JP2024075522A - Embolus material and embolus material production method - Google Patents

Abstract

To prevent an embolus material from blocking a branched blood vessel branched from an aneurysm (causing distal embolism).SOLUTION: An embolus material 10 is inserted into and retained in a lump in a living body. The embolus material includes an elongated body 11 that extends in the axial direction. The body has expansion properties such that it expands more in a direction orthogonal to the axial direction than in the axial direction upon contact with blood.SELECTED DRAWING: Figure 1

Description

The present invention relates to an embolic material that is delivered into a lump by a catheter, and a method for producing the embolic material.

There is no medical treatment for aneurysms (aortic aneurysms) that develop in a patient's aorta to prevent the aneurysm from growing larger or rupturing, and surgical treatment (operation) is generally performed for aneurysms large enough to rupture. In addition, surgery for aortic aneurysms has traditionally been dominated by artificial vascular replacement surgery, in which an artificial blood vessel is implanted via laparotomy or thoracic opening, but in recent years, the use of the less invasive stent graft insertion procedure (Endovascular Aneurysm Repair; EVAR) has been rapidly expanding.

As an example, in stent graft insertion surgery for abdominal aortic aneurysm (AAA), a catheter with a stent graft at its tip is inserted through the patient's peripheral blood vessels, and the stent graft is deployed and placed at the site of the aneurysm, blocking blood flow to the aneurysm and preventing the aneurysm from rupturing.

Generally, stent grafts used in stent graft insertion have a structure that can be assembled from two types of components: a "main body" with a branching section that branches into an approximately Y shape, and "legs" that are attached to the branching section and are attached to the right iliac artery and left iliac artery, respectively.

Therefore, during stent graft insertion surgery, blood may leak from around the stent graft due to insufficient adhesion of the inserted stent graft, or blood may flow back from small blood vessels (branch vessels) that branch off from the aneurysm, resulting in a so-called "end leak," in which blood remains flowing inside the aneurysm. In this case, the blood flow that has entered the aneurysm puts pressure on the aneurysm wall, creating a potential risk of the aneurysm rupturing.

The following Patent Document 1 discloses a device that includes a catheter capable of holding a compressed, relatively elongated sponge (embolus) in its lumen, and a plunger that pushes the embolus held in the catheter into the aneurysm filled with blood, in order to block the remaining blood flow into an aortic aneurysm caused by an end leak. The sponge used in this device expands immediately when exposed to blood, so when it is pushed into the aneurysm and absorbs the blood in the aneurysm, it expands (swells), and is left in that state in the aneurysm to block the blood flow and prevent rupture.

U.S. Pat. No. 9,561,096

The embolus of Patent Document 1 can block blood flow to the aneurysm by expanding as described above. However, depending on the direction in which the embolus expands, the branch blood vessels branching off from the aneurysm may be larger (thicker) than the expanded embolus. As a result, the embolus placed in the aneurysm may enter the branch blood vessels and block an unintended area, resulting in so-called distal embolization.

The present invention has been made in consideration of the above problems, and aims to provide an embolic material that can reduce the risk of distal embolism, and a method for manufacturing the embolic material.

The embolic object according to the present invention is an embolic object that is inserted and retained in a lump in a living body, and has a long main body portion that extends in an axial direction, and the main body portion has an expansion characteristic that, when it comes into contact with blood, expands more in a direction perpendicular to the axial direction than in the axial direction.

The method for manufacturing an embolic object according to the present invention is a method for manufacturing an embolic object that is inserted and retained in a lump in a living body, and includes cross-linking and polymerizing a monomer in a monomer solution to form a porous expandable material, and drying the expandable material in an axially stretched state.

When the embolic material constructed as described above comes into contact with an aqueous liquid containing blood under physiological conditions, it tends to expand in a direction perpendicular to the axial direction. This makes the embolic material more likely to become clogged on the proximal side of a branch blood vessel and less likely to stray to the distal side of the branch blood vessel. Therefore, the embolic material can reduce the risk of distal embolism.

The method for manufacturing an embolic object configured as described above can produce an embolic object that is likely to expand in a direction perpendicular to the axial direction when it comes into contact with an aqueous liquid containing blood under physiological conditions. As a result, the embolic object manufactured by the above manufacturing method can reduce the risk of distal embolization.

FIG. 2 is a diagram showing an embolus according to the present embodiment. FIG. 13 shows an embolus swelling within a lump. 1A to 1C are diagrams for explaining a method for producing an embolus according to the present embodiment. 1A to 1C are diagrams for explaining a method for producing an embolus according to the present embodiment. 4A and 4B are diagrams for explaining a dry state and a swollen state of the embolus according to the present embodiment. 4A and 4B are diagrams for explaining a dry state and a swollen state of the embolus according to the present embodiment. FIG. 1 is a diagram showing the configuration of a medical instrument set and a delivery set. FIG. 1 is a diagram showing the configuration of an embolic material delivery medical system. 1 is an example of the operation of an embolic material delivery medical system. 1 is an example of the operation of an embolic material delivery medical system. 1 is an example of the operation of an embolic material delivery medical system. 1 is an example of the operation of an embolic material delivery medical system.

