Embolization with transient materials

Abstract

To use a biodegradable embolic material to provide for embolizing a hypervascular vessel formed in response to chronic inflammation in a musculoskeletal vasculature or a vessel related to production of ghrelin.SOLUTION: The embolic material is biodegradable within a predetermined period of time. Medical systems are configured for delivery of embolic material for embolizing the hypervascular vessel or the vessel related to production of ghrelin.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to co-pending U.S. Provisional Patent Application No. 62 / 846,464, filed May 10, 2019 by Sawhney et al., entitled "Embolization with Transient Materials," which is incorporated herein by reference.

[0002] The technical field is embolization materials and methods for treating hypervascularity, particularly in response to chronic inflammation. [Background technology]

[0003] Osteoarthritis (OA) is a common degenerative joint disease. Osteoarthritis is characterized by pain and is generally recognized as an inflammatory disease of synovial joints. Angiogenesis may be the cause of chronic inflammation and contributes to further inflammation that may lead to joint pain and further destruction. Non-Patent Document 1. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Okuno et al., J Vasc Interv Radiol(2017)28:995-1002 Summary of the Invention [Means for solving the problem]

[0005] Disclosed herein are materials and methods for embolization of angiogenesis or other blood vessels or lumens with a transient material. These materials and methods include the use of an embolization that is completely biodegradable over a period ranging from 15 minutes to 48 hours. Because the material biodegrades, blood flow returns to normal vasculature without the need for further intervention. The transient nature of the embolization contrasts with permanent embolization, non-permanent embolization of uncontrolled duration, or materials that may biodegrade over an extended period of time.

[0006] In a first aspect, the present invention relates to the use of an embolic material to embolize hypervascular blood vessels that form in response to chronic inflammation of the musculoskeletal vasculature, comprising advancing a catheter through the vascular system to a parent artery and releasing an embolic material from a distal end of the catheter into the hypervascular blood vessel, whereby the embolic material blocks blood flow in the hypervascular blood vessel. The embolic material may be biodegradable within a predetermined period of time.

[0007] In a further aspect, the present invention relates to the use of an embolic material to embolize a blood vessel associated with ghrelin production, the method comprising advancing a catheter through the vascular system to a parent artery; and releasing the embolic material from the distal end of the catheter into the blood vessel associated with ghrelin production, the embolic material blocking blood flow within the blood vessel. The embolic material is biodegradable within a predetermined period of time.

[0008] In another aspect, the invention relates to a medical system configured for use in embolizing musculoskeletal vasculature or hypervascular blood vessels formed in response to chronic inflammation of blood vessels associated with ghrelin production, the medical system including a catheter and a delivery component including a reservoir of embolic material configured to be delivered via the catheter.

[0009] In another aspect, the present invention relates to a medical system for the treatment of hypervascular vessels formed in response to chronic inflammation of the musculoskeletal vasculature or vessels associated with ghrelin production, the medical system comprising a catheter and a delivery component. The catheter may be adapted for delivery through a patient's vasculature to reach the hypervascular vessels or vessels associated with ghrelin production. The delivery component may include a reservoir of embolic material and a delivery device configured to deliver the embolic material via the catheter.

[0010] The drawings contained in this application are incorporated in and constitute a part of this specification. These drawings illustrate embodiments of the present disclosure and, together with the description, serve to explain the principles of the disclosure. The drawings are merely illustrative of particular embodiments and are not intended to limit the disclosure. [Brief description of the drawings]

[0011] [Figure 1] FIG. 1 illustrates a catheter system suitable for delivery of embolic material to practice the methods of the present invention. [Figure 2A] FIG. 2A shows a guidewire placed in a branch artery. [Figure 2B] FIG. 2B shows a catheter shaft introduced over a guidewire placed in the branch artery shown in FIG. 2A. [Figure 2C] FIG. 2C shows the release of embolic beads from a catheter shaft positioned as shown in FIG. 2B. [Figure 2D] FIG. 2D shows the release of embolic beads from the catheter shaft and bridging of the beads across the branch arteries. [Figure 2E] FIG. 2E shows an embolization in a branch artery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Disclosed herein are materials and methods for embolization of the vascular system where the embolic effect is transient, including embolization to treat hypervascularity in response to chronic inflammation.

