JP2001299769A - Coil for speeding up organization used for surgery in blood vessel and indweller for coil in blood vessel - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an indwelling coil which promotes organization around the coil for an intravascular surgery. SOLUTION: The indwelling coil 1 in the blood vessel for the intravascular surgery is provided with a metallic coil body 2 and a vector 5 containing cell proliferating factors or genes of cell proliferation fixed on the surface 2a of the coil body 2. The cell proliferating factors or the vectors 5 are released from the coil 1 to the specified points in the blood vessel, for example, vascular disorder sites such as aneurysm, arterial and venous malformation, alterial and venous tumor, and the like, and embolic points of nutrition artery to tumors for promoting tissue growth.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a coil used for endovascular treatment.

[0002]

2. Description of the Related Art In endovascular treatment using a catheter and embolic material, embolization treatment of a vegetative artery for a vascular disorder or tumor such as an aneurysm, arteriovenous malformation or arteriovenous fistula has been performed. Various embolic materials have been used, but coils have recently been frequently used due to their safety and simplicity. In this case, the distal end of the catheter is guided to the vicinity of the treatment site, and a coil is injected into the treatment portion from the distal end, or a guide wire having a coil at the distal end is inserted into the treatment portion through the catheter, and the coil portion is detached. And place it in the treatment section. By the coil itself and the thrombus formed on the coil, the blood flow to the treatment section is cut off, and the treatment is performed.

[0003]

Although the efficacy and safety of this treatment method are clear, the number of cases in which coils have been rapidly applied in recent years has been increasing, and the limitations have been gradually but clearly increased. It has become For example, in the treatment of an aneurysm, the goal has been to set the volume fraction of the coil placed in the aneurysm to 30% or more in order to prevent blood from flowing into the aneurysm. Initially, when the coil is placed at a volume fraction of 30% or more, a thrombus is formed in the aneurysm, fibroblasts and vascular endothelial cells proliferate, the thrombus is organized in the aneurysm, and the aneurysm is further reduced. The entrance was covered with endothelial cells and was expected to be cured. However, when observing the treated part of an animal experimental model or an autopsy case, the surroundings of the coil are not organized even after a long time after the placement of the coil, and the coil is in direct contact with the blood flow, especially at the opening of the aneurysm Condition. In such a condition, the thrombus sometimes formed in the coil is detached, which can occlude blood vessels and cause cerebral infarction. In addition, the risk of rupture of the aneurysm due to blood flow flowing into the aneurysm cannot be ignored. For this reason, development of a coil that promotes organization is desired.

[0004] As a coil for promoting organization, a platinum coil subjected to ion implantation and a coil in which collagen protein is adsorbed on a platinum coil subjected to ion implantation have been developed, and are effective in animal experiments. [(Y. Murayama, Y. Suzuki, F. Vinuela, et a
l. (Developement of a Biologically active Guglielm
i Detachable Coil for the Treatment of Cerebral An
eurysms.Part I: InVitro Study), AJNR Am J. Neuror
adiol, 20, 1986-1991 (1999): Y. Murayama, F. Vi
nuela, Y. Suzuki, (Developement of a Biologically
active Guglielmi Detachable Coil for the Treatment
of Cerebral Aneurysms.Part II: An Experimental S
tudy in a Swine Aneurysm Model, AJNR Am J. Neurora
diol, 20,1992-1999 (1999)]. However, this only improves the adhesion of cells to the surface of the coil,
The organization is not actively promoted. Therefore, its effect is limited. In addition, because ion implantation is expensive,
It has not spread to date.

[0005] It is an object of the present invention to provide a coil which is to be placed in a blood vessel during an intravascular operation and which can promote organization around the coil.

[0006]

SUMMARY OF THE INVENTION The present invention relates to a coil for indwelling in a blood vessel during an intravascular operation, comprising a metal coil body, and a cell proliferation fixed on the surface of the coil body. And a vector containing a gene of a factor or a cell growth factor.

The inventor of the present invention carried a cell growth factor for promoting cell growth or a vector containing a gene for the cell growth factor on the surface of the coil, placed the coil in the treatment section, and then gradually released the cell growth factor from the coil. By injecting the vector containing the gene for the cell growth factor into surrounding cells, it was found that the cell growth could be promoted in the treatment part, and the organization could be further promoted. Thus, the present invention was completed. Since such a coil solves the limitation of the intravascular indwelling coil, the limitation of which has become apparent as clinical cases have increased, the probability of being used by medical device manufacturers worldwide is extremely high, The industrial advantages are significant.

