Simulated thrombus

Abstract

To solve ethical and sanitary problems in a simulated thrombus and to improve the elasticity of the simulated thrombus.SOLUTION: The simulated thrombus includes a gel-like blood portion containing simulated blood made of a non-biological substance as a main component, and graphite powder contained in the blood portion.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present disclosure relates to simulated thrombi. [Background technology]

[0002] Thrombectomy devices such as aspiration catheters and stent retrievers are effective methods for treating thromboembolism, and the development of these devices continues. In the development of thrombus removal devices, one common method has been to create simulated thrombi using animal blood and evaluate the success rate of thrombus removal by the thrombus removal device.

[0003] For example, Patent Document 1 discloses simulated blood and simulated thrombus made of non-biological materials that simulate human blood, and that have been developed for training in the treatment of bleeding. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 9,542,861 Summary of the Invention [Problem to be solved by the invention]

[0005] The simulated thrombus created using biological blood from animals or other living organisms changes its physical properties over time and varies significantly between animals, making it difficult to properly evaluate thrombus removal devices. Furthermore, creating simulated thrombus using biological blood from animals or other living organisms raises ethical and hygienic issues.

[0006] There are various types of thrombi, each with different physical properties. There is room for improvement in how simulated thrombi can be made to resemble the physical properties of actual thrombi.

[0007] The present disclosure has been made to solve at least part of the above-mentioned problems, and aims to solve the ethical and hygienic issues in simulated thrombi and to improve the elasticity of simulated thrombi. [Means for solving the problem]

[0008] The present disclosure has been made to solve at least part of the above-mentioned problems, and can be realized in the following aspects.

[0009] (1) According to one aspect of the present disclosure, there is provided a simulated thrombus, which includes a gel-like blood portion mainly composed of simulated blood made of a non-biological material, and graphite powder contained in the blood portion.

[0010] According to this configuration, since the simulated blood is made of a non-biological substance, ethical and hygienic issues can be resolved compared to when a simulated thrombus is made from the blood of a living organism such as an animal. Furthermore, since the simulated thrombus contains graphite powder, the elasticity of the simulated thrombus can be improved. Here, the term "major component" means the component that is most abundant.

[0011] (2) In the simulated thrombus of the above form, the amount of graphite powder added may be 1 wt % or more and 2 wt % or less relative to the simulated blood, thereby providing a simulated thrombus having elasticity similar to that of a human thrombus.

[0012] The present disclosure can be realized in various forms, for example, a blood vessel model including a simulated thrombus, an organ model including the blood vessel model and simulating an organ such as the heart, liver, or brain, a human body simulation device including these blood vessel models or organ models, a control method for a human body simulation device, etc. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a diagram schematically illustrating the appearance of a simulated thrombus. [Figure 2] FIG. 2 is an enlarged schematic view of a portion of a simulated thrombus. [Figure 3] FIG. 1 shows the evaluation results of simulated thrombus samples 1 to 26. DETAILED DESCRIPTION OF THE INVENTION

[0014] <Embodiment> FIG. 1 is a diagram schematically illustrating the appearance of a simulated thrombus 100 according to an embodiment. FIG. 2 is a diagram schematically illustrating an enlarged portion of the simulated thrombus 100. As shown in FIG. 1, the simulated thrombus 100 is formed in a substantially cylindrical shape and is a gel-like substance as a whole. The simulated thrombus 100 includes a gel-like blood portion 10 composed primarily of simulated blood made of a non-biological substance, and graphite powder 20 contained in the blood portion 10 (FIG. 2). The term "gel" is a concept that encompasses both solids and semi-solids. The simulated thrombus is also called a chemical thrombus.

