Intravascular drug delivery device and uses thereof

Abstract

The present invention relates to an intravascular drug delivery device (preferably an intravascular drug delivery implant). The present invention further relates to a device for use in a method for the prevention or treatment of neurological diseases, neoplastic diseases, cardiac diseases, vascular diseases, immune diseases, carcinoids, infectious diseases, and / or edema.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a device for intravascular drug delivery, preferably an implant for intravascular drug delivery. The present invention further relates to a device for use in a method for the prevention or treatment of neurological diseases, neoplastic diseases, cardiac diseases, vascular diseases, immune diseases, carcinoids, infectious diseases, edema, and / or any disease that can be treated by angiography. [Background technology]

[0002] Background of the Invention Currently, pharmaceuticals are typically administered orally or intravenously and reach their target sites via the circulatory system. However, when administered systemically, pharmaceuticals may also reach non-target sites, such as non-target tissues, thereby causing side effects. For example, in chemotherapy, the desired effect on tumor tissue is typically accompanied by undesired cytotoxic effects in the areas of hair follicles, intestinal and oral mucosa, and / or bone marrow. These non-target effects can be burdensome and, in some cases, can result in life-threatening side effects. In some cases, the side effects are so severe that tumor treatment must be discontinued. Another disadvantage of systemic application of active agents is that the active agent is diluted by the blood circulation, and therefore high doses of the active agent may be required to achieve a therapeutic effect.

[0003] Non-target effects of applied pharmaceuticals are also a major challenge in the treatment of other symptoms, such as neurological symptoms, during post-ischemic stroke treatment. During an ischemic stroke, a blood clot blocks blood flow in the brain's blood vessels. Depending on the size of the clot, it must be removed by mechanical thrombectomy using a stent retriever. Even if thrombectomy is successful, the formation of cerebral edema can lead to irreversible brain damage. Traditionally, anti-inflammatory glucocorticoids have been applied systemically to treat diseases such as brain cancer. Recent advances in the immune response in the brain have led to the development of new therapeutic approaches for treating inflammatory brain symptoms, such as post-stroke cerebral edema. However, many active agents that may protect brain cells after ischemic stroke cannot be applied in sufficient doses due to severe systemic side effects. For example, bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma, is a potential candidate for post-ischemic stroke treatment. However, when administered systemically, bortezomib can induce cerebral hemorrhage by inducing thrombocytopenia through inhibition of megakaryocyte progenitor platelet formation. Currently available therapeutic options for treating diseases such as post-stroke cerebral edema are inadequate. In particular, current therapeutic options are inadequate in terms of active agents crossing the blood-brain barrier and / or side effects.

[0004] Thus, there is a need for improved treatment options. In particular, there is a need for devices that allow for the application of active agents in a localized manner. Furthermore, there is a need for devices that can locally release active agents, particularly in a controlled and, optionally, sequential manner. There is also a need for devices that allow for the release of active agents in a sustained manner. Furthermore, there is a need for devices that allow for improved treatment of diseases such as neurological disorders, neoplastic diseases, cardiac diseases, vascular diseases, immune disorders, carcinoids, infectious diseases, and / or edema. There is also a need for improved intravascular drug delivery devices. Furthermore, there remains a need for improved means for treating diseases such as cerebral edema associated with stroke. There also remains a need for improved devices that allow for a reduction in the dose of active agents. Summary of the Invention

[0005] Elements of the present invention are described below. While these elements are listed with specific embodiments, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The various described examples and preferred embodiments should not be construed as limiting the invention to only the explicitly described embodiments. The description should be understood to support and encompass embodiments combining two or more of the explicitly described embodiments, or combining one or more of the explicitly described embodiments with any number of the disclosed and / or preferred elements. Furthermore, all permutations and combinations of all elements described herein should be considered disclosed by the description herein, unless the context indicates otherwise.

[0006] In a first aspect, the present invention relates to an intravascular drug delivery device (preferably an intravascular drug delivery implant), comprising: the device has a substantially cylindrical configuration; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow blood flow through the device; the device is preferably elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device optionally comprises a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0007] In one embodiment, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polycaprolactam, elastin, fibrillin, fibrillin, poly(1-acrylonitrile), poly(vinyl alcohol), polygluconate, polyglycolide, dextran, type I collagen, type II collagen, type IV collagen, elastin, silk fibroin, polymandelide, poly(trimethylene carbonate), polydioxanone, poly(4-hydroxybutyrate), poly(butylene succinate), polyphosphazene, polyanhydride, polyphosphoester, polyoxalate, silica gel, alginate, polyethylene glycol, poly(2-oxazoline), gelatin, polyglycidol, polyurethane, and combinations thereof; Preferably, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), and combinations thereof; More preferably, the biocompatible polymer is poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof.

[0008] In one embodiment, the device comprises a fiber (1) (preferably a nanofiber, such as a polymer nanofiber, and / or a microfiber); optionally, the fiber (1) (preferably a polymer nanofiber) comprises silicon dioxide and / or titanium oxide; Preferably, the device comprises nanofibers, which are preferably selected from poly(lactic-co-glycolic acid) nanofibers, polycaprolactone nanofibers, poly(lactic acid) nanofibers, poly(lactic acid) nanofibers with titanium oxide, silica gel nanofibers, and combinations thereof.

[0009] In one embodiment, the fibers (1) are aligned along the longitudinal axis of the device; the fibers (1) are aligned at an angle between 0° and 180° relative to the longitudinal axis of the device; the fibers (1) are aligned along the circumferential direction of the device; the fibers (1) are aligned along the radial direction of the device; the fibers (1) are oriented in a grating; and / or the fibers (1) are randomly oriented.

[0010] In one embodiment, the device comprises nanoparticles, which are preferably mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles.

[0011] In one embodiment, the device comprises a hydrogel; Optionally, the hydrogel is configured to release the active agent (preferably into the channel (6)) when the hydrogel comes into contact with a fluid (particularly blood).

[0012] In one embodiment, the device has a first layer (7) and a second layer (8); optionally, a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); optionally, the first layer (7) comprises nanofibers, nanoparticles, hydrogels, active agents, and / or cell adhesion molecules; The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone); optionally, the second layer (8) comprises nanofibers, nanoparticles, hydrogels, and / or active agents; said third layer (9), if present, comprising said active agent, and optionally comprising a third biocompatible polymer, nanofibers, nanoparticles, and / or hydrogel; At least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent.

[0013] In one embodiment, the device has a first layer (7) and a second layer (8); optionally, a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); optionally, the first layer (7) comprises fibers (1), nanoparticles, a hydrogel, an active agent, and / or cell adhesion molecules; The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone); optionally, the second layer (8) comprises fibers (1), nanoparticles, a hydrogel, and / or an active agent; said third layer (9), if present, comprising said active agent, and optionally comprising a third biocompatible polymer, fibers (1), nanoparticles, and / or a hydrogel; At least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent. In one embodiment, the fibers (1) are nanofibers and / or microfibers.

[0014] In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent, such as an immunosuppressant; optionally, the second layer (8) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the second layer (8) comprises nanoparticles comprising the active agent; The third layer (9) comprises a third biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent, such as a chemotherapeutic agent; optionally, the third layer (9) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the third layer (9) comprises nanoparticles comprising the active agent; Optionally, the density of said third layer (9) is lower than the density of said second layer (8); Optionally, the molar mass of said third layer (9) is lower than the molar mass of said second layer (8); Optionally, the active agent in the second layer (8) is different from the active agent in the third layer (9).

[0015] In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent, such as an immunosuppressant; optionally, the second layer (8) comprises fibers (1), nanoparticles, and / or a hydrogel; preferably, the second layer (8) comprises nanoparticles comprising the active agent; The third layer (9) comprises a third biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent, such as a chemotherapeutic agent; optionally, the third layer (9) comprises fibers (1), nanoparticles, and / or a hydrogel; preferably, the third layer (9) comprises nanoparticles comprising the active agent; Optionally, the density of said third layer (9) is lower than the density of said second layer (8); Optionally, the molar mass of said third layer (9) is lower than the molar mass of said second layer (8); Optionally, the active agent in the second layer (8) is different from the active agent in the third layer (9). In one embodiment, the fibers (1) are nanofibers and / or microfibers.

[0016] In one embodiment, the cylindrical form is a hollow cylindrical form and / or an open cylindrical form.

[0017] In one embodiment, the device comprises: having a length ranging from about 0.25 mm to about 80 mm, preferably from about 0.5 mm to about 50 mm, more preferably from about 1 mm to about 25 mm, and even more preferably from about 3 mm to about 20 mm; an outer radius ranging from about 2 μm to about 6 mm, preferably from about 0.5 mm to about 4 mm, more preferably from about 1 mm to about 3.5 mm, and even more preferably from about 1.4 mm to about 3 mm; and / or an inner radius ranging from about 1 μm to about 5.9 mm, preferably from about 0.4 mm to about 3.9 mm, more preferably from about 0.9 mm to about 3.4 mm, and even more preferably from about 1.3 mm to about 3 mm; It has a thickness ranging from about 1 μm to about 1 mm, preferably from about 20 μm to about 500 μm, more preferably from about 50 μm to about 250 μm, and even more preferably from about 75 μm to about 150 μm, for example about 100 μm.

[0018] In one embodiment, the device has a cutting line (5), optionally a cutting line (5) along the longitudinal axis of the device.

[0019] In one embodiment, the device is biodegradable (preferably bioabsorbable); Optionally, the device is biodegradable (preferably bioabsorbable) at a temperature ranging from about 34°C to about 43°C.

[0020] In one embodiment, the active agent is embedded in the polymer matrix, optionally embedded in a hydrogel present in the polymer matrix, and / or encapsulated in nanoparticles present in the polymer matrix; the active agent is attached to the device (preferably the inner surface of the device), preferably via a linker; and / or the active agent is coated on the inner surface of the device (preferably the surface of the channel (6)).

[0021] In one embodiment, the active agent is a chemotherapeutic agent such as a proteasome inhibitor (e.g., bortezomib) or an anthracycline (e.g., doxorubicin); an immunosuppressant such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker such as nimodipine; an antithrombotic agent such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; an antibody such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; a radiomodulatory agent; fingolimod or anti-inflammatory compounds, such as NRLP3 inflammasome inhibitors (e.g., MCC50); antihypertensive agents, such as angiotensin-converting enzyme inhibitors or beta-blockers; matrix metalloproteinase inhibitors; cytokines, such as interleukins; chemokines; Parkinson's disease medications, such as levodopa, dopamine agonists, or monoamine oxidase B inhibitors; Huntington's disease medications, such as tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, amantadine, levetiracetam, or clonazepam; and combinations thereof; Preferably, the active agent is selected from a chemotherapeutic agent, such as a proteasome inhibitor (e.g., bortezomib); an immunosuppressant, such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker, such as nimodipine; an antibody, such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; and combinations thereof; optionally, the active agent is selected from bortezomib, dexamethasone, nimodipine, an anti-ICAM-1 antibody, and combinations thereof; More preferably, said active agent is selected from chemotherapeutic agents, preferably proteasome inhibitors (eg bortezomib).

[0022] In one embodiment, a device according to one embodiment of the present invention comprises at least one contrast agent. In one embodiment, a device of the present invention comprises an inner layer comprising an active agent, optionally at least one intermediate layer comprising an active agent, and an outer layer without an active agent, wherein the outer layer, at least one intermediate layer, the inner layer, or a combination thereof comprises at least one contrast agent.

[0023] In one embodiment, a device according to one embodiment of the present invention comprises at least one contrast agent, Optionally, the device has an outer layer and at least one contrast agent in said outer layer, further optionally, said outer layer is a first layer (7); Preferably, the at least one contrast agent is oriented helically along the device (preferably helically along the longitudinal axis of the device); Optionally, at least one contrast agent is oriented and / or aligned along a lattice, and further optionally, is oriented and / or aligned along a lattice on an outer layer of the device.

[0024] In one embodiment, a device according to one embodiment of the present invention comprises at least one contrast agent, Optionally, the device has an outer layer, an inner layer, and optionally at least one intermediate layer, and has at least one contrast agent in the outer layer, optionally in the at least one intermediate layer, in the inner layer, or a combination thereof, further optionally, the outer layer is a first layer (7), the at least one intermediate layer is a second layer (8), and the inner layer is a third layer (9); Preferably, the at least one contrast agent is oriented helically along the device (preferably helically along the longitudinal axis of the device); Optionally, at least one contrast agent is oriented and / or aligned along a grid, and further optionally, is oriented and / or aligned along a grid in an outer layer of the device, at least one intermediate layer of the device, an inner layer of the device, or a combination thereof.

[0025] In a further aspect, the present invention relates to a kit comprising a device as defined herein and a protective cover (preferably a protective covering material); optionally, the protective cover comprises an active agent and / or saline, such as cold saline. In one embodiment, the cold saline has a temperature ranging from 1°C to 10°C, preferably about 4°C.

[0026] In a further aspect, the present invention relates to a device as defined herein for use in a method for preventing or treating a neurological disease, a neoplastic disease, a cardiac disease, a vascular disease, an immune disease, a carcinoid, an infectious disease, and / or an edema; Preferably, said neurological disease is a brain disease and / or a neurodegenerative disease, preferably said brain disease is selected from stroke (especially ischemic stroke), subarachnoid hemorrhage, and basal ganglia disease, and preferably said neurodegenerative disease is Parkinson's disease; Preferably, the neoplastic disease is cancer, preferably a solid cancer, more preferably a solid cancer selected from liver cancer, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, brain cancer, and melanoma; Preferably, the cardiac disease is cardiac disease (preferably myocardial infarction); Preferably, the vascular disease is an ischemic disease (preferably, peripheral vascular disease); Preferably, the immune disease is graft-versus-host disease; Preferably, the edema is cerebral edema.

[0027] In one embodiment, the device is administered (especially inserted) into a blood vessel (preferably a cerebral vessel) of a patient in need thereof.

[0028] In a further aspect, the present invention relates to a device (preferably a drug delivery implant) for delivery into tubular, cylindrical, and / or channel-like structures in the human or animal body, the device has a substantially cylindrical configuration; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow fluid flow in or through the device (in particular bile acid flow, pancreatic juice flow, cerebrospinal fluid flow, and / or blood flow); the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0029] In one embodiment, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polycaprolactam, elastin, fibrillin, fibrillin, poly(1-acrylonitrile), poly(vinyl alcohol), polygluconate, polyglycolide, dextran, type I collagen, type II collagen, type IV collagen, elastin, silk fibroin, polymandelide, poly(trimethylene carbonate), polydioxanone, poly(4-hydroxybutyrate), poly(butylene succinate), polyphosphazene, polyanhydride, polyphosphoester, polyoxalate, silica gel, alginate, polyethylene glycol, poly(2-oxazoline), gelatin, polyglycidol, polyurethane, and combinations thereof; Preferably, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), and combinations thereof; More preferably, the biocompatible polymer is poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof.

[0030] In one embodiment, the device comprises a fiber (1) (preferably a nanofiber, such as a polymer nanofiber, and / or a microfiber); optionally, the fiber (1) (preferably a polymer nanofiber) comprises silicon dioxide and / or titanium oxide; Preferably, the device comprises nanofibers, which are preferably selected from poly(lactic-co-glycolic acid) nanofibers, polycaprolactone nanofibers, poly(lactic acid) nanofibers, poly(lactic acid) nanofibers with titanium oxide, silica gel nanofibers, and combinations thereof.

[0031] In one embodiment, the fibers (1) are aligned along the longitudinal axis of the device; the fibers (1) are aligned at an angle between 0° and 180° relative to the longitudinal axis of the device; the fibers (1) are aligned along the circumferential direction of the device; the fibers (1) are aligned along the radial direction of the device; the fibers (1) are oriented in a grating; and / or the fibers (1) are randomly oriented.

[0032] In one embodiment, the device comprises nanoparticles, which are preferably mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles.

[0033] In one embodiment, the device comprises a hydrogel; Optionally, the hydrogel is configured to release the active agent (preferably into the channel (6)) when the hydrogel comes into contact with a fluid (e.g., bile acids, pancreatic juices, cerebrospinal fluid, and / or blood).

[0034] In one embodiment, the device has a first layer (7) and a second layer (8); optionally, a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); optionally, the first layer (7) comprises nanofibers, nanoparticles, hydrogels, active agents, and / or cell adhesion molecules; The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone); optionally, the second layer (8) comprises nanofibers, nanoparticles, hydrogels, and / or active agents; said third layer (9), if present, comprising said active agent, and optionally comprising a third biocompatible polymer, nanofibers, nanoparticles, and / or hydrogel; At least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent.

[0035] In one embodiment, the device has a first layer (7) and a second layer (8); optionally, a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); optionally, the first layer (7) comprises fibers (1), nanoparticles, a hydrogel, an active agent, and / or cell adhesion molecules; The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone); optionally, the second layer (8) comprises fibers (1), nanoparticles, a hydrogel, and / or an active agent; said third layer (9), if present, comprising said active agent, and optionally comprising a third biocompatible polymer, fibers (1), nanoparticles, and / or a hydrogel; At least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent. In one embodiment, the fibers (1) are nanofibers and / or microfibers.

