Catheter embolization training method, training kit, and training system

Abstract

This catheter embolization training method includes: a step for using a substrate 20 having a first opening part 22, a second opening part 23, and a passage 24 extending between the first opening part 22 and the second opening part 23, and administering, into the passage 24, a liquid 14 containing a polymer having a nucleophilic group so as to flow from the first opening part 22 to the second opening part 23 through the passage 24; and a step for administering a liquid 42 containing a cyanoacrylate-based adhesive from the first opening part 22 of the substrate 20.

Description

Vascular embolization training method, training kit, and training system

[0001] The present invention relates to a training method, a training kit, and a training system for vascular embolization.

[0002] Cyanoacrylate adhesives are widely known as medical adhesives, and n-butyl-2-cyanoacrylate (NBCA), an embolic agent used in endovascular treatment, is a liquid drug that was recently covered by insurance in 2023. B. Braun sells NBCA with the dye D&C Violet No. 2 as Histoacryl (approval number 22500BZX00183000). NBCA instantly solidifies within blood vessels, making it an irreplaceable agent that quickly embolizes even life-threatening massive bleeding.

[0003] However, its rapid solidification rate and lack of visibility under X-ray fluoroscopy preclude its use in endovascular procedures alone. Mixing NBCA with Lipiodol® 480 allows for the adjustment of the solidification rate and the enhancement of X-ray visibility, making it an embolic material suitable for endovascular procedures. However, its use requires a somewhat complicated procedure, requiring the surgeon to determine the dilution and dosage of NBCA at their discretion, and completing the treatment with a single, irreversible administration. This makes the procedure significantly more difficult than other embolic materials, such as gelatin sponges, beads, and coils. Furthermore, the use of NBCA intravascularly can result in serious complications, such as adhesion of the catheter to the vessel wall, resulting in inability to remove the embolic material, subsequent vascular injury, peripheral leakage of the embolic material, and unintended organ ischemia due to reflux.

[0004] Skilled use is required because incorrect judgment or technique before or during use can lead to serious complications or treatment failure. While the use of NBCA / Lipiodol mixed solution requires the surgeon to be an interventional radiologist or equivalent, the training required by the medical association is e-learning (Non-Patent Document 1), and not all interventional radiologists have sufficient experience or skill. Therefore, the establishment of a method for surgeon education is urgently needed. However, currently, training is primarily conducted in actual clinical settings and with patients, with methods that are not standardized across facilities. Therefore, the establishment of off-the-job training that does not involve invasive intervention is urgently needed.

[0005] Patent Document 1 discloses a training kit for embolization using a balloon.

[0006] Non-Patent Document 2 discloses a training kit using bovine serum, which differs from the present invention in that it uses a straight tube as a blood vessel model.

[0007] Non-Patent Document 3 examines the embolization effect of Onyx, an embolic material used in the intravascular treatment of arteriovenous malformations, by applying it to a pulsatile flow model made of ABS resin that mimics the human vascular structure using a 3D printer. The fluid flowing through the pulsatile flow model is water.

[0008] Patent Publication No. 2023-099619

[0009] Expanded indications for Histoacryl: e-learning information, B. Braun Aesculap Co., Ltd. [Retrieved March 14, 2024], Internet: https: / / www.jsir.or.jp / docs / nbca / e_learning / register.pdf. N. Hayashi et al., Cardiovascular Interventional Radiology, Volume 43(4), pages 630-645, 2020, DOI: 10.1007 / s00270-019-02393-5F. Ayabe et al., Journal of Neuroendovascular Therapy, Vol. 15, No. 11, pp.741-746, 2021, DOI: 10.5797 / jnet.tn.2020-0141

[0010] Patent Document 1 does not address vascular embolization training using an embolic solution. Non-Patent Document 2 measures the polymerization time of a mixed solution of NBCA and Lipiodol using fetal bovine serum, but using serum itself is inferior in terms of quality stability and safety management. Furthermore, since a straight tube is used as the vascular model, its structure is significantly different from that of actual blood vessels with branches. Non-Patent Document 3 examines Onyx and cannot be used for NBCA-based embolization training.

[0011] The problem to be solved by the present invention is to provide a vascular occlusion training method, a vascular embolization training kit, and a vascular embolization training system that use reagents with excellent quality stability and that can train occlusion of branched ducts using cyanoacrylate adhesives.