[0015] The simulated blood is not particularly limited as long as it is a liquid made of non-biological materials and mimics the physical properties of human blood. The simulated blood may contain, for example, chitosan dissolved in an acidic aqueous liquid, or chitosan turbid in an acidic aqueous liquid, or an alginate compound (e.g., sodium alginate) dissolved in water, or an alginate compound (e.g., sodium alginate) turbid in water, and may further contain a colorant sufficient to achieve a red color simulating whole blood. The simulated blood may be concentrated simulated blood diluted with pure water, deionized water (DI water), or the like, or may be a stock solution that does not require dilution. For example, a premix blood solution (LUNA INNOVATIONS) can be used as the simulated blood.

[0016] The blood portion 10 is a gel whose main component is simulated blood. The main component is the component that is most abundant. The blood portion 10 is a reacted substance formed by the reaction of liquid simulated blood with a gelling agent. Examples of gelling agents that can be used include sodium tripolyphosphate (NaTPP), calcium salts, β-glycerophosphate, sodium carbonate, sodium bicarbonate, sodium citrate, citric acid, and rose bengal. The gelling agent is also called a "clotting liquid."

[0017] The type of graphite powder 20 is not particularly limited. For example, natural graphite powder such as flake graphite or amorphous graphite, which are used in pencil leads, may be used, or artificial graphite powder may be used. The shape of the graphite powder 20 is also not particularly limited, and it may be spherical or flaky. Graphite has high hardness, so by including graphite powder 20 in the simulated thrombus 100, the hardness and elasticity of the simulated thrombus can be increased compared to when the graphite powder 20 is not included.

[0018] The content of the graphite powder 20 is not particularly limited. The content of the graphite powder 20 is preferably 1 wt% or more and 2 wt% or less with respect to the simulated blood. By setting the content of the graphite powder to 1 wt% or more and 2 wt% or less with respect to the simulated blood, elasticity close to that of a human thrombus can be obtained. Secant modulus can be used as an index of elasticity.

[0019] The presence of graphite powder in the simulated clot can be determined using a fluorescence microscope, a scanning electron microscope (SEM), and energy dispersive X-ray spectrometry (EDX). The graphite powder content in the simulated clot can be determined using the following method. Because graphite is highly insoluble in solvents, the operator dissolves the simulated clot in a solvent and separates it into simulated blood and graphite. The operator then dries the graphite and measures its weight. After measuring the weight of the simulated blood, the operator separates and analyzes it using liquid chromatography mass spectrometry (LCMS) to calculate the mass ratio of the simulated blood to the gelling agent and the solvent. The operator then calculates the weight of the simulated blood using the weight of the simulated blood and the mass ratio. The operator then calculates the ratio of graphite to simulated blood using the measured weight of graphite and the calculated weight of the simulated blood. To identify whether or not the material is graphite, elemental analysis such as EDX is used. The operator can also separate the simulated blood using column chromatography and further analyze the extract after separation to identify the material.

[0020] The simulated thrombus 100 may further contain cellulose contained in the blood portion 10. Cellulose can increase the toughness of the simulated thrombus 100 due to its fibrous structure.

[0021] The simulated thrombus 100 of this embodiment can be produced, for example, by the following method. The operator places the simulated blood and graphite powder in a vacuum test tube and mixes them using a vortex mixer or similar. Then, the operator places a gelling agent (clotting liquid) in the vacuum test tube, caps it, and stirs it up and down. This produces a gel-like simulated blood clot. The operator may also add a viscosity adjuster (e.g., a cellulose-based agent such as methylcellulose) along with the graphite powder.

[0022] Previously, simulated thrombi using animal blood (hereinafter referred to as animal thrombus models) have been used to simulate thrombi for treatment simulations. To create animal thrombus models, researchers with sufficient training to perform tests and surgical interventions are required to handle these animals, and ethical considerations must be approved. Animal-derived simulated thrombi are difficult to store for long periods of time and have hygiene issues such as the risk of bacteria and decay.