[0008] The coil is preferably placed at a site of vascular injury. By placing the coil of the present invention in a blood vessel, particularly at a vascular injury site, organization around the coil can be promoted. The vascular disorder site is, for example, an aneurysm, arteriovenous malformation, arteriovenous fistula, or the like. It is also useful for the treatment of embolism of a feeding artery to a tumor.

FIG. 1 is a schematic diagram showing a state where the coil of the present invention is placed in an aneurysm 8 of a blood vessel 7. This coil 1
It is found that the indwelling of the aneurysm 8 allows fibroblasts 9 to proliferate in the aneurysm 8 to organize the aneurysm 8, and that the opening of the aneurysm 8 can be covered with vascular endothelial cells 10. As a result, scattering of thrombus and rupture of an aneurysm can be effectively prevented.

In order to immobilize a cell growth factor or a vector on the surface of the coil body in the present invention, it is preferable to have a dissociable polar group 4 of a basic or acidic group, as shown in FIG. The film of substance 3 is applied to coil body 2
Of the cell growth factor 5 on the surface of this membrane.
Is immobilized by ionic interaction with the dissociative polar group 4 to obtain the coil 1. In the example of FIG. 2B, when the cell growth factor 5 is negatively charged, it is necessary to use a compound having a basic dissociable polar group.

In another embodiment of the present invention, FIG.
As shown in (a) and (c), the surface 2a of the coil body 2
A substance 3 having a basic or acidic dissociable polar group 4
Is provided. Then, the polymer compound 6 having a charged acidic group or basic group opposite to the dissociable polar group is immobilized on the membrane by ionic interaction. Therefore, when the dissociative polar group 4 of the membrane is positively charged, that is, when it is a basic group, the polymer compound 6 is negatively charged, that is, it is necessary to have an acidic group. is there. When the dissociative polar group 4 of the membrane is negatively charged, that is, when it is an acidic group, the polymer compound 6 must be positively charged, that is, have a basic group. Next, the cell growth factor 5 is immobilized on the polymer compound 6 by ionic interaction, hydrogen bonding, or affinity interaction.

The substance 3 constituting the membrane is not limited, but is preferably a chain hydrocarbon compound having a thiol group at one end and a dissociable polar group at the other end.
More preferably, this chain hydrocarbon has a self-organizing ability. The hydrocarbon compound is preferably an alkyl compound or an olefin compound, and more preferably an alkyl compound. The hydrocarbon compound may be branched or linear, but is particularly preferably linear for ease of self-organization.

The dissociable polar group 4 of the substance 3 is an acidic group or a basic group. As the basic group, a primary amino group, a secondary amino group, a tertiary amino group, and a quaternary amino group are preferable. As the acidic group, a carboxyl group, a sulfonic group, and a sulfate group are preferable.

When the substance 3 is composed of a hydrocarbon compound, the number of carbon chains (CH2 groups) in the hydrocarbon compound, especially the alkanethiol substituted with a dissociative polar group, is 1-30.
Are preferred, and 5-20 are more preferred.

When a thiol group is provided on the substance 3, it is particularly preferable to form a gold film on the surface of the coil body 2. The gold film can be formed by an evaporation method, a sputtering method, a chemical vapor deposition method, or the like. Gold film thickness is 5-100
It is preferably set to nm. In this case, the material of the coil body is preferably platinum or an alloy of platinum because of its biocompatibility. However, since it is difficult to perform surface treatment on platinum itself, it is preferable to provide a gold film on the surface of platinum. Examples of the metal alloyed with platinum include tungsten and iridium.

The film 3 may be a film formed by a silane coupling process. This is particularly suitable when an oxide film is present on the surface of the coil body.
As an oxide film on the surface of the coil body,
For example, there is a coil made of a nitinol alloy. In such a case, a silane coupling agent having a dissociable polar group (acidic group or basic group) at one end is attached to the surface of the coil body. Such a basic group includes a primary amino group, a secondary amino group, a tertiary amino group, and a quaternary amino group. As the silane coupling agent, γ-aminopropyltriethoxysilane, N-β- (amino) -γ-aminopropyltrimethoxysilane, and silaneoctadecyldimethyl (3- (trimethoxysilyl) propyl) ammonium chloride are preferable. Cell growth factors can be adsorbed on the surface by direct ionic interaction.

