Biocopolymer backbones for intravascular scaffolds

Abstract

Devices, systems, and methods are provided to maintain or enhance blood flow through the blood vessel. Balloon-expandable vascular stent elements comprise biocopolymer backbones which combine and exploit certain favorable properties of two or more pure biopolymers in order to create the optimal bioresorbable scaffolding system for the human vasculature.

Description

BIOCOPOLYMER BACKBONES FOR INTRAVASCULAR SCAFFOLDSCROSS REFERENCE RELATED TO APPLICATION

[0001] This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 526,496, entitled “BIOCOPOLYMER BACKBONES FOR INTRAVASCULAR SCAFFOLDS”, filed on July 13, 2023, 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 maintain patency (blood flow) of blood vessels (arteries and veins).BACKGROUND

[0003] Cardiovascular disease is a tremendous burden on human health and longevity; by the year 2030, over 400 million people will be directly affected. Vascular disease of the lower extremity arteries, known as “peripheral arterial occlusive disease” (PAOD), is a virtual epidemic, afflicting approximately 10% of the population over the age of 50 and 20% of the population over the age of 70. Its prevalence has increased by more than 20% over the last decade. Symptomatic PAOD causes poor physical health, loss of mobility and independence, decreased quality of life, premature functional decline and early mortality. The physical burden of PAOD is greater than having congestive heart failure and the long-term prognosis is worse than having coronary artery disease. An estimated 11% of patients with PAOD have its most severe form: chronic limb-threatening ischemia (CLTI). CLTI arises when the occlusive lesions of PAOD have become so numerous and severe that the baseline perfusion of the extremity is inadequate to sustain its viability. It carries a dismal prognosis; only about half of diagnosed patients will be alive after six months and only about half of the survivors will have intact limbs. Revascularization with restoration of blood flow remains the only reliable therapeutic path to limb preservation.

[0004] The historical revascularization strategy of patients with symptomatic PAOD is open surgical bypass of chronically diseased arterial segments. The results are often favorable but the procedure is attended by excessive mortality and morbidity. Indeed, between 14 and 44% of long bypass incisions in the leg become infected and up to 69% of patients undergoing bypass surgery will require re-hospitalization during the first year. With the primary goal of achieving effective revascularization with reduced complications, endovascular techniques including balloon angioplasty and stent implantation have been aggressively developed. Current paradigms of endovascular therapy employ balloon dilatation, mechanical disruption(percutaneous atherectomy), dilatation with specialty balloons coated with antiproliferative drugs and / or self-expanding nitinol stent technology. These modalities are generally effective in treating short lesions. However, the results of endovascular intervention in the long, chronic occlusions typically observed in critically ischemic patients remains dismal. In one contemporary clinical study, the 3 -year primary patency of endovascular intervention with paclitaxel-eluting stents or paclitaxel-coated balloons in lesions >10 cm was achieved in only 45% and 26% of patients, respectively. In the aggregate of real-world clinical practice, recurrence of symptoms and / or stenosis still complicates up to 50% of all conventional endovascular procedures after only one year.

[0005] It has long been theorized that a non-permanent stent that provides effective scaffolding immediately following percutaneous angioplasty then dissolves after the artery has healed might be the ideal device for intravascular intervention. So-called “bioresorbable vascular scaffolds” (BVS) offer the theoretical advantages of, (1) effective scaffolding that maximizes post-procedure lumen diameter and prevents post-dilation elastic recoil, (2) avoiding chronic foreign body reaction and late, in-stent restenosis, (3) allowing adaptive remodeling, (4) preserving vasoactive function, and (5) facilitating follow-up intravascular imaging and surveillance. To date, the most studied BVS is the Absorb Bioresorbable Scaffold System (Abbott Laboratories, Abbott Park, IL) originally indicated for implantation into the coronary arteries. The Absorb BVS is comprised of a pure poly-L-lactide (PLLA) polymer scaffold and a poly-D,L-lactide (PDLLA) coating containing everolimus. It was tested in a large series of clinical investigations, most notably the pivotal ABSORB III trial. In this multicenter, randomized investigation, 2008 patients with stable or unstable angina were assigned to receive either the Absorb scaffold (1322 patients) or the Xience everolimus-eluting metal stent (686 patients) in a 2: 1 ratio. After one year, target-lesion failure (TLF) occurred in 7.8% of patients in the Absorb group and in 6.1% of patients in the Xience group (p=0.007 for noninferiority).Device thrombosis within one year occurred in 1.5% of patients in the Absorb group and in 0.7% of patients in the Xience group (p=0.13). It was concluded that the two devices were statistically equivalent within the pre-specified non-inferiority margin of 4.5% TLF and the device was released commercially in the U.S. in 2016.