[0013] Hypervascular tissue is characterized by a vascular network that begins as branches from a normal-looking artery. The branches give rise to further branches and / or fine blood vessels. The fine blood vessels are visualized as "whitening" on an angiogram using radiopaque compounds for visualization in a manner conventional in these arteries. Without being bound to a particular theory, it is believed that removal of the fine blood vessels is typically adequate for treating pain associated with hypervascularity, and that it is not necessary to place an embolization in the largest branch vessels. Thus, the procedure can be directed to embolize the fine branch vessels but avoid embolization of the larger branch vessels. As a result, undesirable side effects resulting from targeting the larger branch vessels can be avoided. As part of this theory, because a rapidly degrading substance is used to embolize the fine vasculature, there is little or no recanalization, i.e., the effect of the embolization is permanent. The same rapidly degrading substance can also temporarily embolize larger blood vessels without compromising the effectiveness of the procedure or causing adverse side effects resulting from procedures that target the larger blood vessels. Additionally, biodegradable materials can be used such that only a biocompatible residue remains, a term used herein to mean a residue of the embolic material that is a soluble component that can be removed locally by dissolution in the blood and eventually systemically over time by excretory mechanisms.

[0014] Potential adverse events with embolization of a size that targets larger blood vessels include accidental embolization of distant blood vessels, which can result in undesirable effects ranging from minimal to catastrophic. When methods for embolizing larger blood vessels are used in the context of treating hypervascularity in response to chronic inflammation, adverse side effects such as skin necrosis / color change, peripheral paresthesia / numbness, and one or more of muscle weakness, blunting, and pain have been observed. These undesirable adverse side effects can be reduced or eliminated using certain embodiments of the invention described herein.

[0015] One embodiment of the present invention is an embolization technique that includes emboli that biodegrade within a specific time period and / or that are within a specific size range. Biodegradation can be characterized by in vitro or in vivo methods. Particles are useful embolic materials. Microspheres have several advantages in mechanical and fluid flow properties.

[0016] The technique for delivering emboli uses a catheter system 8. FIG. 1 shows a catheter 10 having a hub assembly 12 and a shaft 14. The hub assembly 12 has a midsection 16, a strain relief member 18, and a hub 20 with hub wings 22 and a proximal hub connector 24. The shaft 14 has a distal exit tip 26. The strain relief member 18 provides a transition from the flexible shaft 14 to the hub 20. The midsection 16 is optional and can be provided as an additional strain relief member on the shaft 14 and / or as part of the shaft 14 having a larger inner diameter (ID) and / or outer diameter (OD). With reference to FIG. 1, the catheter system 8 also includes an emboli delivery component having an emboli reservoir 13, and a delivery device 15, such as a syringe or pump, a flow tube or the like 17, and a common connector 19, such as a luer fitting, for attachment to the proximal hub connector 24. 1, the delivery device 15 is a syringe with a plunger 21, a barrel 23, and a connector 25 for attaching the flow tube 17. Those skilled in the art are familiar with these components and their operation, as well as their introduction and use in conjunction with guidewires, hemostatic introducers, and other components for catheter procedures.

[0017] Embolization can be performed by placing a guidewire at the desired location, such as in FIG. 2A, which shows an artery 28 having a branching artery 30 with a guidewire 32 placed in the branching vessel 30. With reference to FIGS. 2B-2E, a catheter shaft 14 is introduced over the guidewire 32 and positioned in the target vasculature, such as the branching artery 30. An embolus-forming material, such as embolization beads 34, is injected through the lumen of the shaft 14. The beads 34 form an embolus 36 that spans the arterial branch 30 and blocks blood flow, and the catheter shaft 14 is withdrawn.

[0018] Others have reported that embolization of the geniculate artery and / or neovessels descending from it is useful in alleviating knee pain in mild and / or early stage osteoarthritic joints. It is theorized that hypervascularity of the knee joint increases the access of inflammatory cells and drugs to the joint. Okuno et al. (2017) reported the results of an experiment using embolization of neovessels in the geniculate artery with 75 μm polymethylmethacrylate microspheres coated with polyzene-F (EMBOZENE) or imipenem / cilastatin sodium (IPM / CS; PRIMAXIN; Merck, Whitehouse Station, New Jersey) in iodine contrast medium (HEXABRIX; Terumo, Tokyo, Japan). IPM / CS is reported to be a crystalline compound that is slightly soluble in water and forms particles with embolic effects when suspended in contrast medium. The terms "permanent" or "non-biodegradable" in these contexts mean that the embolic materials, when used to embolize a patient, will remain as a discernible mass at the site where they are placed as an embolus for at least five years. In fact, such materials will usually outlast the lifespan of the patient.

[0019] Permanent embolization has several drawbacks, such as necrosis and being permanent and irreversible. IPM / CS is not a permanent embolic material. However, the size and shape of the particles formed by IPM / CS are unclear and not well controlled. In addition, IPM / CS particles are considered to be rigid and non-expandable, and may result in inconsistent blood flow blockage, as the particles are not necessarily optimized to pack together to prevent fluid channeling through the embolus. Furthermore, IPM / CS is unnecessarily bioactive, as it is primarily an antibiotic, and the effect of antibiotics is not required in embolizing the geniculate artery. Also, the delivery of small amounts of antibiotics is undesirable, as it promotes the development of microbial resistance.