[0036] In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9); The first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer); The second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent such as an immunosuppressant, an antibiotic, or a glucocorticoid; optionally, the second layer (8) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the second layer (8) comprises nanoparticles comprising the active agent; The third layer (9) comprises a third biocompatible polymer (preferably poly(lactic-co-glycolic acid) or polycaprolactone) and an active agent such as a chemotherapeutic agent, an antibiotic, or a glucocorticoid; optionally, the third layer (9) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the third layer (9) comprises nanoparticles comprising the active agent; Optionally, the density of said third layer (9) is lower than the density of said second layer (8); Optionally, the molar mass of said third layer (9) is lower than the molar mass of said second layer (8); Optionally, the active agent in the second layer (8) is different from the active agent in the third layer (9). In one embodiment, the fibers (1) are nanofibers and / or microfibers.

[0037] In one embodiment, the cylindrical form is a hollow cylindrical form and / or an open cylindrical form.

[0038] In one embodiment, the device comprises: having a length ranging from about 0.25 mm to about 80 mm, preferably from about 0.5 mm to about 50 mm, more preferably from about 1 mm to about 25 mm, and even more preferably from about 3 mm to about 20 mm; an outer radius ranging from about 2 μm to about 6 mm, preferably from about 0.5 mm to about 4 mm, more preferably from about 1 mm to about 3.5 mm, and even more preferably from about 1.4 mm to about 3 mm; and / or an inner radius ranging from about 1 μm to about 5.9 mm, preferably from about 0.4 mm to about 3.9 mm, more preferably from about 0.9 mm to about 3.4 mm, and even more preferably from about 1.3 mm to about 3 mm; It has a thickness ranging from about 1 μm to about 1 mm, preferably from about 20 μm to about 500 μm, more preferably from about 50 μm to about 250 μm, and even more preferably from about 75 μm to about 150 μm, for example about 100 μm.

[0039] In one embodiment, the device has a cutting line (5), optionally a cutting line (5) along the longitudinal axis of the device.

[0040] In one embodiment, the device is biodegradable (preferably bioabsorbable); Optionally, the device is biodegradable (preferably bioabsorbable) at a temperature ranging from about 34°C to about 43°C.

[0041] In one embodiment, the active agent is embedded in the polymer matrix, optionally embedded in a hydrogel present in the polymer matrix, and / or encapsulated in nanoparticles present in the polymer matrix; the active agent is attached to the device (preferably the inner surface of the device), preferably via a linker; and / or the active agent is coated on the inner surface of the device (preferably the surface of the channel (6)).

[0042] In one embodiment, the device is for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery, preferably an implant for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery, and / or for intrathecal drug delivery, preferably an implant for intrathecal drug delivery; Preferably, the tubular, cylindrical, and / or channel-like structure is a bile duct, pancreatic duct, biliary pancreatic ampulla, or spinal cord.

[0043] In one embodiment, the device is for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery, preferably an implant for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery; the tubular, cylindrical, and / or channel-like structure is a bile duct, pancreatic duct, or biliary pancreatic ampulla; the active agent is a glucocorticoid and / or an anti-infective agent such as an antibiotic, antiviral or antifungal agent; Preferably, the glucocorticoid is prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, flumethasone pivalate, diflorasone diacetate, fluocinolone acetonide, fluorometholone, fluorometholone acetate, clobetasol propionate, desoximetasone, fluocinolone acetonide Xymesterone, fluprednisolone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone cypionate, hydrocortisone probutate, hydrocortisone valerate, cortisone acetate, paramethasone acetate, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, clocortilone pivalate, dexamethasone 21-acetate, betamethasone 17-valerate, isoflupredone, 9-fluorocortisone, 6-hydroxydexamethasone, dichlorisone, mechlorisone, flupredone, doxybetasol, halopredone, halometasone, clobetasone, diflucortolone, isoflupredone acetate, fluorohydroxyandrostenedione, flumethasone, diflorasone, fluocinolone, clobetasol, cortisone, paramethasone, clocortolone, prednisolone 21-hemisuccinate free acid, prednisolone metasulfobenzoate, triamcinolone acetonide 21-palmitate, cortisol, triamcinolone, and combinations thereof; Preferably, the antibiotic is amikacin, amoxicillin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, geldanamycin, herbimycin, carbacephem (loracarbef), ertapenem, doripenem, imipenem, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefopodoxime, cefatazidime. , ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, clarithromycin, clavulanic acid, clavulanate, clindamycin, teicoplanin, azithromycin, dirithromycin, erythromycin, troleandomycin, tetrithromycin, aztreonam, ampicillin, azlocillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, norfloxacin, oxacillin, penicillin G, penicillin V, piperacillin , pivampicillin, pivmecillinam, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, afenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfamethoxazole, sulfisoxazole, metronidazole, trimethoprim, trimethoprim-sulfamethoxazole, demeclocycloline , doxycycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, lincomycin, ethambutol, fosfomycin, furazolidone, isoniazid, linezolid, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinupristin / dalfopristin, rifampin, thiamphenicol, rifampicin, minocycline, sultamicillin, sulbactam, sulfonamides, mitomycin, spectinomycin, spiramycin, roxithromycin, meropenem, andselected from combinations thereof; Preferably, the antiviral agent is abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, atazanavir, baravir, boceprevir, boceprevireltate, cidofovir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxodine, efavirenz, emtricitabine, epivir, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, lamivudine, loxacillus casei, fluticasone, fluoxetine ... selected from pinavir, loviride, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rilpivirine, rimantadine, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, traporved, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof; Preferably, the antifungal agent is selected from clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nystatin, amphotericin, and combinations thereof.

[0044] In one embodiment, the device is for intrathecal drug delivery, preferably an intrathecal drug delivery implant; The tubular, cylindrical, and / or channel-like structure is the spinal cord, The active agent can be a chemotherapeutic agent such as a proteasome inhibitor (e.g., bortezomib, carfilzomib, or ixazomib) or an anthracycline (e.g., doxorubicin); an antibody such as nivolumab, daratumumab, isatuximab, an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; an immunomodulatory agent such as lenalidomide or pomalidomide; an immunosuppressant such as a glucocorticoid (e.g., dexamethasone); a proteasome inhibitor such as bortezomib, carfilzomib, or ixazomib; cyclophosphamide or a cytostatic agent such as melphalan; a steroid such as testosterone, trenbolone, oxymetholone, methandrostenolone, nandrolone, stanozolol, boldenone, or oxandrone; a nuclear export inhibitor such as leptomycin B; a matrix metalloproteinase inhibitor such as marimastat; an antifibrotic agent such as pirfenidone or nintedanib; a small molecule; an anti-infective agent such as an antibiotic, antiviral, or antifungal; a glucocorticoid; a cytokine; a chemokine; and combinations thereof; Preferably, the antibiotic is amikacin, amoxicillin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, tobramycin, geldanamycin, herbimycin, carbacephem (lorakabef), ertapenem, doripenem, imipenem, cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cefazolin, cephalosporin ... ceftozumab, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, clarithromycin, clavulanic acid, clavulanate, clindamycin, teicoplanin, azithromycin, dirithromycin, erythromycin, troleandomycin, teritomycin, aztreonam, ampicillin, azlocillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, norfloxacin, oxacillin, penicillin G, penicillin V, piperacillin, Vampicillin, pivmecillinam, ticarcillin, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, afenide, prontosil, sulfacetamide, sulfamethizole, sulfanilimide, sulfamethoxazole, sulfisoxazole, metronidazole, trimethoprim, trimethoprim-sulfamethoxazole, demeclocycloline, Doxycycline, oxytetracycline, tetracycline, arsphenamine, chloramphenicol, lincomycin, ethambutol, fosfomycin, furazolidone, isoniazid, linezolid, mupirocin, nitrofurantoin, platensimycin, pyrazinamide, quinpristin / dalfopristin, rifampin, thiafenicol, rifampicin, minocycline, sultamicillin, sulbactam, sulfonamides, mitomycin, spectinomycin, spiramycin, roxithromycin, meropenem, andselected from combinations thereof; Preferably, the antiviral agent is abacavir, acyclovir, adefovir, amantadine, amprenavir, ampligen, atazanavir, baravir, boceprevir, boceprevireltate, cidofovir, dolutegravir, darunavir, delavirdine, didanosine, docosanol, edoxodine, efavirenz, emtricitabine, epivir, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, immunovir, idoxuridine, imiquimod, indinavir, lamivudine, loxacillus casei, fluticasone, fluoxetine ... selected from pinavir, loviride, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rilpivirine, rimantadine, pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir, tenofovir, tipranavir, trifluridine, trizivir, tromantadine, traporved, truvada, valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, and combinations thereof; Preferably, the antifungal agent is selected from clotrimazole, econazole, miconazole, terbinafine, fluconazole, ketoconazole, nystatin, amphotericin, and combinations thereof; Preferably, the glucocorticoid is prednisone, prednisolone, triamcinolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, flumethasone pivalate, diflorasone diacetate, fluocinolone acetonide, fluorometholone, fluorometholone acetate, clobetasol propionate, desoximetasone, fluocinolone acetonide Xymesterone, fluprednisolone, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone cypionate, hydrocortisone probutate, hydrocortisone valerate, cortisone acetate, paramethasone acetate, methylprednisolone acetate, methylprednisolone sodium succinate, prednisolone acetate, prednisolone sodium phosphate, prednisolone tebutate, clocortilone pivalate, dexamethasone 21-acetate, betamethasone 17-valerate, isoflupredone, 9-fluorocortisone, 6-hydroxydexamethasone, dichlorisone, mechlorisone, flupredone, doxybetasol, halopredone, halometasone, clobetasone, diflucortolone, isoflupredone acetate, fluorohydroxyandrostenedione, flumethasone, diflorasone, fluocinolone, clobetasol, cortisone, paramethasone, clocortolone, prednisolone 21-hemisuccinate free acid, prednisolone metasulfobenzoate, triamcinolone acetonide 21-palmitate, cortisol, triamcinolone, and combinations thereof; Preferably, the cytokine is selected from G-CSF, Kit-ligand (KL), IL-1, IL-7, IL-8, IL-11, Flt3-ligand, SCF, thrombopoietin, GM-CSF, and combinations thereof; Preferably, the chemokine is CCL1, CCL11, CCL12, CCL13, CCL14-1, CCL14-2, CCL14-3, CCL15-1, CCL15-2, CCL16, CCL17, CCL18, CCL19, CCL19, CCL2, CCL20, CCL21, CCL22, CCL23-1, CCL23-2, CCL24, CCL25-1, CCL25-2, CCL26, CCL27, CCL28, CCL3, CCL3L1, CCL4, CCL4L1, CCL5, CCL6, CCL7, CCL8, Selected from CCL9, CCR10, CCR2, CCR5, CCR6, CCR7, CCR8, CCRL1, CCRL2, CX3CL1, CX3CR, CXCL1, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL15, CXCL16, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8, CXCL9, CXCL9, CXCR1, CXCR2, CXCR4, CXCR5, CXCR6, CXCR7, XCL2, and combinations thereof.

[0045] In a further aspect, the present invention relates to a method for preventing or treating a neurological disease, a neoplastic disease, a cardiac disease, a vascular disease, an immune disease, a carcinoid, an infectious disease, and / or an edema, comprising applying (in particular administering) a device as defined herein to a patient in need thereof.

[0046] In one embodiment, the device is administered (especially inserted) into a blood vessel (preferably cerebrovascular), bile duct, pancreatic duct, biliary ampulla, or spinal cord of a patient in need thereof. In one embodiment, the neurological disease, neoplastic disease, cardiac disease, vascular disease, immune disease, carcinoid, infectious disease, and / or edema are as defined herein.

[0047] In a further aspect, the present invention relates to an active agent for use in a method for preventing or treating a neurological disease, a neoplastic disease, a cardiac disease, a vascular disease, an immune disease, a carcinoid, an infectious disease, and / or an edema, wherein said active agent is administered in a form or manner as defined herein (in particular by administering said device to a patient in need thereof, preferably by inserting said device into a blood vessel of a patient in need thereof); The active agent can be a chemotherapeutic agent such as a proteasome inhibitor (e.g., bortezomib) or an anthracycline (e.g., doxorubicin); an immunosuppressant such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker such as nimodipine; an antithrombotic agent such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; an antibody such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; a radiation modulating agent; fingolimod or NRLP3 inhibitor. anti-inflammatory compounds such as inflammatory cell proliferation inhibitors (e.g., MCC50); antihypertensive agents such as angiotensin-converting enzyme inhibitors or beta-blockers; matrix metalloproteinase inhibitors; cytokines such as interleukins; chemokines; Parkinson's disease medications such as levodopa, dopamine agonists, or monoamine oxidase B inhibitors; Huntington's disease medications such as tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, amantadine, levetiracetam, or clonazepam; and combinations thereof; Preferably, the active agent is selected from a chemotherapeutic agent, such as a proteasome inhibitor (e.g., bortezomib); an immunosuppressant, such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker, such as nimodipine; an antibody, such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; and combinations thereof; optionally, the active agent is selected from bortezomib, dexamethasone, nimodipine, an anti-ICAM-1 antibody, and combinations thereof; More preferably, the active agent is selected from a chemotherapeutic agent, preferably a proteasome inhibitor (e.g., bortezomib). In one embodiment, the neurological disease, neoplastic disease, cardiac disease, vascular disease, immune disease, carcinoid, infectious disease, and / or edema is as defined herein.

[0048] In a further aspect, the present invention relates to the use of an active agent for the manufacture of a medicament for the prevention or treatment of a neurological disease, a neoplastic disease, a cardiac disease, a vascular disease, an immune disease, a carcinoid, an infectious disease, and / or edema, wherein said medicament is formulated in the form of a device as defined herein and wherein the active agent is an active agent as defined herein.

[0049] In one embodiment, the active agent, the neurological disorder, neoplastic disorder, cardiac disorder, vascular disorder, immune disorder, carcinoid, infectious disease, and / or edema are as defined herein. DETAILED DESCRIPTION OF THE INVENTION

[0050] Detailed Description The present invention aims to provide a drug delivery device that reduces the side effects of various active agents, particularly those resulting from local administration of the active agent. Targeted and precise drug delivery at the target site prevents side effects, such as adverse effects in non-target tissues. While not wishing to be bound by any theory, the inventors believe that, advantageously, due to a significantly smaller volume of distribution, local drug delivery using the device of the present invention requires a much smaller dose of the active agent to achieve a desired active agent level in the target tissue compared to systemic administration. Advantageously, implantation of the device directly at the target site allows for better control of the released active agent and improved pharmacokinetics, particularly because the active agent concentration does not significantly change before reaching the target tissue, even when kidney and / or liver function is significantly impaired. Advantageously, at the target site, the device completely dissolves into a bioabsorbable component, thereby releasing the active agent. For example, multiple active agents can be released sequentially. The device may also be applied to improve the efficiency and / or effectiveness of multiple treatment options.

[0051] For example, the device of the present invention can be used to prevent or treat ischemic stroke and / or the edema associated with ischemic stroke.However, far beyond its potential application in the treatment and prevention of ischemic stroke, the limited crossing of the blood-brain barrier is a core problem in translational research (especially for various diseases, such as neurological diseases, involving most active agents).Advantageously, the device of the present invention allows the safety-related dose limit to be shifted due to the better local permeability of the blood-brain barrier.Advantageously, the device of the present invention can achieve a high dose locally in target tissue while preventing side effects in remote organs.

[0052] The advantage of the device of the present invention is that it can be applied immediately after mechanical recanalization of a blood vessel, with minimal invasiveness, using a catheter system already placed in the blood vessel for recanalization. Preferably, the device of the present invention is prepared using electrospinning, centrifugal spinning, melt spinning, melt blowing, melt electrowriting, coating (e.g., dip coating or spray coating), casting, inkjet printing, and / or 3D printing. For example, the device of the present invention can be prepared using an electrospinning device, a centrifugal spinning device, a melt spinning device, a melt blowing device, a melt electrowriting device, a nanocoating device, and / or a 3D printer. The advantage of melt electrowriting is that the material (e.g., a polymer matrix) can be precisely molded into the desired shape. The advantage of electrospinning is that even thermolabile active agents such as antibodies can be directly incorporated into the electrospun product (e.g., the produced polymer matrix). The device of the present invention can be prepared using different techniques, such as electrospinning, centrifugal spinning, melt spinning, melt blowing, melt electrowriting, coating (e.g., dip coating or spray coating), casting, and 3D printing; for example, one layer of the device can be prepared by electrospinning, and one layer can be prepared by electrowriting, and optionally, any of these layers can be additionally coated by dip coating or spray coating. In one embodiment, the preparation of the device comprises coating a layer (e.g., an outer layer or an inner layer) by dip coating and / or spray coating.For example, the device may be fabricated by electrowriting a layer (e.g., around a rotating target) and then electrospinning fibers (1) (e.g., nanofibers and / or microfibers loaded with an active agent) around the electrowritten layer; optionally, any of the layers may be coated, for example, by dip coating or spray coating.

[0053] In one embodiment, a device according to an embodiment of the present invention is prepared using electrospinning (preferably solution electrospinning). An advantage of preparing a device according to an embodiment of the present invention by electrospinning (preferably solution electrospinning) is that the size and thickness of each layer of the device can be precisely adjusted during the electrospinning process. Thus, films and / or layers of different thicknesses can be prepared and combined in a device according to an embodiment of the present invention.