[0006] Unfortunately, in follow-up studies, the performance of the first-generation Absorb device was found to be slightly inferior to the remarkable clinical effectiveness of the third-generation metal drug-eluting stent that had enjoyed more than a decade of clinical experience and iteration. For instance, in the ABSORB III trial, although the rates of TLF were comparably low after one year (7.8% v. 6.1%), by two years the difference had widened and was now statistically significant (11% v. 7.9%; p=0.03). In response, a “Letter to Health Care Providers” was issued by the United States Food & Drug Administration (FDA) advising practitioners to follow the label instructions to assure optimal device performance. Predictably, this warning led to complete withdrawal of the device from the international market and it is no longer commercially available.

[0007] Interestingly, several recent reports have suggested that Absorb is, indeed, substantially equivalent or superior to traditional metal drug-eluting stents, particularly in certain clinically important patient subgroups, and that the withdrawal of the first generation device may have been premature. The long-term outcome of arteries and patients after complete dissolution of the device is particularly noteworthy as the five-year results of the ABSORB III trial suggest that thebrief period of excess risk observed during device dissolution in the first three years completely resolves after the device is fully resorbed (the relative hazard for TLF of 1.35 between 0-3 years had decreased to a non-significant 0.83 between 3-5 years). Similarly, the relative hazard for device thrombosis of 3.23 between 0-3 years (1.25-8.30) that had been the primary reason for market withdrawal had decreased to a non-significant 0.26 between 3-5 years (0.02-2.87). These data led a co-principal investigator to conclude that, “After the 3 -year time point, the excess risk with BVS was no longer apparent and, if anything, the point estimate between the two randomized devices favored BVS.” This finding has led many to argue that bioresorbable scaffolds might be more effective if they dissolved more quickly.

[0008] The first use of biopolymers in medicine can be traced back to the original “catgut” surgical suture, first evident in the historical record some four millennia ago. Catgut sutures were derived from dried sheep, goat or bovine intestine, but retained the name “catgut” probably because they were also used as strings for musical instruments sometimes referred to as “kits”. Catgut sutures are enzymatically degraded and resorbed in vivo so can be chemically classified as bioresorbable. Most contemporary bioresorbable surgical sutures are synthetic, including variants of polyglycolide, polydioxanone, polyglyconate, and poly(glycolide-L-lactide). Other, more recently developed bioresorbable medical devices includes bioresorbable screws and fracture plates for the treatment of traumatic injuries, indwelling scaffolds that serve as a basis for tissue engineering and regenerative medicine, chemotherapy-loaded polymers for therapeutic oncology, inert synthetic wraps for the prevention of post-operative peritoneal adhesions, bioabsorbable scaffolds for stenting of the upper airways and Eustachian tubes, and bioresorbable intravascular scaffolds (BVS), which is the subject of this patent.

[0009] A variety of biopolymers and polymer blends have been considered for the formulation of the backbone of BVS. Although a fairly wide range of physical properties are available, no polymer exhibits the optimal combination of high strength, ductility (high elongation at break) and biodegradability between 12 and 24 months. However, if two pure polymers were combined via biocopolymerization, they might exhibit a composite of physicochemical properties that were optimal and effective. At least some of these objectives will be met by the embodiments described below.SUMMARY

[0010] The embodiments herein describe a method for designing and manufacturing an intravascular scaffold with a biocopolymer backbone. In an embodiment the stent material is selected from the group consisting 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, poly caprolactone (PCL), salicylate based polymer, polydioxanone (PDS), poly(hydroxybutyrate), polyorthoester, polyanhydride, 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, poly acrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof. In an embodiment, the stent segment is coated with an anti-proliferative agent.