[0012] The present invention includes the following embodiments: Item 1. A method for training tube occlusion, comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening, the passage including a main passage and a plurality of branch passages extending from the main passage at branch portions; dispensing a liquid containing a polymer having a nucleophilic group into the passage from the first opening through the passage and to the second opening; and dispensing a liquid containing a cyanoacrylate adhesive from the first opening of the substrate. Item 2. The cyanoacrylate adhesive is a cyanoacrylate adhesive represented by the formula HC=C(CN)-COOR (wherein R is C 1-15 Item 3. The method according to item 1, wherein the cyanoacrylate adhesive-containing liquid further comprises an oil-based contrast agent. Item 4. The method according to item 1, wherein the polymer having a nucleophilic group comprises a protein having the same structure as a protein present in blood. Item 5. The method according to item 1, wherein the liquid containing the polymer having a nucleophilic group is pumped by a pump. Item 6. A vascular embolization training kit, comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening; and a liquid containing a polymer having a nucleophilic group. Item 7. The kit according to item 6, wherein the polymer having a nucleophilic group comprises albumin, and the concentration of albumin in the liquid containing the polymer having a nucleophilic group is 0.5 g / dL to 6.0 g / dL. Item 8. Item 9. A vascular embolization training system comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening; a liquid containing a polymer having a nucleophilic group; a tube for fluidly connecting the liquid containing the polymer having a nucleophilic group with the passage of the substrate; and a pump for pumping the liquid containing the polymer having a nucleophilic group into the passage of the substrate. Item 10. The training system according to Item 8, further comprising a container containing a liquid containing a cyanoacrylate adhesive.

[0013] Schematic diagram of a vascular embolization training system according to an embodiment of the present invention. Plan view of an embodiment of a substrate. Plan view of another embodiment of a substrate. Plan view of another embodiment of a substrate. Plan view of another embodiment of a substrate. Evaluation of completion of solidification of an NBCA / lipiodol mixed solution using a viscoelasticity measuring device. Solidification curves of an NBCA / lipiodol mixed solution for various blood substitute solutions. Solidification curves of an NBCA / lipiodol mixed solution with various concentrations. Graph showing the relationship between the concentration of an NBCA / lipiodol mixed solution and the time constant τ. Solidification curves of an NBCA / lipiodol mixed solution for various blood substitute solutions. (A)-(D) Preparation of a substrate by the ESCARGOT method. (A)-(C) Photographs showing the behavior of an NBCA / lipiodol mixed solution when injected into a substrate. Photographs of the passageway when whole blood, albumin solution (BSA solution), and normal saline solution were administered into the passageway, and the NBCA / Lipiodol mixed solution flowed backward for 2 cm from the catheter tip. Graph of the embolization distance in each passageway in Figure 10A.

[0014] As used herein, the singular forms "a," "an," and "the" are intended to include both the singular and the plural unless otherwise expressly stated herein or clearly contradicted by context.

[0015] In this specification, the terms "contain" and "comprise" are concepts that also encompass "consist essentially of" and "consist only of."

[0016] Hereinafter, embodiments for carrying out the present invention will be described. Note that the embodiment described below shows an example of a typical embodiment of the present invention, and the scope of the present invention should not be construed as being narrow.

[0017] FIG. 1 is a schematic diagram of a vascular embolization training system 1 according to an embodiment of the present invention. The vascular embolization training system 1 includes a container 10 containing a liquid 14 containing a polymer having a nucleophilic group (hereinafter, abbreviated as the liquid 14 containing a polymer having a nucleophilic group), a substrate 20, a pump 30, a container 40 containing a liquid 42 containing a cyanoacrylate adhesive (hereinafter, abbreviated as the cyanoacrylate adhesive-containing liquid 42), and a series of tubes 50. The liquid 14 containing a polymer having a nucleophilic group can function as an artificial blood or blood substitute. The nucleophilic group in the polymer is advantageous in that it allows the cyanoacrylate adhesive to solidify in a manner similar to that of blood. Examples of nucleophilic groups include, but are not limited to, amino groups and thiol groups. The polymer having a nucleophilic group preferably contains a protein, more preferably a protein with the same structure as a protein present in blood. Examples of proteins include albumin and hemoglobin. In certain embodiments, the protein does not include proteins that are precursors to their active forms (e.g., fibrinogen). Proteins with the same structure as proteins present in blood are not limited to purified proteins present in blood, but also include artificially synthesized proteins with the same structure as proteins present in blood. As used herein, a protein refers to a polymer composed of 50 or more amino acids.