As shown in FIG. 2C, by further immobilizing the polymer compound 6 having a dissociative polar group,
Cell growth factor loading can be significantly increased. For example, as shown in FIG. 2C, when the dissociable polar group 4 of the substance 3 is a basic group (positively charged), the polymer compound 6 having an acidic group (negatively charged) ) Is adsorbed. On the other hand, when the dissociable polar group 4 of the substance 3 is an acidic group (negatively charged), the polymer compound 6 having a basic group (positively charged) is adsorbed.

Further, by alternately and repeatedly adsorbing the polymer compound having an acidic group and the polymer compound having a basic group, a larger amount of functional groups can be introduced to the coil surface. Cell growth factor 5 is ion-adsorbed, hydrogen-bonded or affinity-adsorbed onto the surface coated with the polymer compound, and is carried.

According to the present invention, a treating agent having a basic group or an acidic group on the surface or a long-chain polymer is further laminated on the surface so that the group on the surface is a basic group or an acidic group. Either of them can be the main component, and a coil capable of carrying a positively or negatively charged cell growth factor by ionic interaction can be produced. By using a natural polymer, a cell growth factor having affinity for the natural polymer can be carried.

Further, by appropriately selecting the length, density, etc. of the polymer having an affinity interaction site with the cell growth factor, the molecular aggregate of the cell growth factor having a large particle size, the encapsulation of the cell growth factor or the vector can be obtained. Microcapsules can be carried regardless of the sign of the charge. Such molecular assemblies and microcapsules are usually difficult to carry. Further, the cell growth factor can be locally administered at a high concentration continuously.

Examples of the high molecular compound having an acidic group include synthetic polymers such as acrylic acid, methacrylic acid, polymaleic acid, polystyrene sulfonic acid, polyvinyl sulfonic acid ester, polymers having a phosphoric acid group in the side chain, and glutamic acid. Polymers, carboxymethylcellulose which is a semi-synthetic polymer, cellulose sulfate, alginic acid which is a natural polymer, chondroitin sulfate, heparan sulfate,
Dermatan sulfate, keratan sulfate, hyaluronic acid, heparin and the like. Further, two or more of these materials may be combined.

Examples of the high molecular compound having a basic group include:
Synthetic polymer polyallylamine, polyethyleneimine, polylysine, 2-diethylaminomethylmethacrylate, N-3-N, N-dimethylaminopropylacrylamide, polypropylene, semi-synthetic polymer diethylaminoethyldextran, natural polymer Oxosan and protamine. Further, two or more of these materials may be combined.

The cell growth factor only has to be capable of proliferating cells at a target site. For this reason, the type of cell growth factor required can be selected depending on the target placement site, and there is no limitation on the type of cell growth factor. For example, various growth factors such as basic fibroblast growth factor, acidic fibroblast growth factor, vascular endothelial cell growth factor, hepatocyte growth factor, and platelet-derived growth factor are exemplified. In addition, examples of vectors containing these cell growth factor genes include plasmids and viral vectors. Further, a combination of two or more cell growth factors and vectors may be used.

The cell growth factor may be immobilized on only a part of the surface of the coil body, but is preferably provided on the entire surface of the coil.

The molecular weight of the high molecular compound can be appropriately adjusted depending on the kind of physiological activity to be carried, etc., preferably 500 to 100,000,000, particularly preferably 10,000-1.
Preferably it is 0,000,000. Further, the amount of the polymer compound laminated on the coil surface can be appropriately adjusted depending on the kind of physiological activity to be carried. Although it depends on the material and molecular weight of the polymer compound, it is preferably 0.1-1000
μg / cm 2, particularly preferably 1-200 μg / cm 2.

In order to carry the cell growth factor or vector on the surface-treated coil, a coil having a charged surface opposite to that of the cell growth factor or vector is immersed in an aqueous solution of the cell growth factor or vector. The growth factor or vector is ion-adsorbed to the coil surface. Alternatively, a coil carrying a polymer compound that has an affinity interaction with the cell growth factor is immersed in an aqueous solution of the cell growth factor, and the cell growth factor is affinity-adsorbed to the coil surface.