[0054] In a first aspect, the present invention relates to a device for delivery into tubular, cylindrical and / or channel-like structures in the human or animal body, especially for intravascular drug delivery, biliary targeted drug delivery, pancreatic duct targeted drug delivery and / or intrathecal drug delivery, preferably a drug delivery implant (especially an intravascular drug delivery implant, a biliary targeted drug delivery implant, a pancreatic duct targeted drug delivery implant and / or an intrathecal drug delivery implant); the device has a substantially cylindrical configuration; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow fluid flow in or through the device (e.g., blood flow, bile acid flow, pancreatic juice flow, and / or cerebrospinal fluid flow); the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0055] In one embodiment, the device is for intravascular drug delivery, preferably an intravascular drug delivery implant; the device has a substantially cylindrical configuration; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow blood flow through the device; the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0056] Advantageously, the devices of the present invention allow for the administration of active agents at target tissues supplied by the distal flow channels of the blood vessel in which the device is implanted, thereby allowing for specific targeting of the target tissue and reducing systemic side effects.

[0057] The term "implant" as used herein refers to a medical device manufactured for placement in a patient's body. Typically, medical implants are artificial devices, as opposed to transplants, which are transplanted living tissue. Optionally, such devices (e.g., artificial devices) may comprise cells (e.g., human cells, such as proinflammatory T cells and / or CAR-T cells). Preferably, the device of the present invention has at least one layer, and preferably, the at least one layer comprises or consists of the biocompatible polymer matrix. For example, an intravascular drug delivery implant is an implant placed in a patient's blood vessel, such as the blood vessel of the patient's brain. In particular, an intravascular drug delivery implant is an implant placed in a patient's blood vessel for administering an active agent (e.g., a drug) to a target tissue, such as brain tissue, located downstream of the device implanted in the blood vessel. Preferably, the device of the present invention is configured to be placed intravascularly (e.g., in the lumen surrounded by the endothelium of a blood vessel). In one embodiment, the device of the present invention is configured to be placed intravascularly. In one embodiment, the device of the present invention is configured to be placed in a patient's blood vessel, and the device is not a vascular graft, particularly not a vascular substitute, i.e., it does not replace a blood vessel, such as a defective blood vessel, in the patient. The device of the present invention differs from a vascular graft (particularly a vascular substitute) at least in that it is configured to be placed in a blood vessel rather than replacing the blood vessel. In one embodiment, the device is not for angiogenesis and / or the device is not used for angiogenesis and / or the device does not achieve angiogenesis. In one embodiment, the device is configured to be implanted in an intact blood vessel of the patient. The device of the present invention is preferably configured to be placed in a blood vessel. In one embodiment, the device is deployed intravascularly. In one embodiment, the device is configured to be deployed intravascularly. In one embodiment, the device has the shape and / or dimensions of a stent.In one embodiment, the device does not have struts (especially metal struts) and / or wires (especially metal wires). In a preferred embodiment, the device is sterile. The device may be non-sterile, for example, when it comprises therapeutic cells or fragments thereof. In one embodiment, the device comprises cells (especially therapeutic cells) or fragments thereof; preferably, the cells are therapeutic bacteria, therapeutic viruses, immune cells such as proinflammatory T cells, and / or CAR-T cells. In one embodiment, the device does not comprise cells. In one embodiment, the device is non-immunogenic. In one embodiment, the device is non-cytotoxic. In one embodiment, the device is not ferromagnetic. Advantageously, patients having a device of the present invention implanted in any part of the body, such as the brain, where the device is not ferromagnetic, may be examined using nuclear magnetic resonance, such as cranial nuclear magnetic resonance. In one embodiment, the device is configured to be placed in the patient's blood vessels by a stent retriever system and / or a balloon catheter system. In one embodiment, the device comprises plasma, cytokines such as proinflammatory cytokines, and / or cells such as CAR-T cells. For example, any of the layers of the device may comprise plasma, cytokines such as pro-inflammatory cytokines, and / or cells such as CAR-T cells.

[0058] In one embodiment, the blood vessel is an artery, arteriole, capillary, venule, or vein. In a preferred embodiment, the blood vessel is an artery. In one embodiment, the device is configured to be placed in a patient's blood vessel by a stent retriever system and / or a balloon catheter system in an artery that directly supplies a selected target tissue, and optionally, the device is configured to release at least one active agent or dye into the capillary system of the target tissue.

[0059] In one embodiment, the device is configured to release an active agent into the blood flowing through the channel (6), where the active agent reaches a target tissue downstream of the device and binds to a receptor in the target tissue, such as an endothelial receptor in a capillary. It is an advantage of the present invention that blood flow in the capillary system is very slow, thereby improving and / or facilitating binding of the active agent to the endothelial receptor in the capillary.

[0060] In one embodiment, the device is for intravascular drug delivery (preferably an intravascular drug delivery implant), for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery (preferably an bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery implant), and / or for intrathecal drug delivery (preferably an intrathecal drug delivery implant); The tubular, cylindrical, and / or channel-like structure is a blood vessel, a bile duct, a pancreatic duct, a biliary ampulla, or a spinal cord.

[0061] In one embodiment, the device is for intravascular drug delivery (preferably, an intravascular drug delivery implant); the device has a substantially cylindrical configuration; The tubular, cylindrical, and / or channel-like structures are blood vessels; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow the flow of fluids in or through the device (in particular the flow of bile acids and / or pancreatic juices in or through the device); the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0062] In one embodiment, the device is for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery (preferably, an implant for bile duct targeted drug delivery and / or pancreatic duct targeted drug delivery), the device has a substantially cylindrical configuration; the tubular, cylindrical, and / or channel-like structure is a bile duct, pancreatic duct, or biliary pancreatic ampulla; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow the flow of bile acids and / or pancreatic juices through the device; the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0063] As used herein, the term "bile duct" refers to one or more ducts that carry bile from the liver of a human or animal to the gallbladder and duodenum. As used herein, the terms "bile duct," "bile ducts," and "common bile duct" may be used interchangeably. As used herein, the term "pancreatic duct" refers to one or more ducts that carry pancreatic juice from the pancreas of a human or animal to the duodenum. As used herein, the terms "pancreatic duct," "pancreatic ducts," and "common pancreatic duct" may be used interchangeably. As those skilled in the art are well aware, small bile ducts empty into the common bile duct, and small pancreatic ducts empty into the main pancreatic duct. The main pancreatic duct and common bile duct meet at a duct called the biliary ampulla before emptying into the duodenum.

[0064] Bacteria ascending from the intestine through the papilla of Vater into the bile duct and / or pancreatic duct can cause infections of the liver, bile duct, pancreatic duct, bile, and / or pancreas. Such infections can be accompanied by swelling of the biliary ampulla, bile duct, and / or pancreatic duct. A device according to one embodiment of the present invention is configured for insertion into the bile duct, pancreatic duct, or biliary pancreatic ampulla and for locally releasing at least one active agent (such as an antibiotic and / or glucocorticoid) into the lumen of the biliary duct, pancreatic duct, and / or biliary pancreatic ampulla, where the at least one active agent prevents bacterial entry from the intestine into the biliary pancreatic ampulla, bile duct, and / or pancreatic duct and / or reduces swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct.

[0065] In one embodiment, the device is configured to be inserted into the bile duct, pancreatic duct, or biliary-pancreatic ampulla and to release at least one active agent into the target tissue. In this embodiment, the implantation site is the target site and / or target tissue. In one embodiment, the active agent is released at the implantation site, and the implantation site is the bile duct, pancreatic duct, or biliary-pancreatic ampulla. In one embodiment, the device is not configured to release the at least one active agent into the capillary system and / or tissue downstream of the implantation site of the device.

[0066] It is an advantage of the present invention that the device according to the present invention locally releases high doses of one or more active agents. In one embodiment, the device is configured to be inserted into the bile duct, pancreatic duct, or biliary-pancreatic ampulla and to release at least one active agent into the bile duct, pancreatic duct, or biliary-pancreatic ampulla. The device is configured to release at least one active agent into the pancreatic duct or pancreaticobiliary duct. In one embodiment, the target tissue is the bile duct, pancreatic duct, or biliary-pancreatic ampulla.

[0067] A device according to one embodiment of the invention is configured to be inserted into the bile duct, pancreatic duct, or biliary-pancreatic ampulla and to locally release at least one active agent (such as an antibiotic and / or glucocorticoid) into the lumen of the bile duct, pancreatic duct, and / or biliary-pancreatic ampulla, where the at least one active agent has a local effect on bacteria, thereby preventing bacteria from entering the biliary-pancreatic ampulla, bile duct, and / or pancreatic duct from the intestine and / or reducing swelling of the biliary-pancreatic ampulla, bile duct, and / or pancreatic duct. It is an advantage of the device according to this aspect of the invention that when using a device (e.g., for the treatment of cholangitis (e.g., recurrent cholangitis)), no, or only a small amount of, the active agent, such as an antibiotic, enters the stomach or the portion of the intestine above the papilla of Vater, so that the natural microflora of the intestine is not affected by treatment with the at least one active agent. In contrast, active agents applied orally or systemically (eg, for the treatment of cholangitis (eg, recurrent cholangitis)) have the side effect of damaging the entire gut microbiota.

[0068] In one embodiment, the present invention relates to an intrathecal drug delivery device (preferably, an implant for intrathecal drug delivery), comprising: the device has a substantially cylindrical configuration; The tubular, cylindrical, and / or channel-like structure is the spinal cord; The device has a channel (6) (preferably an internal channel); preferably, the channel (6) is configured to allow the flow of bile acids and / or pancreatic juices through the device; the device is elastically deformable (preferably elastically deformable in a direction substantially perpendicular to a longitudinal axis of the device); The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6).

[0069] A device according to one embodiment of the present invention is configured to be inserted into the spinal cord and to locally release at least one active agent (such as a cytokine, chemokine, matrix metalloproteinase inhibitor, glucocorticoid, antibiotic, and / or chemotherapeutic agent) into the spinal cord. In one embodiment, the device is configured to be inserted into the spinal cord and to locally release at least one active agent into the spinal cord. In this embodiment, the implantation site is the target site and / or target tissue. In one embodiment, the active agent is released at the implantation site, which is the spinal cord. In this embodiment, the device is not configured to release the at least one active agent into the capillary system and / or tissue downstream of the implantation site of the device. It is an advantage of the present invention that a device according to the present invention locally releases one or more active agents at high doses. In one embodiment, the target tissue is the spinal cord. A device according to this embodiment may, for example, aid in the treatment of patients with multiple myeloma (e.g., after the patient has been diagnosed using a PET-CT scan).

[0070] It is a further advantage of the present invention that the devices of the present invention are not ferromagnetic and therefore can be inspected using nuclear magnetic resonance, such as magnetic resonance tomography (MRT). In one embodiment, the devices of the present invention can be inspected using nuclear magnetic resonance, such as magnetic resonance tomography (MRT). In another embodiment, the devices of the present invention can be inspected using computed tomography (CT). In another embodiment, the interventional device can be inspected using ultrasound (ultrasound diagnosis). In another embodiment, the interventional device can be inspected using ionizing or non-ionizing radiation, wherein the ionizing or non-ionizing radiation is not X-rays.

[0071] In one embodiment, the device provides unidirectional release of the active agent, particularly release into the channel (6). In one embodiment, the device is configured to release the active agent unidirectionally into the channel (6). In one embodiment, the device is configured to release the active agent unidirectionally into the channel (6); preferably, the active agent is released into the channel (6) from an inner layer of the device, and optionally subsequently from at least one intermediate layer, and optionally from an outer layer. The term "unidirectional" as used herein preferably refers to the active agent being released into the channel (6) but not into the outer surface and / or endothelium contacted by the outer layer of the device. In one embodiment, the device is configured to release the active agent into the channel (6) but not into the endothelium in direct contact with the outer surface and / or outer layer of the device. For example, the device may be configured for unidirectional release by providing an inner layer, and optionally at least one intermediate layer, of the device with an active agent, and an outer layer of the device without the active agent.

[0072] The term "substantially cylindrical in shape" as used herein refers to a shape that is substantially cylindrical (especially a cylindrical shape that is a three-dimensional solid having straight, parallel sides and a circular or elliptical cross section). The device may have the shape of a solid cylinder with circular ends perpendicular to the longitudinal axis of the cylinder. In particular, the device may have straight, parallel sides and a circular or elliptical cross section. In one embodiment, the cylinder is in the shape of a right cylinder or an oblique cylinder (preferably a right cylinder). In one embodiment, the device has a substantially right cylindrical or substantially oblique cylindrical shape, preferably a right cylindrical shape. In one embodiment, the device of the present invention has the shape of a substantially right cylindrical hollow cylinder. In one embodiment, the terms "shape" and "form" used in the context of a cylindrical shape of a device are used interchangeably.

[0073] As used herein, the term "hollow cylindrical form" preferably refers to the form of a cylinder that is hollow inside (especially having a void inside and an inner radius and an outer radius). The thickness of a device having a substantially hollow cylindrical form refers to the difference between the outer and inner radii of the substantially hollow cylinder. The shape formed at the end of the hollow cylinder is typically a ring (especially an annular ring). In one embodiment, the device is in the form of a hollow cylinder, and the channel (6) of the device is the void of the hollow cylinder. As used herein, the term "open cylindrical form" preferably refers to the form of a cylinder that is open at both ends. In one embodiment, the terms "open cylinder," "hollow cylinder," and "tube" are used interchangeably. In one embodiment, the cylindrical form is a hollow cylindrical form and / or an open cylindrical form. In one embodiment, the device is in the form of a tube. In one embodiment, the device (e.g., in the form of a tube) has an opening, such as a cut line (5), along the longitudinal axis of the device.

[0074] As used herein, the term "channel (6)" in the context of a device preferably refers to a void in a device of the present invention that allows for fluid flow in or through the device (particularly blood flow, bile acid flow, pancreatic juice flow, and / or cerebrospinal fluid flow) in or through the device. In one embodiment, the channel (6) is a linear channel (6) from an open end of the device to another opening of the device. In one embodiment, for example, if the device has a porous matrix, the channel (6) has two or more interconnected channels (6). The term "internal channel" as used herein preferably refers to a channel (6) that extends along the longitudinal axis of the device. In one embodiment, the channel (6) is a lumen. In one embodiment, the channel (6) (preferably an internal channel) has or consists of a lumen. Preferably, the lumen is a cavity (particularly a channel (6)) in a tube or tube-like structure, such as in a hollow cylinder. In one embodiment, the terms "channel," "internal channel," and "lumen" are used interchangeably. In one embodiment, a device has a lumen; preferably, the lumen is configured to allow fluid flow from upstream of the device through the lumen of the device to downstream of the device. In one embodiment, the terms "upstream" and "downstream" refer to the device's location, respectively, relative to blood flow through the blood vessel; for example, "upstream" refers to the blood flow in the blood vessel upstream of the implanted device, and "downstream" refers to the blood flow in the blood vessel downstream of the implanted device.

[0075] In one embodiment, the polymer matrix does not have pores with a diameter of 20 μm or more (preferably 15 μm or more). In one embodiment, the polymer matrix does not have pores. By providing a device with no pores or pores less than 20 μm, substantially physiological flow of fluids in or through the device can be achieved, particularly substantially physiological flow of blood, substantially physiological flow of bile acids, substantially physiological flow of pancreatic juice, and / or substantially physiological flow of cerebrospinal fluid, and bleeding flow through the polymer matrix (instead of through channel (6)) is prevented. In one embodiment, the device is configured such that fluids (particularly blood, bile acids, pancreatic juice, and / or cerebrospinal fluid) flow through channel (6) of the device and fluids (particularly blood, bile acids, pancreatic juice, and / or cerebrospinal fluid) do not flow through the polymer matrix.

[0076] In one embodiment, the channel (6) has a radius ranging from about 1 μm to about 5.9 mm, preferably from about 0.4 mm to about 3.9 mm, more preferably from about 0.9 mm to about 3.4 mm, even more preferably from about 1.3 mm to about 3 mm, and / or a length ranging from about 0.25 mm to about 80 mm, preferably from about 0.5 mm to about 50 mm, more preferably from about 1 mm to about 25 mm, even more preferably from about 3 mm to about 20 mm.

[0077] In one embodiment, the device is configured to release the active agent into the channel (6) when the device comes into contact with fluids (especially blood, bile acids, pancreatic juices, and / or cerebrospinal fluid). Advantageously, in one embodiment, when the device is implanted in a blood vessel and comes into contact with blood flowing through the channel (6) of the device, the active agent is released into a target tissue (especially a target tissue downstream of the device). For example, the active agent is released into the blood flowing through the channel (6) and then reaches a target tissue immediately downstream of the device.

[0078] In one embodiment, the active agent is not released at the implantation site. In one embodiment, the active agent is released at a site and / or tissue distant from the implantation site and / or the implanted tissue. In one embodiment, the implantation site is not the target site and / or target tissue. In one embodiment, the active agent is released at a site and / or tissue downstream from the implantation site and / or the implanted tissue. In one embodiment, the active agent is released in an organ distant from the implanted organ.

[0079] In one embodiment, the active agent is released into a fluid, such as blood, bile acids, pancreatic juice, or cerebrospinal fluid, flowing through channel (6) and then reaches a target tissue downstream of the device, where the active agent binds to a receptor in the target tissue.

[0080] As used herein, the terms "allowing blood flow through the device" or "allowing fluid flow through the device" preferably relate to allowing the flow of fluids, such as blood, bile acids, pancreatic juices, or cerebrospinal fluid, through the device in a manner that substantially corresponds to physiological flow; e.g., blood flow, such as laminar and / or turbulent flow, that substantially corresponds to physiological blood flow through the respective blood vessel in which the device is located. In one embodiment, the channel (6) configured to allow fluid flow through the device has an appropriate diameter, and optionally, appropriate surface properties, to allow substantially physiological flow of the fluid through the device (especially the channel (6) of the device).