[0018] The container 10 comprises a lid 11 and a container body 12 having a space for accommodating a liquid 14 containing a polymer having a nucleophilic group. The lid 11 is attached to the top of the container body 12.

[0019] The concentration of the nucleophilic group-containing polymer in the nucleophilic group-containing polymer liquid 14 is not particularly limited, but is preferably 0.1 g / dL to 50.0 g / dL, more preferably 0.1 g / dL to 6.0 g / dL, and even more preferably 0.5 g / dL to 6.0 g / dL, so that solidification with the cyanoacrylate adhesive occurs and the viscosity of the nucleophilic group-containing polymer liquid 14 does not become too high. When the nucleophilic group-containing polymer contains albumin, the concentration of albumin in the nucleophilic group-containing polymer liquid 14 is preferably 0.1 g / dL to 6.0 g / dL, more preferably 0.5 g / dL to 6.0 g / dL. When the polymer having a nucleophilic group includes hemoglobin, the hemoglobin concentration in the liquid 14 containing the polymer having a nucleophilic group is preferably 0.1 g / dL to 50.0 g / dL, more preferably 1.0 g / dL to 20.0 g / dL. The albumin may be albumin from animals, including humans and cows, particularly mammals, and may be albumin with a native sequence or recombinant albumin. In a preferred embodiment, the albumin includes bovine serum albumin. Commercially available purified albumin may also be used. For quality stability, the liquid 14 containing the polymer having a nucleophilic group preferably does not contain blood, serum, or plasma. The liquid 14 containing the polymer having a nucleophilic group may further contain a thickener, one or more salts (e.g., sodium chloride, magnesium chloride, etc.), etc.

[0020] While the artificial blood or blood substitute solutions used in the prior art only produced very weak polymer formation compared to blood, making it impossible to simulate clinical practice, the present inventors have discovered that solutions containing albumin or hemoglobin, which are macromolecules with nucleophilic groups found in blood, act as solidification factors for cyanoacrylate adhesives and can be used as artificial blood or blood substitute solutions. While not wishing to be bound by theory, it is believed that nucleophilic groups such as -SH and -NH groups in albumin and hemoglobin attack the vinyl groups of cyanoacrylate, causing anionic polymerization and contributing to the solidification of the adhesive.

[0021] The series of tubes 50 includes a tube 51 having one end disposed in the liquid 14 containing a polymer having a nucleophilic group in the container body 12 of the container 10 and the other end connected to the pump 30, and a tube 52 having one end connected to the pump 30, a tube portion 53 which is the portion of the tube 52 connected to the pump 30, which branches into tube portions 55 and 56 at a T-shaped branch 54, the tube portion 55 being disposed in the container body 12 of the container 10, the tube portion 56 further branches into tube portions 58 and 59 at a branch 57, and a connecting member 60 such as a Y-connector which is connected to a catheter is attached to the end of the tube portion 59 opposite to the branch 57. The end of the tube portion 58 opposite to the branch 57 is connected to the first opening 22 of the substrate 20.

[0022] The substrate 20 includes a substantially rectangular substrate body 21, a first opening 22 provided at one end of the substrate body 21, a second opening 23 provided at another end of the substrate body 21, and a passage 24 extending through the substrate body 21 between the first opening 22 and the second opening 23. The first opening 22 may be referred to as an inlet, and the second opening 23 may be referred to as an outlet.

[0023] 2 is a plan view of an embodiment of a substrate 20 as a blood vessel model. The substrate 20 can also be referred to as an occluded part because it is occluded by mixing a liquid 14 containing a polymer having a nucleophilic group with a liquid 42 containing a cyanoacrylate adhesive. The passage 24 includes a main passage 24a extending from the first opening 22, a plurality of first branch passages 24c branching off from the main passage 24a at a first branch point 24b and extending into a plurality of passages (two in this embodiment), a plurality of second branch passages 24e branching off from each of the first branch passages 24c at a second branch point 24d and extending into a plurality of passages (two in this embodiment), a plurality of third branch passages 24g branching off from each of the second branch passages 24e at a third branch point 24f and extending into a plurality of passages (two in this embodiment), a plurality of fourth branch passages 24i branching off from each of the third branch passages 24g at a fourth branch point 24h and extending into a plurality of passages (two in this embodiment), and a terminal passage 24j that joins the ends of the branch passages 24i and connects to the second opening 23.