The following describes in detail the embodiments of the present invention with reference to the drawings. The embodiments shown here are illustrative in order to embody the technical ideas of the present invention, and do not limit the present invention. Furthermore, all other possible embodiments, examples, and operational techniques that can be conceived by those skilled in the art without departing from the gist of the present invention are included in the scope and gist of the present invention, and are included in the scope of the inventions described in the claims and their equivalents.

Furthermore, for the convenience of illustration and ease of understanding, the drawings attached to this specification may be represented diagrammatically with appropriate changes in scale, aspect ratio, shape, etc. from the actual product, but these are merely examples and do not limit the interpretation of the present invention.

In this specification, the operation direction of each part constituting the embolus delivery medical system 300 capable of delivering the embolus 10 into the aneurysm is, for example, a direction along the axial direction of the delivery catheter 30 for delivering the embolus loading catheter 20 into the aneurysm, and the side where the embolus 10 is transported into the aneurysm is referred to as the "distal side (or distal end)", and the side located axially opposite the distal side and operated by the surgeon (the side where the delivery catheter 30 is removed) is referred to as the "base side (or proximal end)". Note that "distal" refers to a certain range in the axial direction including the most distal end, and "base end" refers to a certain range in the axial direction including the most proximal end.

In addition, the embolus 10 can be applied, for example, to endoleak embolization for stent graft insertion of abdominal aortic aneurysm (AAA), which is a treatment method for preventing the rupture of aneurysms (e.g., aneurysms) occurring in blood vessels. In addition, the treatment methods to which the embolus 10 can be applied are not limited to the above-mentioned endoleak embolization, and the embolus 10 can also be applied to other intervention treatment methods for preventing the rupture of aneurysms occurring in blood vessels.

In addition, in this specification, the range "M to N" includes M and N and means "greater than or equal to M and less than or equal to N." In this specification, "M and/or N" means including at least one of M and N, and includes "M alone," "N alone," and "a combination of M and N."

As used herein, the term "(meth)acrylic" includes both acrylic and methacrylic. Thus, for example, the term "(meth)acrylic acid" includes both acrylic acid and methacrylic acid. Similarly, the term "(meth)acryloyl" includes both acryloyl and methacryloyl. Thus, for example, the term "(meth)acryloyl group" includes both acryloyl and methacryloyl groups.

[composition]
The configurations of the embolic object 10 according to this embodiment, the medical instrument set 100 for delivering the embolic object 10 into the aneurysm, the delivery system 200, and the embolic object delivery medical system 300 will be described.

Figures 1 to 6 are diagrams for explaining the embolic material 10. Figure 7 is a diagram showing the medical instrument set 100 and the devices constituting the delivery system 200, and Figure 8 is a diagram showing the devices constituting the embolic material delivery medical system 300. In Figures 7 and 8, the embolic material 10 is loaded into the loading lumen of the embolic material loading catheter 20.

In addition, the arrow X in Figures 1, 2, 5, and 6 indicates the "axial direction (longitudinal direction)" of the embolus 10, the arrow Y indicates the "width direction (depth direction)" of the embolus 10, the arrow Z indicates the "height direction" of the embolus 10, and the arrow r indicates the "radial direction (radiating direction)" of the embolus 10.

＜Embolism＞
The embolus 10 is placed in a swell such as an aneurysm that occurs in a blood vessel, and expands by absorbing liquid, including blood, that flows into the swell. The embolus 10 is loaded into an embolus loading catheter 20, and with the embolus loading catheter 20 attached to a delivery catheter 30, it is pushed out by a delivery pusher 40 and placed in the swell.

The embolus 10 is a long, thin, fibrous filament (linear body). The embolus 10 is a long, thin, filamentary body with a substantially circular cross-sectional shape in a direction perpendicular to the axial direction, and is relatively fragile before being placed in the aneurysm in an expanded state. The cross-sectional shape of the embolus 10 is not particularly limited, and may be a polygon such as an ellipse or a rectangle. The shape of the embolus 10 is not limited to a filament, and may be a shape that can be deformed and stored in the loading lumen (for example, a flat shape) as long as it can be stored in the loading lumen of the embolus loading catheter 20. When the embolus 10 has a flat shape, the embolus 10 is stored in the loading lumen in a rolled state, and is configured to return to a flat state or approach a flat state due to a restoring force derived from the physical properties of the material constituting the embolus 10 when the embolus 10 is removed from the loading lumen (in an unexpanded state).

The embolus 10 can be made of an expandable material (such as a polymeric material (water-absorbing gel material)) that expands upon contact with aqueous liquids, including blood, under physiological conditions, and can be made of a hydrogel containing a reaction product of an ethylenically unsaturated monomer, a crosslinking agent, and, if necessary, a bifunctional macromer. Details of the reaction product of the ethylenically unsaturated monomer and the crosslinking agent will be described later.

