Embolism using temporary material

Abstract

The use of a biodegradable embolic material for embolizing multivascular blood vessels formed in response to chronic inflammation in musculoskeletal vasculature or blood vessels associated with the production of auxin-releasing peptides is provided. The embolic material is biodegradable for a predetermined period of time. A medical system is configured for delivering an embolic material to embolize multi-vascular blood vessels or blood vessels associated with the production of auxin-releasing peptides.

Description

[0001] This application is a divisional application of an application with an application date of May 8, 2020, an invention name of “Embolization using temporary materials”, an international application number of PCT / US2020 / 032178, and a Chinese national application number of 202080034723.7. CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to co-pending U.S. Provisional Patent Application No. 62 / 846,464 filed on May 10, 2019 by Sawhney et al., entitled “Embolization Using Transient Materials,” which is incorporated herein by reference. Technical Field

[0003] The technical field is materials and methods for embolization, particularly for treating hypervascularity in response to chronic inflammation. Background Art

[0004] Osteoarthritis (OA) is a common degenerative joint disease. It is characterized by pain and is generally considered an inflammatory disease of the synovial joints. Neovascularization can be caused by chronic inflammation and contribute to further inflammation that may cause pain and further degeneration of the joints. Okuno et al., J Vasc Interv Radiol (2017) 28:995-1002. Summary of the Invention

[0005] Disclosed herein are materials and methods for embolizing neovascularization or other blood vessels or lumen using temporary materials. These materials and methods include using embolic materials that are fully biodegradable within a time period ranging from 15 minutes to 48 hours. The material biodegrades so that flow returns to normal vasculature and does not require further intervention. The temporary nature of the embolic material contrasts with permanent embolism, non-permanent embolism in an uncontrolled time period, or biodegradable materials over a longer period of time.

[0006] In a first aspect, the present invention relates to the use of an embolic material for embolizing a hypervascular vessel formed in response to chronic inflammation in the musculoskeletal vasculature, wherein the use comprises advancing a catheter through the vasculature to a parent artery and releasing the embolic material from a distal end of the catheter into the hypervascular vessel, wherein the embolic material blocks blood flow in the hypervascular vessel. The embolic material may be biodegradable over a predetermined period of time.

[0007] In another aspect, the present invention relates to the use of an embolic material for embolizing a blood vessel associated with ghrelin production, wherein the method comprises advancing a catheter through the vasculature to a maternal artery; and releasing the embolic material from the distal end of the catheter into the blood vessel associated with ghrelin production, wherein the embolic material blocks blood flow in the blood vessel. The embolic material is biodegradable within a predetermined period of time.

[0008] In another aspect, the present invention relates to a medical system configured for use in performing embolization of a multivascularized vessel formed in response to chronic inflammation in the musculoskeletal vasculature or a vessel associated with ghrelin production. The medical system comprises a catheter and a delivery component comprising a reservoir of embolic material configured for delivery via the catheter.

[0009] In other aspects, the present invention relates to a medical system for treating hypervascular vessels or vessels associated with ghrelin production that develop in response to chronic inflammation in the musculoskeletal vasculature, wherein the medical system comprises a catheter and a delivery component. The catheter can be adapted for delivery through the patient's vasculature to reach the hypervascular vessels or vessels associated with ghrelin production. The delivery component can include a reservoir of embolic material and a delivery device configured to deliver the embolic material through the catheter. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The accompanying drawings included in this application are incorporated into and form a part of the specification. They illustrate embodiments of the present disclosure and, together with the description, serve to explain the principles of the present disclosure. The accompanying drawings are merely illustrative of certain embodiments and do not limit the present disclosure.

[0011] Figure 1 A catheter system suitable for delivering embolic material to perform the methods of the present invention is depicted.

[0012] Figure 2A A guidewire positioned in a branch artery is depicted.

[0013] Figure 2B Depicts a catheter shaft that has been used in Figure 2A The guidewire shown is introduced over the branch artery.

[0014] Figure 2C Describe the embolic beads from Figure 2B Release of the catheter shaft positioned as shown.

[0015] Figure 2D Depicted is the release of an embolic bead from the catheter shaft and the bridging of the bead across a branching artery.

[0016] Figure 2EAn embolus in a branch artery is depicted.

[0017] Details

[0018] Disclosed herein are materials and methods for embolizing vasculature with a transient embolic effect, and include embolization for treating hypervascularity in response to chronic inflammation.