[0024] Since the passages in the substrate 20 mimic blood vessels with branches and capillaries, the vascular embolization training system 1 can be suitably used for training in vascular embolization, particularly in the case of vascular occlusion.

[0025] The substrate 20 with the passages 24 can be manufactured by various known methods. For example, a model (internal replica) that mimics the blood vessels of the human body and has a branched structure can be produced by using a 3D printer to print a first synthetic resin, then embedding the printed model in a second synthetic resin and solidifying it, and then dissolving the first synthetic resin in a solvent that dissolves the first synthetic resin but not the second synthetic resin, thereby exposing the branched passages that mimic the blood vessels.

[0026] The model mimicking the blood vessels of the human body is created, for example, using CT images of human blood vessels. The branched passages are the spaces remaining after dissolving the model mimicking the blood vessels of the human body. The first synthetic resin is preferably a water-soluble polymer, such as polyvinyl alcohol or ABS resin. The second synthetic resin is preferably transparent or translucent to allow visual observation of the interior and is made of a flexible material similar to actual biological tissue. For example, the second synthetic resin may be a silicone resin. Silicone resin, particularly silicone rubber, is preferred because it is transparent and has flexibility and elasticity similar to that of blood vessels in an actual living body. When solidified, the second synthetic resin forms the substrate body 21. Examples of solvents include warm water and acetone.

[0027] 1, the container 40 may be a syringe, a catheter, or a syringe connected to a catheter, or may consist of two components. Cyanoacrylate adhesives 42 are known and may be, for example, H2C=C(CN)-COOR (where R is C 1-15 A cyanoacrylate adhesive selected from the group consisting of alkyl, alkoxyalkyl, cycloalkyl, alkenyl, aralkyl, aryl, aryl, and haloalkyl can be used. In a preferred embodiment, the cyanoacrylate adhesive 42 comprises n-butyl-2-cyanoacrylate (NBCA).

[0028] Adding a dye visible to the naked eye to the cyanoacrylate adhesive-containing liquid 42 allows for observation of the position and solidification of the cyanoacrylate adhesive-containing liquid 42. Examples of such dyes include D&C Violet No. 2 (CAS No. 81-48-1). Adding an oil-based contrast agent to the cyanoacrylate adhesive-containing liquid 42 allows for observation of the solidification process under X-ray fluoroscopy. Furthermore, the oil-based contrast agent can slow or adjust the rate of polymerization of the cyanoacrylate adhesive due to reaction with a polymer having a nucleophilic group. Examples of oil-based contrast agents include iodized poppy seed oil fatty acid ethyl esters, which are commercially available under the generic name Lipiodol (registered trademark).

[0029] A series of tubes 50 connects the liquid 14 containing the polymer having nucleophilic groups to the passage 24 in the substrate 20 so as to be in fluid communication with each other. In this embodiment, the pump 30 circulates a portion of the liquid 14 containing the polymer having nucleophilic groups, and also acts to pump a portion of the liquid 14 containing the polymer having nucleophilic groups into the passage 24 of the substrate 20. The pumping by the pump 30 can generate a pulsation that reproduces a pulse. When the pump 30 is operated, as shown by the arrows in Figure 1, the liquid 14 containing the polymer having nucleophilic groups in the container 10 passes through the tubes 51 and the tube section 53 of the tube 52, and at the branch 54, a portion of the liquid 14 containing the polymer having nucleophilic groups passes through the tube section 55 and returns to the container body 12 of the container 10, while another portion of the liquid 14 containing the polymer having nucleophilic groups passes through the tube section 56, the branch 57, and the tube section 58, passes through the first opening 22 of the substrate 20, flows through the passage 24 in the substrate body 21, and is discharged from the second opening 23.