Here, "physiological conditions" refers to conditions having at least one environmental characteristic within or on the surface of a mammalian (e.g., human) body. Such characteristics include an isotonic environment, a pH buffer environment, an aqueous environment, a pH near neutral (about 7), and a combination. In addition, "aqueous liquid" includes, for example, isotonic liquid, water; and mammalian (e.g., human) body fluids such as blood, cerebrospinal fluid, plasma, serum, vitreous humor, and urine. The outer diameter of the embolus 10 may be any diameter that can be accommodated in the embolus loading catheter 20. In addition, the total length of the embolus 10 is not particularly limited, but may be appropriately determined depending on the size of the aneurysm to be placed, taking into consideration the ease of loading and the shortening of the procedure time.

The material of the embolus 10 is not particularly limited, so long as it can expand by absorbing at least a liquid such as blood, and is not (or is extremely low in) harmful to the human body when placed in the aneurysm. The embolus 10 may also contain a visualization agent that allows its location in the body to be confirmed by a method such as X-rays, fluorescent X-rays, ultrasound, fluorescence, infrared rays, or ultraviolet rays.

The main body 11 of the embolus 10 (see FIG. 1) is configured to expand in the radial direction (r direction) compared to the axial direction (X direction) when it comes into contact with an aqueous liquid containing blood under physiological conditions. The embolus 10 becomes larger than the branch blood vessel t due to expansion (in other words, the outer diameter d1 of the embolus 10 becomes larger than the inner diameter d2 of the branch blood vessel t, see FIG. 2), or becomes larger than the branch blood vessel t when folded inside the aneurysm s, so that it is more likely to get stuck on the proximal side of the branch blood vessel t and less likely to get lost in the distal side of the branch blood vessel t. Therefore, the embolus 10 configured in this way can reduce the risk of distal embolization. In addition, when the embolus 10 has a flat shape, the embolus 10 expands from a rolled shape to a flat shape or a shape close to a flat shape when it is placed inside the aneurysm, and when it comes into contact with an aqueous liquid containing blood under physiological conditions in that state, it can be configured to expand in the width direction or thickness direction compared to the axial direction (longitudinal direction).

(Reaction product of ethylenically unsaturated monomer and crosslinker)
(Reaction product of a bifunctional macromer, an ethylenically unsaturated monomer, and a crosslinker)
The reaction product constituting the fibrous embolus 10 (hydrogel filament) is a reaction product of an ethylenically unsaturated monomer, a crosslinking agent, and, if necessary, a bifunctional macromer. That is, the reaction product constituting the hydrogel filament is a reaction product of an ethylenically unsaturated monomer and a crosslinking agent, or a reaction product of a bifunctional macromer, an ethylenically unsaturated monomer, and a crosslinking agent. In the following, the "reaction product of an ethylenically unsaturated monomer and a crosslinking agent" and the "reaction product of a bifunctional macromer, an ethylenically unsaturated monomer, and a crosslinking agent" are collectively referred to simply as "reaction products".

Here, the ethylenically unsaturated monomer is a monomer having a double bond at its terminal, such as an acryloyl group (CH ₂ ═CH-C(═O)-), a methacryloyl group (CH ₂ ═C(CH ₃ )-C(═O)-), a vinyl group (CH ₂ ═CH-), an acrylamide group (CH ₂ ═CH-C(═O)-NH-) or a methacrylamide group (CH ₂ ═C(CH ₃ )-C(═O)-NH-). Specific examples include (meth)acrylic acid, 2-(meth)acryloylethanesulfonic acid, 2-(meth)acryloylpropanesulfonic acid, 2-(meth)acrylamido-2-methylpropanesulfonic acid, vinylsulfonic acid, styrenesulfonic acid, and salts thereof (e.g., alkali metal salts, ammonium salts, amine salts); (meth)acrylamide, N-substituted (meth)acrylamide, 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate; N,N-dimethylaminoethyl (meth)acrylate, N,N-diethylaminoethyl (meth)acrylate, N,N-diethylaminopropyl (meth)acrylate, and derivatives thereof; N,N-dimethylaminopropyl (meth)acrylamide and quaternized products thereof; N-vinylpyrrolidinone and derivatives thereof. The above ethylenically unsaturated monomers may be used alone or in combination of two or more. From the viewpoints of higher swelling property, biocompatibility, non-biodegradability, etc., when contacting with body fluids, the ethylenically unsaturated monomer is preferably N-vinylpyrrolidinone, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, and derivatives thereof, as well as acrylic acid, methacrylic acid, and salts thereof. That is, in a preferred embodiment of the present invention, the ethylenically unsaturated monomer is at least one selected from the group consisting of N-vinylpyrrolidinone, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, and derivatives thereof, as well as acrylic acid, methacrylic acid, and salts thereof. Furthermore, from the viewpoints of even higher swelling property, biocompatibility, non-biodegradability, etc., when contacting with body fluids, the ethylenically unsaturated monomer is more preferably (meth)acrylic acid or an alkali metal salt thereof (sodium salt, lithium salt, potassium salt), and particularly preferably acrylic acid and/or sodium acrylate.