[0081] As used herein, the term "elastically deformable" preferably refers to the ability of the device of the present invention to return to its original shape and size when a deforming influence or force, such as pulsation of the blood system or a balloon used to deploy the device, is removed. For example, elastically deformable refers to a temporary change in the length, volume, or shape of the device due to stress, such as an inflated balloon or pulsation (especially due to stress less than the elastic limit of the device). In one embodiment, each layer of the device is elastically deformable. In one embodiment, the device of the present invention has an elastic modulus ranging from about 1 kPa to about 100 mPa. In one embodiment, the device is elastically deformable in a direction substantially perpendicular to the longitudinal axis of the device. In one embodiment, the device is elastically deformable in the radial direction of the device and, optionally, in the longitudinal direction of the device. For example, the elastic deformability of the device may be due to material properties of the device (e.g., the polymer matrix is ​​elastically deformable) and / or due to geometric properties of the device (e.g., the shape of the device, such as a clasp, a spiral, or a mesh). In one embodiment, the device has a clasp shape, a spiral shape, or a mesh shape. In one embodiment, at least a portion of the device is elastically deformable. In one embodiment, at least a portion of the device along its circumference is elastically deformable. For example, at least half of the device along its circumference (e.g., in the form of a tube) is elastically deformable.

[0082] In one embodiment, the device has a longitudinal axis and a transverse axis; preferably, the channel (6) is oriented along the longitudinal axis. In one embodiment, the device (especially in cylindrical form) has an inner radius and an outer radius; preferably, the thickness of the device is the difference between the outer and inner radii. In one embodiment, the length of the device is the length along the longitudinal axis. In one embodiment, the terms "aligned along" and "oriented substantially parallel to," especially in the context of alignment of the fiber (1), are used interchangeably.

[0083] As used herein, the term "biocompatible polymer matrix" refers to a polymer matrix that is not harmful or toxic to animals (especially vertebrates such as humans). In one embodiment, the biocompatible polymer matrix comprises or consists of a biocompatible polymer; and, optionally, comprises or consists of any of fibers (1), nanoparticles, hydrogels, and combinations thereof.

[0084] The term "polymer matrix" as used herein preferably refers to a structure (especially a three-dimensional object) comprising one or more polymers or consisting of one or more polymers. In one embodiment, the polymer matrix is ​​a layer of a device comprising one or more polymers and, optionally, an active agent. In one embodiment, the polymer matrix comprises one or more polymers in the form of fibers (1) and / or a hydrogel. Preferably, the term "fiber" as used herein refers to nanofibers and / or microfibers. For example, the polymer matrix may comprise fibers (1) in an amount ranging from 30% to 90% by volume. Advantageously, the fibers (1) reinforce the polymer matrix, thus enhancing the stability of the device. In one embodiment, the terms "polymer matrix" and "polymer scaffold" are used interchangeably. In one embodiment, the device and / or polymer matrix does not have pores with diameters greater than 1 μm, preferably greater than 100 nm, and even more preferably greater than 50 nm. In one embodiment, the polymer matrix does not have interconnected pores. In one embodiment, the device has multiple layers; optionally, each layer of the multiple layers has a polymer matrix. In one embodiment, the device has at least two layers, a first layer (7) having a first polymer matrix and a second layer (8) having a second polymer matrix, the first polymer matrix and the second polymer matrix being the same or different. For example, the first polymer matrix and the second polymer matrix may have different polymer compositions and / or densities (such as polymer densities). For example, the inner layer of the device may have a first polymer matrix (e.g., a poly(lactic-co-glycolic acid) matrix or a polycaprolactone matrix) whose density is lower than the density of a second polymer matrix (e.g., a poly(lactic-co-glycolic acid) matrix or a polycaprolactone matrix) forming at least one middle or outer layer of the device.In one embodiment, the polymer matrix and / or device comprises a mineral and / or an organic material. In one embodiment, the polymer matrix and / or device comprises said biocompatible polymer matrix and a mineral.

[0085] As used herein, the term "biocompatible polymer" refers to a polymer that is not harmful or toxic to animals (especially vertebrates such as humans). In particular, biocompatible polymers are not harmful or toxic to living tissues, organs, bodies, and organisms such as animals. In one embodiment, the biocompatible polymer is selected from the group consisting of poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polycaprolactam, elastin, fibrillin, fibrillin, poly(1-acrylonitrile), poly(vinyl alcohol), polygluconate, polyglycolide, dextran, type I collagen, type II collagen, type IV collagen, elastin, silk fibroin, polymandelide, poly(trimethylene carbonate), polydioxanone, poly(4-hydroxybutyrate), poly(butylene succinate), polyphosphazene, polyhydroxybenzoate ... Preferably, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), and combinations thereof; more preferably, the biocompatible polymer is poly(lactic-co-glycolic acid), polycaprolactone, or combinations thereof. When referring to "combinations thereof" in the context of polymers, such "combinations" may also refer to copolymers thereof. In one embodiment, the phrase "combinations thereof" used herein in the context of polymers is meant to be understood to include copolymers thereof. In one embodiment, the phrases "combinations thereof" and "combinations and copolymers thereof" are used interchangeably herein in the context of polymers. In one embodiment, the first biocompatible polymer, the second biocompatible polymer, and, if present, the third biocompatible polymer are the same or different biocompatible polymers.In one embodiment, the term "poly(lactic acid)" as used herein refers to poly(L-lactide) (PLLA) and / or poly(DL-lactide). The device and / or polymer matrix may comprise random and / or block copolymers of the above polymers, such as poly(L-lactide-co-caprolactone). Biocompatible polymers are preferably biodegradable, more preferably bioabsorbable.

[0086] As used herein, the term "biodegradable" preferably refers to the degradation of a device when implanted in a patient's body. This degradation may include the degradation of the device's materials (such as the polymer matrix), which may then be excreted and / or absorbed. For example, the polymer matrix may degrade and each polymer may be excreted, and / or the active agent may be released and absorbed by the body. As used herein, the term "bioresorbable" preferably refers to the degradation of a device when implanted in a patient's body and the absorption of its components. Advantageously, biodegradable (especially bioresorbable) devices do not need to be surgically removed. Thus, biodegradable (especially bioresorbable) devices increase patient comfort and prevent the risks associated with additional surgery. In one embodiment, the device is biodegradable, preferably bioresorbable. In one embodiment, the device is biodegradable, preferably bioresorbable, at a temperature ranging from about 4°C to about 43°C, preferably from about 34°C to about 43°C. In one embodiment, the device is biodegradable, preferably bioabsorbable, at body temperature. In one embodiment, the device is biodegraded, preferably bioabsorbed, within a period ranging from about 10 minutes to about 600 days, preferably from about 30 minutes to about 300 days, more preferably from about 45 minutes to about 90 days, and even more preferably from about 60 minutes to about 10 days. For example, the second or third layer (9) containing bortezomib may be biodegraded (preferably bioabsorbed) within a period ranging from about 30 minutes to about 4 hours, and the first or second layer (7) containing dexamethasone may be biodegraded (preferably bioabsorbed) within a period ranging from about 10 minutes to about 10 hours. Preferably, the third layer (9) degrades before the second layer (8) and the first layer (7). Preferably, the second layer (8) degrades before the first layer (7). Preferably, the device degrades from the inside out (e.g., from the inner layer to the outer layer). In one embodiment, at least 95% of the device degrades within 90 days (preferably 60 days) after implantation.

[0087] The term "active agent" as used herein relates to any component that provides an effect, such as a biologically active effect or other direct effect, in the diagnosis, cure, mitigation, treatment or prevention of disease and / or affects the structure or function of the human or animal body, in particular to active pharmaceutical ingredients, and preferably to drugs. The term "active agent" as used herein preferably refers to chemotherapeutic agents such as proteasome inhibitors (e.g., bortezomib) or anthracyclines (e.g., doxorubicin); immunosuppressants such as glucocorticoids (e.g., dexamethasone); calcium channel blockers such as nimodipine; antithrombotic agents such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; antibodies such as anti-ICAM-1 antibodies, anti-MCH2 antibodies, or anti-VEGF antibodies; radiomodulatory agents; fingolimod or N-methylpropional; the active agent being selected from anti-inflammatory compounds such as RLP3 inflammasome inhibitors (e.g., MCC50); antihypertensive agents such as angiotensin-converting enzyme inhibitors or beta-blockers; matrix metalloproteinase inhibitors; cytokines such as interleukins; chemokines; Parkinson's disease medications such as levodopa, dopamine agonists, or monoamine oxidase B inhibitors; Huntington's disease medications such as tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, amantadine, levetiracetam, or clonazepam; and combinations thereof. In preferred embodiments, the active agent is selected from a chemotherapeutic agent such as a proteasome inhibitor (e.g., bortezomib); an immunosuppressant such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker such as nimodipine; an antibody such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; and combinations thereof; optionally, the active agent is selected from bortezomib, dexamethasone, nimodipine, an anti-ICAM-1 antibody, and combinations thereof.In a preferred embodiment, the active agent is selected from a chemotherapeutic agent (preferably a proteasome inhibitor, more preferably bortezomib) alone or in combination with an additional active agent (preferably an immunosuppressant, more preferably a glucocorticoid, even more preferably dexamethasone). In one embodiment, the device has multiple layers, at least one layer comprising an active agent. In one embodiment, the device has at least two layers, at least two of the at least two layers comprising an active agent, and the active agents present in the layers are the same or different. For example, the device may have at least two layers, one layer comprising a first active agent (e.g., a chemotherapeutic agent such as a proteasome inhibitor) and one layer comprising a second active agent (e.g., an immunosuppressant such as a glucocorticoid). In one embodiment, the chemotherapeutic agent is selected from a proteasome inhibitor, preferably bortezomib. In one embodiment, the immunosuppressant is selected from a glucocorticoid, preferably dexamethasone. In one embodiment, the terms "active agent," "active ingredient," and "drug" are used interchangeably.In one embodiment, the active agent may be, independently (e.g., independently of its presence in the first, second, and / or third layer (9)), a chemotherapeutic agent such as a proteasome inhibitor (e.g., bortezomib); an immunosuppressant such as a glucocorticoid (e.g., dexamethasone); a calcium channel blocker such as nimodipine; an antithrombotic agent such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; an antibody such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; a radiation modulating agent; The antithrombotic agent may be selected from anti-inflammatory compounds such as ingolimod or NRLP3 inflammasome inhibitors (e.g., MCC50); antihypertensive agents such as angiotensin-converting enzyme inhibitors or beta-blockers; matrix metalloproteinase inhibitors; cytokines such as interleukins; chemokines; Parkinson's disease treatments such as levodopa, dopamine agonists, or monoamine oxidase B inhibitors; Huntington's disease treatments such as tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, amantadine, levetiracetam, or clonazepam; and combinations thereof. In one embodiment, the term "antithrombotic agent" refers to a thrombolytic agent, an antiplatelet agent, and / or an anticoagulant. The angiotensin-converting enzyme inhibitor may be selected from benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril. In one embodiment, the active agent is not an antibiotic such as vancomycin, not aspirin, not vascular endothelial growth factor (VEGF), not fibroblast growth factor beta (b-FGF), not stromal-derived factor-1 alpha, and / or not heparin. In one embodiment, the active agent is not vancomycin and / or aspirin. In one embodiment, the first layer (7) comprises an antithrombotic agent such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin.In one embodiment, the outer layer contains an active agent selected from an antithrombotic agent such as tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; preferably, the inner layer contains an active agent other than the active agent of the outer layer (preferably, an active agent other than an antithrombotic agent). Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, inhibits vasodilation by reducing nitric oxide (NO) production. Fingolimod is known to achieve anti-inflammatory effects when applied directly to the endothelium at sufficient concentrations. In one embodiment, the device is configured to release fingolimod as an active agent into the flowing blood through the channel (6), where it reaches a target tissue downstream of the device and binds to receptors in the target tissue (such as endothelial receptors in capillaries), thereby achieving an anti-inflammatory effect.

[0088] For example, highly advantageous release characteristics can be achieved when the active agent is provided as follows: in one embodiment, the active agent is embedded in the polymer matrix, optionally embedded in a hydrogel present in the polymer matrix, and / or encapsulated in nanoparticles present in the polymer matrix; the active agent is attached to the device (preferably the inner surface of the device), preferably via a linker; and / or the active agent is coated on the inner surface of the device (preferably the surface of the channel (6)). Advantageously, by embedding the active agent in the polymer matrix, the release of the active agent can be fine-tuned. The active agent may be embedded directly in the polymer matrix, for example, by mixing the active agent with a polymer solution for the polymer matrix during device preparation. Alternatively or additionally, the active agent may be embedded in a hydrogel that is part of the polymer matrix and / or interspersed in the polymer matrix. Advantageously, the hydrogel enhances the mechanical properties of the device. Alternatively or additionally, the active agent may be encapsulated in nanoparticles (e.g., nanoparticles present in the polymer matrix (e.g., mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles)). Advantageously, nanoparticles allow for a controlled and fine-tuned release of the active agent. Alternatively or additionally, the active agent may be bound to the device (preferably to the inner surface of the device, in particular to the surface of the channel (6)), for example by a covalent bond. Advantageously, by binding an active agent to the device, even large active agents such as antibodies may be administered using the device of the present invention. Alternatively or additionally, the active agent may be coated on the inner surface of the device (preferably to the surface of the channel (6)), for example in the form of a coating layer, such as the third layer (9). Advantageously, coating the inner surface with the active agent allows for an enhanced release of the active agent into the bloodstream.

[0089] As used herein, the term "configured to release the active agent into the channel (6)" preferably refers to properties that allow the release of the active agent into the channel (6) (particularly, allowing the release of the active agent into fluids such as blood, bile acids, pancreatic juice, and / or cerebrospinal fluid flowing through the channel (6) when the device is placed in a patient's blood vessel). For example, these properties may include any of the following: a suitable composition of the polymer matrix, a suitable density of the polymer matrix, and a suitable layer structure of the device. For example, the density of the inner layer may be lower than the density of the middle or outer layer to facilitate the release of the active agent from the inner layer into the channel (6) (particularly, fluids such as blood, bile acids, pancreatic juice, and / or cerebrospinal fluid flowing through the channel (6)).

[0090] In one embodiment, the device comprises nanofibers (preferably polymeric nanofibers). As used herein, the term "polymeric nanofiber" refers to nanofibers comprising or consisting of one or more polymers. In one embodiment, the nanofibers comprise silicon dioxide and / or titanium oxide. For example, the nanofibers may be polymeric nanofibers comprising silicon dioxide and / or titanium oxide. In one embodiment, the nanofibers comprise or consist of one or more biocompatible polymers as defined herein. In one embodiment, the nanofibers comprise or consist of poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polyurethane, silk fibroin, or a combination thereof, preferably poly(lactic-co-glycolic acid), polycaprolactone, polyurethane, silk fibroin, or a combination thereof, more preferably poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof. In one embodiment, the fibers (1), such as microfibers, comprise or consist of one or more biocompatible polymers as defined herein. In one embodiment, the fibers (1), such as microfibers, comprise or consist of poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polyurethane, silk fibroin, or a combination thereof, preferably poly(lactic-co-glycolic acid), polycaprolactone, polyurethane, silk fibroin, or a combination thereof, more preferably poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof.In one embodiment, the nanofibers are selected from poly(lactic-co-glycolic acid) nanofibers, polycaprolactone nanofibers, poly(lactic acid) nanofibers, poly(lactic acid) nanofibers with titanium dioxide, silica gel nanofibers, and combinations thereof. In one embodiment, the biocompatible polymer matrix comprises or consists of nanofibers and / or microfibers (preferably nanofibers). Advantageously, fibers have reinforcing properties and enhance the mechanical properties of the device. Nanofibers may be fibers with diameters in the nanometer range; typically, 1 nm to 1 μm. In one embodiment, nanofibers have a diameter that is less than 1000 nm. As used herein, the term "fiber" preferably relates to nanofibers and / or microfibers (preferably nanofibers).

[0091] In one embodiment, the fibers (1) are aligned along the longitudinal axis of the device; the fibers (1) are aligned at an angle greater than 0° and less than 180° relative to the longitudinal axis of the device; the fibers (1) are aligned along the circumferential direction of the device; the fibers (1) are aligned along the radial direction of the device; the fibers (1) are oriented as a lattice; and / or the fibers (1) are randomly oriented. Advantageously, the alignment of the fibers (1) can be tailored to provide desired properties (especially mechanical properties) for each vessel in which the device is to be placed. If the device has multiple layers, these layers may have the same or different nanofiber alignments. For example, the fibers (1) in the first layer (7) may be aligned along the longitudinal axis of the device, and the fibers (1) in the second layer (8) may be randomly oriented. For example, the fibers (1) in the first layer (7) may be aligned along the longitudinal axis of the device, and the fibers (1) in the second layer (8) may be aligned along the circumferential direction of the device. The lattice may have any pattern. In one embodiment, the lattice has a substantially hexagonal pattern, a substantially triangular pattern, or a substantially rectangular pattern. For example, the fibers (1) may be prepared using electrospinning and / or melt electrowriting. An advantage of electrospinning and melt electrowriting is that materials (especially polymers) can be precisely shaped into fibers (1), such as nanofibers and / or microfibers. An advantage of spinning is that even heat-labile active agents, such as antibodies, can be processed using spinning, such as electrospinning. An advantage of melt electrowriting is that fibers (1), such as microfibers, can be precisely deposited into a predetermined shape and it is a solvent-free process.For example, when preparing the fiber (1) using spinning, such as electrospinning, the antibody may be directly associated with the fiber (1).