P of aqueous solution of cell growth factor or vector
H is appropriately adjusted by the functional group on the coil surface and the cell growth factor, but is preferably 2-11, particularly preferably 4-11. Further, a plurality of types of cell growth factors may be carried on the coil. Furthermore, a negatively charged polymer is provided on a part of the surface of the coil, and a positively charged polymer is provided on the other part, so that a positively charged cell growth factor and a negatively charged cell growth factor are combined into one. It can also be carried on a coil.

[0028]

(Example 1) A platinum-tungsten (8%) alloy wire having a wire diameter of 50 μm was wound to obtain a platinum coil having a diameter of 250 μm. 30 μm of gold was deposited on the platinum coil using an ion coater manufactured by Hitachi, Ltd. The gold-deposited coil was immersed in a nitrogen-substituted ethanol solution containing 11-mercaptoundecanoic acid containing 0.001 mole / dl for 24 hours, and
A self-assembled film of 11-mercaptoundecanoic acid was formed. By this treatment, a large number of carboxyl groups are introduced into the coil surface. This coil was alternately immersed three times in a 2% aqueous solution of polyethyleneimine at pH 10 and a 2% aqueous solution of heparin at pH 7, thereby laminating a polyion complex of polyethyleneimine-heparin on the coil surface. The final immersion is performed with a heparin solution, so that the outermost layer of the coil is covered with heparin. The coil whose outermost layer was coated with heparin was immersed in a 1 ml solution containing 50 μg of basic fibroblast growth factor for 1 hour to carry the basic fibroblast growth factor.

A coil carrying basic fibroblast growth factor was implanted subcutaneously in ddY mice.
On days 7, 7 and 14, the coil and surrounding tissue were removed subcutaneously. After removing the coil from the tissue, a thin section of the tissue was prepared, stained with hematoxylin-eosin, and the tissue image was observed with an optical microscope. Numerous new blood vessels were seen in the tissue around the site where the coil was present, and fibroblast proliferation was also seen. This phenomenon is due to basic fibroblast growth factor released from the coil.

Comparative Example 1 A platinum-tungsten (8%) alloy wire having a wire diameter of 50 μm was wound to obtain a coil having a diameter of 250 μm. The untreated platinum coil was implanted subcutaneously in ddY mice, and the coil and surrounding tissue were removed subcutaneously on days 4, 7 and 14 after implantation. After removing the coil from the tissue, a thin section of the tissue was prepared, stained with hematoxylin-eosin, and the tissue image was observed with an optical microscope.
Although some connective tissue was formed in the tissue around the site where the coil was present, the degree was extremely small.

Example 2 A nitinol alloy wire having a wire diameter of 50 μm was wound to obtain a nitinol coil having a diameter of 250 μm. This coil was immersed in a hexane solution containing 1% of N-β- (amino) -γ-aminopropyltrimethoxysilane for 1 hour, and further dried by heating at 60 ° C. to perform a silane coupling treatment. By this treatment, a large number of amino groups are introduced into the surface of the coil body. The coil was alternately immersed in a 2% aqueous solution of heparin at pH 7 and a 2% aqueous solution of polyethyleneimine at pH 10. However, heparin 2
% Aqueous solution three times, and twice in a 2% aqueous solution of polyethyleneimine. Thus, the heparin-polyethyleneimine polyion complex was carried on the coil surface. The final immersion is performed with a heparin solution,
The outermost layer of the coil is covered with heparin. By immersing the coil whose outermost layer is coated with heparin in a 1 ml solution containing 50 μg of basic fibroblast growth factor for 1 hour,
Basic fibroblast growth factor was carried.

A coil carrying basic fibroblast growth factor was implanted subcutaneously in ddY mice.
On days 7, 7 and 14, the coil and surrounding tissue were removed subcutaneously. After removing the coil from the tissue, a thin section of the tissue was prepared, stained with hematoxylin-eosin, and the tissue image was observed with an optical microscope. Numerous new blood vessels were seen in the tissue around the site where the coil was present, and fibroblast proliferation was also seen. This phenomenon is due to basic fibroblast growth factor released from the coil.

(Comparative Example 2) A nitinol alloy wire having a wire diameter of 50 µm was wound, and a Nitinol coil having a diameter of 250 µm was d dY
The mouse was implanted subcutaneously, and on days 4, 7 and 14 after implantation, the coil and surrounding tissue were removed from the skin.
After removing the coil from the tissue, a thin section of the tissue was prepared, stained with hematoxylin-eosin, and the tissue image was observed with an optical microscope. Although some connective tissue was formed in the tissue around the site where the coil was present, the degree was extremely small.

