Cylindrical organ-associated lesion model and its manufacturing method

Abstract

To provide a novel tubular organ-related lesion model which realistically simulates tubular organ lesions such as cardiac valve disease.SOLUTION: A tubular organ-related lesion model simulating a lesion related to a tubular organ including collagenous tissue or tissue constituting the tubular organ is provided, where at least a portion of the collagenous tissue of the tubular organ is degraded.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present invention relates to a tubular organ-associated lesion model and a method for producing the same, etc. In particular, the present invention relates to a tubular organ-associated lesion model, a tubular organ-associated lesion simulation test device, a medical device testing method, and a method for producing the tubular organ-associated lesion model. [Background technology]

[0002] As tubular organs (broadly including organs and tissues that are tubular, sac-shaped, or have a constricted part such as a valve), solid organs such as the heart, blood vessels, the digestive tract, and the ureter are known. For example, the human heart has four heart valves. Specifically, they are the tricuspid valve between the right atrium and the right ventricle, the pulmonary valve between the right ventricle and the pulmonary artery, the mitral valve between the left atrium and the left ventricle, and the aortic valve between the left ventricle and the aorta. For example, the aortic valve plays a role of opening the valve cusps at the same time as the left ventricle starts to contract, sending blood from the left ventricle to the aorta, and closing the valve cusps at the same time as the left ventricle starts to expand, preventing blood from flowing back from the aorta to the left ventricle. The shape of these tubular organs may change due to lesions. Lesions related to these tubular organs are referred to as tubular organ-related lesions in this specification. In particular, lesions related to the heart valves or the base of the blood vessels connected to the heart are referred to as heart valve-related lesions in this specification. Heart valve-related conditions include, for example, aortic valve disease and mitral valve disease.

[0003] Aortic valve diseases include aortic valve disease, in which the aortic valve becomes insufficient to open and close normally, and aortic annulus dilatation. Aortic valve disease is broadly divided into two categories: aortic valve stenosis and aortic valve regurgitation. Stenosis is a condition in which blood flow is obstructed due to poor valve opening, while regurgitation is a condition in which blood flow reverses due to insufficient valve closure. Aortic annulus dilatation is mainly caused by an ectatic lesion at the aortic root, and can present in a variety of pathologies, including aortic aneurysm and aortic valve regurgitation. Treatments for these aortic valve diseases include artificial valve replacement, treatment using an artificial valve ring, and valve repair, which preserves the patient's own valve cusps as much as possible. For patients at high risk of open-heart surgery using a cardiopulmonary bypass and for adolescent patients, there is hope for the development of new treatment devices that are less invasive and can treat patients with short hospital stays, rather than the current highly invasive treatments. However, there are no models to evaluate the performance of the medical devices being developed, and it is difficult to prepare animals with aortic valve regurgitation for animal testing.

[0004] Meanwhile, with regard to blood vessels, various vascular lesion models that imitate actual lesions have been proposed for the purpose of improving the technique of operators (see, for example, Patent Document 1). Patent Document 1 describes a vascular lesion model formed from a plurality of small lesions with different hardnesses. Patent Document 1 describes that by forming a lesion model from a plurality of small lesions with different hardnesses, it is possible to approximate an actual lesion. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 2012-189909 A Summary of the Invention [Problem to be solved by the invention]

[0006] However, the vascular lesion model in Patent Document 1 uses agarose gel and silicone and does not use biological tissue, making it difficult to say that it imitates an actual lesion.