[0092] In one embodiment, the device comprises nanoparticles (preferably mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles). In a preferred embodiment, the nanoparticles comprise the active agent. Advantageously, by incorporating the active agent into nanoparticles (particularly by encapsulating the active agent in nanoparticles), the active agent is stabilized and protected. For example, the active agent may be stabilized and protected by the nanoparticles until the nanoparticles are released into the channel (6). Advantageously, when the active agent is incorporated into nanoparticles, the release profile of the active agent can be efficiently controlled and fine-tuned. In one embodiment, the device comprises nanoparticles comprising bortezomib and / or nanoparticles comprising dexamethasone. For example, the device may comprise mesoporous silica nanoparticles comprising bortezomib. In one embodiment, the mesoporous silica nanoparticles comprise poly(ethylene glycol)-block-poly(d,l-lactide). In a preferred embodiment, the nanoparticles comprise the active agent.

[0093] In one embodiment, the device comprises a hydrogel. Advantageously, the hydrogel enhances the mechanical properties of the device. Advantageously, the hydrogel enhances the active agent release properties of the device. In one embodiment, the hydrogel is configured to release the active agent (preferably into the channel (6)) when the hydrogel comes into contact with a fluid (particularly blood). In one embodiment, the hydrogel is interspersed among fibers (1) of a polymer matrix. For example, the polymer matrix may comprise or consist of fibers (1) (preferably nanofibers and / or microfibers) and a hydrogel. For example, the fibers (1) may be aligned in the form of a lattice, with the hydrogel dispersed in the lattice. In one embodiment, the hydrogel fills any pores present in the polymer matrix, preferably such that the device is pore-free.

[0094] In one embodiment, the hydrogel comprises poly(ethylene glycol), gelatin, poly(2-oxazoline), polyglycidol, silk fibroin, polyurethane, alginate, gelatin methacrylate, collagen, chitosan, hyaluronic acid, heparin, chondroitin sulfate, styrenated gelatin, synthetic extracellular matrix analogs, polyfumaric acid, phosphate esters, PEGylated fibrinogen, poly(vinyl alcohol), poly(propylene fumarate), polypeptides, polyphosphazene, poly(trimethylene carbonate), or any combination thereof. In a preferred embodiment, the hydrogel comprises poly(ethylene glycol), gelatin, alginate, gelatin methacrylate, collagen, or any combination thereof. In one embodiment, the hydrogel is poly(ethylene glycol) hydrogel, poly(2-oxazoline) hydrogel, gelatin hydrogel, polyglycidol hydrogel, silk fibroin hydrogel, and / or polyurethane hydrogel. In one embodiment, the hydrogel comprises or consists of a swellable material such as poly(2-ethyl-2-oxazine). In one embodiment, the hydrogel is a swellable hydrogel.

[0095] The device of the present invention may have multiple layers. For example, the device of the present invention may have multiple layers of polymer matrix. In one embodiment, each layer has a polymer matrix. In one embodiment, the device of the present invention has two or more layers, such as three layers. Advantageously, the active agent can be released in a controlled and sustained manner using the device of the present invention, especially when the device has multiple layers.

[0096] In one embodiment, the device has a first layer (7) and a second layer (8); optionally a third layer (9); preferably, at least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent. In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9).

[0097] In one embodiment, the first layer (7) comprises a first biocompatible polymer (preferably a shape memory polymer) and / or a swellable material; optionally, the first layer (7) comprises fibers (1), nanoparticles, a hydrogel, an active agent, and / or cell adhesion molecules. In one embodiment, the first layer (7) is the outer layer of the device. In one embodiment, the first layer (7) forms the outer surface of the device. In a preferred embodiment, the first layer (7) comprises fibers (1) (preferably nanofibers). Cell adhesion molecules are typically selected from cell surface proteins involved in binding of cells to other cells or the extracellular matrix. Cell adhesion molecules may be selected from integrins, claudins, desmosomes, catechol, fibrin, thrombin, tannic acid, and combinations thereof. In a preferred embodiment, the first layer (7) comprises poly(lactic-co-glycolic acid) and / or polycaprolactone (preferably polycaprolactone). In one embodiment, the first layer (7) has a polymer matrix comprising or consisting of poly(lactic-co-glycolic acid) and / or polycaprolactone (preferably polycaprolactone). In one embodiment, the terms "first layer (7)" and "outer layer" are used interchangeably. In one embodiment, the first layer (7) has fibers (1) (especially nanofibers, preferably fibers (1) comprising polycaprolactone).

[0098] Advantageously, the shape memory polymer and the swellable material enhance the morphological stability of the device. The shape memory polymer may comprise or consist of polycaprolactone, oligo(ε-caprolactone), methyl methacrylate, poly(ethylene glycol) dimethacrylate, polyurethane, poly(D,L-lactide), poly(vinyl alcohol), ethylene vinyl acetate copolymer, and combinations thereof. In one embodiment, the first layer (7) comprises the shape memory polymer and a further biocompatible polymer. In one embodiment, the first layer (7) comprises a swellable material and optionally a biocompatible polymer. In one embodiment, the first layer (7) comprises the shape memory polymer (preferably polycaprolactone) and a swellable material (preferably poly(2-ethyl-2-oxazine)). In one embodiment, the device comprises a swellable material (preferably poly(2-ethyl-2-oxazine)). In one embodiment, the first layer (7), the second layer (8), and / or the third layer (9), if present, comprises a swellable material, preferably poly(2-ethyl-2-oxazine). In one embodiment, the first layer (7) comprises a swellable material, preferably poly(2-ethyl-2-oxazine). In one embodiment, the swellable material is poly(2-ethyl-2-oxazine). In one embodiment, the first layer (7) comprises polycaprolactone and poly(2-ethyl-2-oxazine). A first layer (7) comprising polycaprolactone and optionally poly(2-ethyl-2-oxazine) exhibits advantageous properties both in terms of efficient fabrication of the device and in vivo use. For example, the first layer (7) may be prepared using melt electrowriting. Advantageously, melt electrowriting allows for precise formation of the 3D structure of the layer. Advantageously, the layer comprising poly(2-ethyl-2-oxazine) may swell when implanted in a blood vessel, thereby anchoring the device to the vessel.

[0099] In one embodiment, the second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid), polycaprolactone, poly(glycolic acid), or a combination thereof); optionally, the second layer (8) comprises fibers (1), nanoparticles, a hydrogel, and / or an active agent. The first biocompatible polymer, the second biocompatible polymer, and, if present, the third biocompatible polymer are biocompatible polymers as defined herein. In one embodiment, the second layer (8) comprises nanoparticles comprising the active agent and / or comprises fibers (1), such as nanofibers. In one embodiment, the second layer (8) comprises a second biocompatible polymer (preferably poly(lactic-co-glycolic acid), polycaprolactone, poly(glycolic acid), or a combination thereof); and comprises an active agent, such as an immunosuppressant; optionally, the second layer (8) comprises fibers (1), such as nanofibers, nanoparticles, and / or a hydrogel; preferably, the second layer (8) comprises nanoparticles comprising the active agent. In one embodiment, the second layer (8) is an inner layer of the device if the third layer (9) is not present, or a middle layer of the device if the third layer (9) is present. In a preferred embodiment, the second layer (8) comprises poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof; preferably, poly(glycolic acid). In one embodiment, the second layer (8) has a polymer matrix comprising or consisting of poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof (preferably poly(glycolic acid)). In one embodiment, the device has two layers, preferably each layer having a biocompatible polymer matrix. In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9), and after implantation, the second layer (8) degrades when the third layer (9) has partially or completely degraded (preferably completely).In one embodiment, the device has a first layer (7), a second layer (8), and a third layer (9), wherein the second layer (8) has a first active agent and the third layer (9) has a second active agent; preferably, the second active agent is released into the blood vessel before the first active agent is released into the blood vessel. For example, the third layer (9) may be the inner layer of the device, having the active agent released first, and the second layer (8) is the middle layer of the device, having the active agent released second. Advantageously, this may provide sequential therapy using a single device.

[0100] In one embodiment, the inner layer (particularly the third layer (9) or, if the third layer (9) is not present, the second layer (8)) comprises a biocompatible polymer, preferably selected from poly(lactic-co-glycolic acid), poly(glycolic acid), poly(vinyl alcohol), polyoxalate, polyethylene glycol, poly(2-oxazoline), gelatin, polyglycidol, polyurethane, silk fibroin, silica gel, alginate, and combinations thereof. Advantageously, the inner layer comprising the biocompatible polymer has highly advantageous active agent release characteristics. Preferably, the inner layer comprises an active agent (e.g., an active agent that is released prior to another active agent, such as an active agent present in at least one intermediate or outer layer). In one embodiment, the third layer (9), if present, comprises the active agent and, optionally, a third biocompatible polymer, nanofiber-like fibers (1), nanoparticles, and / or a hydrogel. In one embodiment, the third layer (9) comprises nanoparticles having the active agent. In one embodiment, the third layer (9) comprises a third biocompatible polymer (preferably poly(lactic-co-glycolic acid), polycaprolactone, poly(glycolic acid), or a combination thereof; and comprises an active agent, such as a chemotherapeutic agent; optionally, the third layer (9) comprises fibers (1), such as nanofibers, nanoparticles, and / or a hydrogel; preferably, the third layer (9) comprises nanoparticles having the active agent. In one embodiment, the third layer (9) comprises a coating having the active agent. In one embodiment, the third layer (9) is a coating on the second layer (8), the coating comprising or consisting of an active agent. In one embodiment, when the device has a first layer (7), a second layer (8), and a third layer (9), the terms "third layer (9)" and "inner layer" are used interchangeably. In one embodiment, when the device has a first layer (7) and a second layer (8) but no third layer (9), the terms "second layer (8)" and "inner layer" are used interchangeably.In one embodiment, when the device has a first layer (7), a second layer (8), and a third layer (9), the terms "second layer (8)" and "intermediate layer" are used interchangeably. As used herein, the terms "second layer (8)" and "intermediate layer" shall refer to at least one second layer (8) and at least one intermediate layer. As used herein, the term "second layer (8)" may always include multiple second layers (8), and the term "intermediate layer" may always include multiple intermediate layers. In a preferred embodiment, the third layer (9) comprises poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof; preferably poly(glycolic acid). In one embodiment, the third layer (9) comprises a polymer matrix comprising or consisting of poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof (preferably poly(glycolic acid)). In one embodiment, the device has three layers, preferably each layer having a biocompatible polymer matrix. Advantageously, a device having three layers is highly stable and allows for the controlled and sustained release of one or more active agents.

[0101] In a preferred embodiment, the first layer (7) comprises polycaprolactone; the second layer (8) comprises poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof (preferably poly(glycolic acid)); and the third layer (9) comprises poly(lactic-co-glycolic acid), poly(glycolic acid), or a combination thereof (preferably poly(glycolic acid)). In one embodiment, the first layer (7) and the second layer (8) comprise fibers (1), such as nanofibers, and the third layer (9) comprises nanoparticles; optionally, the first layer (7), the second layer (8), and / or the third layer (9) comprise a hydrogel. In one embodiment, the first layer (7) and the second layer (8) comprise fibers (1), such as nanofibers, and the second layer (8) and the third layer (9) comprise nanoparticles; optionally, the first layer (7), the second layer (8), and / or the third layer (9) comprise a hydrogel. In one embodiment, the first layer (7) comprises fibers (1), such as nanofibers, and the second layer (8) comprises nanoparticles; optionally, the third layer (9) comprises nanoparticles; optionally, the first layer (7), the second layer (8), and / or the third layer (9) comprise a hydrogel. In a preferred embodiment, the nanoparticles comprise the active agent.

[0102] In one embodiment, the device has an outer layer having nanofiber-like fibers (1) and an inner layer having nanoparticles with an active agent. In one embodiment, the device has a first layer (7) having nanofiber-like fibers (1) and a second layer (8) having nanoparticles with an active agent; optionally, the first layer (7) and / or the second layer (8) have a hydrogel. In one embodiment, the device has an outer layer having nanofiber-like fibers (1), at least one middle layer having nanofiber-like fibers (1) and / or nanoparticles, and an inner layer having nanoparticles with an active agent; optionally, the first layer (7), the second layer (8), and / or the third layer (9) have a hydrogel. In one embodiment, the device has an outer layer having nanofiber-like fibers (1), at least one middle layer having nanofiber-like fibers (1), and an inner layer having an active agent; optionally, the first layer (7), the second layer (8), and / or the third layer (9) comprise a hydrogel.

[0103] In one embodiment, the first layer (7) is radially disposed above the second layer (8); preferably, the second layer (8) is disposed above the third layer (9), if present. In one embodiment, the first layer (7) faces the endothelium of the blood vessel. In one embodiment, the second layer (8) and the third layer (9), or the first layer (7) and the second layer (8), comprise poly(lactic-co-glycolic acid), polycaprolactone, poly(glycolic acid), or a combination thereof; optionally, the outer layer has a higher density than the inner layer.

[0104] Advantageously, by using different layers (especially different polymer matrices) that sequentially release different active agents, drugs can be administered in a controlled, sequential manner for hours / days even after removal of the stent retriever-wire-tube system or balloon catheter system with which the device may be applied. Advantageously, two or more drugs may be released sequentially into damaged tissue, such as brain tissue.

[0105] In one embodiment, the density of the third layer (9) is lower than that of the second layer (8). In one embodiment, the density of the third layer (9) is lower than that of the second layer (8) and the first layer (7). As used herein, the term "density" preferably relates to the mass of a substance (particularly the mass of a layer and / or the mass of a polymer matrix) per unit of volume. Density may also refer to the packing density of a polymer in a polymer matrix (e.g., the polymer matrix of a layer). Without wishing to be bound by any theory, the inventors believe that the time period during which a layer dissolves is based on the density of the substrate (particularly the polymer matrix) in each layer. The device preferably dissolves from the inside (e.g., from the second or third layer (9)) to the outside (e.g., to the first layer (7)). Preferably, the density of the polymer matrix is ​​lower inside the device than outside. In one embodiment, the molar mass of the third layer (9) is lower than the molar mass of the second layer (8). In one embodiment, the molar mass of the inner layer is lower than the molar mass of the outer layer.

[0106] Active agents according to the present invention can be characterized by a particular size, a particular charge, and / or specific properties such as lipophilicity, hydrophilicity, or amphiphilicity. Those skilled in the art are familiar with methods for determining the size, charge, and / or lipophilicity, hydrophilicity, or amphiphilicity of an active agent, and properties such as molecular size, charge, and lipophilicity, hydrophilicity, or amphiphilicity can be evaluated in different ways. For example, the molecular weight of an active agent can be easily calculated from the molecular formula of the active agent. Furthermore, those skilled in the art are familiar with the fact that simple atomic number can be used as a rough measure of the molecular size of an active agent. In one embodiment, active agents according to the present invention can be characterized by a larger size relative to other active agents or a smaller size relative to other active agents. In a device according to one embodiment of the present invention having at least two active agents, the first active agent can be characterized by a smaller size relative to the size of the second active agent, or the second active agent can be characterized by a smaller size relative to the size of the first active agent.

[0107] In the device of the present invention having at least three different active agents characterized by three different sizes, (i) the first active agent may be characterized by a small size relative to the size of the second active agent and the third active agent, and the second active agent may be characterized by a small size relative to the third active agent, or (ii) the first active agent may be characterized by a small size relative to the size of the second active agent and a large size relative to the size of the third active agent, and the second active agent may be characterized by a large size relative to the size of the third active agent; or (iii) the first active agent may be characterized by a larger size relative to the size of the second active agent and the third active agent, and the second active agent may be characterized by a larger size relative to the third active agent; or (iv) the first active agent may be characterized by a larger size relative to the size of the second active agent and the third active agent, and the second active agent may be characterized by a smaller size relative to the third active agent; or (v) The first active agent may be characterized by a smaller size relative to the size of the second active agent and the third active agent, and the second active agent may be characterized by a larger size relative to the third active agent.

[0108] In one embodiment, a device according to one embodiment of the present invention has different layers characterized by different types of mesh, such as a tight mesh, a medium mesh, a wide mesh, or any type in between. Importantly, different layers characterized by different types of mesh, such as a tight mesh layer, a medium mesh layer, a wide mesh layer, or any type in between, dissolve at different frequencies. For example, layers characterized by a tight mesh dissolve first, layers characterized by a medium mesh dissolve second, and layers characterized by a wide mesh dissolve last.

[0109] In accordance with the present invention, the terms "layer" and "membrane" may be used interchangeably. In one embodiment, the layers and / or membranes of the device are configured as or in the form of a "filter," such as a "mesh." As used herein, the terms "filter" and "mesh" may be used interchangeably.

[0110] In one embodiment, the device of the present invention has at least two layers, a first layer (7) being a tight mesh layer and a second layer (8) being a wide mesh layer, optionally the device having different active agents, and further optionally the first layer (7) of tight mesh configured to first release into the channels (6) an active agent characterized by a smallest size compared to the other active agents, and the second layer (8) of wide mesh configured to secondly release into the channels (6) an active agent characterized by a larger size compared to the smallest active agent. In one embodiment, the device of the present invention has at least three layers, a first layer (7) being a tight mesh layer, a second layer (8) being a medium mesh layer, and a third layer (9) being a wide mesh layer, and optionally the device has different active agents, and further optionally the first layer (7) of tight mesh is configured to first release into the channel (6) an active agent characterized by a smallest size relative to the other active agents, the second layer (8) of medium mesh is then configured to release into the channel (6) an active agent characterized by a larger size relative to the smallest active agent but smaller than the largest active agent, and the second layer (8) of wide mesh is then configured to release an active agent characterized by a largest size relative to the other active agents. Advantageously, the device of the present invention thereby allows for the sequential release and / or administration of different active agents in a controlled manner.