[0023] In contrast, the simulated thrombus 100 of this embodiment uses simulated blood made of a non-biological substance, and therefore, compared to creating a simulated thrombus from biological blood such as an animal, there is no risk of bacterial infection, and hygiene and ethical issues can be resolved. Because the simulated thrombus 100 of this embodiment does not use biological blood, it can be stored for a long period of time. Furthermore, compared to creating a simulated thrombus from biological blood, the simulated thrombus can be created in a shorter time.

[0024] By including graphite powder in the simulated thrombus, the elasticity of the simulated thrombus can be improved, and a simulated thrombus having elasticity similar to that of a human thrombus can be provided. As a result, for example, in the development of a thrombus removal device, the thrombus removal device can be evaluated using the simulated thrombus in an environment similar to that of a real clinical setting.

[0025] The simulated thrombus 100 of this embodiment can be used, for example, in a blood vessel model including a simulated thrombus, an organ model including the blood vessel model and simulating an organ such as the heart, liver, or brain, or a human body simulation device including these blood vessel models or organ models. [Example]

[0026] The present disclosure will be explained more specifically with reference to examples. Figure 3 shows the evaluation results of simulated thrombus samples 1 to 26. In Figure 3, literature values ​​for fibrin-rich thrombus and RBC-rich thrombus collected from actual patients with thromboembolism and the evaluation results of thrombus prepared using porcine blood are shown as samples 27 to 29.

[0027] The values ​​for samples 27 and 28 were taken from the following research paper, which investigated the composition and mechanical properties of patients with thromboembolism. Sample 27 is a non-calcified thromboembolism removed by carotid endarterectomy (CEA) and is a fibrin-rich thrombus. Sample 28 is a red blood cell (RBC)-rich thrombus recovered from an acute ischemic stroke patient (AIS). Research paper: Chueh, JY, Wakhloo, AK, Hendricks, GH, Silva, CF, Weaver, JP, & Gounis, MJ (2011). Mechanical characterization of thromboemboli in acute ischemic stroke and laboratory embolus analogs. American Journal of Neuroradiology, 32(7), 1237-1244.

[0028] Thromboembolism is a disease characterized by arterial occlusion due to thrombus formation. This disease impairs blood circulation to organs, leading to organ failure and resulting in high morbidity and mortality worldwide, particularly from stroke and pulmonary embolism. Thrombi are classified as fibrin-rich or red blood cell-rich and can originate from either atrium. Thrombi removed by carotid endarterectomy (CEA) are white blood cells rich in leukocytes and fibrin and platelets. In this example, we aimed to obtain secant moduli similar to those of fibrin-rich and RBC-rich thrombi in simulated thrombi for use in evaluating mechanical thrombus removal devices, such as aspiration catheters and stent retrievers, used in the treatment of thromboembolism. In the following description, fibrin-rich thrombi are also referred to as CEA thrombi, and RBC-rich thrombi are also referred to as RBC thrombi.

[0029] 1. Sample Preparation Samples 1 to 26 were prepared as follows. First, the operator mixed the simulated blood stock solution with DI water to prepare the simulated blood. Pre-mix blood solution (LUNA INNOVATIONS) was used as the simulated blood stock solution. The simulated blood stock solution had the following two concentrations: (1) Concentration: 0.075 vol%: 7.5 ml of the simulated blood stock solution was diluted with 100 ml of DI water. (2) Concentration 0.2 vol%: 20 ml of the simulated blood stock solution was diluted with 100 ml of DI water.

[0030] The operator placed the simulated blood and a composite filler containing at least one of graphite powder and cellulose into a 6 ml vacuum test tube and mixed them using a vortex mixer. Super Hi-Polymer Lead 2B (Pentel Co., Ltd.) was used as the graphite powder. Super Hi-Polymer is a registered trademark. Cellulose fibers powder (medium) (Sigma-Aldrich) was used as the cellulose. The concentrations of graphite powder and cellulose were 0 wt%, 1 wt%, 1.5 wt%, and 2 wt%, as shown in Figure 3. The concentrations are shown as a percentage of the simulated blood. The graphite powder concentration was calculated by dividing the weight of the graphite powder by the weight of the simulated blood × 100. The cellulose concentration was similarly calculated by dividing the weight of the cellulose fiber powder by the weight of the simulated blood × 100.