[0030] With liquid 14 containing a polymer having a nucleophilic group flowing through tubes 51 and 52, the tip of container 40 is penetrated through connecting member 60 (for example, by puncturing connecting member 60 with the needle-like tip of container 40), and liquid 42 containing a cyanoacrylate adhesive is pushed out of container 40 toward tube 58. Liquid 42 containing a cyanoacrylate adhesive passes through first opening 22 and mixes with liquid 14 containing a polymer having a nucleophilic group in passage 24 within substrate 20, where it begins to solidify. Therefore, vascular embolization training system 1 can be used for vascular embolization training.

[0031] By connecting a circuit with an appropriate afterload to the substrate 20 and delivering a liquid 14 containing a polymer with a nucleophilic group and / or a liquid 42 containing a cyanoacrylate adhesive using a pump 30, the pulse rate, pressure, and flow rate can be freely changed, and it is possible to reproduce, for example, the pulse rate, blood pressure, and flow rate of an actual human body.

[0032] According to one aspect of the present invention, there is provided a method for training tube occlusion, the method comprising the steps of: dispensing a liquid 14 containing a polymer having a nucleophilic group into the passage 24 of the substrate 20, the passage 24 having a first opening 22, a second opening 23, and a passage 24 extending between the first opening 22 and the second opening 23, the passage 24 including a main passage 24a and a plurality of branch passages extending from the main passage 24a at branching portions, so that the liquid 14 flows from the first opening 22 through the passage 24 to the second opening 23; and dispensing a liquid 42 containing a cyanoacrylate adhesive from the first opening 22 of the substrate 20.

[0033] The step of dispensing the liquid 14 containing a polymer having a nucleophilic group so that it flows from the first opening 22 through the passage 24 to the second opening 23 can be performed by pumping the liquid 14 containing a polymer having a nucleophilic group into the first opening 22 of the substrate 20 with a pump 30, as described with reference to Fig. 1. The step of dispensing the liquid 42 containing a cyanoacrylate adhesive from the first opening 22 of the substrate 20 can be performed by pushing the cyanoacrylate adhesive-containing liquid 42 from a container 40 and passing it through the first opening 22, as described with reference to Fig. 1.

[0034] According to another aspect of the present invention, there is provided a vascular embolization training kit comprising a substrate 20 having a first opening 22, a second opening 23, and a passage 24 extending between the first opening 22 and the second opening 23, and a liquid 14 containing a polymeric albumin having a nucleophilic group.

[0035] The kit allows physicians and non-physician practitioners to easily and inexpensively perform vascular embolization training. The pump 30, tubing 50, and container 40 containing the cyanoacrylate adhesive liquid 42 may be provided by the practitioner or may be purchased commercially. The training kit may further include at least one of the pump 30, tubing 50, and container 40 containing the cyanoacrylate adhesive liquid 42.

[0036] Until now, training in NBCA embolization has been conducted in actual clinical settings or through the expensive sacrifice of experimental animals. However, using the ductal occlusion training system, ductal occlusion training method, and ductal occlusion training kit of the present invention allows training at significantly lower cost and without the burden on experimental animals. Furthermore, the use of NBCA, which was previously only performed once in most cases, can now be repeated under the same circumstances, resulting in a significant training effect. The ductal occlusion training system, ductal occlusion training method, and ductal occlusion training kit of the present invention provide operators with an opportunity to use NBCA / Lipiodol with minimal stress, making them useful not only for inexperienced operators but also for those with limited experience. Training is also expected to reduce the risk of complications and lead to the acquisition of troubleshooting techniques for embolic material adhering to the catheter tip. In addition to the geometric vascular models used in general training, three-dimensional data of the blood vessels can be extracted from CT images of the patient's blood vessels, and then a passageway 24 can be 3D printed to create a substrate 20 for pre-treatment simulation. This will enable detailed pre-treatment planning, and is expected to shorten treatment times, improve success rates, and reduce radiation exposure for patients and surgeons.

[0037] Although the present invention has been described above using several embodiments as examples, the present invention is not limited to these and various modifications such as those described below are possible.