[0111] In one embodiment, the device of the present invention has a barrier. A "barrier" or "barricade" according to the present invention is any type of physical structure that blocks or impedes something (such as blocking or impeding the release of an active agent). As used herein, the terms "barrier" and "barricade" can be used interchangeably. In one embodiment, the barrier is achieved by encapsulation of the active agent (e.g., nanoencapsulation, microencapsulation, and / or encapsulation in at least one liposome, at least one polymeric nanoparticle (such as by emulsion polymerization, solvent evaporation, or nanoprecipitation), at least one molecular inclusion complex, at least one solid lipid nanoparticle (SLN), and / or at least one nanostructured lipid carrier (NLC)). In one embodiment, the barrier is achieved by coating, such as spray coating, fluidized bed coating, or layer-by-layer assembly. In one embodiment, the barrier is achieved by using different charges and / or magnetization (such as differently charged active agents).

[0112] Advantageously, the devices of the present invention may include barriers and / or barricades, thereby allowing for further fine-tuning of the sequential release and / or administration of different active agents in a controlled manner. In one embodiment, the use of barriers and / or barricades allows for fine-tuning of the release of different active agents. For example, the use of barriers may facilitate the release of an active agent characterized by a larger size relative to other active agents prior to an active agent characterized by a smaller size relative to the other active agents. In one embodiment, the devices of the present invention have at least one barrier that prevents the release of an active agent (such as preventing release of the active agent for a period of time), and optionally, the active agent is characterized by a smaller size relative to the other active agents. In one embodiment, the device of the present invention has at least two barriers, where at least one first barrier prevents the release of a first active agent (so as to prevent the release of the first active agent for a certain period of time) and at least one second barrier prevents the release of a second active agent (so as to prevent the release of the second active agent for a certain period of time). Advantageously, the device of the present invention thereby allows for fine-tuning of the sequential release and / or administration kinetics of different active agents, such as active agents characterized by different sizes. In one embodiment, the active agent in the second layer (8) is different from the active agent in the third layer (9). In one embodiment, the active agent in the second layer (8) is different from the active agent in the first layer (7). In one embodiment, the active agent in the third layer (9) is different from the active agent in the first layer (7). In one embodiment, the active agent in the first layer (7), the active agent in the second layer (8), and the active agent in the third layer (9) are different active agents. For example, one of the layers may comprise a chemotherapeutic agent (preferably a proteasome inhibitor, more preferably bortezomib) and another of the layers may comprise an immunosuppressant (preferably a glucocorticoid, more preferably dexamethasone).Reference to "the layer" refers to the first layer (7), the second layer (8), and / or the third layer (9). The device may have two or more layers (e.g., two, three, four, or more layers). In one embodiment, the device has four layers. Preferably, each of the layers has a polymer matrix. In one embodiment, the device has multiple active agents (e.g., a combination of a chemotherapeutic agent (preferably a proteasome inhibitor, more preferably bortezomib) and an immunosuppressant (preferably a glucocorticoid, more preferably dexamethasone)). In one embodiment, the active agents are a combination of bortezomib and dexamethasone. In one embodiment, the first layer (7) has a first active agent and the second layer (8) has a second active agent. In one embodiment, the first layer (7) comprises a first active agent, the second layer (8) comprises a second active agent, and the third layer (9) comprises a third active agent. In one embodiment, the second layer (8) comprises a first active agent, and the third layer (9) comprises a second active agent. The first active agent, the second active agent, and, if present, the third active agent are independently selected from active agents defined herein. In one embodiment, the first active agent, the second active agent, and, if present, the third active agent are the same or different active agents. In one embodiment, an active agent is coated on the inner surface of the device. In one embodiment, the active agent is on the first layer (7) or the second layer (8) to form the second layer (8) or the third layer (9), respectively. In one embodiment, the device has a first layer (7) and a second layer (8), the first layer (7) having a first active agent and the second layer (8) having a second active agent, the first active agent and the second active agent being different active agents. In one embodiment, the device has an outer surface coated with a cell adhesion molecule (preferably selected from integrins, claudins, desmosomes, catechols, fibrin, thrombin, tannic acid, and any combination thereof).In one embodiment, the device has two or more layers, one layer having bortezomib and PLGA and one layer having dexamethasone and PLGA.

[0113] In one embodiment, the device has a length ranging from about 0.25 mm to about 80 mm, preferably from about 0.5 mm to about 50 mm, more preferably from about 1 mm to about 25 mm, and even more preferably from about 3 mm to about 20 mm. The length of the device is preferably the length from one end (preferably the open end) of the device to the other end (preferably the open end) of the device (particularly the length along the longitudinal axis of the device). As used herein, the terms "length" and "longitudinal extension" may be used interchangeably. In one embodiment, the device has openings, such as cut lines (5), along its length.

[0114] In one embodiment, the device has an outer radius ranging from about 2 μm to about 6 mm, preferably from about 0.5 mm to about 4 mm, more preferably from about 1 mm to about 3.5 mm, and even more preferably from about 1.4 mm to about 3 mm. Preferably, the device is in the form of a hollow cylinder with an outer radius ranging from about 2 μm to about 6 mm. The outer radius is preferably the distance from the axial center of the device (particularly the longitudinal axis of the device) to the outer surface region of the device. For example, the outer radius of a device configured for the middle cerebral artery (particularly the M1 segment of the middle cerebral artery) may be in the range of about 1.4 mm to about 3 mm. In one embodiment, the device is configured to be implanted in the middle cerebral artery (particularly the M1 segment of the middle cerebral artery).

[0115] In one embodiment, the device has an inner radius ranging from about 1 μm to about 5.9 mm, preferably from about 0.4 mm to about 3.9 mm, more preferably from about 0.9 mm to about 3.4 mm, and even more preferably from about 1.3 mm to about 3 mm. Preferably, the device is in the form of a hollow cylinder with an inner radius ranging from about 1 μm to about 5.9 mm. Typically, the inner radius of a ring, tube, or other hollow object is the radius of its cavity. Preferably, the inner radius is the radius of the channel (6) of the device. For example, the inner radius may be the distance from the axial center of the device (e.g., the longitudinal axis of the device) to the inner surface area of ​​the device.

[0116] In one embodiment, the device has a thickness ranging from about 1 μm to about 1 mm, preferably from about 20 μm to about 500 μm, more preferably from about 50 μm to about 250 μm, and even more preferably from about 75 μm to about 150 μm, e.g., 100 μm. The term "thickness" as used herein in the context of a device preferably refers to the difference between the outer and inner radii of the device. For example, the thickness may refer to the thickness of the polymer matrix and / or the thickness of the layers of the device. For example, the thickness may be the combined thickness of the first, second, and, if present, third layers (9) of the device. Having the above-described specific lengths, outer radii, inner radii, and / or thicknesses may provide devices with advantageous mechanical properties, stability, and / or active agent release characteristics. Advantageously, having the above-described specific lengths, outer radii, inner radii, and / or thicknesses may provide devices suitable for a variety of blood vessels.

[0117] In one embodiment, the device has a cut line (5), optionally a cut line (5) along the longitudinal axis of the device. The cut line (5) may be the result of a preparation process, for example, a cut line (5) to facilitate removal of the device from a spinning mandrel. Advantageously, the cut line (5) may facilitate application of the device to the body, for example, when applying the device to a blood vessel using a balloon. A device having a cut line (5) may be easily wrapped around a medical instrument used to apply the device, such as a balloon, needle (2), and / or wire. In one embodiment, the terms "cut line (5)" and "opening" are used interchangeably. Preferably, the cut line (5) is an opening along the length of the device. In one embodiment, the cut line (5) is an opening along the longitudinal axis of the device, preferably the opening has the length of the device.

[0118] In one embodiment, the device comprises a protective cover (preferably a protective covering material); optionally, the protective cover comprises an active agent. In one embodiment, the device is provided in the form of a kit comprising the device and a protective cover (preferably a protective covering material); optionally, the protective cover comprises an active agent. The protective cover preferably covers a surface (particularly an outer surface) of the device. The protective covering material preferably covers the device, particularly a longitudinal extension of the device. In one embodiment, the protective covering (particularly the protective covering material) comprises an active agent. For example, the protective covering (particularly the protective covering material) may be configured to directly administer an active agent when the device is implanted in a blood vessel. The device covered by the protective covering may be administered using a stent retriever system and / or a balloon catheter system; optionally, the protective covering may be removed using a stent retriever system and / or a balloon catheter system immediately after implantation of the device.

[0119] In one embodiment, the device of the present invention comprises at least one contrast agent. In one embodiment, the device of the present invention comprises an inner layer comprising an active agent, optionally at least one intermediate layer comprising an active agent, and an outer layer without an active agent, the outer layer comprising at least one contrast agent. In one embodiment, the device of the present invention comprises at least one contrast agent in its outer layer. In one embodiment, the outer layer is the first layer (7) of the device.

[0120] The contrast agent according to the present invention is a substance used to enhance the contrast of structures or fluids within the body during medical imaging. As used herein, the terms "contrast agent" and "contrast medium" may be used interchangeably. Contrast agents typically absorb or alter external electromagnetic or ultrasonic waves. In X-ray imaging, contrast agents increase the radiodensity of target tissues or structures. In magnetic resonance imaging, contrast agents shorten (or in some cases lengthen) the relaxation time of nuclei within body tissues, thereby altering the contrast in MRI images.

[0121] For X-ray imaging, such as computed tomography (CT), iodine and barium are commonly used as contrast agents. Various iodinated contrast agents exist, differing in osmolality, viscosity, and absolute iodine content. In one embodiment, nonionic dimers are preferred due to their low osmolality and low toxicity. In a preferred embodiment, at least one contrast agent contains iodine.

[0122] For magnetic resonance imaging (MRI), gadolinium, gadolinium-based contrast agents (GBCAs), or derivatives thereof can be used as MRI contrast agents. Like many rare earth metals, gadolinium typically adopts the oxidation state +3, and gadolinium has seven unpaired electrons. These unpaired electrons cause rapid relaxation of water around the gadolinium contrast agent, thereby improving the quality of MRI scans. In a preferred embodiment, at least one contrast agent comprises gadolinium or is a gadolinium-based contrast agent (GBCA).

[0123] For ultrasound examinations (especially echocardiography), microbubbles can be used as contrast agents, which can be useful, for example, in detecting cardiac shunts. Microbubbles according to the present invention consist of agitated saline or trace amounts of nitrogen or perfluorocarbons reinforced and supported by a protein, lipid, or polymer shell. In a preferred embodiment, at least one contrast agent comprises microbubbles.

[0124] In one embodiment, at least one contrast agent is embedded in a polymer matrix, optionally embedded in a hydrogel present in the polymer matrix, and / or encapsulated in nanoparticles present in the polymer matrix. In one embodiment, at least one contrast agent is bound to the device (preferably the outer surface of the device), preferably via a linker. Additionally or alternatively, the at least one contrast agent is coated on the outer surface of the device (preferably the surface of the channel). At least one contrast agent may be embedded directly in the polymer matrix, for example, by mixing the at least one contrast agent with a polymer solution for the polymer matrix during device preparation. Alternatively or additionally, the at least one contrast agent may be part of the polymer matrix and / or embedded in a hydrogel interspersed in the polymer matrix. Alternatively or additionally, the at least one contrast agent may be encapsulated in nanoparticles (e.g., nanoparticles present in the polymer matrix (e.g., mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles)).

[0125] In one embodiment, the device is fabricated by electrowriting a layer, for example, around a rotating target, and then electrospinning fibers (e.g., nanofibers and / or microfibers loaded with at least one contrast agent) around the electrowritten layer. The advantages of melt electrowriting are that fibers, such as microfibers, can be precisely deposited in a predetermined shape and that it is a solvent-free process. For example, at least one contrast agent may be directly associated with the fiber when preparing the fiber using spinning, such as electrospinning.

[0126] In one embodiment, at least one contrast agent is oriented and / or aligned along a grid, preferably along a grid of an outer layer of the device, at least one intermediate layer of the device, an inner layer of the device, or a combination thereof. In one embodiment, the grid has a substantially rectangular pattern, a substantially hexagonal pattern, or a substantially triangular pattern. In one embodiment, the grid has chambers (e.g., rectangular chambers, hexagonal chambers, or triangular chambers). In one embodiment, a device of the invention has at least one contrast agent in at least one of the chambers (such as at least one of the rectangular chambers, at least one of the hexagonal chambers, or at least one of the triangular chambers). In one embodiment, a device of the invention has at least one contrast agent in some (but not all) of the chambers (e.g., some (but not all) of the rectangular chambers, some (but not all) of the hexagonal chambers, or some (but not all) of the triangular chambers). In one embodiment, the chambers having at least one contrast agent are oriented in a spiral, mesh, or clasp pattern along the device (e.g., a spiral, mesh, or clasp pattern along the longitudinal axis of the device).

[0127] In a preferred embodiment, at least one contrast agent is oriented helically along the device (preferably helically along the longitudinal axis of the device). An advantage of orienting at least one contrast agent helically along the device (preferably helically along the longitudinal axis of the device) is the ease of visualization of the endothelial wall and / or blood vessel. Thus, a device having at least one contrast agent oriented helically along the device (preferably helically along the longitudinal axis of the device) allows and / or facilitates visualization of whether the device is correctly positioned after administration (e.g., insertion) into a patient's blood vessel (such as a cerebral blood vessel).

[0128] Preferably, the device of the present invention is configured to be placed in a blood vessel, bile duct, pancreatic duct, biliary pancreatic ampulla, or spinal cord (so as to be placed in the endothelial lumen of the blood vessel), and at least one contrast agent is oriented helically along the device (preferably helically along the longitudinal axis of the device). The at least one contrast agent oriented helically along the device (preferably helically along the longitudinal axis of the device) allows visualization of the endothelial wall, thus providing a method for determining whether the device is correctly placed in the blood vessel (particularly whether it is placed in the endothelial lumen of the blood vessel), because each side of the endothelial lumen of the blood vessel is visualized by at least one contrast agent oriented helically in a similar manner.

[0129] In one embodiment, at least one contrast agent oriented helically along the device (preferably helically along the longitudinal axis of the device) allows for localization and / or visualization of the blood vessel (particularly the lumen surrounded by the endothelium of the blood vessel) in which the device of the present invention is configured to be placed. Advantageously, the contrast agent according to the present invention is used to enhance the contrast of the device placed within the blood vessel (particularly the lumen surrounded by the endothelium of the blood vessel), i.e., to improve the visibility of the device placed within the blood vessel. Alternatively or additionally, the contrast agent according to the present invention is used to enhance the contrast of the blood vessel, i.e., to improve the visibility of the blood vessel. In one embodiment, the outer layer is the first layer (7) of the device.

[0130] In a preferred embodiment, the device of the present invention comprises at least one contrast agent, Optionally, the device has an outer layer, an inner layer, and optionally at least one intermediate layer, and at least one contrast agent in the outer layer, and optionally at least one contrast agent in the at least one intermediate layer, the inner layer, or a combination thereof, and further optionally, the outer layer is a first layer (7), the at least one intermediate layer is a second layer (8), and the inner layer is a third layer (9); Preferably, the at least one contrast agent is oriented helically along the device (preferably helically along the longitudinal axis of the device); Optionally, at least one contrast agent is oriented and / or aligned along a grid, and further optionally, is oriented and / or aligned along a grid in an outer layer of the device, at least one intermediate layer of the device, an inner layer of the device, or a combination thereof.

[0131] Preferably, the device is for use in a method for preventing or treating a neurological disease, a neoplastic disease, a cardiac disease, a vascular disease, an immune disease, a carcinoid, an infectious disease, and / or an edema. In one embodiment, the neurological disease is a brain disease and / or a neurodegenerative disease. In one embodiment, the brain disease is selected from stroke (especially ischemic stroke), subarachnoid hemorrhage, and a basal ganglia disease. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neoplastic disease is a cancer such as a solid cancer or a liquid cancer (e.g., a solid cancer selected from liver cancer, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, brain tumor, and melanoma, or a liquid cancer selected from multiple myeloma and leukemia (preferably multiple myeloma)). The neoplastic disease may also be a carcinoid. In one embodiment, the cardiac disease is a cardiac disease (preferably myocardial infarction). In one embodiment, the vascular disease is an ischemic disease (preferably, peripheral vascular disease). In one embodiment, the carcinoid is a neuroendocrine tumor, such as a slow-growing type of neuroendocrine tumor that arises in cells of the neuroendocrine system. In one embodiment, the immune disease is graft-versus-host disease. In one embodiment, the edema is cerebral edema (preferably edema associated with ischemic stroke). The infection may be any infection, such as cholangitis. For example, the device may be applied to a blood vessel using a stent retriever system and / or a balloon catheter system. In one embodiment, the device is for use in a method of preventing or treating ischemic stroke and / or edema (especially edema associated with ischemic stroke); for example, a device having an immunosuppressant such as bortezomib and / or dexamethasone (e.g., a device having a layer having bortezomib and a layer having dexamethasone). In one embodiment, the device is for use in a method of preventing or treating subarachnoid hemorrhage; for example, a device having a calcium channel blocker (preferably nimodipine).