The crosslinking agent is not particularly limited as long as it can crosslink an ethylenically unsaturated monomer or a bifunctional macromer and an ethylenically unsaturated monomer, and any known crosslinking agent can be used. Specific examples include N,N'-methylenebis(meth)acrylamide, (poly)ethylene glycol di(meth)acrylate, 2-hydroxy-3-acryloyloxypropyl (meth)acrylate, 1,10-decanediol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, 1,9-nonanediol di(meth)acrylate, (poly)propylene glycol di(meth)acrylate, (poly)tetramethylene glycol di(meth)acrylate, and derivatives thereof. The above crosslinking agents may be used alone or in combination of two or more. From the viewpoints of ease of control of swelling when in contact with body fluids, biocompatibility, non-biodegradability, and the like, it is preferable that the crosslinking agent is N,N'-methylenebis(meth)acrylamide, ethylene glycol dimethacrylate, and derivatives thereof. That is, in a preferred embodiment of the present invention, the crosslinking agent is at least one selected from the group consisting of N,N'-methylenebisacrylamide, ethylene glycol dimethacrylate, and derivatives thereof. Furthermore, from the viewpoints of easier control of swelling upon contact with body fluids, biocompatibility, non-biodegradability, etc., the crosslinking agent is more preferably N,N'-methylenebis(meth)acrylamide, and particularly preferably N,N'-methylenebisacrylamide.

The bifunctional macromer crosslinks the polymer chains during polymerization, imparting flexibility to the reaction product (and thus the embolus). As a result, the reaction product (and thus the embolus) containing the bifunctional macromer has excellent conformability to curved sections. Therefore, even when the embolus is placed in the aneurysm via a catheter, the embolus can easily pass through the curved section and be placed in the aneurysm. Therefore, the embolus of the present invention is preferably composed of a hydrogel filament containing a reaction product of a bifunctional macromer, an ethylenically unsaturated monomer, and a crosslinking agent, and a visualization agent.

The bifunctional macromer is not particularly limited as long as it contains two functional sites, but it is preferable that it contains one or more ethylenically unsaturated groups and two functional sites (bifunctional ethylenically unsaturated moldable macromer). Here, the one or more ethylenically unsaturated groups may form one or both of the functional sites. Examples of bifunctional macromers include, but are not limited to, polyethylene glycol, polypropylene glycol, poly(tetramethylene oxide), poly(ethylene glycol) diacrylamide, poly(ethylene glycol) dimethacrylamide, poly(ethylene glycol) diacrylate, poly(ethylene glycol) dimethacrylate, poly(propylene glycol) diacrylate, poly(propylene glycol) dimethacrylate, and derivatives thereof. Among these, from the viewpoint of the effect of imparting flexibility (flexibility) to the embolus, the bifunctional macromer is preferably polyethylene glycol, polypropylene glycol, poly(tetramethylene oxide), poly(ethylene glycol) diacrylamide, poly(ethylene glycol) dimethacrylamide, poly(ethylene glycol) diacrylate, poly(ethylene glycol) dimethacrylate, and derivatives thereof. Here, the bifunctional macromer may be used alone or in combination of two or more. That is, in a preferred embodiment of the present invention, the bifunctional macromer is at least one selected from the group consisting of polyethylene glycol, polypropylene glycol, poly(tetramethylene oxide), poly(ethylene glycol) diacrylamide, poly(ethylene glycol) dimethacrylamide, poly(ethylene glycol) diacrylate, poly(ethylene glycol) dimethacrylate, and derivatives thereof. From the viewpoint of biocompatibility and solubility in a solvent, the bifunctional macromer is more preferably poly(ethylene glycol) di(meth)acrylamide. From the viewpoint of degradability, the bifunctional macromer is more preferably poly(ethylene glycol) di(meth)acrylate.

The molecular weight of the bifunctional macromer is not particularly limited, but from the viewpoint of imparting flexibility (pliability) to the embolus and improving the swelling ratio, a low molecular weight (bifunctional low molecular weight ethylenically unsaturated moldable macromer) is preferable. Specifically, the molecular weight of the bifunctional macromer is preferably about 100 to about 50,000 g/mol, more preferably about 1,000 to about 20,000 g/mol, and particularly preferably about 2,000 to about 15,000 g/mol.