[0019] Hypervascular tissue is characterized by a network of blood vessels that branch from normal-looking arteries. Branches give rise to further branches and / or capillaries. Visualized using radiopaque compounds in a conventional manner in these fields, capillaries are visualized as a "blush" on angiograms. Without being bound by a particular theory, it is believed that eliminating capillaries is generally sufficient to treat pain associated with hypervascularization, and that embolic material need not be placed in the largest branches. Thus, treatment can involve embolizing capillaries while avoiding embolizing relatively large branches. Undesirable side effects caused by targeting relatively large branches can then be avoided. As part of this theory, rapidly degrading materials are used to embolize capillaries so that there is little or no recanalization, i.e., the effects of the embolization are permanent. The same rapidly degrading material can temporarily embolize larger vessels without compromising the efficacy of the treatment and without causing the harmful side effects caused by treatments targeting relatively large vessels. Additionally, biodegradable materials may be used to leave only a biocompatible residue, which term is used herein to refer to a residue of the embolic material that is a soluble component that can be cleared locally by dissolving into the blood and ultimately systemically over time by excretion mechanisms.

[0020] Adverse events that may be associated with embolic objects of a size that targets relatively large blood vessels include accidental embolization of off-site vessels, with undesirable effects ranging from minimal to catastrophic. In the treatment of vascular hyperplasia in response to chronic inflammation, others using methods of embolizing relatively large blood vessels have observed harmful side effects such as skin necrosis / discoloration, peripheral paresthesia / numbness, and one or more of muscle weakness, dullness, and pain. These undesirable and harmful side effects can be reduced or eliminated using certain embodiments of the invention described herein.

[0021] One embodiment of the present invention is an embolic technology involving biodegradable embolic materials that biodegrade within a specific time period and / or fall within a specific size range. Biodegradation can be characterized by in vitro or in vivo methods. Particles are a useful embolic material. Microspheres offer several advantages in terms of mechanical and fluid flow properties.

[0022] One technique for delivering embolic materials is through the use of a catheter system 8 . Figure 1 A catheter 10 is depicted having a hub assembly 12 and a shaft 14. The hub assembly 12 has an intermediate portion 16, a strain relief member 18, and a hub 20 having 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 intermediate portion 16 is optional and may be provided as another strain relief member above the shaft 14 and / or as a portion of the shaft 14 having a larger inner diameter (ID) and / or outer diameter (OD). Figure 1 The catheter system 8 also includes an embolic delivery component having an embolic reservoir 13 and a delivery device 15 (such as a syringe or pump), a flow tube or the like 17 and a typical connector 19 (such as a Luer fitting for connection to a proximal hub connector 24). Figure 1 As shown, delivery device 15 is a syringe having a plunger 21, a barrel 23, and a connector 25 for connecting to flow tube 17. Skilled artisans are familiar with these components and their operation, as well as their introduction and use in conjunction with guidewires, hemostatic introducers, and other components used in catheter procedures.

[0023] Embolization can be performed by placing a guidewire at the desired location, e.g. Figure 2A , which depicts an artery 28 having a branch artery 30 with a guidewire 32 positioned in the branch 30. Figures 2B-2E , the catheter shaft 14 is introduced over a guidewire 32 and positioned at the target vasculature, such as a branch artery 30. Embolic material, such as embolic beads 34, is injected through the lumen of the shaft 14. The beads 34 bridge across the arterial branch 30 to form an embolus 36 that blocks blood flow, and the catheter shaft 14 is withdrawn.

[0024] Others have reported that embolization of the geniculate artery and / or the neovascularization suspended from the geniculate artery can be used to relieve pain in the knee joint of mild and / or early osteoarthritis joints. In theory, excessive vascularization of the knee joint leads to an increase in inflammatory cells and factors entering the joint. Okuno et al. (2017) reported the results of an experiment using the following method: in an iodinated contrast agent (HEXABRIX; Terumo, Tokyo (Tokyo), Japan), 75-μm polymethyl methacrylate microspheres with a polyzene-F (EMBOZENE) coating or imipenem (Imipenem) / cilastatin sodium (cilastatinsodium) (IPM / CS; PRIMAXIN; Merck, Whitehouse Station, New Jersey (New Jersey)) were used to embolize the neovascularization of the geniculate artery. It is reported that IPM / CS is a crystalline compound that is slightly soluble in water and forms particles with an embolic effect when suspended in a contrast agent. In these contexts, the term "permanent" or "non-biodegradable" means that when used for embolization in a patient, the embolic materials remain as an identifiable mass in the location where they were placed as an embolus for at least 5 years. In fact, such materials will typically last beyond the life of the patient.

[0025] Permanent embolization has some disadvantages, 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, it is believed that IPM / CS particles are rigid, non-swelling, and can potentially provide inconsistent blood flow blockage because the particles are not necessarily optimized to be stacked together in a way that prevents the formation of channels for fluid to pass through the embolus. In addition, IPM / CS does not have to be bioactive because it is primarily an antibiotic, and antibiotic action is not required in the embolization of the geniculate artery. In addition, the delivery of small doses of antibiotics is disadvantageous because it promotes the development of microbial resistance.

[0026] Furthermore, unwanted embolization at off-target locations can be a challenge. Permanent embolic materials can have a permanent effect. Furthermore, in some cases, reflux occurs, and embolic components can flow back into the aorta near the distal tip of the delivery catheter, thereby carrying the embolic components to unknown and off-target vasculature. As a result, numerous blood vessels that nourish the skin can become embolic, leading to numbness and discoloration, which are adverse effects.

