsignificant, dose-dependent increases in blood flow (by Doppler imaging), capillary density and collateral formation (by angiography). Similarly, ischemic rat hind limbs injected with plasmids encoding soluble TNF-a receptor 1 (sTNFRl) showed significantly increased capillary density compared with control plasmid-transfected muscles. More recently, proteoliposomes containing FGF and / or PDGF were created and it was found that intramuscular injection into ischemic rabbit hind limbs induced collateralization as measured by peripheral contrast angiography. Finally, bioabsorbable poly-lactic / glycolic acid (PLGA) nanoparticles containing pitavastatin were injected into the ischemic hind limbs of mice and rabbits and demonstrated enhanced perfusion and angiogenesis by laser Doppler imaging and angiography.

[0013] In the experimental myocardium, it was found that either FGF or VEGF delivered to dog hearts significantly enhanced collateral artery formation and salvaged ischemic myocardium. Similarly, a single dose of VEGF was injected into the coronary arteries of pigs made ischemic by left circumflex occlusion. They noted significant, dose-dependent increases in collateral index, myocardial blood flow, coronary vasodilatory reserve and regional ventricular function. It was also shown that intracoronary infusion of bFGF reduced myocardial infarct size following coronary artery occlusion in dogs. Also, naked plasmids encoding VEGF or VEGF-transfected H9c2 myoblasts were injected into the cryodamaged hearts of Sprague-Dawley rats and found that capillary density was enhanced in both groups compared to controls. Finally, ischemic rat myocardium was injected with a Dex-PCL-HEMA / PNIPAAm timed-release hydrogel loaded with VEGF165 and documented significantly increased levels of VEGF165 protein along with improved cardiac function.

[0014] The impressive pre-clinical results of therapeutic angiogenesis (reproduced in many laboratories and experimental models) quickly led to human clinical trials. Most first-in-man (FIM) and early phase experiences were positive. However, when subjected to rigorous randomization and blinding, larger clinical trials of therapeutic angiogenesis proved disappointing. For instance, a trial randomized 105 patients with critical claudication to receive twenty intramuscular injections of replication-deficient adenovirus encoding the 121 -amino-acid isoform of VEGF (AdVEGF121) or placebo and found no differences in peak walking time (PWT), ankle-brachial index (ABI), claudication onset time or quality-of-life measures (SF-36 and Walking Impairment Questionnaire). The authors opined that the lack of efficacy was likely due to the transient duration of expression of the transgene. Similarly, a trial randomized 104 patients with chronic limb-threatening ischemia (CLTI) to receive intramuscular injections of either plasmids encoding HGF or placebo over a one month period. After six months, patients in the highest-dose group exhibited a statistically significant increase in limb perfusion (measured by TcPO2) but no differences in ABI, toe-brachial index, pain relief, wound healing, or major amputation. Finally, a trial randomized 178 patients with stable exertional angina that were unsuitable for standard revascularization to receive intracoronary and intravenous recombinant human VEGF or placebo over a nine day period. After two months, there were no differences between VEGF-treated and placebo-treated patients in any metric. (Interestingly, after four months, patients treated with high-dose VEGF did exhibit significantly decreased complaints of angina and favorable trends in exercise tolerance.) These investigators also theorized that these disappointing results were likely due to the inability to deliver the protein in high doses over a sustained schedule.-4- Attorney Docket No. EFML-01200WO

[0015] Therefore, it would be advantageous to have a device that can deliver angiogenic proteins in a dose and duration sufficient to be effective. At least some of these objectives will be met by the embodiments described below.-5- Attorney Docket No. EFML-01200WOSUMMARY

[0016] The embodiments herein describe a device which facilitates intravascular delivery of angiogenic moieties directly to ischemic tissue at a sufficient dose and duration to safely and effectively treat cardiovascular disease. Biologically active angiogenic compounds are loaded onto scaffolds which are implanted into target arteries using a similar procedure as contemporary intravascular stenting. The scaffolds are loaded with angiogenic proteins formulated within a biopolymer coating which controls downstream elution to ischemic tissue for weeks to months. Once exhausted, the resorbable scaffold dissolves leaving no permanent device within the patient.