The reaction product may contain, in addition to the above ethylenically unsaturated monomer and crosslinking agent, and if necessary, a bifunctional macromer, a structural unit derived from another monomer (another structural unit). Here, the other monomer is not particularly limited as long as it does not inhibit the effects of the present invention (swellability, visibility before and after swelling, etc.). Specific examples include 2,4,6-triiodophenylpenta-4-enoate, 5-(meth)acrylamide-2,4,6-triiodo-n,n'-bis-(2,3 dihydroxypropyl)isophthalamide N-vinylpyrrolidinone, etc. The amount (content) of the other structural unit in the case where the reaction product according to the present invention has other structural units is not particularly limited as long as it does not inhibit the effects of the present invention (swellability, visibility before and after swelling, etc.). Specifically, the amount (content) of the other structural unit is less than 10 mol%, preferably less than 5 mol%, and even more preferably less than 1 mol% with respect to the total structural units constituting the reaction product (lower limit: more than 0 mol%). In addition, when the structural unit derived from the other monomer is composed of two or more structural units, the composition of the structural unit derived from the other monomer is the ratio (molar ratio (mol%)) of the total structural units derived from the other monomer to the total of all structural units (100 mol%). Note that this mol% is substantially the same as the ratio of the amount (mol) of the other monomer to the total amount (mol) of all monomers charged when producing the reaction product. Particularly preferably, the reaction product does not contain other structural units (the amount (content) of the other structural units is 0 mol%).

<Method of manufacturing embolus>
Next, a method for manufacturing the embolus 10 will be described. FIG 3 is a flow chart showing the steps of the method for manufacturing the embolus 10.

The manufacturing method of the embolus 10 includes polymerizing and cross-linking the monomer, i.e., cross-linking polymerization (step S1), drying the reaction product after cross-linking polymerization (step S2), removing the porogen from the reaction product by dialysis or the like (step S3), subjecting the reaction product after porogen removal to an acid or alkali treatment (step S4), washing the reaction product after the acid or alkali treatment (step S5), and drying the washed reaction product again (step S6).

Each step will be described below with reference to Figures 4 to 6. Figure 4 is a diagram for explaining the drying process (step S6) of the embolus 10. Also, Figures 5(A) and 6(A) show the dried state of the embolus 10, and Figures 5(B) and 6(B) show the swollen state of the embolus 10.

First, the worker prepares a tubular member and fills the inner cavity of the tubular member with a monomer solution containing solid particles that function as porogens, such as salt particles and barium sulfate particles. The worker then cross-links and polymerizes the monomer filled in the tubular member, and then removes the solid particles that are porogens to form a porous expansion material E (step S1). As a method for cross-linking and polymerizing the monomer, a method that applies heat, a method that irradiates light or radiation, a method that uses a reaction initiator or a reaction accelerator (described in detail later) and a cross-linking agent, or the like, can be used according to the type of monomer. In addition, the material that constitutes the tubular member is not particularly limited, but is preferably a material that does not deform at the reaction temperature. Specifically, resins such as polyethylene, polypropylene, and thermoplastic polyether ester elastomers can be used. In addition, examples of porogens to be contained in the monomer solution include solid particles such as salt particles and barium sulfate particles, as well as polymers that are poor solvents in the monomer solution.

(Reaction initiator and reaction accelerator)
When a reaction initiator is used, there is no particular limitation as long as it can initiate the polymerization reaction, and a known reaction initiator can be used. Specific examples include N,N,N',N'-tetramethylethylenediamine (TEMED). The reaction initiator may be used alone or in combination of two or more. When a reaction accelerator is further used, there is no particular limitation as long as it can accelerate the polymerization reaction, and a known reaction accelerator can be used. Specific examples include ammonium persulfate (APS), sodium persulfate, benzoyl peroxide, azobisisobutyronitrile (AIBN), and water-soluble AIBN derivatives (e.g., 2,2'-azobis(2-methylpropionamidine) dihydrochloride). The reaction accelerator may be used alone or in combination of two or more. At least one of the reaction initiator and the reaction accelerator may be mixed with an ethylenically unsaturated monomer or a crosslinking agent, but it is preferable to mix both the reaction initiator and the reaction accelerator from the viewpoint of the ease of progression of the next polymerization step, reaction time, and the like.

Next, the worker dries the reaction product, the expandable material E, by any drying method such as heat drying, vacuum drying, or air drying (step S2). This causes the expandable material E to shrink and become easier to remove from the tubular member, and also ensures that the cross-linking polymerization reaction is stopped by removing the solvent.

Next, the worker removes solid particles (such as salt particles) that function as porogens in the expandable material E by dialyzing the expandable material E (step S3). This makes it possible to obtain a porous expandable material E having pores F. Therefore, the embolus 10 manufactured by these manufacturing methods has a higher swelling ratio than an expandable material obtained without adding solid particles that are porogens to the monomer solution. In step S3, unreacted residual monomers are also removed by dialysis.