[0020] Additionally, unwanted embolization at non-target sites can be problematic. Permanent embolic material can have permanent effects. Furthermore, in some situations, there can be backflow and embolic material can backflow into the main artery proximal to the distal tip of the delivery catheter, thus carrying the embolic material into unknown non-target vasculature. As a result, some blood vessels that supply the skin can be embolized, causing adverse effects such as numbness and discoloration.

[0021] One embodiment of the present invention is a method of temporarily blocking blood flow in musculoskeletal vasculature that exhibits hypervascularity in response to chronic inflammation, the method comprising the steps of advancing a catheter through the vasculature to a parent artery; releasing an embolic material from a distal end of the catheter into the hypervascular blood vessel, such that the embolic material blocks blood flow to the hypervascular, inflamed vasculature. The embolic material is biodegradable within the vasculature or is biodegradable within a time period ranging from 15 minutes to 48 hours as measured by in vitro tests relevant to physiological conditions.

[0022] Sheth et al. J. Funct. Biomater. 2017,8,12 provides an investigation of intravascular embolization by transcatheter delivery of particles. The authors observed that each category of embolic agent enjoys several niche clinical scenarios, characterized by their respective advantages and disadvantages, for which they are ideally suited. They report that PVA particles adhere to the vessel wall, slowing blood flow and causing thrombosis, and inducing an inflammatory response characterized by vascular necrosis of the vessel wall. Although PVA is not biodegradable, recanalization of vessels embolized with PVA can occur as a result of neovascularization within the thrombus. Gelling sponge is another material that has been used as a transcatheter embolic agent; it is biodegradable but induces thrombosis and causes a necrotizing arteritis response. The authors report that commercially available microspheres were generally composed of PVA, triacrylic gelatin, polyzene-F coated polymethylmethacrylate microspheres, and QUADRASPHERE superabsorbent copolymer. Importantly, they report that microspheres of different formulations, even within the same size range, will have different adhesive and coagulation behavior and embolize blood vessels at different levels of the vascular tree.

[0023] In contrast to such microspheres, useful embolizing materials are starch microspheres, as described, for example, in U.S. Pat. No. 4,124,705, or amylomer, the generic name (INN name) for certain degradable starch spheres. Amylomer is a synthetic microsphere formulation with arterial occlusion properties. Amylomer is a product produced by partial hydrolysis of starch and epichlorohydrin, and contains degradable starch microspheres with a diameter size of 45 micrometers that are easily degraded by amylase. When used in transcatheter arterial chemoembolization (TACE) procedures, injection causes the microspheres to lodge in the precapillary blood vessels, resulting in occlusion of the hepatic artery.

[0024] One embodiment of starch microspheres is EMBOCEPT S DSM 35 / 50 (Pharmacept), a short-term embolus composed of degradable starch microspheres with an average diameter of 50 micrometers. The microspheres are enzymatically degraded by serum α-amylase in the blood, resulting in a half-life of approximately 35-50 minutes both in vivo and in vitro. The reticulocyte system removes the starch fragments. With degradable starch microspheres, partial resumption of blood flow is observed after approximately 10-15 minutes. Schicho et al., Oncotarget (2017) 8:72613-72620.

[0025] Starches that can be used include polysaccharides built up from glucose units (as such or in the form of a physiologically acceptable derivative) incorporated in a crosslinked form within the particle, which polysaccharides can be degraded by d-amylase into water-soluble fragments, i.e. the polysaccharides will contain (1-4) glucosidic bonds hydrolyzable by α-amylase. Examples of such polysaccharides include mainly starch and glycogen or their dextrins. The starch may be amylose or amylopectin or a mixture thereof. Other glucose-containing polysaccharides that can be hydrolyzed by α-amylase can also be used, in this context, said polysaccharides may be synthetic or may be obtained from biological materials, for example microorganisms. Starch may have a number of repeating glucose subunits (n) ranging from 300 to 1,000,000; the skilled artisan will immediately understand that all ranges and values ​​between the explicitly stated boundaries are contemplated.

[0026] The amylose or other starch in the embolic particle or microsphere is preferably cross-linked by covalent bonds. The cross-linking of starch can be carried out using epichlorohydrin or other cross-linking agents. The method for cross-linking starch can include the use of cross-linking agents, such as glutaraldehyde, epichlorohydrin, diacrylate, triacrylate, n-acrylate, cross-linking agents with two or more functional groups to bind to the functional groups on starch or amylose. The amount of cross-linking can be used to control the time of biodegradation, and the more cross-linking, the longer the time required for biodegradation.