[0017] In an embodiment an intravascular medical device comprises segmented bioresorbable scaffolds loaded with a high concentration of an angiogenic compound formulated for downstream therapeutic angiogenesis. The medical device comprises individual scaffold segments, loading the scaffold segments onto an inflatable balloon, the scaffold segments positioned serially along a longitudinal length of the balloon, a position of each stent segment and a resulting distance between each stent segment having a defined distance, wherein the distance between each stent segment allows the medical device to remain longitudinally flexible.

[0018] The scaffold may be formed from a material selected from the group consisting of polymers, copolymers, polymer blends and / or biocopolymers of poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), semicrystalline polylactide, polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(iodinated desamino tyrosyltyrosine ethyl ester) carbonate, polycaprolactone (PCL), salicylate based polymer, polydioxanone (PDS), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), poly(iodinated desaminotyrosyl-tyrosine ethyl ester) carbonate, polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen, cellulose, starch, collagen, polyurethane including polycarbonate urethanes, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, ethylene vinyl alcohol, silicone including polysiloxanes and substituted polysiloxanes, polyethylene oxide, polybutylene terephthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof. In an embodiment, the material is extruded into a cylindrical tubing. The tubing may be laser cut with a pattern to form a stent segment. The scaffold segments are coated with an angiogenic agent. The angiogenic agent may comprise fibroblast growth factors, vascular endothelial growth factors, platelet-derived growth factors, insulin-like growth factor, epidermal growth factors, angiopoietins, hepatocyte growth factors, transforming growth factors, tumor necrosis factors, granulocyte-macrophage colony-stimulating factors, neuregulins, adenosines, bradykinins, hypoxia-inducible factors, matrix metalloproteinases, integrins, rho GTPases, phosphatidylinositol kinases, protein kinases, mitogen-activated protein kinases, astragaloside, ginsenoside, aucubin, caffeine, liraglutide, resveratrol, protopanaxadiol, apabetalone, kanglexin, oroxylin, salidroside, cilostazol, dapagliflozin, naringin, liraglutide, sitagliptin, or bavachalcone.

[0019] This and other aspects of the present disclosure are described herein.-6- Attorney Docket No. EFML-01200WOBRIEF DESCRIPTION OF THE DRAWINGS

[0020] Present embodiments have other advantages and features which will be more readily apparent from the following detailed description and the appended claims, when taken in conjunction with the accompanying drawings, in which:

[0021] FIG. 1 shows angiogenesis and arteriogenesis.

[0022] FIG. 2A illustrates one embodiment of a multi-element stent. FIG. 2B is a magnified view of the stent elements in FIG. 2A.

[0023] FIG. 3 depicts individual biocopolymer scaffolds that have been extruded, laser cut and mounted on a single delivery balloon.

[0024] FIG. 4A shows an implanted multi-element stent in a popliteal artery during full flexion of the hip and knee. FIG. 4B depicts the implanted device of FIG. 4A shown in three dimensions.

[0025] FIG. 5 shows an embodiment of a stent pattern.

[0026] FIG. 6 depicts human tibial arteries which have been paved with multiple scaffolds for the sustained delivery of high doses of angiogenic compounds directly to chronically ischemic skeletal muscle

[0027] FIG. 7 shows an angiographic example of device deployment in the experimental animal.-7- Attorney Docket No. EFML-01200WODETAILED DESCRIPTION

[0028] While the invention has been disclosed with reference to certain embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the scope of the invention. In addition, many modifications may be made to adapt to a particular situation or material to the teachings of the invention without departing from its scope.

[0029] Throughout the specification and claims, the following terms take the meanings explicitly associated herein unless the context clearly dictates otherwise. The meaning of “a”, “an”, and “the” include plural references. The meaning of “in” includes “in” and “on.” Referring to the drawings, like numbers indicate like parts throughout the views. Additionally, a reference to the singular includes a reference to the plural unless otherwise stated or inconsistent with the disclosure herein.

[0030] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” is not necessarily to be construed as advantageous over other implementations.

[0031] Various embodiments are described herein with reference to the figures. The figures are not drawn to scale and are only intended to facilitate the description of the embodiments. They are not intended as an exhaustive description of the invention or as a limitation on the scope of the invention. In addition, an illustrated embodiment needs not have all the aspects or advantages shown. An aspect or an advantage described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced in any other embodiments even if not so illustrated.