[0007] On the other hand, unlike the field of vascular lesion models that do not use biological tissue as described in Patent Document 1, the reality in the field of heart disease is that there are no heart valve-related lesion models that simulate heart valve disease in a manner that closely resembles actual lesions. For example, there is currently no aortic root dilatation model using biological tissue. Although artificial incisions can be made in the aortic tissue and tissue walls added to simulate tissue dilatation, this is far removed from the clinical pathology. Therefore, it is necessary to create an aortic root dilatation model using biological tissue that is close to the actual aortic root dilatation lesion, and quantitatively evaluate the effects of aortic valve repair in vitro. In addition, there are currently very few practical mitral valve disease models using biological tissue. Mitral valve diseases include mitral stenosis and mitral regurgitation. Mitral regurgitation is a disease in which the valve does not close normally and blood flows backwards. Mitral regurgitation caused by annular dilation and papillary muscle displacement due to left ventricular dilation is called functional mitral regurgitation. When creating a mitral regurgitation model that simulates these mitral valve diseases, a method is used to expand the annulus by applying tension, but this method generates unnecessary tension in the annulus, which is different from biological tissue that is close to the actual disease. As a result, there was a problem that the effect of valvuloplasty could not be accurately measured outside the body.

[0008] The problem to be solved by the present invention is to provide a novel heart valve-related lesion model that simulates lesions of tubular organs, such as heart valve disease, in a manner close to actual lesions. [Means for solving the problem]

[0009] According to the present invention, by using a heart valve-related lesion model in which at least a portion of the collagen tissue of a tubular organ (e.g., a heart valve or a blood vessel base) is decomposed, it has been found that lesions of tubular organs, such as heart valve disease, can be simulated in a manner close to actual lesions, and the effects of therapeutic devices and valvuloplasty based on novel ideas can be quantitatively evaluated ex vivo, thereby solving the above-mentioned problems. The configuration of the present invention, which is a specific means for solving the above-mentioned problems, and preferred configurations of the present invention are described below.

[0010] [1] A tubular organ lesion model simulating a lesion of a tubular organ containing collagen tissue or a tissue constituting a tubular organ, comprising: A tubular organ associated pathology model in which at least a portion of the collagen tissue of the tubular organ is degraded. [2] A tubular organ-associated pathology model as described in [1], wherein the tubular organ is a heart valve or a vascular base connecting to the heart. [3] A tubular organ-associated lesion model according to [1] or [2], in which the strength of the tissues constituting the tubular organ is weakened compared to that of each normal tissue. [4] A tubular organ-associated lesion model described in [3], in which the strength of collagen tissue among the tissues that make up the tubular organ is weakened compared to the respective normal tissues, and the strength of the other tissues is the same as the respective normal tissues. [5] A tubular organ-associated lesion model described in any one of [1] to [4], in which at least one of the valve annulus area and other sizes or features of the tubular organ is enlarged compared to the respective normal tissue. [6] A tubular organ-associated lesion model described in any one of [1] to [5], which is formed by applying a collagen-degrading enzyme to a tubular organ precursor isolated from an animal to degrade collagen in the tubular organ precursor. [7] A heart valve-related lesion model described in any one of [1] to [6], which is a mitral valve regurgitation model, an aortic root dilatation model, a left ventricular enlargement model, a right ventricular enlargement model, a left atrial enlargement model, a right atrial enlargement model or a vascular aneurysm model. [8] A simulation test device for tubular organ-related lesions, which incorporates a tubular organ-related lesion model described in any one of [1] to [7] into the tubular organ-related portion of a circulation simulator. [9] A method for testing a medical device using the tubular organ-associated lesion model according to any one of [1] to [7] or the tubular organ-associated lesion simulation test device according to [7], A method for testing a medical device, comprising contacting the medical device with a tubular organ-associated lesion model to perform a characteristic test of the medical device outside the human body.

[10] A method for testing a medical device described in [9], comprising conducting a reflux inhibition performance test of the medical device outside the human body by contacting the medical device with a tubular organ-related lesion model and conducting a circulatory flow test.

[11] A method for producing a tubular organ lesion model that simulates a lesion in a tubular organ containing collagen tissue or a tissue that constitutes a tubular organ, comprising: A method for producing a tubular organ-associated lesion model, comprising a decomposition step of applying a collagen-decomposing enzyme to a tubular organ precursor excised from an animal to decompose at least a portion of the collagen tissue of the tubular organ precursor.