[0027] One embodiment of the diameter of the starch microspheres is 20 to 300 microns; one of ordinary skill in the art will immediately understand that all ranges and values ​​between the explicitly stated boundaries are contemplated, e.g., all spheres are 20 to 100 or less than 100 microns in diameter, have an average or median diameter of 20 to 100 microns, or have endpoints and / or portions of the range selected as 20 microns, 30 microns, 40 microns, 50 microns, 60 microns, 70 microns, 80 microns, 90 microns, 100 microns, 110 microns, 120 microns, 150 microns, 190 microns, 200 microns, 250 microns, 290 microns, or 300 microns.

[0028] Unless otherwise stated, the diameter of a particle or microsphere is in MMD. Particles can be characterized in terms of certain properties, such as: D 50 : Mass Median Diameter (MMD). Mass median diameter of a log-normal distribution. MMD is considered as the mass mean particle size.

[0029] Embolic materials such as starch beads are non-bioactive, deformable, spherical for delivery through small catheters and in situ packing, and can be delivered through catheters, e.g., 2.1F-3F catheters. Starch beads are easily suspended in aqueous media, reducing settling during delivery. Starch beads are biodegradable such that only a biocompatible residue remains.

[0030] Other embolization particles can be configured and used to provide a transient embolization. One embodiment includes biodegradable particles of polymeric origin. The term biodegradable refers to the degradation of a material by in vivo causes, whether enzymatic, cellular, or hydrolytic. Hydrolysis (also referred to herein as hydrolytic) can be a subcategory of biodegradable and refers to the degradation of bonds of a polymer or other material by water, e.g., cleavage of ester bonds. Particles can be formed so that upon hydration in physiological solutions, a material is formed that is hydrolytic, measurable by the loss of its mechanical strength, and ultimately disappears in vitro in excess water by hydrolysis of hydrolytic groups. This test predicts degradation by hydrolysis in vivo, a process that contrasts with degradation by cells or proteases. Exemplary hydrolytic biodegradable bonds include polymers, copolymers, and oligomers of glycolide, dl-lactide, 1-lactide, dioxanone, esters, carbonates, and trimethylene carbonate. Exemplary biodegradable linkages include peptide bonds cleavable by metalloproteinases and collagenases. Examples of biodegradable linkages include polymers and copolymers of poly(hydroxy acids), poly(orthocarbonates), poly(anhydrides), poly(lactones), poly(amino acids), poly(carbonates), and poly(phosphonates). Furthermore, biodegradable materials can be used such that only a biocompatible residue remains.

[0031] The embolic particles or spheres may be formed from polymers. Examples of polymers are polymers of natural and / or certain synthetic materials. Natural materials are materials found in nature, including polymers found in nature and their derivatives. Natural polymers include glycosaminoglycans, such as dermatan sulfate, hyaluronic acid, chondroitin sulfate, chitin, heparin, keratan sulfate, keratosulfate, and their derivatives. Generally, glycosaminoglycans are extracted from natural sources, purified, and derivatized. This modification can be achieved by various well-known techniques, such as by combining or replacing ionizable or hydrogen-bondable functional groups, such as carboxyl and / or hydroxyl or amine groups, with other more hydrophobic groups. For example, the carboxyl groups of hyaluronic acid can be esterified with alcohol to reduce the solubility of hyaluronic acid. Such processes are used by various manufacturers of hyaluronic acid products to produce hyaluronic acid-based sheets, fibers, and fabrics that form hydrogels.Other natural polysaccharides, such as carboxymethylcellulose or oxidized regenerated cellulose, natural gum, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, arbinogalactan, pectin, amylopectin, gelatin, hydrophilic colloids, such as carboxymethylcellulose gum or alginate gum.

[0032] Naturally occurring substances include proteins and peptides. Peptide is a term used herein to refer to a chain of 10 or fewer amino acids. One of skill in the art will immediately understand that all ranges and values ​​within these explicit ranges are included, e.g., 1-10, 2-9, 3-10, 1, 2, 3, 4, 5, 6, or 7. Some amino acids have nucleophilic groups (e.g., primary amines or thiols) or groups that can be derivatized as needed to incorporate nucleophilic or electrophilic groups (e.g., carboxyl or hydroxyl). Synthetically produced polyamino acid polymers are typically considered synthetic if they are engineered to be non-identical to naturally occurring biomolecules that do not occur in nature.

[0033] The advantage of natural substances is that they tend to be available from cost-effective sources and have known biological properties. The disadvantage of such substances is that they may be allergenic or immunogenic. Thus, particles can be formed that are free or essentially free of amino acids, peptides, proteins, natural substances, or any combination thereof. Alternatively, the particles may be free or essentially free of allergenic and / or immunogenic substances (both natural and synthetic). Essentially, in this context, this means that there is not enough natural substance present, e.g., 1-10% or less, that it is of concern as an allergen / immunogen and would cause discomfort to the patient; one of skill in the art will immediately understand that all ranges and values ​​between the explicitly stated boundaries are contemplated, and any of 1 percent, 2 percent, 3 percent, 4 percent, 5 percent, 6 percent, 7 percent, 8 percent, 9 percent, or 10 percent can be utilized as upper or lower limits.