[0032] The pathologic process of atherosclerosis accounts for nearly half of all human morbidity and mortality. Affected arteries in the coronary, cerebrovascular and peripheral vasculatures caused heart attacks, strokes and amputations, respectively. Atherosclerosis is a degenerative disease in which aging human arteries become inelastic, lose their pulsatility, blunt their intravascular velocity profiles and attract and absorb circulating inflammatory cells which slowly form cholesterol plaques that foul, narrow and, ultimately, occlude the lumen. The result is decreased blood flow to vital structures that causes dysfunction (ischemia) or frank cell death (infarction).

[0033] To combat this progressive disease, the human body has developed several important compensatory mechanisms. The most essential is the phenomenon of collateralization in which small, usually dormant arterial branches grow larger to create alternate pathways for blood for flow. The physiologic process by which collateral arteries develop in response to ischemia is called angiogenesis. Many of the intercellular signals that stimulate angiogenesis have been identified including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF) and insulin-like growth factor (ILGF).

[0034] Described herein is a device which facilitates intravascular delivery of angiogenic moieties directly to ischemic tissue at a sufficient dose and duration to safely and effectively treat cardiovascular disease. Biologically active angiogenic compounds are loaded onto-8- Attorney Docket No. EFML-01200WOscaffolds which are implanted into target arteries using a similar procedure as contemporary intravascular stenting. In an embodiment the scaffolds are loaded with angiogenic proteins or other angiogenic agents formulated within a biopolymer coating which controls downstream elution to ischemic tissue for weeks to months. Once exhausted, the resorbable scaffold dissolves leaving no permanent device within the patient. In various embodiments the scaffolds are configured to deliver the angiogenic proteins or agents to the ischemic tissue for one to two weeks, two to four weeks, two to six weeks, two to eight weeks, four to six weeks, four to eight weeks, or six to eight weeks. The scaffolds may be configured to deliver the angiogenic proteins or agents to the ischemic tissue for one to two months, one to three months, one to four months, one to six months, one to nine months, one to twelve months, two to three months, two to four months, two to six months, two to nine months, two to twelve months, three to four months, three to six months, three to nine months, three to twelve months, four to six months, four to nine months, four to twelve months, six to nine months, six to twelve months, or nine to twelve months. In other embodiments scaffolds may be configured to deliver the angiogenic proteins or agents to the ischemic tissue for a year or more, for example, twelve to eighteen months, twelve to twenty four months, or eighteen to twenty four months.

[0035] One embodiment of the device is shown in FIG. 2A. In this embodiment, the device is comprised of a series of short, strong, balloon-expandable, stents or scaffolds all mounted on a single delivery balloon and all deployed simultaneously via a single balloon inflation. The length and spacing of the stents / scaffolds are tightly controlled to allow flexibility during the procedure then, once deployed, unencumbered movement of the target artery. The endovascular device with separated and segmented intravascular stents enables miniaturization, simplifies manufacturability, enhances flexibility and facilitates endovascular delivery to the target lesion. A single balloon inflation and device deployment can treat a long segment of artery while still preserving the critical ability of the artery to bend with skeletal motion such as sitting or walking. Multi-element stent 200 comprises multiple stent elements 201. Individual balloon-expandable stent elements 201 are crimped onto an inflatable balloon 203 to facilitate delivery. FIG. 2B is a magnified view of the stent elements 201 in FIG. 2A. Individual elements 201 are positioned serially along a longitudinal length of the balloon 203 and spaced such that the stent elements 201 do not touch one another. Further, the spacing is such that after deployment, the stent elements 201 do not touch or overlap during skeletal movement. The number of elements 201, length of elements, and gap 202 between elements 201 may vary depending on the target vessel location. In an embodiment, each element 201 in the multielement stent 200 has the same length. In multi-element stents having three or more elements 201, and thus two or more gaps 202, the gaps may be of the same length.

[0036] Each segment can be loaded with angiogenic compounds and inserted into the bloodstream for sustained delivery. Following therapeutic angiogenesis, the device dissolved leaving the artery intact. An embodiment of such a device is shown in FIG. 3. Multiple individual biocopolymer scaffolds have been extruded, laser cut and mounted on a single delivery balloon. This embodiment is designed to be implanted in an artery of 3 mm lumen diameter.