[0011] This and other aspects of the present disclosure are described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] 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:

[0013] FIG. 1 shows the typical radial resistive forces of intravascular stents.

[0014] FIG. 2A illustrates one embodiment of a multi-element stent. FIG. 2B is a magnified view of the stent elements in FIG. 2A.

[0015] FIGs. 3A-3C depict deployment of a balloon-expandable multi-element stent.

[0016] 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.

[0017] FIG. 5 shows an embodiment of a stent pattern.

[0018] FIG. 6 shows the radial resistive force of intravascular stents and scaffolds.

[0019] FIG. 7 shows a biocopolymer intravascular scaffold that disappears between the first and second years after implantation.

[0020] FIG. 8 shows a biocopolymer intravascular scaffold that disappears between the first and second years after implantation.

[0021] FIG. 9 shows a schematic diagram of a micro-stereolithograph used to create a stent, according to one embodiment.DETAILED DESCRIPTION

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] FIG. 1 shows the typical radial resistive forces of intravascular stents. A typical “bioresorbable vascular scaffold” (BVS) or absorbable stent has a radial resistive force of under 2 N / cm. Similarly, a typical self-expanding metal stent (SES) has a radial resistive force of under 2 N / cm. Typical balloon-expandable metal stents (BES) have a much higher radial resistive force, sometimes above 18 N / cm.

[0027] One embodiment of the fully assembled device in shown in FIG. 2A. A single balloon inflation and device deployment can treat a long segment of diseased 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 multi-element 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.

[0028] FIGs. 3A-3C depict deployment of a balloon-expandable multi-element stent. In FIG. 3 A a multi-element stent mounted on a balloon is advanced to the lesion. In FIG. 3B the balloon and stent are expanded. In FIG. 3C the balloon is withdrawn leaving the multi-element stent still within the artery.

[0029] 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.

[0030] 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.

[0031] 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 diamond 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 largerthan the width of struts 207 between two comers of longitudinally aligned diamond shaped cells 205.

[0032] 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.

[0033] Table 1 shows physical properties of pure bioabsorbable polymers. Review of the data presented in Table 1 reveals fairly wide ranges of tensile strength and ductility. For instance, the biopolymer polyglycolide (PGA) is very strong (tensile strength 90-100 MPa) but also fairly brittle (1-2% elongation at break). In contrast, the biopolymer polycaprolactone (PCL) is elastic (elongation at break >300%) but also relatively weak (tensile strength 25-35 MPa). Because BVS must be both elastic (to allow crimping) and strong (to prop open arterial plaque), intravascular scaffolds made from either of these pure polymers are unlikely to be functional.Table #1: Physical properties of pure bioabsorbable polymers.

[0034] The embodiments herein describe the formulation of biocopolymer backbones which combine and exploit certain favorable properties of two or more pure biopolymers in order to create an optimal scaffolding system for the human vasculature.

[0035] Biocopolymers contain both monomer types within a single polymer chain. As opposed to simple polymer blends, biocopolymers can be reliably synthesized with sufficient quality and purity as to confer a range of physicochemical properties for specific medical applications. Depending on the application, the repeating units of copolymers can be distributed regularly, randomly, or in blocks. The properties of a given copolymer are defined by the characteristics of each monomer, the ratio of each within the copolymer and the synthetic processing conditions.

[0036] FIG. 6 shows the experimental results of one embodiment of a biocopolymer scaffold designed to optimize the physical properties of strength and ductility. In this experiment, uniform tubes of a biocopolymer of poly-L-lactide (PLLA) and polycaprolactone (PCL) were created using the industrial process of extrusion. Following extrusion, the tube was heat-expanded in order to align polymer chains and enhance strength. The expanded tube was then mounted on the mandrel of a laser cutter programmed with a closed, repeating pattern. The laser-cut scaffold was then crimped to approximately 30% of its original diameter using the repeated application of graded radial stress and heat in a machine specifically designed for that purpose. Following crimping, the scaffolds were balloon-expanded to their nominal diameter and placed in a commercially available (but modified) circumferential radial force tester. The generated radial force was measured at 0.1 mm increments during continuous compression of the scaffold at a rate of 15 mm / s. The forces were recorded, divided by device length and co-plotted with test data for metal stents as well as samples from the literature. The results are shown in FIG. 6. The bars in labeled NiTi are representative of nitinol stents; the bars labeled SS are representative of balloon-expandable metal stents. The right bar depicts the relatively high radial strength of the biocopolymer scaffold which is the subject of this patent. Although the crimped and expanded (ductile) device is comprised of a biocopolymer, it exhibits radial resistive forces equal to or greater than similarly sized, conventional metal stents.