[0034] Area of ​​embolization There are various musculoskeletal vasculatures that show hypervascularity in response to chronic inflammation. Transient embolization is an option for them. These musculoskeletal regions include the knee (Example 3, for arthritis), rotator cuff (Example 4, for tendinopathy), elbow (Example 5, for lateral epicondylitis), foot (Example 6, for heel pain), shoulder (Example 7, for frozen shoulder), and knee (Example 8, for patellar tendinopathy). Also, certain regions around the stomach can be embolized for the control of ghrelin production, as in Example 12.

[0035] Co-delivery of therapeutic agents The embolization component can further be co-delivered with a therapeutic agent present in the liquid vehicle used to deliver the component and / or in the component itself, e.g., the embolization bead. The therapeutic agent can be added to treat embolization syndrome, a transient effect felt by the patient undergoing embolization, with symptoms including pain and discomfort. This effect is known from uterine artery embolization and embolization of other tumor types. Agents for co-delivery to treat embolization syndrome include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and anti-inflammatory drugs. EXAMPLES

[0036] Example 1: Demonstration of recanalization of normal vasculature 6-24 hours after embolization with degradable starch microspheres Starch beads EMBOCEPT S (Pharmacept, Berlin) with a diameter of 20-100 μm are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast agent solution (Bayer Healthcare, 300 mgI / mL). The suspension is stirred before administration to obtain a homogenous suspension. The femoral artery of New Zealand White rabbits is surgically accessed and a 4F introducer sheath is inserted. A 2.1F single-lumen microcatheter is used to enter the kidney via the renal artery. The distal part of the cranial lateral aspect of the kidney is embolized by instillation of starch beads and contrast agent, visualized under X-ray. Complete embolization is achieved, which is confirmed by performing an angiogram immediately after delivery of the bead suspension. After 6 hours, the controlled degradation of the starch beads is complete, allowing recanalization of the vessels. Blood flow is restored, which is confirmed by performing an angiogram 6 hours after the initial delivery of the starch beads.

[0037] Example 2: Demonstration of permanent occlusion of normal vasculature following embolization with permanent or semi-permanent microbeads EMBOZENE microbeads (Boston Scientific Corporation, Minneapolis) with a diameter of 40 μm are prepared by diluting 7 mL of the substance and carrier solution (2 mL of microbeads per 7 mL total volume) with ULTRA VIST 300 contrast agent solution (300 mgI / mL) to a final bead concentration of 0.18 mL / mL. The suspension is stirred before administration to ensure a homogenous suspension. The femoral artery of New Zealand White rabbits is surgically accessed and a 4F introducer sheath is inserted. A 2.1F single-lumen microcatheter is then used to enter the kidney via the renal artery. The distal portion of the cranial aspect of the kidney is embolized by instillation of EMBOZENE microbeads and contrast agent under visualization under X-ray. Complete embolization is confirmed by angiogram. After 3 months, the animals can be sacrificed and necrosis of the embolized portion of the kidney (cranial aspect) can be observed. Due to the permanent nature of the non-degradable EMBOZENE microbeads, blood vessels do not recanalize and healthy tissue necrosis occurs.

[0038] OMNISPHERE microbeads with a size of 100 μm in diameter can be prepared by diluting 7 mL equivalent of substance and carrier solution (2 mL microbeads per 7 mL total volume) with ULTRA VIST 300 contrast agent solution (300 mgI / mL) to a final bead concentration of 0.18 mL / mL. The suspension is stirred before administration to obtain a homogenous suspension. The femoral artery of a New Zealand White rabbit is surgically accessed and a 4F introducer sheath is inserted. A 1.7F single-lumen microcatheter is then used to enter the kidney via the renal artery. The distal portion of the cranial aspect of the kidney is embolized by instillation of OMNISPHERE microbeads and contrast agent under visualization under X-ray. Complete embolization is confirmed by angiogram. After 6 hours, complete and continuous occlusion is confirmed by angiogram. The semi-permanent microbeads are completely degraded in 3 months. At 3 months, the animals can be sacrificed and necrosis of the embolized portion of the kidney (cranial aspect) can be observed. Due to the semi-permanent nature of OMNISPHERE microbeads, blood vessels do not recanalize and healthy tissue necrosis occurs.