[0037] The device is designed to be intravascularly implanted in patent arteries proximal to ischemic tissue for the purpose of therapeutic angiogenesis. FIG. 6 depicts how the device may be used for therapeutic angiogenesis in the human tibial arteries. These figures depict human -9- Attorney Docket No. EFML-01200WOtibial arteries which have been paved with multiple scaffolds for the sustained delivery of high doses of angiogenic compounds directly to chronically ischemic skeletal muscle.

[0038] FIG. 7 shows an angiographic example of device deployment in the experimental animal. A New Zealand White rabbit was anesthetized and the carotid artery exposed. The device was inserted through a sheath and delivered over a wire to the thoracoabdominal aorta. During balloon inflation, the individual segments are easily appreciated (left and middle panels). Once delivered, the aorta appears angiographically normal (right panel).

[0039] FIG. 4A shows an implanted multi-element stent in a popliteal artery during full flexion of the hip and knee. FIG. 4B depicts the implanted device of FIG. 4A shown in three dimensions. The individual stent elements 401 are spaced such that they do not overlap even when the artery is highly bent. Unencumbered arterial movement is afforded through flexion or extension of the unstented gaps 402.

[0040] Stent elements may comprise various shapes and configurations. Some or all of the stent elements may comprise closed-cell structures formed by intersecting struts. Closed-cell structures may comprise diamond, rhombus, rhomboid, trapezium, kite, square, rectangular, parallelogrammatic, triangular, pentagonal, hexagonal, heptagonal, octagonal, clover, lobular, circular, elliptical, and / or ovoid geometries. Closed-cells may also comprise slotted shapes such as H-shaped slots, I-shaped slots, J-shaped slots, and the like. Additionally or alternatively, stent may comprise open cell structures such as spiral structures, serpentine structures, zigzags structures, etc. Strut intersections may form pointed, perpendicular, rounded, bullnosed, flat, beveled, and / or chamfered cell corners. In an embodiment, stent may comprise multiple different cells having different cell shapes, orientations, and / or sizes. Various cell structures have been described in PCT International Application Number PCT / US 16 / 20743, entitled “MULTI-ELEMENT BIORESORBABLE INTRAVASCULAR STENT”, PCT International Application Number PCT / US20 / 19132, entitled “ABSORBABLE INTRAVASCULAR DEVICES THAT EXHIBIT THEIR GREATEST RADIAL STRENGTH AT THEIR NOMINAL DIAMETERS”, PCT International Application Number PCT / US 19 / 35861, entitled “ABSORBABLE INTRAVASCULAR DEVICES THAT SHORTEN UPON EXPANSION CREATING SPACE FOR VASCULAR MOVEMENT”, and PCT International Application Number PCT / US22 / 43920, entitled “TEMPORARY INTRAVASCULAR SCAFFOLDS FOR THE TREATMENT OF RESIDUAL STENOSIS FOLLOWING BALLOON ANGIOPLASTY”, the full disclosures of which are herein incorporated by reference.

[0041] Returning to FIG. 2B, in this exemplary embodiment, the stent elements 201 have a diamond or rhombus shaped closed-cell pattern. Elements 201 comprise intermixed diamond shaped closed cells 204, 205. The stent elements may have cell patterns with relatively thick strut widths and obliquely-angled links. Elements 201 may comprise wide struts 206 of 225 microns or larger. Elements 201 may similarly comprise thick struts 206 of 225 microns or larger. In an embodiment, elements 201 comprise struts 206 with a width and / or thickness of approximately 250 microns. Diamond shaped cells 204 may be aligned in the longitudinal and / or the circumferential directions in a repeating pattern. Similarly, diamond shaped cells 205 may be aligned in the longitudinal and / or the circumferential directions in a repeating pattern. Additionally or alternatively, diamond shaped cells 204 and diamond shaped cells 205 may be helically aligned in an alternating pattern. In an embodiment, diamond shaped cells 204 and-10- Attorney Docket No. EFML-01200WOdiamond shaped cells 205 are circumferentially offset. Additionally, diamond shaped cells 205 may be formed at a central location between four adjacent diamond shaped cells 204. The width of struts 206 between two corners of longitudinally aligned diamond shaped cells 204 are larger than the width of struts 207 between two corners of longitudinally aligned diamond shaped cells 205.