[0037] The stent elements may comprise a biocopolymer backbone comprising two or more monomer types within a single polymer chain. In an embodiment, the biocopolymer comprises monomer types poly(L-lactic acid) (PLLA) and polycaprolactone (PCL). In an embodiment, the biocopolymer comprises two or more monoper types selected from the group consisting of poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), polyglycolic acid (PGA), polycaprolactone (PCL), and poly(lactic-co-glycolic acid) (PLGA).

[0038] In various embodiments, monomer types, a ratio of each monomer type within the biocopolymer, and synthetic processing conditions may be configured to give desired tensile strength or radial resistive force, ductility, and / or dissolution rates. In various embodiments, monomer types, a ratio of each monomer type within the biocopolymer, and synthetic processing conditions may be configured to give a dissolution rate after implantation of 12 to 24 months, 12 to 18 months, 12 to 30 months, 12 to 36 months, 18 to 24 months, 18 to 30 months, 18 to 36 months, 20 to 24 months, 20 to 26 months, 22 to 26 months, 24 to 26 months, 24 to 30 months, 24 to 36 months, more than 36 months, or any other period of time.

[0039] In various embodiments, monomer types, a ratio of each monomer type within the biocopolymer, and synthetic processing conditions may be configured to give a radial resistive force after implantation of 10 N / cm or more, 15 N / cm or more, 18 N / cm or more, 20 N / cm or more, 22 N / cm or more, 25 N / cm or more, 28 N / cm or more, 30 N / cm or more, 31 N / cm or more, 32 N / cm or more, 33 N / cm or more, 34 N / cm or more, 35 N / cm or more, more than 35 N / cm, or any other radial resistive force.

[0040] A critical design element of a bioresorbable scaffold (BVS) is its kinetics of dissolution. As shown in Table 2, pure biopolymer scaffolds have traditionally been formatted to dissolve either quickly (within about 6 months) or very slowly (>3 years). However, too rapid dissolution will allow the treated artery to collapse (recoil) before it is sufficiently healed and too slow dissolution will generate untoward chronic inflammation leading to excess neointima formationand thrombosis. The creation of a “biocopolymer” marries the degradation properties of two or more pure polymers generating a dissolution profile in an intermediate range that facilitates more favorable vessel healing. One embodiment of such a biocopolymer resorbable scaffold is shown in FIG. 7. In this experiment, Yucatan mini-swine were anesthetized, intubated and mechanically ventilated. The carotid artery was surgically exposed with the animal in dorsal recumbency. A guiding sheath was inserted and advanced to the aortic bifurcation using fluoroscopy. Heparin was administered to achieve an activated clotting time >300 s and nitroglycerin boluses were administered to mitigate secondary arterial vasospasm. Five paclitaxel-eluting biocopolymer scaffolds (6 mm in diameter) were deployed by advancing a delivery system through the guiding sheath and over the guidewire retrograde to the deployment site. Biocopolymer scaffolds were deployed using slow inflation with an at least 15 s / atm. The peak pressure was maintained for approximately 30 seconds; the target balloon-to-artery ratio was 1.1 : 1 (oversize = 10%). Vacuum was applied to the inflation device in order to deflate and withdraw the balloon. Animals in this chronic study received oral acetylsalicylic acid 325 mg and clopidogrel 75 mg continuing daily. At each of the intervals of 30-, 90-, 180-, 365- and 730-days, the animals were re-anesthetized and the treated arteries re-imaged. Optical coherence tomographic (OCT) imaging revealed that the biocopolymer scaffold struts became covered by a thin rim of tissue after the first month, became fully enveloped into the arterial wall by 6-mos. and fully degraded after 2-years (FIG. 7).Table #2: Dissolution kinetics of pure biopolymer intravascular scaffolds.