Next, the worker controls the swelling by subjecting the expandable material E to an acid or alkali treatment (step S4). The term "acid treatment" here means incubating the reaction product in a solution with a low or high pH. In particular, when the ethylenically unsaturated monomer has a carboxyl group (or a group derived from a carboxylate salt) such as (meth)acrylic acid or a salt thereof, it is preferable to incubate the reaction product in a solution with a low pH. This allows free protons in the solution to protonate the carboxyl group in the hydrogel network. The hydrogel filament does not swell until the carboxyl group is deprotonated, so that the swelling can be controlled. Also, when the ethylenically unsaturated monomer has an amine group such as N,N-dimethylaminoethyl (meth)acrylate, it is preferable to incubate the reaction product in a solution with a high pH, i.e., to alkali treatment. This deprotonates the amine group. The hydrogel does not swell until the amine group is protonated, so that the swelling can be controlled. Here, the incubation time and temperature, as well as the pH of the solution, are not particularly limited and can be appropriately selected depending on the desired degree of swelling (e.g., swelling rate). In general, the incubation time and temperature are directly proportional to the degree of swelling control, and the solution pH is inversely proportional. In addition, it is preferable to incubate in a sufficient amount of solution. This allows the hydrogel filament to swell more in the solution. In addition, since a larger number of carboxyl groups can be used for protonation or a larger number of amine groups can be used for deprotonation, the swelling rate can be controlled to a more desired degree.

Next, the operator washes the expandable material E to remove the acid and impurities from the acid treatment (step S5), and dries the expandable material E again by blowing air through it (step S6). For example, the hydrogel filament treated with the low pH solution can be dehydrated to a smaller size than the untreated one. Therefore, the embolus 10 produced by this process can be loaded with the hydrogel filament into a catheter with a smaller diameter, and the hydrogel filament can be delivered to the desired site via the catheter, further reducing the invasiveness to the patient.

When performing step S6, the worker suspends the expandable material E from the jig M, and dries the expandable material E in a state in which the expandable material E is stretched in the axial direction due to its own weight (see FIG. 4). The method for drying the expandable material E is not particularly limited, and for example, heat drying, reduced pressure drying, and natural drying can be used. The method for stretching the expandable material E in the axial direction is also not particularly limited, and for example, a method of fixing one end of the expandable material E and pulling the other end, or a method of pulling the expandable material E from both ends can be used.

The expandable material E that has been dried in an axially stretched state (in other words, the main body 11 of the embolus 10 obtained by drying the expandable material E) is fixed in a state in which the pores F are stretched in the axial direction, as shown in (A) and (B) of FIG. 5. Therefore, when the embolus 10 comes into contact with an aqueous liquid containing blood under physiological conditions, the pores F tend to return to their original shape, making them more likely to expand in the radial direction than in the axial direction. Note that the pores F are only formed when the expandable material E is formed using solid particles that function as porogens, and the size of the pores F is on the order of microns (a size that can be expressed in micro units).

In addition, the expandable material E that is dried while stretched in the axial direction (in other words, the main body 11 of the embolus 10 obtained by drying the expandable material E) has a high orientation of the polymer chains G in the axial direction, as shown in (A) and (B) of Figure 6. Therefore, when the embolus 10 comes into contact with an aqueous liquid containing blood under physiological conditions, the polymer chains G tend to return to their original state, and so the embolus 10 tends to expand in the radial direction compared to the axial direction.

In this way, the worker can produce a dehydrated hydrogel filament by performing steps S1 to S6, and obtain the hydrogel filament (embolus 10) of the present invention.

The manufacturing method of the above-mentioned embolus 10 can be modified in various ways. For example, an operator can select a process for manufacturing the embolus 10 according to the type of solid particles and the type of monomer selected in advance, and combine each process.

In addition, in step S1 described above, cross-linking is performed while polymerization is performed, but the procedure may be such that cross-linking is performed after polymerization.

In addition, since the porous expandable material E can be obtained even if steps S2, S4, and S5 are omitted, these steps may be omitted.

Although the above describes the case where the expandable material E is formed using solid particles that function as porogens, the expandable material may be a non-porous (having no pores) material formed without using the solid particles. Note that since the porous expandable material E can be obtained even when steps S2 to S5 are omitted, these steps may be omitted. The orientation of the polymer chains in the non-porous expandable material follows a mechanism similar to that of the polymer chains in the porous expandable material (see FIG. 6). Therefore, when the non-porous expandable material manufactured by the above manufacturing method comes into contact with an aqueous liquid containing blood under physiological conditions, the polymer chains G tend to return to their original state, and therefore expand more easily in the radial direction than in the axial direction.

<Medical instrument set>
Next, a description will be given of the configuration of the medical instrument set 100. As shown in Fig. 7, the medical instrument set 100 includes an embolic material loading catheter 20 and a delivery catheter 30.

The embolic material loading catheter 20 includes a main body 21 having a loading lumen and a base end hub 22 provided on the base end side of the main body 21. The embolic material loading catheter 20 is used in a state in which the embolic material 10 is accommodated in the loading lumen and attached to the delivery catheter 30. At this time, the embolic material 10 loaded in the loading lumen is pushed toward the inside of the aneurysm by inserting the delivery pusher 40 from the base end hub 22. The embolic material loading catheter 20 is generally provided in a state in which the embolic material 10 is loaded in advance, but the embolic material 10 to be loaded in the main body 21 may be held by an operator or the like and loaded into the main body 21. In addition, as a method of loading the embolic material 10, the operator can hold the embolic material 10 and insert it from the tip side opening or the base end hub 22 side of the embolic material loading catheter 20.