[0042] One embodiment of a stent pattern is shown in a single stent element 501 in FIG. 5. Its strength is imparted through a design composed of tightly closed cells 504, 505 with relatively thick struts 506. When compressed radially (crimped) onto a balloon, the struts 506 are oriented axially (along the length of the blood vessel). When expanded, however, the struts 506 become oriented with the vessel’s diameter, and, like the columns of a building, lend additional resistance to the circumferential compression forces acting to collapse the blood vessel. The closed cell configuration also spreads the compressive load throughout the repeating structure making it highly resistant to deformation. This particular embodiment of a closed cell configuration pattern is attended by significant foreshortening during expansion. This foreshortening further concentrates the struts 506 into a smaller area and increases strength.

[0043] The stents described herein may be formed from various different materials. In an embodiment, stents may be formed as a polymer or co-polymer. In various alternative embodiments, the stent or stent element may be made from any suitable bioresorbable material such that it will dissolve non-toxically in the human body, such as but not limited to polyesters such as Polylactic acid, Polyglycolic acid, and Polyhydroxyalkanoate, amino acid based polymers such as Polyesteramide, polycarbonates such as Polytrimethylene carbonate as well as any and all copolymers of the types described herein. In alternative embodiments, the stents may be formed from a permanent material such as a metal.

[0044] In various embodiments, any suitable polymer or copolymer may be used to construct the stent. The term “polymer” is intended to include a product of a polymerization reaction inclusive of homopolymers, copolymers, terpolymers, etc., whether natural or synthetic, including random, alternating, block, graft, branched, cross-linked, blends, compositions of blends and variations thereof. The polymer may be in true solution, saturated, or suspended as particles or supersaturated in the beneficial agent. The polymer can be biocompatible, or biodegradable. For purpose of illustration and not limitation, the polymeric material may include, but is not limited to, L-lactide, poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), poly(iodinated desamino tyrosyl-tyrosine ethyl ester) carbonate, poly(lactic-co-glycolic acid) (PLGA), poly(iodinated desaminotyrosyl-tyrosine ethyl ester) carbonate, salicylate based polymer, semicrystalline polylactide, phosphorylcholine, polycaprolactone (PCL), poly-D,L-lactic acid, poly-L-lactic acid, poly(lactideco- glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone (PDS), polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen, cellulose, starch, collagen, polyurethane including polycarbonate urethanes, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, ethylene vinyl alcohol, silicone including polysiloxanes and substituted polysiloxanes, polyethylene oxide, polybutylene terephthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, PLLA-co-PCL, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof. Non- -11- Attorney Docket No. EFML-01200WOlimiting examples of other suitable polymers include thermoplastic elastomers in general, polyolefin elastomers, EPDM rubbers and polyamide elastomers, and biostable plastic material including acrylic polymers, and its derivatives, nylon, polyesters and expoxies. In some embodiments, the stent may include one or more coatings, with materials like poly-L-lactide (PLLA) or poly(D,L-lactic acid) (PDLLA). These materials are merely examples, however, and should not be seen as limiting the scope of the invention. The coating may comprise a drug and a solvent capable of dissolving the drug and swelling or softening the scaffold structural polymer. The solvent may be any single solvent or a combination of solvents. For purpose of illustration and not limitation, examples of suitable solvents include water, aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones, dimethyl sulfoxide, tetrahydrofuran, dihydrofuran, dimethylacetamide, acetonitrile, acetates, and combinations thereof.

[0045] The devices described herein may include the incorporation of one or more drugs or beneficial agents. The drug or beneficial agent may be an angiogenic protein or other angiogenic agent. For purposes of illustration and not limitation, the drug or beneficial agent may include fibroblast growth factors, vascular endothelial growth factors, platelet-derived growth factors, insulin-like growth factor, epidermal growth factors, angiopoietins, hepatocyte growth factors, transforming growth factors, tumor necrosis factors, granulocyte-macrophage colony-stimulating factors, neuregulins, adenosines, bradykinins, hypoxia-inducible factors, matrix metalloproteinases, integrins, rho GTPases, phosphatidylinositol kinases, protein kinases, mitogen-activated protein kinases, astragaloside, ginsenoside, aucubin, caffeine, liraglutide, resveratrol, protopanaxadiol, apabetalone, kanglexin, oroxylin, salidroside, cilostazol, dapagliflozin, naringin, liraglutide, sitagliptin, bavachalcone, and / or pitavastatin. The beneficial agent can include a solvent. The solvent can be any single solvent or a combination of solvents. For purpose of illustration and not limitation, examples of suitable solvents include water, aliphatic hydrocarbons, aromatic hydrocarbons, alcohols, ketones, dimethyl sulfoxide, tetrahydrofuran, dihydrofuran, di methyl acetamide, acetates, and combinations thereof.