[0132] The device may be applied to enhance the efficiency of cellular immunotherapy. The device may be applied to enhance the efficiency of CAR-T cell therapy (particularly to enhance cancer treatment). For example, the efficiency of CAR-T cell therapy may be enhanced by influencing the microenvironment and activating CAR-T cells in the region of the tumor; for example, by increasing the release of proinflammatory cytokines and / or chemokines and / or matrix metalloproteinases in blood vessels supplying the tumor. In one embodiment, the increased release of proinflammatory cytokines and / or chemokines and / or matrix metalloproteinases generates and / or creates a gradient of proinflammatory cytokines and / or chemokines and / or matrix metalloproteinases. In one embodiment, increased release of proinflammatory cytokines and / or chemokines and / or matrix metalloproteinases in blood vessels supplying a tumor and / or a gradient of proinflammatory cytokines and / or chemokines and / or matrix metalloproteinases facilitates attraction and / or attraction and / or recruitment of CAR-T cells to the tumor.

[0133] In one embodiment, the term "patient", as used herein, relates to a human or animal (preferably a human).

[0134] As used herein, the terms "of the present invention," "according to the present invention," "according to the present invention," and the like are intended to refer to all aspects and embodiments of the present invention described and / or claimed herein. As used herein, the term "having" should be interpreted as encompassing both "comprising" and "consisting of," and both meanings are specifically intended, thus separately disclosing embodiments according to the present invention. As used herein, "and / or" should be interpreted as specifically disclosing each of the two specified features or components, with or without the other. For example, "A and / or B" should be interpreted as specifically disclosing (i) A, (ii) B, and (iii) A and B, respectively, as if each were listed individually. In the context of the present invention, the terms "about" and "approximately" indicate an interval of precision that a person skilled in the art would understand to still ensure the technical effect of the feature in question. This term typically indicates a deviation of ±20%, ±15%, ±10%, and, for example, ±5% from the indicated numerical value. As will be appreciated by those skilled in the art, the specific deviations in the numerical values ​​for a given technical effect will depend on the nature of the technical effect. For example, natural or biological technical effects may generally have larger deviations than artificial or engineered technical effects. When an indefinite or definite article (e.g., "a," "an," or "the") is used when referring to a singular noun, this includes the plural of that noun unless something else is specifically stated. [Brief explanation of the drawings]

[0135] The invention will now be further described by reference to the following drawings.

[0136] All methods referred to in the following figure descriptions were performed as detailed in the Examples.

[0137] [Figure 1]FIG. 1 shows an exemplary setup for preparing a device of the invention, specifically an electrospinning device for preparing fibers (1) for the polymer matrix of the device. The active agent may be incorporated into the polymer composition used to prepare the fibers (1), or the active agent may be incorporated into the device after preparing the fibers (1) for the polymer matrix. A needle (2) ejects the polymer composition deposited on a rotating mandrel (3) to form nanofibers. The rotating mandrel (3) rotates to align the fibers (1), for example, to form a substantially cylindrical device with circumferentially aligned fibers (1). A voltage (4) is applied. For example, the diameter of the rotating mandrel (3) may be 3.5 mm to obtain a device with an advantageous radius. [Figure 2] Figure 2 shows an exemplary device of the invention having circumferentially aligned fibers (1) and cut lines (5) along the longitudinal axis of the device. For example, as depicted, the polymer matrix of the device may have or consist of fibers (1), such as the circumferentially aligned fibers (1) of the device. The device may have cut lines (5) if convenient for, for example, device manufacturing and / or application of the device to a blood vessel, such as by using a balloon. The device has channels (6) (e.g., internal channels) that allow the flow of fluids, such as blood, bile acids, pancreatic juice, and / or cerebrospinal fluid, through the device. [Figure 3] 3 shows an exemplary device of the present invention having a substantially cylindrical configuration and having a channel (6). The device has a thickness (t), an inner radius (r), an outer radius (R), and a length (l). [Figure 4]4 shows an exemplary device of the present invention having a first layer (7) with circumferentially aligned fibers (1) (i.e., aligned along the circumference of the device) and a second layer (8) with nanoparticles. The nanoparticles may incorporate an active agent. The first layer (7) and / or the second layer (8) may further comprise a hydrogel. The device of the present invention has a circumferential, longitudinal, and radial direction. [Figure 5] 5 shows an exemplary device of the present invention having a first layer (7) with longitudinally aligned fibers (1) (i.e., aligned along the longitudinal axis of the device) and a second layer (8) with nanoparticles and / or longitudinally aligned fibers (1). The nanoparticles may incorporate an active agent. The first layer (7) and / or second layer (8) may further comprise a hydrogel. [Figure 6] Figure 6 shows an exemplary device of the present invention having a first layer (7) with fibers (1) oriented as a lattice, a second layer (8) with nanoparticles, and a third layer (9) with nanoparticles and / or longitudinally aligned fibers. For example, an active agent may be encapsulated by the nanoparticles. The first layer (7), second layer (8), and / or third layer (9) may further comprise a hydrogel. [Figure 7] 7 shows an exemplary device of the present invention having a first layer (7) with randomly oriented fibers (1), a second layer (8) with randomly oriented fibers (1), and a third layer (9) with or consisting of an active agent. For example, an active agent may be incorporated into the second layer (8) and the same or a different active agent may be contained by the third layer (9). For example, the second layer (8) may have a lower density than the first layer (7). [Figure 8A]Figure 8 shows photographs of an exemplary device of the present invention. The device shown in photographs (A, B) has electrospun randomly oriented fibers (1) with a diameter of approximately 2 micrometers and precisely aligned and stacked fused electrolighting fibers (1) with a diameter of 15 micrometers. The inner diameter of the device is 3 mm. The length of the device is 20 mm. [Figure 8B] Figure 8 shows photographs of an exemplary device of the present invention. The device shown in photographs (A, B) has electrospun randomly oriented fibers (1) with a diameter of approximately 2 micrometers and precisely aligned and stacked fused electrolighting fibers (1) with a diameter of 15 micrometers. The inner diameter of the device is 3 mm. The length of the device is 20 mm. [Figure 9] FIG. 9 is a photograph showing an exemplary device of the present invention having an opening along the longitudinal axis of the device. [Figure 10] FIG. 10 is a photograph showing an exemplary device of the present invention with fibers (1) oriented as a grating. [Figure 11] FIG. 11 is a photograph showing an exemplary device of the present invention with fibers (1) oriented as a grating and with an opening along the longitudinal axis of the device. [Figure 12A] FIG. 12 is a photograph (A, B) showing an exemplary device of the present invention. [Figure 12B] FIG. 12 is a photograph (A, B) showing an exemplary device of the present invention. [Figure 13] FIG. 13 shows a device according to one embodiment of the invention loaded with two active agents embedded in a hydrogel (one active agent shown in light gray and the other active agent shown in dark gray). [Figure 14]Figure 14 shows that a device according to one embodiment of the invention filled with hydrogel and dye releases the hydrogel / dye through the intima but not through the adventitia (a) at time 1, b) at time 2, and c) at time 3). The arrows at the bottom of Figure 14c) indicate the direction of hydrogel / dye release through the intima for a device according to this embodiment of the invention. [Figure 15] 15 shows a device according to one embodiment of the invention that was filled with dye, implanted in a pig heart, and imaged using computed tomography (CT) at (a) time 1, b) time 2, c) time 3, d) time 4, e) time 5, and f) time 6. The white arrows depict the front points of dye released through the intima into the lumen in the coronary artery. [Figure 16A] Figure 16 illustrates the use of an exemplary device of the present invention for the treatment of inflammatory diseases. A illustrates the location of the bile duct, pancreatic duct, and biliary pancreatic ampulla in a human. B illustrates inflammation caused by enteric bacteria, which may be accompanied by swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. C illustrates enteric bacteria ascending into the biliary pancreatic ampulla, bile duct, and pancreatic duct during inflammation. D illustrates a device according to one embodiment of the present invention, which is configured to be inserted into the biliary pancreatic ampulla and locally release at least one active agent into the lumen of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. [Figure 16B] Figure 16 illustrates the use of an exemplary device of the present invention for the treatment of inflammatory diseases. A illustrates the location of the bile duct, pancreatic duct, and biliary pancreatic ampulla in a human. B illustrates inflammation caused by enteric bacteria, which may be accompanied by swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. C illustrates enteric bacteria ascending into the biliary pancreatic ampulla, bile duct, and pancreatic duct during inflammation. D illustrates a device according to one embodiment of the present invention, which is configured to be inserted into the biliary pancreatic ampulla and locally release at least one active agent into the lumen of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. [Figure 16C]Figure 16 illustrates the use of an exemplary device of the present invention for the treatment of inflammatory diseases. A illustrates the location of the bile duct, pancreatic duct, and biliary pancreatic ampulla in a human. B illustrates inflammation caused by enteric bacteria, which may be accompanied by swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. C illustrates enteric bacteria ascending into the biliary pancreatic ampulla, bile duct, and pancreatic duct during inflammation. D illustrates a device according to one embodiment of the present invention, which is configured to be inserted into the biliary pancreatic ampulla and locally release at least one active agent into the lumen of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. [Figure 16D] Figure 16 illustrates the use of an exemplary device of the present invention for the treatment of inflammatory diseases. A illustrates the location of the bile duct, pancreatic duct, and biliary pancreatic ampulla in a human. B illustrates inflammation caused by enteric bacteria, which may be accompanied by swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. C illustrates enteric bacteria ascending into the biliary pancreatic ampulla, bile duct, and pancreatic duct during inflammation. D illustrates a device according to one embodiment of the present invention, which is configured to be inserted into the biliary pancreatic ampulla and locally release at least one active agent into the lumen of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct.

[0138] Reference will now be made to the following examples, which are given by way of illustration and not by way of limitation of the invention. [Example]

[0139] Example 1: Device Preparation A polymer such as poly(lactic-co-glycolic acid) (PLGA) or poly(caprolactone) (PCL) and an active agent (especially bortezomib) are dissolved in an organic solvent such as 1,1,1,3,3,3-hexafluoro-2-propanol or chloroform, or in an aqueous solvent. For example, a PLGA polymer with a lactide:glycolide ratio of 50:50 is used. The resulting solution of the polymer and active agent is electrospun into nanotubes or printed into hollow cylindrical shapes using a 3D printer.

[0140] Example 2: Device Preparation Step 1: Poly(lactic-co-glycolic acid) (PLGA) polymer and the active agent, bortezomib, are dissolved in an organic solvent such as 1,1,1,3,3,3-hexafluoro-2-propanol or chloroform. Other organic solvents are also suitable. For example, PLGA polymer with a 50:50 lactide:glycolide ratio is used. Other ratios are also suitable. The resulting polymer and active agent solution is electrospun into nanofibers, which collect around a rotating target until they form thin, hollow tubes. Step 2: Following step 1, a polymer such as PLGA and the active agent, dexamethasone, are dissolved in an organic solvent such as 1,1,1,3,3,3-hexafluoro-2-propanol or chloroform. As noted above, other organic solvents are also suitable for any of the polymers used. The resulting polymer and active agent solution is electrospun into nanofibers and collected around the thin, hollow tubes spun around the rotating target in step 1. The target continues to rotate during steps 1 and 2. After step 2, the electrospun nanotubes have two walls. Step 3: Another layer can be printed around the two layers spun around the rotating target, for example by melt electrowriting. This outer layer provides additional stability and elasticity. It consists of polycaprolactone (PCL) combined with hydrophilic poly(2-ethyl-2-oxazine) (PEtOzi). By using the melt electrowriting technique, the shape of the outer layer can be precisely determined. Step 4: The exemplary three-layer device can then be cut into a mesh pattern, for example, by a laser or microkeratome. Alternatively, the three-layer device can be cut into a spiral pattern, for example, by a laser or microkeratome.

[0141] Example 3: Device Preparation Step 1: A thin polycaprolactone (PCL) layer is 3D printed on top of a rotating target by fusion electrowriting. Step 2: A polymer matrix with 3D structures ("walls", e.g., 36 μm) with PCL, perpendicular to the longitudinal axis of the rotating target, is printed on top of the first layer (7) by melt electrowriting, leaving air gaps in between. Step 3: Another thin layer of PCL is printed on top of the polymer matrix (particularly the 3D structures (e.g., walls)). Step 4: A liquid having plasma, pro-inflammatory cytokines, and CAR-T cells is optionally injected into the void.

[0142] Example 4: Device Preparation Step 1: A polymer such as PLGA and an active agent, a matrix metalloproteinase inhibitor, are dissolved in a solvent. Step 2: The resulting solution of PLGA and MMP inhibitor is subsequently electrospun into nanofibers, which collect around a rotating target until they form a thin, hollow tube. Step 3: A thin polycaprolactone (PCL) layer is 3D printed on the same rotating target by fusion electrowriting. Step 4: 3D structures ("walls") with PCL, perpendicular to the longitudinal axis of the rotating target, are printed layer by layer by fusion electrowriting, leaving air gaps in between. Step 5: Another thin layer of PCL is printed on top of the polymer matrix (particularly the 3D structures (e.g., walls)). Step 6: A fluid containing plasma, pro-inflammatory cytokines, a nutrient solution, and optionally CAR-T cells is injected into the void.

[0143] Example 5: Analysis of prepared devices Nanofiber Analysis The microstructure of the device is examined by microscopy, such as scanning electron microscopy, optical coherence tomography, or fluorescence microscopy. The average fiber diameter is determined by measuring approximately 20 to 60 randomly selected fibers from a microscopy image (e.g., a fluorescence image or SEM micrograph). Mechanical characterization The devices are analyzed for their mechanical properties in accordance with the standard ISO / DIN 7198 "Cardiovascular Implants - Tubular Vascular Prostheses". Advantageously, the devices of the present invention are elastically deformable in the radial direction, allowing the device to adapt to blood flow and vessels.