The delivery catheter 30 includes a sheath 31 in which a sheath lumen (not shown) is provided, and is configured to allow insertion of the main body 51 of the insertion assistance member 50 (described later). The delivery catheter 30 is placed in the body lumen and can function as an introduction path for delivering the embolus loading catheter 20 into the aneurysm.

<Delivery system>
Next, a description will be given of the configuration of the delivery system 200. As shown in Fig. 7, the delivery system 200 according to the first embodiment includes, in addition to the medical instrument set 100, a delivery pusher 40 for pushing the embolus 10 into the aneurysm.

The delivery pusher 40 has a pusher body 41 made of a long rod-shaped member, and is inserted by the surgeon from the base end hub 22 with the embolus loading catheter 20 inserted into the delivery catheter 30. When the delivery pusher 40 is inserted into the embolus loading catheter 20, it can push the embolus 10 contained in the loading lumen into the aneurysm.

<Embolization delivery medical system>
Next, a description will be given of the configuration of the embolic object delivery medical system 300. As shown in Fig. 8, the embolic object delivery medical system 300 according to this embodiment includes, in addition to the delivery system 200, an insertion assist member 50 for delivering the delivery catheter 30 into a biological lumen.

The insertion assistance member 50 has a main body 51 in which a guidewire lumen 52 is provided, and can assist in the operation of delivering the delivery catheter 30 into the aneurysm along a guidewire that has been previously inserted into the biological lumen.

[motion]
Next, a description will be given of the operation of the embolus delivery medical system 300 according to the first embodiment. Figures 9A to 9D are diagrams for explaining main procedural steps in endoleak embolization for stent graft insertion of abdominal aortic aneurysm.

As shown in FIG. 9A, the surgeon inserts the sheath 31 of the delivery catheter 30 with the guidewire GW inserted therein percutaneously into the biological lumen via an introducer from the patient's limb that will be the puncture site, and delivers the distal end opening of the delivery catheter 30 to the abdominal aortic aneurysm. When the distal end opening of the delivery catheter 30 is delivered to the inside of the aneurysm (inside the aneurysm) s, the surgeon removes the guidewire GW. Note that the delivery catheter 30 may be delivered to the aneurysmal site with the guidewire GW inserted into the insertion assisting member 50 and the guidewire GW and the insertion assisting member 50 inserted into the delivery catheter 30.

Next, as shown in FIG. 9B, the surgeon inserts a catheter (stent graft device) with the stent graft SG compressed and inserted via an introducer into the biological lumen, and moves it to the affected area of the aneurysm using a guide wire previously inserted into the aneurysm s. The stent graft SG is then deployed and placed from the catheter at the affected area. As a result, the delivery catheter 30 is placed in the biological lumen with the tip of the delivery catheter 30 inserted between the legs of the stent graft SG and the blood vessel wall of the aneurysm, i.e., into the aneurysm s, through the gap between the legs of the stent graft SG and the blood vessel wall, and with the tip opening positioned within the aneurysm s.

When the delivery catheter 30 is placed, the surgeon attaches the distal end of the embolus-loading catheter 20, which is loaded with the embolus 10, to the proximal end of the delivery catheter 30. The surgeon then inserts the distal end of the delivery pusher 40 from the proximal end of the proximal hub 22. The distal end of the delivery pusher 40 inserted from the proximal hub 22 comes into contact with the proximal end of the embolus 10 loaded in the embolus-loading catheter 20, and the embolus 10 is pushed out and moved into the sheath lumen of the delivery catheter 30 by a pushing operation.

Next, as shown in FIG. 9C, the surgeon pushes out the delivery pusher 40 inserted from the base hub 22 to push the embolus 10 out of the sheath lumen of the delivery catheter 30 into the aneurysm s. After that, the surgeon detaches the empty embolus loading catheter 20 together with the delivery pusher 40 from the delivery catheter 30. The delivery pusher 40 can be detached from the delivery catheter 30 while still inserted in the embolus loading catheter 20. This completes the first insertion of the embolus 10 into the aneurysm s. Note that in the insertion operation, the delivery pusher 40 may be pulled out of the embolus loading catheter 20 before the embolus loading catheter 20 is detached. This series of embolus placement operations is repeated until the required amount of embolus 10 is loaded into the aneurysm s. The required amount is calculated by calculating the volume of the aneurysm based on the patient's CT data, and subtracting from that value the volume of the stent graft SG that would be deployed in that aneurysm.