[0039] Example 3: Demonstration of permanent occlusion of the abnormal inflammatory vasculature present in knee osteoarthritis following transient geniculate artery embolization (GAE) using degradable starch microspheres Starch beads, 20-100 μm in diameter, are diluted to a final bead concentration of 30 mg / mL using Ultravist 300 contrast solution (300 mgI / mL). This suspension can be stirred prior to administration to ensure a uniform suspension. An abnormal inflammatory vasculature bed that would diagnose the patient with knee osteoarthritis is visualized by angiogram and appears as a blanching of the vessels in the main geniculate artery. This area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization of the abnormal vessels is confirmed by angiogram using contrast. After a known resolution period of 3 hours, the inflammatory vasculature remains occluded and complete embolization of this area is maintained as confirmed by angiogram. This treatment reduces or eliminates abnormal neovascularization, reduces local tenderness, and reduces arterial flow in the target lesion. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as Lipiodol or non-degradable microspheres, which are unpredictable.

[0040] Example 4: Demonstration of permanent occlusion of abnormal disorganized hypervascularity present in rotator cuff tendinopathy following transient transcatheter arterial embolization (TAE) using degradable starch microspheres Starch beads, 20-100 μm in diameter, are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). The suspension is stirred prior to administration to ensure a homogenous suspension. Abnormal hypervascularity around the shoulder is confirmed by angiogram. The area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. After a known degradation period of 3 hours, blood flow does not recover and complete embolization of the area is maintained, as confirmed by angiogram. This treatment reduces arterial flow to the hypervascular area and prevents further tissue degeneration. In addition, changes from baseline are observed in various clinical parameters, including visual analog scale pain scales, and reduction or elimination of conventional treatments such as painkillers or corticosteroid injections. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as lipiodol or non-degradable microspheres, which are unpredictable. Adverse events that may occur with permanent emboli, such as skin necrosis / color change, peripheral paresthesia / numbness, and muscle weakness / dull pain, may not occur with transient emboli.

[0041] Example 5: Demonstration of permanent occlusion of the abnormal inflammatory vasculature present in lateral epicondylitis following transient transcatheter arterial embolization (TAE) using degradable starch microspheres Starch beads, 20-100 μm in diameter, are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). The suspension is stirred prior to administration to ensure a homogenous suspension. The abnormal inflammatory vasculature bed present in lateral epicondylitis is visualized by angiogram and appears as blanching of the main arterial vessels. The area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. After a known degradation period of 3 hours, blood flow does not return and complete embolization of the area is maintained as confirmed by angiogram. This treatment reduces or eliminates abnormal neovascularization, reduces local tenderness, and reduces arterial flow in the target lesion. In addition, changes from baseline are observed in various clinical parameters including visual analog scale pain scale, patient-rated tennis elbow assessment score, and pain-free grip strength. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as lipiodol or non-degradable microspheres, which are unpredictable. Adverse events that may occur with permanent embolization, such as skin necrosis / color change, peripheral paresthesia / numbness, and muscle weakness / dull pain, may not occur with transient embolization.

[0042] Example 6: Demonstration of permanent occlusion of abnormal inflammatory vasculature present in heel pain following transient transcatheter arterial embolization (TAE) using degradable starch microspheres Starch beads with a diameter of 20-100 μm can be diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). This suspension can be stirred prior to administration to ensure a homogenous suspension. The abnormal inflammatory vasculature bed present in the heel pain is visualized by angiogram and appears as a blanch of the vessels of the main posterior tibial artery. This area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. After a known degradation period of 3 hours, blood flow does not return and complete embolization of the area is maintained as confirmed by angiogram. This treatment reduces or eliminates abnormal neovascularization, reduces local tenderness, and reduces arterial flow in the target lesion. In addition, this treatment may also improve ambulation. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as lipiodol or non-degradable microspheres, which are unpredictable. Adverse events that may occur with permanent emboli, such as skin necrosis / color change, peripheral paresthesia / numbness, and muscle weakness / dull pain, may not occur with transient emboli.

[0043] Example 7: Demonstration of permanent occlusion of abnormal inflammatory vasculature present in adhesive capsulitis following transient transcatheter arterial embolization (TAE) using degradable starch microspheres Starch beads, 20-100 μm in diameter, are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). The suspension is stirred prior to administration to ensure a homogenous suspension. The abnormal inflamed vasculature bed present in adhesive capsulitis is visualized by angiogram and appears as a blanching of the main arterial vessel at the rotator cuff interval. This area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. After a known degradation period of 3 hours, blood flow does not return and complete embolization of the area is maintained as confirmed by angiogram. This treatment reduces or eliminates abnormal neovascularization, reduces local tenderness, and reduces arterial flow in the target lesion. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as lipiodol or non-degradable microspheres, which are unpredictable. Adverse events that may occur with permanent emboli, such as skin necrosis / color change, peripheral paresthesia / numbness, and muscle weakness / dull pain, may not occur with transient emboli.