[0027] One embodiment of the present invention is a method for temporarily blocking blood flow in musculoskeletal vasculature exhibiting hypervascularity in response to chronic inflammation, the method comprising advancing a catheter through the vasculature to a parent artery; releasing an embolic material from a distal end of the catheter into the hypervascular vessel, wherein the embolic material blocks blood flow to the hypervascular, inflamed vasculature. The embolic material is biodegradable within the vasculature or, as measured by in vitro tests relevant to physiological conditions, is biodegradable within a time range of 15 minutes to 48 hours.

[0028] Sheth et al., J. Funct. Biomater. 2017, 8, 12, provide an investigation of intravascular embolization via transcatheter delivery of particles. The authors observed that each class of embolic agents is characterized by its own advantages and disadvantages and enjoys several well-suited niche clinical scenarios. They report that PVA particles adhere to the vessel wall, slowing blood flow and triggering thrombosis, as well as inducing an inflammatory response characterized by angionecrosis of the vessel wall. PVA is not biodegradable, but recanalization of vessels embolized with PVA can occur due to angiogenesis within the thrombus. Gelatinized sponges are another material that has been used as transcatheter embolic agents; they are biodegradable but induce thrombosis and cause a necrotizing arteritis reaction. The authors report that commercially available microspheres are typically composed of PVA, trisacryl-gelatin, polymethyl methacrylate microspheres with a polyzene-F coating, and QUADRASPHERE superabsorbent copolymer. Notably, they reported that even within the same size range, microspheres with different formulations have different adhesion and aggregation behaviors and will embolize vessels at different levels of the vascular tree.

[0029] Compared with such microspheres, useful embolic materials are starch microspheres, such as those described in US 4,124,705 or amilomer, which is the common name (INN name) for certain degradable starch spheres. Amilomer is a synthetic microsphere preparation with arterial occlusive properties. Amilomer (a product produced by partially hydrolyzing starch and epichlorohydrin) contains degradable starch microspheres with a diameter of 45 microns that are easily degraded by amylase. When used in transcatheter arterial chemoembolization (TACE) procedures, infusion causes the microspheres to become lodged in the precapillary vessels and, therefore, occlude the hepatic artery.

[0030] One embodiment of starch microspheres is EMBOCEPT S DSM 35 / 50 (Pharmacept), a short-term embolic agent composed of degradable starch microspheres with an average diameter of 50 microns. 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. Reticulocytes systematically clear starch debris. With degradable starch microspheres, partial restoration of blood flow was observed after approximately 10 to 15 minutes. Schicho et al., Oncotarget (2017) 8:72613-72620.

[0031] The starch that can be used includes polysaccharides that are composed of glucose units incorporated in a cross-linked form (as is or in the form of physiologically acceptable derivatives) into the granules and that are capable of being degraded into water-soluble fragments by d-amylases, i.e. the polysaccharide should contain (1-4) glycosidic bonds that can be hydrolyzed by α-amylases. Examples of such polysaccharides include mainly starch and glycogen or its dextrins. Starch can be amylose or amylopectin or a mixture thereof. Other glucose-containing polysaccharides that can be hydrolyzed by α-amylases can also be used, and the polysaccharides in this regard can be synthetic or can be obtained from biological materials, such as microorganisms. Starch can have a number of repeating glucose subunits (n) in the range of 300 to 1,000,000; the skilled person will immediately understand that all ranges and values ​​between the explicitly stated limits are taken into account.

[0032] The amylose or other starch in the embolic particles or microspheres is cross-linked, preferably with covalent bonds. Cross-linking of the starch can be carried out using epichlorohydrin or other cross-linking agents. Methods for cross-linking starch can include the use of cross-linking agents such as glutaraldehyde, epichlorohydrin, diacrylates, triacrylates, n-acrylates, or cross-linking agents having two or more functional groups for binding to the functional groups on the starch or amylose. The amount of cross-linking can be used to control the time of biodegradation, wherein a higher amount of cross-linking provides a longer time required for biodegradation.

[0033] One embodiment of the starch microspheres has a diameter of 20 to 300 microns; the skilled artisan will immediately understand that all ranges and values ​​between the explicitly stated limits are contemplated, for example, all spheres have a diameter of 20 to 100 or less than 100 microns and a mean or median diameter of 20-100 microns, or 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 190, 200, 250, 290 or 300 are selected for endpoints and / or portions of ranges.

[0034] Unless otherwise specified, the diameter of a particle or microsphere is MMD. Particles can be characterized by certain properties, such as:

[0035] D 50 : Mass median diameter (MMD). Mass median diameter of a log-normal distribution. MMD is considered the average particle size by mass.