[0046] Stents may be manufactured using an additive or a subtractive method. In any of the described embodiments, stents or stent elements may be manufactured as a sheet and wrapped into cylindrical form. Alternatively, stents or stent elements may be manufactured in cylindrical form using an additive manufacturing process. In an embodiment, stents maybe formed by extruding a material into a cylindrical tubing. In some embodiments, a longer stent element, may be formed during the manufacturing process and then cut into smaller stent elements / elements to provide a multi-element stent. In an embodiment, stent tubing may be laser cut with a pattern to form a stent element.

[0047] Referring now to FIG. 8, in one embodiment, stents may be manufactured using a micro-stereolithography system 100 (or “3D printing system”). Several examples of currently available systems that might be used in various embodiments include, but are not limited to: MakiBox A6, Makible Limited, Hong Kong; CubeX, 3D Systems, Inc., Circle Rock Hill, SC; and 3D-Bioplotter, (EnvisionTEC GmbH, Gladbeck, Germany).

[0048] The micro-stereolithography system may include an illuminator, a dynamic pattern generator, an image-former and a Z-stage. The illuminator may include a light source, a filter, an electric shutter, a collimating lens and a reflecting mirror that projects a uniformly intense light on a digital mirror device (DMD), which generates a dynamic mask. FIG. 8 shows some of these-12- Attorney Docket No. EFML-01200WOcomponents of one embodiment of the micro-stereolithography system 100, including a DMD board, Z-stage, lamp, platform, resin vat and an objective lens. The details of 3D printing / micro-stereolithography systems and other additive manufacturing systems will not be described here, since they are well known in the art. However, according to various embodiments, any additive manufacturing system or process, whether currently known or hereafter developed, may potentially be used to fabricate stents within the scope of the present invention. In other words, the scope of the invention is not limited to any particular additive manufacturing system or process.

[0049] In one embodiment, the system 100 may be configured to fabricate stents using dynamic mask projection micro-stereolithography. In one embodiment, the fabrication method may include first producing 3D microstructural scaffolds by slicing a 3D model with a computer program and solidifying and stacking images layer by layer in the system. In one embodiment, the reflecting mirror of the system is used to project a uniformly intense light on the DMD, which generates a dynamic mask. The dynamic pattern generator creates an image of the sliced section of the fabrication model by producing a black-and-white region similar to the mask. Finally, to stack the images, a resolution Z-stage moves up and down to refresh the resin surface for the next curing. The Z-stage build subsystem, in one embodiment, has a resolution of about 100 nm and includes a platform for attaching a substrate, a vat for containing the polymer liquid solution, and a hot plate for controlling the temperature of the solution. The Z-stage makes a new solution surface with the desired layer thickness by moving downward deeply, moving upward to the predetermined position, and then waiting for a certain time for the solution to be evenly distributed.

[0050] Although particular embodiments have been shown and described, they are not intended to limit the invention. Various changes and modifications may be made to any of the embodiments, without departing from the spirit and scope of the invention. The invention is intended to cover alternatives, modifications, and equivalents.-13- Attorney Docket No. EFML-01200WO

Claims

WHAT IS CLAIMED IS:

1. An intravascular medical device, the device comprising:multiple balloon-expandable, bioresorbable, vascular stent elements configured to be implanted into a target artery upstream from ischemic tissue;wherein the stent elements are coated with one or more angiogenic proteins formulated for downstream therapeutic angiogenesis.

2. The device of claim 1, wherein the angiogenic proteins are formulated within a biopolymer coating which controls downstream elution to the ischemic tissue for weeks to months.

3. The device of claim 1, wherein the one or more angiogenic proteins comprises fibroblast growth factor.

4. The device of claim 1, wherein the one or more angiogenic proteins comprises vascular endothelial growth factor.

5. The device of claim 1, wherein the one or more angiogenic proteins comprises hepatocyte growth factor or hypoxia-inducible factor.