[0044] Example 8: Demonstration of permanent occlusion of the abnormal inflammatory vasculature present in patellar tendonopathy following transient transcatheter arterial embolization (TAE) using degradable starch microspheres Starch beads, 20-100 μm in diameter, are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). The suspension is stirred prior to administration to ensure a homogenous suspension. The abnormal inflammatory vasculature bed associated with tendinopathy is visualized by angiogram and appears as blanching of the vessels of the main geniculate artery. This area is selectively accessed using a 2.1 F single-lumen microcatheter on a 0.014 inch guidewire. Starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. After a known degradation period of 3 hours, blood flow does not return and complete embolization of the area is maintained as confirmed by angiogram. This treatment reduces or eliminates abnormal neovascularization, reduces local tenderness, and reduces arterial flow in the target lesion. This approach is unique because the degradation period of starch beads is predictable, unlike other emboli such as lipiodol or non-degradable microspheres, which are unpredictable. Adverse events that may occur with permanent emboli, such as skin necrosis / color change, peripheral paresthesia / numbness, and muscle weakness / dull pain, may not occur with transient emboli.

[0045] Example 9: Enzymatic degradation of starch beads using saliva biofluid EMBOCEPT S starch beads are degraded by enzymatic degradation with amylase, an enzyme found primarily in saliva and pancreatic juice. This enzyme converts starch and glycogen into monosaccharides. 10 mL of a 60 mg / mL stock solution of EMBOCEPT S starch beads is added to a 20 mL scintillation vial. At t=0 hours, a sample of salivary biofluid is added to the vial, at which point a stopwatch is started. Over time, enzymatic degradation of the starch beads is visualized as the suspension becomes a homogenous solution with no visible particles. Complete degradation is confirmed by weighing the dry filter paper before and after filtering the solution.

[0046] Example 10: Co-delivery of lidocaine with degradable starch beads 2 mL of 60 mg / mL starch beads, 20-100 μm in diameter, are diluted to a concentration of 30 mg / mL using 2 mL of a 2% solution of lidocaine. The suspension is then further diluted using ULTRA VIST 300 contrast agent solution (300 mgI / mL) to a final bead concentration of 15 mg / mL. This suspension is stirred before administration to ensure a homogenous suspension. The patient's abnormal inflamed vasculature bed is visualized by angiogram, appearing as vascular blanching of the major arterial vessels. This area is selectively accessed using a 2.1 F single-lumen microcatheter over a 0.014 inch guidewire. The starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. Lidocaine provides an anesthetic effect to suppress some of the transient pain associated with vascular closure during embolization (post-embolization syndrome). After a known resolution period of 3 hours, there is no recanalization of the inflamed vasculature and blood flow to the fine inflamed vasculature is blocked, but the feeding arteries remain patent, which can be confirmed by an angiogram.

[0047] Example 11: Co-delivery of dexamethasone sodium phosphate with degradable starch beads Two mL of 60 mg / mL starch beads, 20-100 μm in diameter, are diluted to a concentration of 30 mg / mL using 2 mL of a 1% solution of dexamethasone sodium phosphate. The suspension can then be further diluted using ULTRA VIST 300 contrast agent solution (300 mgI / mL) to a final bead concentration of 15 mg / mL. This suspension can be stirred prior to administration to ensure a homogenous suspension. The patient's abnormal inflamed vasculature bed is visualized by angiogram and appears as vascular blanch of the major arterial vessels. This area is selectively accessed using a 2.1 F single-lumen microcatheter over a 0.014 inch guidewire. The starch beads are delivered to the target and embolization is confirmed by angiogram using contrast. Dexamethasone provides an anti-inflammatory effect to help treat and prevent inflammation associated with the condition as well as vascular closure during embolization (post-embolization syndrome). After a known resolution period of 3 hours, there is no recanalization of the inflamed vasculature and blood flow to the fine inflamed vasculature is blocked, but the feeding arteries remain patent, which can be confirmed by angiogram.

[0048] Example 12: Conjugate delivery technology of starch beads and EMBOZENE beads in obese conditions Conjugate delivery of permanent and temporary embolization is performed as follows: EMBOZENE embolic beads (>100 μm) are introduced using a 2.8 F catheter system that is delivered to target the larger normal vasculature that nourishes the fundus of the stomach, responsible for the production of ghrelin, for permanent embolization. After embolization, the larger less selective catheter system is removed. For follow-up of the transient embolization, starch beads with a diameter of 20-100 μm are diluted to a final bead concentration of 30 mg / mL using ULTRA VIST 300 contrast solution (300 mgI / mL). This suspension is stirred prior to administration to ensure a homogenous suspension. The interventional radiologist (IR) uses a selective 2.1 F microcatheter to access the desired site of the gastric artery that nourishes the fundus of the stomach. Starch beads are delivered to embolize the finer vasculature and effectively stop blood flow to this fine vasculature. The starch beads degrade in a predictable and controlled manner by design, and then the abnormal vasculature cannot recanalize, resulting in blockage of blood flow. This can be confirmed by angiograms. This would be an effective way to provide combined temporary and permanent embolization or conjugate treatment to the fundus region of the stomach as an interventional approach to treat obesity.