[0036] Embolic materials such as starch beads are non-bioactive, spherical, and deformable for delivery through small catheters and in situ packaging, and can be delivered through catheters such as 2.1F-3F catheters. Starch beads are easily suspended in aqueous media, resulting in reduced sedimentation during delivery. Starch beads are biodegradable, leaving only biocompatible residues.

[0037] Other embolic particles can be configured and used to provide temporary embolization. One embodiment includes biodegradable particles composed of a polymer source. The term biodegradable refers to the decomposition of a material by in vivo causes (whether enzymatic, cellular, or hydrolytic). Hydrolytic degradation (also referred to herein as water-degradable) can be a subcategory of biodegradable and refers to the degradation of bonds in a polymer or other material by water, such as the cleavage of ester bonds. Particles can be formed so that upon hydration in physiological fluid, a water-degradable material is formed, as can be measured by the material losing its mechanical strength and ultimately dissipating in excess water in vitro through hydrolytic degradation of the water-degradable groups. This test is a prediction of hydrolytically driven dissolution in vivo (a process as opposed to cellular or protease-driven degradation). Exemplary water-degradable biodegradable bonds include polymers, copolymers, and oligomers of glycolide, dl-lactide, 1-lactide, dioxanone, esters, carbonates, and trimethylene carbonate. Exemplary enzymatic biodegradable bonds include peptide bonds that can be cleaved 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). In addition, biodegradable materials can be used to leave only biocompatible residues.

[0038] Embolic particles or balls can be made of polymers. Examples of polymers are those of natural and / or certain synthetic materials. Natural materials are those found in nature, including polymers found in nature and their derivatives. Natural polymers include glycosaminoglycans, such as dermatan sulfate, hyaluronic acid, chondroitin sulfate, chitin (chitin), heparin, keratan sulfate, keratin sulfate and their derivatives. Generally, glycosaminoglycans are extracted from natural sources and purified and derivatized. This modification can be accomplished by various well-known techniques, such as by conjugating or replacing ionizable or hydrogen-bonded functional groups such as carboxyl and / or hydroxyl or amine groups with other more hydrophobic groups. For example, the carboxyl group on hyaluronic acid can be esterified with alcohol to reduce the solubility of hyaluronic acid. Such a process is utilized by each manufacturer of hyaluronic acid products to manufacture sheets, fibers and fabrics based on hyaluronic acid that form hydrogels. Other natural polysaccharides, such as carboxymethylcellulose or oxidized regenerated cellulose, natural gums, agar, agarose, sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, arbinoglactan, pectin, pullulan, gelatin, hydrophilic colloids such as carboxymethylcellulose gum or alginate gum.

[0039] Natural materials include proteins and peptides. Peptide is a term used herein to refer to an amino acid chain with no more than 10 residues. The skilled person will immediately understand that each range and value within these clear limits, such as 1-10, 2-9, 3-10, 1, 2, 3, 4, 5, 6 or 7, is included. Some amino acids have nucleophilic groups (e.g., primary amines or thiols) or can be derivatized as needed to have a group with a nucleophilic group or an electrophilic group (e.g., carboxyl or hydroxyl). If the polyamino acid polymers generated synthetically are not found in nature and are designed to be different from naturally occurring biomolecules, they are generally considered to be synthetic.

[0040] An advantage of natural materials is that they tend to be available from cost-effective sources and have known biological properties. A disadvantage of such materials is that they may be allergenic or immunogenic. Therefore, particles that do not contain or are substantially free of amino acids, peptides, proteins, natural materials, or any combination thereof can be made. Or particles can be free of or substantially free of allergenic and / or immunogenic materials (both natural and synthetic materials). In essence, in this case, it means that there is not enough natural material to become a problem of causing patient discomfort as an allergen / immunogen, for example, no more than 1% to 10%; the skilled person will immediately understand that all ranges and values ​​between the clearly stated limits are taken into account, wherein any of the following can be used as an upper or lower limit: 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.

[0041] Embolized area

[0042] There are a variety of musculoskeletal vasculatures that show hypervascularity in response to chronic inflammation. Temporary embolization is an option for them. These musculoskeletal areas include the knee (Example 3, for arthritis), the rotator cuff (Example 4, for tendinopathy), the elbow (Example 5, for lateral epicondylitis), the foot (Example 6, for heel pain), the shoulder (Example 7, for frozen shoulder), and the knee (Example 8, for patellar tendinopathy). In addition, certain areas around the stomach can be embolized for ghrelin production control, as in Example 12.