6. The device of claim 1, wherein the one or more angiogenic proteins comprises angiopoietin, insulin-like growth factor, epidermal growth factor, neuregulin, matrix metalloproteinase, phosphatidylinositol kinase, liraglutide, transforming growth factor, protein kinase, or mitogen-activated protein kinase.

7. The device of claim 1, wherein the one or more angiogenic proteins comprises platelet-derived growth factor or tumor necrosis factor.

8. The device of claim 1, wherein the one or more angiogenic proteins comprises granulocyte-macrophage colony-stimulating factor, integrin, or rho GTPase.-14- Attorney Docket No. EFML-01200WOmultiple balloon-expandable, bioresorbable, vascular stent elements configured to be implanted into a target artery upstream from ischemic tissue;9. The device of claim 1, wherein the medical device comprises individual stent elements positioned serially along a longitudinal length of an inflatable balloon; wherein a distance between each stent element has a defined distance; and wherein the distance between each stent element allows the medical device to remain longitudinally flexible when implanted.

10. The device of claim 1, wherein the stent elements are formed from a material selected from the group consisting of polymers, copolymers, polymer blends and / or biocopolymers of poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), semicrystalline polylactide, polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(iodinated desamino tyrosyl-tyrosine ethyl ester) carbonate, polycaprolactone (PCL), salicylate based polymer, polydioxanone (PDS), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), poly(iodinated desaminotyrosyl-tyrosine ethyl ester) carbonate, polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen, cellulose, starch, collagen, polyurethane including polycarbonate urethanes, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, ethylene vinyl alcohol, silicone including polysiloxanes and substituted polysiloxanes, polyethylene oxide, polybutylene terephthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof.

11. The device of claim 10, wherein the stent elements are formed by extruding the material into a cylindrical tubing.

12. The device of claim 11, wherein the tubing is laser cut with a pattern to form the stent element.

13. An intravascular medical device, the device comprising:-15- Attorney Docket No. EFML-01200WOmultiple balloon-expandable, bioresorbable, vascular stent elements configured to be implanted into a target artery upstream from ischemic tissue;wherein the stent elements are coated with one or more angiogenic agents formulated for downstream therapeutic angiogenesis.

14. The device of claim 13, wherein the angiogenic agents are formulated within a biopolymer coating which controls downstream elution to the ischemic tissue for weeks to months.

15. The device of claim 13, wherein the one or more angiogenic agents comprises adenosine, bradykinin, astragaloside, ginsenoside, aucubin, resveratrol, protopanaxadiol, oroxylin, salidroside, naringin, bavachalcone, or caffeine.

16. The device of claim 13, wherein the one or more angiogenic agents comprises cilostazol, dapagliflozin, sitagliptin, apabetalone, or kanglexin,17. The device of claim 13, wherein the medical device comprises individual stent elements positioned serially along a longitudinal length of an inflatable balloon; wherein a distance between each stent element has a defined distance; and wherein the distance between each stent element allows the medical device to remain longitudinally flexible when implanted.

18. The device of claim 13, wherein the stent elements are formed from a material selected from the group consisting of polymers, copolymers, polymer blends and / or biocopolymers of poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), poly(D,L-lactic acid) (PDLLA), semicrystalline polylactide, polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), poly(iodinated desamino tyrosyl-tyrosine ethyl ester) carbonate, polycaprolactone (PCL), salicylate based polymer, polydioxanone (PDS), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride, poly(glycolic acid-co-trimethylene carbonate), poly(iodinated desaminotyrosyl-tyrosine ethyl ester) carbonate, polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes,-16- Attorney Docket No. EFML-01200WOpolyiminocarbonates, and aliphatic polycarbonates, fibrin, fibrinogen, cellulose, starch, collagen, polyurethane including polycarbonate urethanes, polyethylene, polyethylene terephthalate, ethylene vinyl acetate, ethylene vinyl alcohol, silicone including polysiloxanes and substituted polysiloxanes, polyethylene oxide, polybutylene terephthalate-co-PEG, PCL-co-PEG, PLA-co-PEG, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof.

19. The device of claim 18, wherein the stent elements are formed by extruding the material into a cylindrical tubing.

20. The device of claim 19, wherein the tubing is laser cut with a pattern to form the stent element.-17- Attorney Docket No. EFML-01200WO

Images