[0038] In the embodiment of the substrate 20 shown in Fig. 2, the passages 24 branch off two at a time downstream from the main passage 24a. However, it is sufficient that at least some of the passages downstream of the branching portions 24d, 24f, and 24h are branched; not all of the passages need to be branched. Also, Fig. 2 shows passages from the main passage 24a (first-generation passage) to the branch passage 24i (fifth-generation passage), but the number n in the nth generation is not particularly limited as long as it is 2 or greater. The upper limit of n is, for example, 10, 9, 8, 7, or 6.

[0039] Although the embodiment of FIG. 2 shows only one first opening 22 in the substrate 20, the number of first openings 22, i.e., the number of inlets, may be multiple. Also, although the embodiment of FIG. 2 shows only one second opening 23, the number of second openings 23, i.e., the number of outlets, may be multiple. For example, FIGS. 3A-C show different examples of the substrate 20. The substrate 20 of FIG. 3A has one first opening 22 and two second openings 23. The substrate 20 of FIG. 3B has two openings 22 and two second openings 23. The substrate 20 of FIG. 3C has one first opening 22 and four second openings 23. In FIG. 3B, by adjusting the flow rate of the fluid flowing into the three openings 22, the direction of the fluid flowing within the substrate 20 can be changed clockwise or counterclockwise, providing a more diverse training environment. In the embodiment shown in Fig. 2, the first opening 22 and the second opening 23 of the substrate 20 are provided on adjacent side surfaces of the four side surfaces of the substrate body 21, which is generally rectangular in plan view (in Fig. 2, the first opening 22 is on the right side surface and the second opening 23 is on the upper side surface), but the positional relationship is not limited to this. For example, the opening 22 and the second opening 23 may be provided on opposing side surfaces.

[0040] Although the passages 24 of the substrate 20 are designed to allow fluid to move horizontally in the embodiment of FIG. 2, they may also be designed to allow fluid to flow vertically, for example, from top to bottom.

[0041] The disclosures of all patent applications and publications cited herein are hereby incorporated by reference in their entirety.

[0042] The following examples are intended for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Unless otherwise specified, reagents are commercially available or are obtained or prepared according to conventional techniques or literature procedures in the art.

[0043] Example 1: Preparation of a training system for vascular embolization As shown in Figure 1, a training system for vascular embolization was prepared, comprising a container 10 containing a liquid 14 containing albumin, a substrate 20 as the part to be embolized, a pump 30, a container 40 containing a liquid 42 containing a cyanoacrylate adhesive, and a tube 50.

[0044] Example 2 Preparation of blood substitute solution Although artificial blood mimicking the electrolytes contained in blood (Table 1) has been reported (J. Mech. Behav. Biomed. Mater 69 (2017) 307-317), the inventors found through preliminary research that the reaction rate with NBCA / Lipiodol mixed solution is completely different from that in the living body or that using biological materials such as bovine blood. This is because Cl, which is recognized as the main anion in blood, is used. - and HCO3 - This is thought to be due to the fact that the anions in albumin, a major protein in blood, are primarily responsible for solidification (Cardiovasc. Intervent. Radiol. (2020) 43:630-635). Therefore, in this study, we evaluated bovine serum albumin (BSA) solutions using the following engineering techniques and determined their concentrations to prepare a highly reproducible blood substitute solution in terms of the solidification behavior of NBCA. Albumin poses a lower risk of infection than other blood-derived products. Water (0 g / dL albumin), aqueous solutions containing 0.5 g / dL, 1.0 g / dL, 2.0 g / dL, and 4.0 g / dL bovine serum albumin (BSA), 1.0 g / dL polyammonium sulfonate (PSAA) solution, 0.5 g / dL alginate anthracene solution, 1.0 g / dL sodium hydroxide (NaOH) solution, 1.0 g / dL hexamethylenediamine (HMD) solution, and human blood were prepared. The human blood used was whole blood to which the anticoagulant ACD-A liquid had been added.