[0041] A similar embodiment of a biocopolymer resorbable scaffold is shown in FIG. 8. In this human clinical trial, a 75 year-old gentleman with left lower extremity claudication and an ankle-brachial index of 0.72 underwent implantation of five sirolimus-eluting biocopolymer scaffolds in a 6 cm segment of occluded superficial femoral artery. The indwelling scaffolds were visualized by using transcutaneous B-mode ultrasound after 30-days, 6-months, 1-year and 2-years. The boxed numbers 1, 2, and 3 have been placed in the lumens of the three proximal-most scaffolds which are depicted in long section. By 2-years all scaffolds had dissolved (lower right panel of FIG. 8).

[0042] The devices described herein may be comprised of a bioabsorbable biocopolymer that will non-toxically dissolve within the human body. The term “polymer” is intended to include a product of a polymerization reaction inclusive of homopolymers, 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 solute ion, 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, phosphorylcholine, polycaprolactone, poly-D,L-lactic acid, poly-L-lactic acid, poly(lactide- co-glycolide), poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate), polydioxanone, 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 terapthalate, ethylene vinyl acetate, ethylene vinyl alcohol, silicone including polysiloxanes and substituted polysiloxanes, polyethylene oxide, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof. Non-limiting 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 epoxies. In some embodiments, the stent may include one or more coatings, with materials like poly-D,L-lactide (PDLLA).

[0043] The devices described herein may also include incorporation of a therapeutic drug intended to prevent or attenuate pathologic consequences of intraluminal intervention such as inflammation, cell dysfunction, cell activation, cell proliferation, neointimal formation, thickening, late atherosclerotic change and / or thrombosis. Any suitable therapeutic agent (or “drug”) may be incorporated into, coated on, or otherwise attached to the stent, in various embodiments. Examples of such therapeutic agents include, but are not limited to, antithrombotics, anticoagulants, antiplatelet agents, anti-lipid agents, thrombolytics, antiproliferatives, anti-inflammatories, agents that inhibit hyperplasia, smooth muscle cellinhibitors, antibiotics, growth factor inhibitors, cell adhesion inhibitors, cell adhesion promoters, antimitotics, antifibrins, antioxidants, antineoplastics, agents that promote endothelial cell recovery, matrix metalloproteinase inhibitors, antimetabolites, antiallergic substances, viral vectors, nucleic acids, monoclonal antibodies, inhibitors of tyrosine kinase, antisense compounds, oligionucleotides, cell permeation enhancers, hypoglycemic agents, hypolipidemic agents, proteins, nucleic acids, agents useful for erythropoiesis stimulation, angiogenesis agents, antiulcer / antireflux agents, and antinauseants / antiemetics, PPAR-alpha agonists, sodium heparin, LMW heparins, heparoids, hirudin, argatroban, forskolin, vapriprost, prostacyclin and prostacylin analogues, dextran, D-phe-pro-arg-chloromethylketone (synthetic antithrombin), glycoprotein Ilb / IIIa (platelet membrane receptor antagonist antibody), recombinant hirudin, thrombin inhibitors, indomethacin, phenyl salicylate, beta-estradiol, vinblastine, ABT-627 (astrasentan), testosterone, progesterone, paclitaxel, methotrexate, fotemusine, RPR-101511A, cyclosporine A, vincristine, carvediol, vindesine, dipyridamole, methotrexate, folic acid, thrombospondin mimetics, estradiol, dexamethasone, metrizamide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan, iodixanol, and iotrolan.

[0044] Examples of antithrombotics, anticoagulants, antiplatelet agents, and thrombolytics include, but are not limited to, sodium heparin, low molecular weight heparins, heparinoids, hirudin, argatroban, forskolin, vapriprost, prostacyclin and prostacylin analogues, dextran, D- phe-pro-arg-chloromethylketone (synthetic antithrombin), dipyridamole, glycoprotein llb / llla (platelet membrane receptor antagonist antibody), recombinant hirudin, thrombin inhibitors, and thrombolytic agents.