[0049] The above embodiments are intended to be illustrative and not limiting. Additional embodiments are within the scope of the claims. In addition, although the present invention has been described with reference to specific embodiments, those skilled in the art will recognize that changes in form and detail may be made without departing from the spirit and scope of the present invention. Any incorporation by reference of the above documents is limited to not incorporating subject matter contrary to the explicit disclosure of the present specification. To the extent that a particular structure, composition, and / or process is described herein with components, elements, ingredients, or other categories, the disclosure herein should be understood to include specific embodiments, embodiments that include the particular components, elements, ingredients, other categories, or combinations thereof, as well as embodiments that consist essentially of such particular components, ingredients, ingredients, other categories, or combinations thereof, which may include additional features that do not change the fundamental nature of the subject matter, as suggested in the discussion, unless otherwise stated. The use of the word "about" herein refers to the measurement error and / or reporting precision that would be understood by one of ordinary skill in the art in the context of the particular parameters, unless otherwise stated.

Claims

1. 1. Use of an embolic agent to embolize hypervascular blood vessels formed in response to chronic inflammation of the musculoskeletal vasculature, comprising: advancing the catheter through the vascular system to a parent artery; and releasing the embolic material from the distal end of the catheter into a hypervascular blood vessel, such that the embolic material blocks blood flow in the hypervascular blood vessel; The embolic material is biodegradable within a predetermined period of time.

2. 1. Use of an embolic agent to embolize a blood vessel associated with ghrelin production, comprising: advancing the catheter through the vascular system to a parent artery; and The use includes a step of releasing the embolic material from the distal end of the catheter into a blood vessel associated with the production of ghrelin, whereby the embolic material blocks blood flow in the blood vessel; preferably, the embolic material is biodegradable within a predetermined period of time.

3. The use according to claim 2, wherein the blood vessels associated with the production of ghrelin are the vascular system supplying the fundus of the stomach.

4. The use according to any one of claims 1 to 3, wherein said period is between 15 minutes and 48 hours as measured by in vitro tests in biological or artificial biological fluids.

5. The use according to claim 4, wherein the biological fluid comprises amylase in the amount found in human saliva or human blood.

6. The use according to any one of claims 1 to 5, wherein the embolic material comprises a plurality of particles.

7. The use according to claim 6, wherein the particles are substantially spherical embolizing beads.

8. The use according to any one of claims 1 to 7, wherein the particles consist of crosslinked starch.

9. The use according to any one of claims 1 to 7, wherein the particles consist essentially of starch.

10. 10. The use according to claim 8 or 9, wherein the starch comprises amylose.

11. The use according to any one of claims 1 to 10, wherein the particles consist of a hydrolysable hydrogel.

12. The use according to any one of claims 1 to 11, wherein the embolic material comprises particles of polymeric origin.

13. The use according to any one of claims 1 to 12, wherein the embolic material is further biodegradable into a biocompatible residue.

14. The use according to any one of claims 1 to 13, wherein the embolic material is enzymatically biodegradable.

15. The use according to claim 14, wherein the enzyme is an amylase.

16. The use according to any one of claims 1 to 15, wherein the embolic material is biodegradable by hydrolysis of bonds in the embolic material as a result of exposure to an aqueous medium.

17. 17. The use of any one of claims 1 to 16, wherein the time to restore blood flow is between 15 minutes and 48 hours, and in some embodiments the time value is between any two of the following values: 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 16 hours, 24 hours, 30 hours, 36 hours, 40 hours, 44 hours, or 48 hours.

18. The use according to any one of claims 1 to 17 for the treatment of areas relating to the heel, spine, shoulder, hip, knee or elbow.

19. A medical system configured to carry out the use of any one of claims 1 to 18, comprising a catheter and a delivery component including a reservoir of embolic material configured to be delivered via said catheter.

20. 1. A medical system for the treatment of hypervascular blood vessels formed in response to chronic inflammation of the musculoskeletal vasculature or associated with the production of ghrelin, comprising: a catheter suitable for delivery through the patient's vascular system to reach said hypervascular blood vessel or said blood vessel associated with ghrelin production; and A delivery component comprising a reservoir of embolic material and a delivery device configured to deliver the embolic material through the catheter. Including, the health care system.

Images