[0045]

[0046] Example 3: Solidification Behavior with Various Blood Substitute Solutions. The solidification behavior of a blood substitute solution upon contact with an NBCA / Lipiodol mixed solution was evaluated from an engineering perspective to demonstrate the suitability of an albumin aqueous solution as an artificial blood. While conventional methods for observing the shape change of an NBCA / Lipiodol mixed solution dropped into a stationary solution have primarily been visual inspection or high-speed camera observation, this study rigorously evaluated the polymerization behavior from a mechanical perspective using a viscoelasticity measuring device (Figure 4). Specifically, an NBCA / Lipiodol mixed solution 72 was dropped onto a liquid 71 on a rotating disk 70 at a constant speed, and the time at which the shear force reached a constant was determined as the solidification completion time. As shown in Figure 5, PSSA (polystyrene ammonium sulfonate) and sodium alginate did not solidify. Sodium hydroxide (NaOH) and hexamethylenediamine (HMD) resulted in rapid solidification. In comparison with these, it was found that the albumin aqueous solution (BSA) (2.0 g / dL in Figure 5) showed a curve equivalent to the solidification behavior of human blood. Similarly, when the solidification behavior of a hemoglobin-containing aqueous solution (14-18 g / dL) was evaluated when it came into contact with the NBCA / Lipiodol mixed solution, it showed the same solidification behavior as albumin with blood (data not shown).

[0047] Example 4: Solidification Behavior with Varying Albumin Aqueous Solution Concentrations. The shear force and time were investigated when an NBCA / Lipiodol mixed solution was dropped into water (0 g / dL albumin), aqueous solutions containing 0.5 g / dL, 1.0 g / dL, 2.0 g / dL, and 4.0 g / dL bovine serum albumin (BSA), and human blood. As shown in Figures 6A and 6B, the time constant τ decreased with increasing BSA concentration, but saturated at concentrations above 2.0 g / dL. Adding a thickener (glycerol or PAA-Na) to the solution slowed solidification. The addition of fibrinogen had little effect on solidification.

[0048] Example 5: Solidification Behavior with Various Blood Substitute Solutions (2) In this example, the solidification behavior of a solution containing blood components when it contacted an NBCA / Lipiodol mixed solution was evaluated from an engineering perspective to demonstrate the suitability of the solution as an artificial blood. Experimental conditions were the same as in Example 3. RBC refers to red blood cells, lysed RBC refers to hemolyzed red blood cells, BSA refers to bovine albumin, fibrinogen refers to fibrinogen, blood refers to whole blood, and plasma refers to plasma. Whole blood refers to human blood, plasma refers to whole blood centrifuged to remove only the liquid components, and red blood cells refers to the solid components obtained by centrifuging whole blood and then diluting them with saline to achieve a red blood cell concentration equivalent to that of the original blood. The fibrinogen concentration was 200 mg / mL, and the bovine albumin concentration was 2 g / dL. As shown in Figure 7, solutions containing blood macromolecules, such as RBC, lysed RBC, BSA, fibrinogen, whole blood, and plasma components, all showed similar solidification behavior. Fibrinogen was added to increase the viscosity of the solution, but did not accelerate the solidification rate.

[0049] Example 6: Fabrication of a Substrate with Branching Passages The substrate (reference numeral 20 in Figure 1) is a component that mimics the blood vessels to be embolized, i.e., a vascular model. However, simply mimicking the macroscopic morphology is insufficient. Ideally, the substrate should also reproduce the afterload caused by arterioles and capillaries, which cannot be visualized by CT or other methods, and be inexpensive and reusable by washing the passages 24 with an appropriate solvent. In this study, the substrate was fabricated using the ESCARGOT method (Figures 8(A)-(D)). Briefly, a model mimicking a human blood vessel was created using a 3D printer using a polymer (Figure 8(A)), embedded in silicone rubber, and solidified (Figure 8(B)). The polymer was then dissolved in water and an organic solvent (Figure 8(C)), resulting in the exposed blood passages (Figure 8(D)).

[0050] Example 7: Injection of NBCA-Containing Solution into a Substrate Using a Training System. Referring to Figure 1, a circuit with an appropriate afterload setting was connected to the substrate 20. A pulsatile pump 30 delivered albumin solution 14 through the first opening 22 of the substrate 20 to the passageway 24 and the second opening 23, thereby reproducing the pulse rate, blood pressure, and flow rate of a real human (HR 80 bpm, BP 100 / 60 mmHg). The albumin concentration of the albumin solution 14 was 2.0 g / dL, and the salt concentration was 0.9 g / dL. Figures 9(A)-(D) show the behavior of a continuous injection of an NBCA / lipiodol mixed solution into a vascular model. First, the first branch 24c on the lower branch side of the passageway 24 was embolized with the NBCA / lipiodol mixed solution (Figure 9(A)). The NBCA / lipiodol mixed solution initiated reflux (Figure 9(B)). Next, NBCA / Lipiodol (Figure 9(C)) flowed into the upper branch where the flow rate increased due to embolization of the first branch 24c, and moved at a high speed to the more distal branches (24d-24g) on ​​the upper branch.