When the placement of the required amount of embolus 10 in the aneurysm s is completed, the surgeon withdraws the delivery catheter 30 from the aneurysm s and the biological lumen. At this time, the delivery catheter 30 may be withdrawn from the aneurysm s and the biological lumen with the embolus loading catheter 20 attached to the delivery catheter 30 and the delivery pusher 40 inserted into the delivery catheter 30. Also, before withdrawing the delivery catheter 30 from the aneurysm s and the biological lumen, the delivery pusher 40 may be withdrawn from the delivery catheter 30 while detaching the embolus loading catheter 20 from the delivery catheter 30. Also, before withdrawing the delivery catheter 30 from the aneurysm s and the biological lumen, the delivery pusher 40 may be withdrawn from the delivery catheter 30 and the embolus loading catheter 20, and the embolus loading catheter 20 may be detached ... In either case, the introducer is left in place within the biological lumen for the purpose of further expanding the stent graft SG with a balloon after placement of the embolus 10, contrast manipulation, etc.

As shown in FIG. 9D, the embolus 10 placed inside the aneurysm s gradually swells upon contact with liquids such as blood inside the aneurysm s, and when the embolus 10 is fully expanded, it fills the space between the inner surface of the aneurysm and the outer surface of the stent graft, thereby occluding the aneurysm s. This prevents the aneurysm from rupturing.

[Action and Effect]
As described above, the embolus 10 according to this embodiment is an embolus that is inserted into and left in a lump in a living body, and has a long main body portion 11 that extends in the axial direction. The main body portion 11 is characterized by having an expansion characteristic in which, upon contact with blood, it expands more in a direction perpendicular to the axial direction than in the axial direction.

When the embolus 10 configured as described above comes into contact with an aqueous liquid containing blood under physiological conditions, it tends to expand in a direction perpendicular to the axial direction (in the radial direction if the embolus 10 is a linear body, and in the width or thickness direction if the embolus 10 is a flat body). This makes the embolus 10 more likely to become clogged on the proximal side of the branch blood vessel t and less likely to stray into the distal side of the branch blood vessel t. Therefore, the embolus 10 can reduce the risk of distal embolism.

The embolus 10 is also characterized in that the main body 11 is formed from a porous expandable material E, and the pores F of the main body 11 are stretched in the axial direction. Therefore, when the main body 11 comes into contact with an aqueous liquid containing blood under physiological conditions, the pores F tend to return to their original shape, making it easier for the main body 11 to expand in the radial direction compared to the axial direction.

The manufacturing method of the embolus 10 is a manufacturing method of an embolus that is inserted into and retained in a lump s in a living body, and includes cross-linking and polymerizing the monomer in the monomer solution to form an expandable material E, and drying the expandable material E in an axially stretched state.

The manufacturing method for the embolic object 10 configured as described above can manufacture an embolic object 10 that easily expands in a direction perpendicular to the axial direction when it comes into contact with an aqueous liquid containing blood under physiological conditions. As a result, the embolic object 10 manufactured by the above manufacturing method can reduce the risk of distal embolization.

The method is also characterized in that the porogen that forms pores F in the expandable material is contained in the monomer solution, and the porogen is removed after cross-linking polymerization of the monomer to form a porous expandable material E, and the porous expandable material E is dried in an axially stretched state. The porous expandable material E produced by this manufacturing method has a higher swelling ratio than an expandable material obtained without adding solid particles of the porogen to the monomer solution. In addition, when the porous expandable material E is dried in an axially stretched state after removing the porogen, the pores F formed by the porogen are fixed in an axially stretched state, so that when the embolus 10 comes into contact with an aqueous liquid containing blood under physiological conditions, the pores F tend to return to their original shape, and are therefore more likely to expand in the radial direction than in the axial direction.

The porogen is also characterized in that it is a solid particle that can be removed by dialysis after cross-linking polymerization of the monomer. By using such solid particles, the worker can form a porous expansion material E.

10 Embolism,
11 Main body portion,
100 medical instrument sets,
200 Delivery System,
300 Embolic material delivery medical system,
E. Expandable material;
F: voids in the expansive material;
In the X-axis direction,
Y: width direction,
Z height direction,
r Radial direction.

Claims (5)

An embolus that is inserted into and retained in a lump in a living body,
The nozzle has an elongated main body portion extending in an axial direction,
The embolus has an expansion characteristic in which the main body portion expands more in a direction perpendicular to the axial direction than in the axial direction when it comes into contact with blood. The body portion is formed of a porous expandable material;
2. The embolus according to claim 1, wherein the bore of the body portion is elongated in the axial direction. A method for manufacturing an embolus that is inserted into and placed in a lump in a living body, comprising the steps of:
cross-linking the monomers in the monomer solution to form an expandable material;
and drying the expandable material in an axially elongated state. A porogen that forms pores in the expandable material is contained in the monomer solution;
removing the porogen after cross-linking and polymerizing the monomer to form the porous expandable material;
4. The method for producing an embolus according to claim 3, wherein the porous expandable material is dried in a state stretched in the axial direction. The method for producing an embolus according to claim 3 or 4, characterized in that the porogen is a solid particle that can be removed by dialysis after cross-linking polymerization of the monomer.