[0043] Co-delivery with therapeutic agents

[0044] Embolic components can also be co-delivered with therapeutic agents present in the liquid carrier for delivering the components and / or in the components themselves (e.g., in embolic beads). Therapeutic agents can be added to treat embolic syndrome, a temporary effect experienced by patients experiencing embolism, wherein symptoms include pain and discomfort. This effect is known in uterine artery embolism and embolism of other tumor types. Agents used to co-deliver to treat embolic syndrome include analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and anti-inflammatory agents. Example

[0045] Example 1: Demonstration of recanalization of normal vasculature 6-24 hours after embolization with degradable starch microspheres

[0046] The starch beads EMBOCEPT S (Pharmacept, Berlin) with a diameter of 20-100 μm were diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (Bayer Healthcare, 300 mgI / mL). The suspension was stirred before use to obtain a uniform suspension. The femoral artery of a New Zealand white rabbit was surgically entered and a 4F introducer sheath was inserted. A 2.1F single-lumen microcatheter was used to move to the kidney via the renal artery. The distal end of the cranial lateral surface of the kidney was embolized by perfusion of starch beads and contrast solution, visualized under X-rays. Complete embolism was achieved and confirmed by angiography immediately after delivery of the beads suspension. After 6 hours, the controlled degradation of starch beads was complete, thereby allowing the recanalization of blood vessels. 6 hours after initially delivering the starch beads, blood flow was restored, and confirmed by angiography.

[0047] Example 2: Demonstration of permanent occlusion of normal vasculature following permanent or semi-permanent microbead embolization

[0048] By diluting 7 mL of material and carrier solution (2 mL microbeads / 7 mL cumulative volume) to a final bead concentration of 0.18 mL / mL with ULTRAVIST 300 contrast solution (300 mgI / mL), preparation was performed with EMBOZENE microbeads (Boston Scientific Corporation, Minneapolis (Minneapolis)) of a size of 40 μm in diameter. The suspension was stirred before administration to obtain a uniform suspension. Surgery was performed into the femoral artery of a New Zealand white rabbit, and a 4F introducer sheath was inserted. Then, a 2.1F single-lumen microcatheter was used to move to the kidney via the renal artery. The distal end of the cranial lateral aspect of the kidney was embolized by perfusion of EMBOZENE microbeads and contrast solution, visualized under X-ray. Complete embolization was confirmed by angiography. After 3 months, animals could be put to death, and the necrosis of the embolic portion (cranial lateral aspect) of the kidney could be observed. Due to the permanence of non-degradable EMBOZENE microbeads, blood vessels would no longer be accessible, and necrosis of healthy tissue would occur.

[0049] OMNISPHERE microbeads with a diameter of 100 μm were prepared by diluting 7 mL of material and vehicle solution (2 mL microbeads / 7 mL total volume) with ULTRAVIST 300 contrast solution (300 mgI / mL) to a final bead concentration of 0.18 mL / mL. The suspension was stirred before administration to obtain a uniform suspension. The femoral artery of a New Zealand white rabbit was surgically accessed and a 4F introducer sheath was inserted. A 1.7F single-lumen microcatheter was then used to move into the kidney via the renal artery. The distal portion of the cranial side of the kidney was embolized by perfusion of OMNISPHERE microbeads and contrast solution, visualized under X-ray. Complete embolization was confirmed by angiography. After 6 hours, complete and sustained occlusion was confirmed by angiography. The semi-permanent microbeads completely degraded within 3 months. At 3 months, the animals were sacrificed and necrosis of the embolized portion of the kidney (cranial side) was observed. Due to the semi-permanence of the OMNISPHERE microbeads, the blood vessels will no longer be accessible and necrosis of healthy tissue will occur.

[0050] Example 3: Demonstration of permanent occlusion of the aberrant inflammatory vasculature present in knee osteoarthritis following temporary geniculate artery embolization (GAE) using degradable starch microspheres

[0051] Starch beads measuring 20-100 μm in diameter were diluted to a final bead concentration of 30 mg / mL using Ultravist 300 contrast solution (300 mg / mL). The suspension may be stirred prior to administration to obtain a homogenous suspension. The abnormal inflammatory vasculature that leads to knee osteoarthritis in a patient diagnosed with the condition was visualized by angiography as a blush off of the main geniculate artery. The area is selectively accessed using a 2.1F single-lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization of the abnormal vessels is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, the inflamed vasculature remains occluded and complete embolization of the area is maintained, as confirmed by angiography. This therapy reduces or eliminates abnormal neovascularization, decreases local tenderness, and reduces arterial flow over the target lesion. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as lipiodol or non-degradable microspheres.

[0052] Example 4: Demonstration of permanent occlusion of abnormal, disorganized hypervasculature in rotator cuff tendinopathy following temporary transcatheter arterial embolization (TAE) using degradable starch microspheres

[0053] Starch beads measuring 20-100 μm in diameter were diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension was stirred prior to administration to obtain a homogenous suspension. Abnormal hypervascularity around the shoulder was confirmed by angiography. The area is selectively accessed using a 2.1F single lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, flow will not resume and complete embolization of the area will be maintained, as can be confirmed by angiography. This therapy will result in a reduction in arterial flow to the polyvascular site and prevent further tissue degradation. In addition, changes from baseline will be observed in various clinical parameters, including visual analog scale pain scores and a reduction or elimination of conventional treatments such as analgesics or corticosteroid injections. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as iodized oil or non-degradable microspheres. With temporary embolization, possible adverse events such as skin necrosis / discoloration, peripheral paresthesia / numbness, and muscle weakness / dull pain that occur with permanent embolic agents do not occur.