[0051] Example 8: Injection of NBCA-Containing Solution into a Substrate Using a Training System (2) As in Example 7, instead of using the substrate shown in Figure 2, straight polyvinyl chloride tubes with a diameter of 2.1 mm were used to deliver blood, BSA, and saline, respectively, to simulate the pulse rate, blood pressure, and flow rate of a real human body (HR 80 bpm, BP 100 / 50 mmHg). The whole blood was porcine blood, the albumin-containing solution had an albumin concentration of 2.0 g / dL, and the saline solution had a salt concentration of 0.9 g / dL. Figures 10(A) and 10(B) show the results of measuring the embolization distance of the passageway when the NBCA / Lipiodol mixed solution was refluxed 2 cm from the catheter tip under conditions of 80 bpm and 100 / 50 mmHg. The embolization distance for whole blood was 15.6 ± 3 cm, for the albumin-containing solution 16.4 ± 3.3 cm, and for the saline solution 30.2 ± 3.4 cm. Whole blood and the albumin-containing solution embolized the passage over shorter distances than saline solution. Thus, by connecting a circuit with an appropriate afterload setting to the fabricated substrate and pumping blood substitute solutions, the inventors succeeded in reproducing pulse rate, blood pressure, and flow velocity similar to those of the actual human body.

[0052] Furthermore, when NBCA was injected into a training kit consisting of a liquid 14 containing a polymer with nucleophilic groups and a substrate 20 via a thin-diameter treatment tube (catheter), (1) when one blood vessel was embolized, the injected NBCA subsequently flowed back. (2) When a blood vessel was embolized, the flow rate in the adjacent blood vessel increased, causing the backflowing NBCA to splash into the adjacent blood vessels at a fairly high speed. (3) When NBCA adjusted to slow its solidification rate was injected, the NBCA flowed all the way to the periphery of the target blood vessel, reproducing behavior that may actually occur in the human body.

[0053] 1...training system, 10...container, 14...liquid containing a polymer having a nucleophilic group, 20...substrate, 22...first opening, 23...second opening, 24...passage extending between the first opening and the second opening, 30...pump, 40...container, 42...liquid containing a cyanoacrylate adhesive, 50...tubing.

Claims

1. A method for training tube occlusion, comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening, the passage comprising a main passage and a plurality of branch passages extending from the main passage at branching portions; administering a liquid containing a polymer having a nucleophilic group into the passage so that the liquid flows from the first opening through the passage to the second opening; and administering a liquid containing a cyanoacrylate adhesive from the first opening of the substrate.

2. The cyanoacrylate adhesive is H2C=C(CN)-COOR (where R is C 1-15 2. The method of claim 1, wherein the alkyl group is selected from the group consisting of alkyl, alkoxyalkyl, cycloalkyl, alkenyl, aralkyl, aryl, aryl, and haloalkyl.

3. The method of claim 1, wherein the liquid containing the cyanoacrylate adhesive further contains an oil-based contrast agent.

4. The method of claim 1, wherein the polymer having a nucleophilic group comprises a protein having the same structure as a protein present in blood.

5. The method according to claim 1, wherein the liquid containing the polymer having the nucleophilic group is pumped by a pump.

6. A vascular embolization training kit comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening; and a liquid containing a polymer having a nucleophilic group.

7. The kit according to claim 6, wherein the polymer having a nucleophilic group comprises albumin, and the concentration of albumin in the liquid containing the polymer having a nucleophilic group is 0.5 g / dL to 6.0 g / dL.

8. A vascular embolization training system comprising: a substrate having a first opening, a second opening, and a passage extending between the first opening and the second opening; a liquid containing a polymer having a nucleophilic group; a tube for fluidly connecting the liquid containing the polymer having a nucleophilic group with the passage of the substrate; and a pump for pumping the liquid containing the polymer having a nucleophilic group into the passage of the substrate.

9. The training system of claim 8, further comprising a container containing a liquid containing a cyanoacrylate adhesive.

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