(Example 3) A platinum coil ("ED coil" manufactured by Kaneka Medix Co.) connected to the tip of a guide wire via a detachment mechanism was treated according to the method of Example 1,
Fibroblast growth factor was carried. This coil was inserted into the common carotid artery of a mongrel dog and the tip of the microcatheter was guided into the aneurysm through this catheter. Further, a guide wire having a platinum coil at the tip was inserted into the microcatheter, and the tip platinum coil was guided into the aneurysm. After confirming that the platinum coil was within the aneurysm, the guide wire was energized to separate the platinum coil from the guide wire, and the platinum coil was placed in the aneurysm.
This operation was repeated until the coil filling rate in the aneurysm exceeded 30%.

After removing the catheter and the guide wire, the dog was kept under normal conditions for one month. Thereafter, the aneurysm model site was excised from the dog, and the aneurysm was macroscopically viewed from the inside of the blood vessel. The opening of the aneurysm was closed with glossy tissue.

Comparative Example 2 The same operation as in Example 3 was performed except that the ED coil manufactured by Kaneka Medix was used as it was. One month later, when the opening of the aneurysm was observed, a platinum coil having a metallic luster was observed without any tissue in the opening.

[0037]

As described above, according to the present invention, a coil for indwelling in a blood vessel at the time of an intravascular operation, and organization around the coil can be promoted.

[Brief description of the drawings]

FIG. 1 is a schematic view showing a state where a coil is placed in an aneurysm in a blood vessel.

FIG. 2A is a front view of the coil 1. FIG. (B)
This shows a state in which a membrane 3 made of a substance having a dissociable polar group 4 and a cell growth factor or a vector 5 are adsorbed on the surface 2a of the coil body 2. (C) shows a state in which the membrane 3 made of the substance having the dissociable polar group 4, the polymer compound 6, and the cell growth factor or vector 5 are adsorbed on the surface 2a of the coil body 2.

[Description of Signs] 1 coil 2 coil body 2a surface of coil body 2 3 substance having dissociable polar group 4 dissociable polar group 5 cell growth factor or vector 6 polymer compound having dissociable polar group 7 artery 8
Aneurysm 9 Fibroblast 10 Vascular endothelial cell

Claims (11)

[Claims] 1. A coil for indwelling in a blood vessel during an intravascular operation, comprising: a metal coil body; and a cell growth factor or a cell growth factor gene immobilized on the surface of the coil body. And a vector containing the coil. 2. A membrane comprising a substance having a basic or acidic dissociable polar group provided on the surface of the coil body, wherein the cell growth factor or the vector is provided on the surface of the membrane with the dissociable polar group. The coil according to claim 1, wherein the coil is fixed by an ionic interaction with a polar group. 3. A film of a substance having a basic or acidic dissociable polar group provided on the surface of the coil body, and an acidic group or a basic group immobilized on the film by ionic interaction. And a polymer compound having
The coil according to claim 1, wherein the cell growth factor or the vector is immobilized on the polymer compound by an ionic interaction, an affinity interaction, or a hydrogen bond. 4. The film comprises a self-assembled film of a chain hydrocarbon compound having a thiol group at one end and the dissociable polar group at the other end. The coil according to claim 2. 5. The coil according to claim 4, wherein a gold film is formed on a surface of the coil main body. 6. The coil according to claim 2, wherein the film is a film formed by a silane coupling process. 7. The coil according to claim 6, wherein an oxide film is present on a surface of the coil body. 8. The polymer according to claim 3, wherein the polymer compound having an acidic group and the polymer compound having the basic group are alternately laminated on the film. A coil according to one claim. 9. The coil according to claim 3, wherein the polymer compound is selected from the group consisting of proteoglycans and glycosaminoglycans. 10. The coil according to claim 9, wherein said glycosaminoglycan is selected from the group consisting of heparin and heparan sulfate. 11. An indwelling device for indwelling a coil in a blood vessel during an intravascular operation, comprising: a guide wire to be housed in a blood vessel; a coil connected to a tip of the guide wire; A detachment mechanism for allowing detachment of the coil from the guide wire after fixing the coil in a blood vessel,
An indwelling device, wherein the coil is the coil according to any one of claims 1 to 10.