[0054] Example 5: Demonstration of permanent occlusion of the aberrant inflammatory vasculature present in lateral epicondylitis following temporary transcatheter arterial embolization (TAE) using degradable starch microspheres

[0055] Starch beads measuring 20-100 μm in diameter were diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension was stirred prior to administration to obtain a homogenous suspension. The abnormal inflammatory vasculature present in a cluster of lateral epicondylitis was visualized by angiography as reddened vessels of the aorta. The area is selectively accessed using a 2.1F single-lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, flow will not resume and complete embolization of the area will be maintained, as can be confirmed by angiography. This therapy will result in a reduction or elimination of abnormal neovascularization, a decrease in local tenderness, and a decrease in arterial flow over the target lesion. In addition, changes from baseline will be observed in various clinical parameters, including visual analog scale pain scores, Patient-Rated Tennis Elbow Evaluation scores, and pain-free grip strength. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as iodized oil or non-degradable microspheres. With temporary embolization, possible adverse events such as skin necrosis / discoloration, peripheral paresthesia / numbness, and muscle weakness / dull pain, which are common with permanent embolic agents, do not occur.

[0056] Example 6: Demonstration of permanent occlusion of the aberrant inflammatory vasculature present in heel pain following temporary transcatheter arterial embolization (TAE) using degradable starch microspheres

[0057] Starch beads measuring 20-100 μm in diameter can be diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension can be stirred prior to administration to obtain a homogenous suspension. The abnormal inflammatory vasculature present in a cluster of heel pain is visualized by angiography as erythematous blood vessels of the main posterior tibial artery. The area is selectively accessed using a 2.1F single-lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, flow will not resume and complete embolization of the area will be maintained, as confirmed by angiography. This therapy will result in a reduction or elimination of abnormal neovascularization, reduced local tenderness, and reduced arterial flow over the target lesion. Additionally, this therapy may improve gait. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as iodized oil or non-degradable microspheres. With temporary embolization, potential adverse events such as skin necrosis / discoloration, peripheral paresthesia / numbness, and muscle weakness / dull aches that occur with permanent embolic agents do not occur.

[0058] Example 7: Demonstration of permanent occlusion of the aberrant inflammatory vasculature present in adhesive capsulitis following temporary transcatheter arterial embolization (TAE) using degradable starch microspheres

[0059] Starch beads measuring 20-100 μm in diameter were diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension was stirred prior to administration to obtain a homogenous suspension. The abnormal inflammatory vasculature present in a cluster of adhesive capsulitis was visualized by angiography as reddened vessels of the aorta at the rotator interval. The area is selectively accessed using a 2.1F single lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, flow will not resume and complete embolization of the area will be maintained, as can be confirmed by angiography. This therapy results in a reduction or elimination of abnormal neovascularization, reduced local tenderness, and reduced arterial flow at the target lesion. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as iodized oil or non-degradable microspheres. With temporary embolization, possible adverse events such as skin necrosis / discoloration, peripheral paresthesia / numbness, and muscle weakness / dull pain that occur with permanent embolic agents do not occur.

[0060] Example 8: Demonstration of permanent occlusion of the aberrant inflammatory vasculature present in patellar tendinopathy following temporary transcatheter arterial embolization (TAE) using degradable starch microspheres

[0061] Starch beads measuring 20-100 μm in diameter were diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension was stirred prior to administration to obtain a homogenous suspension. Angiography visualized a cluster of abnormal inflammatory vasculature associated with tendinopathy, demonstrating vascular redness of the main geniculate artery. The area is selectively accessed using a 2.1F single lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target and embolization is confirmed by angiography using contrast agent. After a known degradation period of 3 hours, flow will not resume and complete embolization of the area will be maintained, as can be confirmed by angiography. This therapy results in a reduction or elimination of abnormal neovascularization, reduced local tenderness, and reduced arterial flow at the target lesion. This approach is unique due to the predictable degradation period of the starch beads and differs from the unpredictability of other embolic agents such as iodized oil or non-degradable microspheres. With temporary embolization, possible adverse events such as skin necrosis / discoloration, peripheral paresthesia / numbness, and muscle weakness / dull pain that occur with permanent embolic agents do not occur.

[0062] Example 9: Enzymatic degradation of starch beads using salivary biosolution

[0063] EMBOCEPT S starch beads are degraded by enzymatic degradation with amylase, an enzyme primarily found in saliva and pancreatic juice. This enzyme converts starch and glycogen into simple sugars. 10 mL of a 60 mg / mL stock solution of EMBOCEPT S starch beads was added to a 20 mL scintillation vial. At t = 0 h, a sample of salivary biological solution was added to the vial, at which point a stopwatch was started. Over time, the enzymatic degradation of the starch beads was visualized as the suspension became a homogenous solution with no visible particles. Complete degradation was confirmed by the front-to-back weight of the dried filter paper after filtering the solution.