[0045] Examples of cytostatic or antiproliferative agents include, but are not limited to, rapamycin and its analogs, including everolimus, zotarolimus, tacrolimus and pimecrolimus, angiopeptin, angiotensin converting enzyme inhibitors, such as captopril, cilazapril or lisinopril, calcium channel blockers, such as nifedipine, amlodipine, cilnidipine, lercanidipine, benidipine, trifluperazine, diltiazem and verapamil, fibroblast growth factor antagonists, fish oil (omega 3- fatty acid), histamine antagonists, lovastatin, topoisomerase inhibitors, such as etoposide and topotecan, as well as antiestrogens such as tamoxifen.

[0046] Examples of anti-inflammatory agents include, but are not limited to, colchicine and glucocorticoids, such as betamethasone, cortisone, dexamethasone, budesonide, prednisolone, methylprednisolone and hydrocortisone. Non-steroidal anti-inflammatory agents include, but are not limited to, flurbiprofen, ibuprofen, ketoprofen, fenoprofen, naproxen, diclofenac, diflunisal, acetominophen, indomethacin, sulindac, etodolac, diclofenac, ketorolac, meclofenamic acid, piroxicam and phenylbutazone.

[0047] Examples of antineoplastic agents include, but are not limited to, alkylating agents including altretamine, bendamucine, carboplatin, carmustine, cisplatin, cyclophosphamide, fotemustine, ifosfamide, lomustine, nimustine, prednimustine, and treosulfin, antimitotics, including vincristine, vinblastine, paclitaxel, docetaxel, antimetabolites including methotrexate, mercaptopurine, pentostatin, trimetrexate, gemcitabine, azathioprine, and fluorouracil, and antibiotics, such as doxorubicin hydrochloride and mitomycin.

[0048] Antiallergic agents include, but are not limited to, permirolast potassium nitroprusside, phosphodiesterase inhibitors, prostaglandin inhibitors, suramin, serotonin blockers, steroids, thioprotease inhibitors, triazolopyrimidine, and nitric oxide.

[0049] 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.

[0050] Referring now to FIG. 9, 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).

[0051] 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.10 shows some of these components 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.

[0052] 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.

[0053] 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.

Claims

WHAT IS CLAIMED IS:

1. A device for placement within a blood vessel to maintain or enhance blood flow through the blood vessel, the device comprising: one or more balloon-expandable, bioresorbable, vascular stent elements configured to be implanted in the blood vessel, wherein the stent elements comprise a biocopolymer backbone comprising two or more monomer types within a single polymer chain.

2. The device of claim 1, wherein the monomer types comprise poly(L-lactic acid) (PLLA) and polycaprolactone (PCL).

3. The device of claim 1 wherein characteristics of each monomer type, a ratio of each monomer type within the biocopolymer, and synthetic processing conditions are configured such that the stent elements dissolve between eighteen to twenty-four months after implantation.

4. The device of claim 1 wherein characteristics of each monomer type, a ratio of each monomer type within the biocopolymer, and synthetic processing conditions are configured such that the stent elements provide an initial radial rigidity after implantation of 30 N / cm or more.

5. The device of claim 1, wherein the stent element comprises two or more monoper types selected from the group consisting of poly(L-lactic acid) (PLLA), poly(D-lactic acid) (PDLA), polyglycolic acid (PGA), polycaprolactone (PCL), and poly(lactic-co-glycolic acid) (PLGA).

6. The device of claim 1, wherein the stent element comprises monoper types selected from the group consisting 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, poly caprolactone (PCL), salicylate based polymer, polydioxanone (PDS), poly(hydroxybutyrate), polyorthoester, polyanhydride, poly(iodinated desaminotyrosyl-tyrosineethyl ester) carbonate, polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), polyalkylene oxalates, polyphosphazenes, polyiminocarbonates, 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, polyacrylates, polyvinyl pyrrolidone, polyacrylamide, and combinations thereof.

7. The device of claim 1, wherein the stent segment is coated with an anti-proliferative agent.

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