[0031] The operator added clotting liquid to the vacuum test tube, capped the vacuum test tube, and stirred it up and down. The clotting liquid was a clotting solution (LUNA INNOVATIONS) that was included in the set with the above-mentioned simulated blood stock solution. The volume ratio of simulated blood to clotting liquid was 5:1. Samples 1 to 26 were prepared through the above steps.

[0032] Sample 29 was prepared as follows. First, the operator dripped 1 ml of calcium chloride (CaCl2) solution into 9 ml of pig blood. The calcium chloride solution was prepared by adding 22.196 g of CaCl2 to 1000 ml of DI water. The pig blood contained the anticoagulant sodium citrate when purchased, so the operator chelated this with calcium ions. Fresh pig blood was obtained from Tokyo Shibaura Organ Co., Ltd. The operator incubated the pig blood to which the calcium chloride aqueous solution had been added at 37°C for 1 hour to form a clot. This clot was an RBC-rich clot.

[0033] 2. Evaluation Method The workers performed compression tests to determine the secant modulus. The worker cut the sample prepared by the above method to a height of 1 mm to 2 mm. Compression tests were performed using a conventional tensile testing machine equipped with a force sensor. The operator applied compressive stress to the sample cut as described above using a compression jig connected to a force sensor, measuring the load and the displacement of the jig. The operator calculated the secant modulus using two points, 0% and 75% strain, on the SS curve, which shows the deformation of the sample due to compressive stress. A high secant modulus indicates a hard clot.

[0034] 3. Evaluation Results First, samples 1 to 16 will be described. Samples 1 to 16 have a concentration of simulated blood stock solution of 0.075 vol%. Sample 13 contains no graphite powder or cellulose, while samples 1 to 3 contain only graphite powder. Compared to sample 13, samples 1 to 3 were able to improve the secant modulus.

[0035] Sample 14 is made by adding 1 wt% of cellulose alone to Sample 13, and Samples 4 to 6 are made by adding graphite powder to Sample 14. Compared to Sample 14, Samples 4 to 6 were able to improve the secant modulus.

[0036] Sample 15 is made by adding 1.5 wt% of cellulose alone to Sample 13, and Samples 7 to 9 are made by adding graphite powder to Sample 15. Compared to Sample 15, Samples 7 to 9 were able to improve the secant modulus.

[0037] Sample 16 is made by adding 2 wt% of cellulose alone to Sample 13, and Samples 10 to 12 are made by adding graphite powder to Sample 16. Compared to Sample 16, Samples 10 to 12 were able to improve the secant modulus.

[0038] Thus, it was confirmed that the secant modulus can be improved by adding graphite powder to a simulated thrombus having a simulated blood stock solution concentration of 0.075 vol %.

[0039] Next, Samples 17 to 26 will be described. Samples 17 to 26 have a concentration of simulated blood stock solution of 0.2 vol%. Sample 24 contains no graphite powder or cellulose, while Sample 17 contains only graphite powder. Compared to Sample 24, Sample 17 was able to achieve a secant modulus equal to or greater than that of Sample 24.

[0040] Sample 25 is made by adding 1.5 wt% of cellulose alone to Sample 24, and Samples 18 to 20 are made by adding graphite powder to Sample 25. Compared to Sample 25, Samples 18 to 20 were able to improve the secant modulus.

[0041] Sample 26 is obtained by adding 2 wt% of cellulose alone to Sample 24, and Samples 21 to 23 are obtained by further adding graphite powder to Sample 26. Compared to Sample 26, Samples 21 to 23 were able to improve the secant modulus.