[0064] Example 10: Co-delivery of Lidocaine with Degradable Starch Beads

[0065] 2 mL of 60 mg / mL starch beads (measuring 20-100 μm in diameter) were diluted to a concentration of 30 mg / mL using 2 mL of 2% lidocaine solution. The suspension was then further diluted to a final bead concentration of 15 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension was stirred prior to administration to obtain a homogenous suspension. Abnormal inflammatory vasculature in one patient was visualized by angiography, as evidenced by vascular redness in the aorta. The area is selectively accessed using a 2.1F single-lumen microcatheter over a 0.014" guidewire. Starch beads are delivered to the target, and embolization is confirmed by angiography using contrast media. Lidocaine provides anesthesia to quell some of the temporary pain associated with vessel closure during embolization (post-embolization syndrome). After a known degradation period of 3 hours, there will be no recanalization of the inflamed vasculature, and flow to the fine inflamed vasculature will be blocked, while the feeding arteries continue to be patent. This can be confirmed by angiography.

[0066] Example 11: Co-delivery of dexamethasone sodium phosphate with degradable starch beads

[0067] Dilute 2 mL of 60 mg / mL starch beads (measuring 20-100 μm in diameter) to a concentration of 30 mg / mL using 2 mL of 1% dexamethasone sodium phosphate solution. The suspension can then be further diluted to a final bead concentration of 15 mg / mL using ULTRAVIST 300 contrast solution (300 mg / mL). The suspension can be stirred prior to administration to obtain a homogenous suspension. Abnormal inflammatory vasculature in one patient was visualized by angiography, as vascular redness of the aorta. The area will be selectively accessed using a 2.1F single lumen microcatheter over a 0.014" guidewire. Starch beads will be delivered to the target and embolization will be confirmed by angiography using contrast agent. Dexamethasone will provide an anti-inflammatory effect to help treat and prevent inflammation associated with the disease state as well as vessel closure during embolization (post-embolization syndrome). After a known degradation period of 3 hours, there will be no recanalization of the inflamed vasculature and flow to the fine inflamed vasculature will be blocked while the feeding arteries continue to be patent. This can be confirmed by angiography.

[0068] Example 12: Combined delivery technology of starch beads and EMBOZENE beads in a weight loss setting

[0069] The combined delivery of permanent and temporary embolic material is carried out as follows. EMBOZENE embolic beads (>100 μm) are introduced for permanent embolization using a 2.8F catheter system delivered to the larger normal vasculature of the target, which nourishes the gastric fundus portion, which is responsible for the production of ghrelin. After embolization, the larger, less selective catheter system is removed. For subsequent temporary embolization, starch beads with a diameter of 20-100 μm are diluted to a final bead concentration of 30 mg / mL using ULTRAVIST 300 contrast solution (300 mgI / mL). The suspension is stirred before administration to obtain a uniform suspension. An interventional radiologist (IR) will use a selective 2.1F microcatheter to enter the desired position in the gastric artery that nourishes the gastric fundus portion. The starch beads will be delivered to embolize the thinner vasculature and effectively prevent the flow entering the thinner vasculature. The starch beads are degraded in a predictable and controlled manner according to the design, and afterwards, because the abnormal vasculature cannot be recanalized, flow will be closed. This can be confirmed by angiography.This would be an effective way to provide combined temporary and permanent embolization or combined treatment to the gastric fundus region as an interventional approach to treat obesity.

[0070] The present invention includes the following:

[0071] Item 1. Use of an embolic material for embolizing polyangiogenic vessels formed in response to chronic inflammation in the musculoskeletal vasculature, the use comprising:

[0072] Advancing the catheter through the vasculature to the maternal artery; and

[0073] releasing the embolic material from the distal end of the catheter into the polyvascular vessel, wherein the embolic material blocks blood flow in the polyvascular vessel;

[0074] The embolic material is biodegradable within a predetermined period of time.

[0075] Item 2. Use of an embolic material for embolizing a blood vessel associated with ghrelin production, the method comprising:

[0076] advancing the catheter through the vasculature to the maternal artery; and

[0077] The embolic material is released from the distal end of the catheter into a blood vessel associated with ghrelin production, wherein the embolic material blocks blood flow in the blood vessel; preferably wherein the embolic material is biodegradable within a predetermined period of time.

[0078] Item 3. The use according to Item 2, wherein the blood vessels associated with the production of ghrelin are the vasculature nourishing the fundus portion of the stomach.

[0079] Item 4. The use according to any one of items 1 to 3, wherein the period of time is from 15 minutes to 48 hours as measured by in vitro testing in physiological fluid or simulated physiological fluid.