[0144] Example 6: Preparation of various exemplary devices Device preparation (example 1) A polymer, such as poly(lactic-co-glycolic acid) PLGA or poly(caprolactone) PCL, and an active agent (especially bortezomib) are dissolved in an organic solvent, such as HFIP or chloroform. PLGA with a 50:50 lactide:glycolide ratio can be used, although other ratios can also be applied. The resulting polymer and active agent solution is electrospun and collected on a cylindrical collector (which can rotate and translate) to prepare a hollow, cylindrical solution electrospun layer. Device preparation (Example 2) Step 1: A polymer such as poly(caprolactone) PCL and an active agent (especially bortezomib) are dissolved in an organic solvent such as HFIP or chloroform. The resulting polymer and active agent solution is electrospun and collected on a rotating cylindrical collector to prepare a hollow, cylindrical solution electrospun layer. Step 2: Around the solution-electrospun layer spun around the rotating target, another layer can be prepared from PCL using melt electrowriting. The deposition pattern of this layer can be used to influence the mechanical properties of the device. The size and thickness of this layer can be precisely adjusted during the printing process. This layer can be filled with a hydrogel containing an active agent. Prototype based on Example 2: Figures 8-12 show images of the prototype of Example 2. The structure consists of electrospun randomly oriented fibers (1) with a diameter of approximately 2 micrometers and precisely aligned and stacked fused electrolighting fibers (1) with a diameter of 15 micrometers. The inner diameter of the tube is 3 mm. The length of the produced tube is 20 mm. The size can be adjusted by cutting with a scalpel. Both layers are made of PCL, and the structure was cut with a scalpel. Solution electrospinning was used to produce the inner layer. Medical-grade PCL was dissolved in HFIP and transferred to a blunt-tipped syringe. A high voltage of 12 kV (4) was applied to the tip. The distance from the collector to the spinneret was 12 cm. The material was extruded at 0.5 ml / h. A cylindrical collector with a diameter of 3 mm was used to collect the fibers (1). The collector rotated at 120 rpm. After electrospinning, the mandrel was transferred to a molten electrowriting device. The deposition of precisely oriented molten electrowriting fibers (1) was achieved via computer-controlled movement of the collector and by combining rotation and translation. Medical-grade PCL was placed in a heated reservoir and heated to 89°C to melt the material and process it. It was extruded from the reservoir at 0.7 bar, and a high voltage of 4.5 kV (4) was applied to the tip of the collector. After processing, the tubular structure was manually removed from the collector and trimmed with a scalpel. A cut along a cutting line (5) parallel to the tube's major axis was made with the scalpel. Device preparation (Example 3) Step 1: A polymer, such as poly(lactic-co-glycolic acid) PLGA or poly(caprolactone) PCL, and an active agent (especially bortezomib) are dissolved in an organic solvent, such as HFIP or chloroform. PLGA with a 50:50 lactide:glycolide ratio can be used, although different ratios can also be applied. The resulting polymer and active agent solution is electrospun and collected on a cylindrical collector (which can rotate and translate) to prepare a hollow, cylindrical solution electrospun layer. Step 2: A second layer (8) of material is electrospun onto the layer prepared in step 1. This second layer (8) can have different or the same active agent content and different PLGA with varying lactide to glycolide ratios. In this step, co-spinning of PLGA and PCL can be used to create a gradient transition from PLGA to PCL. The PCL content can increase and / or decrease toward the outside of the layer produced in step 2. Step 3: Around the two layers spun around the rotating target, another layer can be prepared from PCL using molten electrowriting. The deposition pattern of this layer can be used to influence the mechanical properties of the device. The size and thickness of this layer can be precisely adjusted during the printing process. This layer can be filled with a hydrogel containing an active agent. Step 4: Another layer of electrospun fibers (1) covers the previous layer. Step 5: The exemplary four-layer device can then be cross-cut, for example by a laser or with a blade. Device preparation (Example 4) Step 1: A thin layer of polymer, such as poly(caprolactone) PCL, is dissolved in an organic solvent, such as HFIP or chloroform. The resulting polymer solution is electrospun and collected onto a cylindrical collector (which can rotate and translate) to prepare a hollow, cylindrical solution electrospun layer. This layer allows diffusion of the active ingredient but is impermeable to silica particles. Step 2: Another polymer layer can be prepared from PCL on top of the first one using fusion electrowriting. The deposition pattern of this layer can be used to influence the mechanical properties of the device. The size and thickness of this layer can be precisely adjusted during the printing process. This layer is filled with a hydrogel containing an active agent. Alternatively, it can be filled with hydrogel and drug-loaded and drug-releasing silica particles. Step 3: A thin layer of polymer, such as poly(caprolactone) PCL, is dissolved in an organic solvent, such as HFIP or chloroform. The resulting polymer solution is electrospun and collected onto a cylindrical collector (which is rotating and capable of translating) to prepare a hollow, cylindrical solution electrospun layer. Step 4: The exemplary layered device may then be cut into a cross-section, for example by a laser or with a blade. Device preparation (Example 5) Step 1: A thin layer of polymer, such as poly(caprolactone) PCL, is dissolved in an organic solvent, such as HFIP or chloroform. The resulting polymer solution is electrospun and collected onto a cylindrical collector (which can rotate and translate) to prepare a hollow, cylindrical solution electrospun layer. This layer allows diffusion of the active ingredient but is impermeable to silica particles. Step 2: Another polymer layer can be prepared from PCL on top of the first one using fusion electrowriting. The deposition pattern of this layer can be used to influence the mechanical properties of the device. The size and thickness of this layer can be precisely adjusted during the printing process. This layer is filled with a hydrogel containing an active agent. Alternatively, it can be filled with hydrogel and drug-loaded and drug-releasing silica particles. Step 3: A thin layer of polymer, such as poly(caprolactone) PCL, is dissolved in an organic solvent, such as HFIP or chloroform. The resulting polymer solution is electrospun and collected onto a cylindrical collector (which is rotating and capable of translating) to prepare a hollow, cylindrical solution electrospun layer. Step 4: The exemplary layered device may then be cut into a cross-section, for example by a laser or with a blade. Analysis of the prepared device (Example 6) Analysis of electrospun fibers: The layers of the device are examined by microscopes such as scanning electron microscopes, optical coherence microscopes, fluorescence microscopes, and confocal microscopes. Based on the images, the layer thicknesses and fiber diameters are analyzed. Sixty randomly selected fibers (1) are analyzed, and the diameters are quantified by automated software analysis (e.g., imageJ scripts). Analysis of Fused Electrolighting Fiber: The microstructure of the device layers is examined by microscopes such as scanning electron microscopes, optical coherence microscopes, fluorescence microscopes, and confocal microscopes. Based on the images, the layer thickness and fiber diameter are analyzed. 20 randomly selected fibers (1) are analyzed, and the diameter is quantified by automated software analysis (e.g., ImageJ script). The quality of the deposition pattern is quantified based on images taken from the layers in terms of the uniformity of the fiber deposition. Mechanical Characterization: The devices are analyzed for their mechanical properties. Longitudinal and circumferential tests are performed under static and cyclic conditions. Additionally, analyses according to the standard ISO / DIN 7198 "Cardiovascular Implants - Tubular Vascular Prostheses" can be performed. Biocompatibility testing: The biocompatibility of materials and combined devices is analyzed through direct and indirect methods, and standardized protocols and test methods are used. Drug release analysis (Example 7) Part 1: Analysis of the release of materials set out for testing to determine the diffusivity of different layers The layers are tested for their permeability or diffusivity for test substances of defined molecular weights. Commercially available fluorescein isothiocyanate dextran (FITC-dextran) of various molecular weights can be used as a fluorescent label to quantify permeability or diffusivity. Part 2: Analysis of the release of test active agents to determine the diffusivity of the different layers The layers are tested for their permeability or diffusivity for the active ingredient. Permeability and release are analyzed using UV / Vis spectroscopy, high performance liquid chromatography mass spectrometry. Part 3: Analysis of drug release in vitro In vitro drug release is analyzed under cell culture conditions using UV / Vis spectroscopy, high performance liquid chromatography mass spectrometry, and the effect of the released active agent is analyzed in indirect cytocompatibility assays and using cell culture methods using markers and gene expression.

[0145] Example 7: In vitro drug release analysis The in vitro release of the active agent from the device is characterized using a suitable method such as high performance liquid chromatography or UV spectrophotometry. Figure 13 shows a device according to one embodiment of the invention filled with two different active agents embedded in a hydrogel (one active agent is shown in light gray and the other active agent is shown in black). The inner membrane of the device according to this embodiment of the invention is semipermeable to both active agents, while the outer membrane is impermeable to the active agents. In one embodiment, the inner membrane is prepared using solution electrospinning and / or the outer membrane is prepared using solution electrospinning. In one embodiment, the wall between the chambers with the hydrogel / active agents is prepared layer-by-layer by melt electrowriting.

[0146] Example 8: Analysis of drug release in vivo The in vivo drug release characteristics are tested by implanting the device into a blood vessel, such as the middle cerebral artery or a vessel of a corresponding size, in an animal such as a mouse, rabbit, or rat, using, for example, a stent retriever system and / or a balloon catheter system.

[0147] Example 9: Analysis of devices implanted in pig hearts FIG. 15 shows a dye-filled device (i.e., a dye-releasing device) according to one embodiment of the present invention implanted in a pig heart. Using a dye as an active agent, or in place of an active agent, can demonstrate that the dye used as an active agent or in place of an active agent is released into the channel (6). FIG. 15 shows that the dye from the dye-releasing device according to the present invention was released through the intima into the lumen and reached the capillary system of the target tissue via blood flow from upstream of the device through the lumen of the device to downstream of the device. The white arrow in FIG. 15 depicts the front point of the dye released through the intima into the lumen in the coronary artery. Importantly, the device according to one embodiment of the present invention (according to FIG. 15 ) remained at the implantation site even after the pig heart was washed multiple times with sodium chloride solution. Furthermore, even when the diameter of the coronary vessel into which the device according to one embodiment of the present invention was implanted changed, the device according to one embodiment of the present invention remained at the implantation site and did not collapse along with the collapsed vessel. Instead, the device according to one embodiment of the present invention remained open even when the vessel collapsed. After the vessel diameter had subsequently expanded again, the device according to one embodiment of the present invention remained stable in place.

[0148] Example 10: A device configured to be implanted in the biliary pancreatic ampulla, bile duct, and / or pancreatic duct 16 illustrates the use of an exemplary device of the present invention for the treatment of infections such as cholangitis (e.g., recurrent cholangitis). For example, intestinal bacteria ascending into the biliary ampulla, bile duct, and pancreatic duct can cause inflammation, which may be accompanied by swelling of the biliary ampulla, bile duct, and / or pancreatic duct. As shown in FIG. 16D , a device according to one embodiment of the present invention is configured to be inserted into the biliary duct, pancreatic duct, or biliary pancreatic ampulla and to locally release at least one active agent (such as an antibiotic and / or glucocorticoid) into the lumen of the biliary duct, pancreatic duct, and / or biliary pancreatic ampulla, where the at least one active agent has a local effect on the bacteria, thereby preventing bacteria from entering the biliary ampulla, bile duct, and / or pancreatic duct from the intestine and / or reducing swelling of the biliary pancreatic ampulla, bile duct, and / or pancreatic duct. It is an advantage of the device according to this aspect of the invention that when using the device (e.g., for the treatment of cholangitis (e.g., recurrent cholangitis)), no or very little active agent, such as an antibiotic, enters the stomach or the portion of the intestine above the papilla of Vater, and the natural intestinal microflora is not affected by treatment with at least one active agent. In contrast, active agents applied orally or systemically (e.g., for the treatment of cholangitis (e.g., recurrent cholangitis)) have the side effect of damaging the entire intestinal microflora.

[0149] The features of the invention disclosed in the specification, the claims and / or the accompanying drawings may, both alone or in any combination thereof, be important for realizing the invention in diverse forms thereof. [Explanation of symbols]

[0150] Reference sign Fiber (1) Needle (2) Rotating mandrel (3) Voltage (4) Cutting line (5) Channel (6) First layer (7) Second layer (8) Third layer (9)

Claims

1. 1. An intravascular drug delivery device, preferably an intravascular drug delivery implant, comprising: the device has a substantially cylindrical configuration; The device has a channel (6), preferably an internal channel; preferably the channel (6) is configured to allow blood flow through the device; the device is elastically deformable, preferably in a direction substantially perpendicular to a longitudinal axis of the device; The device has a biocompatible polymer matrix comprising a biocompatible polymer; and the device has an active agent; Preferably, the device is biodegradable; Preferably, the device is configured to release the active agent into the channel (6). The device.

2. the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), polycaprolactam, elastin, fibrillin, fibrillin, poly(1-acrylonitrile), poly(vinyl alcohol), polygluconate, polyglycolide, dextran, type I collagen, type II collagen, type IV collagen, elastin, silk fibroin, polymandelide, poly(trimethylene carbonate), polydioxanone, poly(4-hydroxybutyrate), poly(butylene succinate), polyphosphazene, polyanhydride, polyphosphoester, polyoxalate, silica gel, alginate, polyethylene glycol, poly(2-oxazoline), gelatin, polyglycidol, polyurethane, and combinations thereof; Preferably, the biocompatible polymer is selected from poly(lactic-co-glycolic acid), poly(lactic acid), polycaprolactone, poly(glycolic acid), poly(glycerol sebacate), and combinations thereof; More preferably, the biocompatible polymer is poly(lactic-co-glycolic acid), polycaprolactone, or a combination thereof. The device of claim 1 .

3. said device comprising fibers (1), preferably nanofibers and / or microfibers such as polymer nanofibers; optionally said fibers (1), preferably polymer nanofibers, comprise silicon dioxide and / or titanium oxide; Preferably, the device comprises nanofibers, preferably selected from poly(lactic-co-glycolic acid) nanofibers, polycaprolactone nanofibers, poly(lactic acid) nanofibers, poly(lactic acid) nanofibers with titanium oxide, silica gel nanofibers, and combinations thereof; 3. A device according to claim 1 or 2.

4. 4. The device of claim 3, wherein the fibers (1) are aligned along the longitudinal axis of the device; the fibers (1) are aligned at an angle ranging from greater than 0° to less than 180° relative to the longitudinal axis of the device; the fibers (1) are aligned along the circumferential direction of the device; the fibers (1) are aligned along the radial direction of the device; the fibers (1) are oriented as a grating; and / or the fibers (1) are randomly oriented.

5. 10. The device according to any one of the preceding claims, wherein the device comprises nanoparticles, preferably mesoporous silica nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, and / or inulin nanoparticles.

6. the device comprises a hydrogel; Optionally, the hydrogel is configured to release the active agent when the hydrogel comes into contact with a fluid, in particular blood, preferably to release the active agent into the channel (6). A device according to any one of the preceding claims.

7. the device having a first layer (7) and a second layer (8); and optionally a third layer (9); The first layer (7) comprises a first biocompatible polymer, preferably a shape memory polymer; optionally, the first layer (7) comprises nanofibers, nanoparticles, hydrogels, active agents, and / or cell adhesion molecules; The second layer (8) comprises a second biocompatible polymer, preferably poly(lactic-co-glycolic acid) or polycaprolactone; optionally, the second layer (8) comprises nanofibers, nanoparticles, hydrogels, and / or active agents; said third layer (9), if present, comprising an active agent and, optionally, a third biocompatible polymer, nanofibers, nanoparticles, and / or hydrogel; At least one of the first layer (7), the second layer (8), and, if present, the third layer (9) comprises the active agent; A device according to any one of the preceding claims.

8. The device has a first layer (7), a second layer (8), and a third layer (9); said first layer (7) comprising a first biocompatible polymer, preferably a shape memory polymer; The second layer (8) comprises a second biocompatible polymer, preferably poly(lactic-co-glycolic acid) or polycaprolactone, and an active agent, such as an immunosuppressant; optionally, the second layer (8) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the second layer (8) comprises nanoparticles comprising the active agent; The third layer (9) comprises a third biocompatible polymer, preferably poly(lactic-co-glycolic acid) or polycaprolactone, and an active agent, such as a chemotherapeutic agent; optionally, the third layer (9) comprises nanofibers, nanoparticles, and / or a hydrogel; preferably, the third layer (9) comprises nanoparticles comprising the active agent; Optionally, the density of said third layer (9) is lower than the density of said second layer (8); Optionally, the active agent in the second layer (8) is different from the active agent in the third layer (9). A device according to any one of the preceding claims.

9. 10. A device according to any one of the preceding claims, wherein the cylindrical form is a hollow cylindrical form and / or an open cylindrical form.

10. the device comprising: having a length ranging from about 0.25 mm to about 80 mm, preferably from about 0.5 mm to about 50 mm, more preferably from about 1 mm to about 25 mm, and even more preferably from about 3 mm to about 20 mm; an outer radius ranging from about 2 μm to about 6 mm, preferably from about 0.5 mm to about 4 mm, more preferably from about 1 mm to about 3.5 mm, and even more preferably from about 1.4 mm to about 3 mm; and / or an inner radius ranging from about 1 μm to about 5.9 mm, preferably from about 0.4 mm to about 3.9 mm, more preferably from about 0.9 mm to about 3.4 mm, and even more preferably from about 1.3 mm to about 3 mm; having a thickness in the range of about 1 μm to about 1 mm, preferably in the range of about 20 μm to about 500 μm, more preferably in the range of about 50 μm to about 250 μm, and even more preferably in the range of about 75 μm to about 150 μm, for example about 100 μm; A device according to any one of the preceding claims.

11. 10. A device according to any one of the preceding claims, wherein the device has a cutting line (5), optionally along the longitudinal axis of the device (5).

12. the device is biodegradable, preferably bioabsorbable; Optionally, the device is biodegradable, preferably bioabsorbable, at a temperature ranging from about 34° C. to about 43° C. A device according to any one of the preceding claims.

13. 10. A device according to any one of the preceding claims, wherein the active agent is embedded in the polymer matrix, optionally embedded in a hydrogel present in the polymer matrix and / or encapsulated in nanoparticles present in the polymer matrix; the active agent is bound to the device, preferably to the inner surface of the device, preferably via a linker; and / or the active agent is coated on the inner surface of the device, preferably the surface of the channel (6).

14. The active agent may be a chemotherapeutic agent such as a proteasome inhibitor, e.g., bortezomib, or an anthracycline, e.g., doxorubicin; an immunosuppressant, e.g., a glucocorticoid, e.g., dexamethasone; a calcium channel blocker, e.g., nimodipine; an antithrombotic agent, e.g., tissue plasminogen activator, acetylsalicylic acid, phenprocoumon, dabigatran, apixaban, edoxaban, or heparin; an antibody, e.g., an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; a radiomodulatory agent; fingolimod or NRLP3 inhibitor. antihypertensive agents such as angiotensin-converting enzyme inhibitors or beta-blockers; matrix metalloproteinase inhibitors; cytokines such as interleukins; chemokines; drugs for treating Parkinson's disease such as levodopa, dopamine agonists, or monoamine oxidase B inhibitors; drugs for treating Huntington's disease such as tetrabenazine, deutetrabenazine, haloperidol, fluphenazine, amantadine, levetiracetam, or clonazepam; and combinations thereof; Preferably, the active agent is selected from a chemotherapeutic agent, such as a proteasome inhibitor, e.g., bortezomib; an immunosuppressant, such as a glucocorticoid, e.g., dexamethasone; a calcium channel blocker, such as nimodipine; an antibody, such as an anti-ICAM-1 antibody, an anti-MCH2 antibody, or an anti-VEGF antibody; and combinations thereof; optionally, the active agent is selected from bortezomib, dexamethasone, nimodipine, an anti-ICAM-1 antibody, and combinations thereof; More preferably, said active agent is selected from chemotherapeutic agents, preferably proteasome inhibitors, such as bortezomib. A device according to any one of the preceding claims.

15. the device having at least one contrast agent; Optionally, the device has an outer layer, an inner layer, and optionally at least one intermediate layer, and the at least one contrast agent is in the outer layer, optionally in the at least one intermediate layer, the inner layer, or a combination thereof; Further optionally, said outer layer is said first layer (7), said at least one intermediate layer is said second layer (8), and said inner layer is said third layer (9); Preferably, at least one contrast agent is oriented helically along the device, preferably helically along the longitudinal axis of the device; Optionally, the at least one contrast agent is oriented and / or aligned along a grid, and further optionally, is oriented and / or aligned along a grid of the outer layer of the device. A device according to any one of the preceding claims.

16. 10. A device according to any one of the preceding claims for use in a method for the prevention or treatment of neurological diseases, neoplastic diseases, cardiac diseases, vascular diseases, immune diseases, carcinoids, infectious diseases and / or edema; Preferably, said neurological disease is a brain disease and / or a neurodegenerative disease, preferably said brain disease is selected from stroke, especially ischemic stroke, subarachnoid hemorrhage, and basal ganglia disease, preferably said neurodegenerative disease is Parkinson's disease; Preferably, said neoplastic disease is cancer, preferably a solid cancer, more preferably a solid cancer selected from liver cancer, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, brain cancer, and melanoma; Preferably, said cardiac disease is cardiac disease, preferably myocardial infarction; Preferably, said vascular disease is an ischemic disease, preferably a peripheral vascular disease; Preferably, the immune disease is graft-versus-host disease; Preferably, the edema is cerebral edema. The device.

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