[0042] Thus, it was confirmed that the secant modulus can be improved by adding graphite powder even in a simulated thrombus having a simulated blood stock solution concentration of 0.2 vol %.

[0043] Sample 1 was confirmed to exhibit a secant modulus equivalent to that of a fibrin-rich thrombus (Sample 27) collected from an actual patient with thromboembolism. Sample 19 was confirmed to exhibit a secant modulus equivalent to that of an RBC-rich thrombus (Sample 28) collected from an actual patient with thromboembolism. Sample 19 was confirmed to exhibit a secant modulus equivalent to that of an RBC-rich thrombus prepared from porcine blood (Sample 29). In other words, by adjusting the concentrations of the simulated blood stock solution, graphite powder, and cellulose in the simulated thrombus, it was possible to provide a non-biological simulated thrombus exhibiting a secant modulus equivalent to that of a porcine blood-based simulated thrombus. Furthermore, it was confirmed that a non-biological simulated thrombus exhibiting a secant modulus equivalent to that of a thrombus collected from an actual patient with thromboembolism could be provided.

[0044] Actual human thrombi can be classified as fibrin-rich or RBC-rich. As described above, by adjusting the concentrations of the simulated blood stock solution, graphite powder, and cellulose, simulated thrombi with secant moduli similar to those of actual human fibrin-rich and RBC-rich thrombi can be created. Therefore, by using these simulated thrombi, thrombus removal devices can be evaluated in an environment similar to that of a real clinical setting for both fibrin-rich and RBC-rich thrombi.

[0045] Samples 1 to 12 and 17 to 23 satisfy the following requirements [1] to [3] and are examples of the above embodiment. [1] Includes a gel-like blood section whose main component is simulated blood made from non-biological materials. [2] Includes graphite powder contained in the blood portion. [3] The content of graphite powder is 1 wt% or more and 2 wt% or less with respect to the simulated blood.

[0046] In contrast, Samples 13 to 16 and 24 to 26 satisfy the above requirement [1] but do not satisfy requirements [2] and [3]. As described above, Samples 1 to 12 had improved secant modulus compared to Samples 13 to 16, and Samples 17 to 23 had improved secant modulus compared to Samples 24 to 26. In other words, it was confirmed that the secant modulus of the simulated thrombus can be improved by satisfying requirements [2] and [3].

[0047] In the simulated clots with a simulated blood stock solution concentration of 0.075 vol%, when both graphite powder and cellulose were added (samples 4 to 12), the secant modulus decreased compared to when only graphite powder was added (samples 1 to 3). In other words, the elasticity decreased. This is thought to be due to the fibrous nature of cellulose.

[0048] In simulated clots with a simulated blood stock solution concentration of 0.075 vol%, the addition of graphite powder significantly improved the secant modulus compared to simulated clots with a simulated blood stock solution concentration of 0.2 vol%. This is thought to be because the simulated blood with a simulated blood stock solution concentration of 0.2 vol% has a higher viscosity than the simulated blood with a simulated blood stock solution concentration of 0.075 vol%, making it difficult for the filler and simulated blood to mix and clots to form.

[0049] This aspect has been described above based on embodiments and modifications. The above-described embodiments of the aspect are intended to facilitate understanding of this aspect and are not intended to limit this aspect. This aspect may be modified or improved without departing from the spirit and scope of the claims, and equivalents thereof are included in this aspect. If a technical feature is not described as essential in this specification, it may be deleted as appropriate. [Explanation of symbols]

[0050] 10…Blood part 20...Graphite powder 100…Simulated blood clot

Claims

1. A simulated thrombus (100), comprising: a gel-like blood portion (10) mainly composed of simulated blood made of non-biological material; Graphite powder (20) contained in the blood portion; Including, Simulated thrombus (100).

2. 2. The simulated thrombus (100) of claim 1, The content of the graphite powder (20) is 1 wt % or more and 2 wt % or less with respect to the simulated blood. Simulated thrombus (100).

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