[0080] Item 5. The use according to Item 4, wherein the fluid contains an amount of amylase found in human saliva or human blood.

[0081] Item 6. The use according to any one of Items 1 to 5, wherein the embolic material comprises a plurality of particles.

[0082] Item 7. The use according to Item 6, wherein the particles are substantially spherical embolic beads.

[0083] Item 8. The use according to any one of Items 1 to 7, wherein the particles are composed of cross-linked starch.

[0084] Item 9. The use according to any one of Items 1 to 7, wherein the granules consist essentially of starch.

[0085] Item 10. The use according to any one of Items 8-9, wherein the starch comprises amylose.

[0086] Item 11. The use according to any one of Items 1 to 10, wherein the particles are composed of a hydrolytically degradable hydrogel.

[0087] Item 12. The use according to any one of Items 1 to 11, wherein the embolic material comprises particles composed of a polymer source.

[0088] Item 13. The use according to any one of Items 1 to 12, wherein the embolic material is further degradable into a biocompatible residue.

[0089] Item 14. The use according to any one of Items 1 to 13, wherein the embolic material is biodegradable by enzymatic action.

[0090] Item 15. The use according to Item 14, wherein the enzyme is amylase.

[0091] Item 16. The use according to any one of Items 1 to 15, wherein the embolic material is biodegradable by hydrolytic degradation of bonds in the embolic material due to exposure to an aqueous medium.

[0092] Item 17. The use according to any one of Items 1-16, wherein the time to restore the blood flow is 15 minutes to 48 hours, and in some embodiments, the time value is between any two values ​​from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 24, 30, 36, 40, 44 or 48 hours.

[0093] Item 18. The use according to any one of Items 1 to 17, which is for the treatment of areas related to the heel, spine, shoulder, hip, knee, elbow.

[0094] Item 19. A medical system configured to perform the use according to any one of Items 1-18, and comprising a catheter and a delivery component comprising a reservoir of embolic material configured for delivery through the catheter.

[0095] Item 20. A medical system for the treatment of hypervascular vessels formed in response to chronic inflammation in the musculoskeletal vasculature or vessels associated with ghrelin production, the medical system comprising:

[0096] a catheter adapted for delivery through the patient's vasculature to reach the polyvascular blood vessel or the blood vessel associated with ghrelin production; and

[0097] A delivery component includes a reservoir of embolic material and a delivery device configured to deliver the embolic material through the catheter.

[0098] The above embodiments are intended to be illustrative and not restrictive. Additional embodiments are within the claims. In addition, although the present invention has been described with reference to specific embodiments, those skilled in the art will recognize that, without departing from the spirit and scope of the present invention, changes can be made in form and detail. Any incorporation by reference of the above documents is limited so that no subject matter contrary to the explicit disclosure herein is incorporated. To the extent that a particular structure, composition and / or method is described herein with components, elements, ingredients or other parts, it should be understood that the disclosure herein covers these specific embodiments, embodiments comprising specific components, elements, ingredients, other parts or combinations thereof, and embodiments consisting essentially of such specific components, ingredients or other parts or combinations thereof, unless otherwise specifically indicated, these embodiments may include additional features that do not change the basic properties of the subject matter, as suggested in the discussion. Unless otherwise specifically indicated, the use of the term "about" herein refers to measurement error and / or reporting accuracy as understood by those of ordinary skill in the art in the context of a particular parameter.

Claims

1. A medical system for the treatment of hypervascular vessels formed in response to chronic inflammation in the musculoskeletal vasculature, the medical system comprising: a catheter adapted for delivery through the patient's vasculature to reach the polyvascular vessel; and A delivery component comprising a reservoir of embolic material and a delivery device configured to deliver the embolic material through the catheter, characterized in that the embolic material does not contain a therapeutic agent and comprises deformable hydrogel particles that are biodegradable within a period of 15 minutes to 48 hours. The medical system according to claim 1 , wherein the time period is from 15 minutes to 8 hours.

3. The medical system of claim 1 or claim 2, wherein the time period is the time to restore blood flow.

4. The medical system according to any one of claims 1 to 3, wherein the embolic material is biodegradable into a biocompatible residue.

5. The medical system of any one of claims 1-4, wherein the deformable hydrogel particles are hydrolytically degradable.

6. The medical system according to any one of claims 1 to 5, wherein the deformable hydrogel particles are enzymatically biodegradable.

7. The medical system of any one of claims 1-6, wherein the deformable hydrogel particles are biodegradable by collagenase.

8. The medical system of any one of claims 1-7, wherein the deformable hydrogel particles comprise polyamino acid polymer particles.

9. The medical system of any one of claims 1-7, wherein the deformable hydrogel particles comprise synthetic polyamino acid polymer particles.

10. The medical system of any one of claims 1-7, wherein the deformable hydrogel particles comprise gelatin.

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