[12] A method for producing a tubular organ-associated lesion model according to

[11] , wherein the tubular organ is a heart valve or a vascular base connected to the heart.

[13] In the decomposition step, an expansion member is inserted into the inside of the tubular organ precursor and the tubular organ precursor is immersed in a solution of a collagen decomposition enzyme, or A method for producing a tubular organ-associated lesion model according to

[11] or

[12] , comprising immersing a tubular organ precursor in a solution of collagen-degrading enzyme and inserting an expansion member into the interior of the tubular organ precursor.

[14] A method for producing a tubular organ-associated lesion model described in

[11] , in which the size of the expansion member is gradually changed from small to large to gradually expand the tubular organ precursor.

[15] A method for manufacturing a tubular organ-associated lesion model described in

[14] , in which at least one of the valve annulus area and other dimensions or features of the tubular organ is adjusted by changing the immersion time and the size of the expansion member. Effect of the Invention

[0011] According to the present invention, it is possible to provide a novel tubular organ-related lesion model that simulates a tubular organ lesion such as a heart valve disease in a manner close to an actual lesion. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a photograph of the aortic root excised from a pig heart, which was used as a vascular root precursor in Example 1. [Diagram 2] FIG. 2 is a photograph of an example of the expansion member used in Example 1. [Diagram 3] FIG. 3 is a photograph of the vascular base precursor in Example 1 with the expansion member inserted therein. [Figure 4] FIG. 4 is a schematic diagram of a pulsatile circulation simulator in the cardiac valve-related lesion simulation test device of Example 1. [Diagram 5] FIG. 5 is a graph showing an example of the relationship between collagenase immersion time and reflux rate. [Figure 6] FIG. 6 is a graph comparing the regurgitation rate between the moderate aortic regurgitation model of Example 2 and the normal root model. [Figure 7] FIG. 7 is a schematic diagram of a cross section of the aortic root. [Figure 8] FIG. 8 is a graph comparing annulus area between the moderate aortic regurgitation model of Example 2 and the normal root model. [Figure 9] FIG. 9 is a graph comparing valve coaptation length between the moderate aortic regurgitation model of Example 2 and the normal root model. [Figure 10] FIG. 10 is a photograph of the heart valve precursor in Example 11, in which the area from the left atrium to the valve annulus is immersed in a collagenase solution. [Figure 11] FIG. 11 is a photograph of an example of the expansion member used in Example 11. [Figure 12] FIG. 12 is a photograph of the heart valve precursor in Example 11 with the expansion member inserted. [Figure 13] FIG. 13 is a photograph of an example of the annulosuturing sheet used in Example 11. [Figure 14] FIG. 14 is a schematic diagram of a pulsatile circulation simulator in the simulation test device for heart valve-related lesions of Example 11. [Figure 15] FIG. 15 is a graph showing an example of the relationship between collagenase immersion time and valve annulus area expansion rate. [Figure 16] FIG. 16 is a schematic diagram of an example of a method for producing an aortic valve lesion model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present invention will be described in detail below. The following description of the constituent elements may be based on representative embodiments or specific examples, but the present invention is not limited to such embodiments. In this specification, a numerical range expressed using "~" means a range including the numerical values ​​before and after "~" as the lower and upper limits.

[0014] [Cylinder-associated lesion model] The tubular organ-associated lesion model of the present invention is a tubular organ-associated lesion model that simulates a lesion relating to a tubular organ containing collagen tissue or to the tissue that constitutes a tubular organ, in which at least a portion of the collagen tissue of the tubular organ is degraded. In particular, the tubular organ is preferably a heart valve or a blood vessel base connected to the heart. That is, a preferred embodiment of the present invention is a heart valve-related lesion model simulating a lesion related to a heart valve or a blood vessel base connected to the heart, in which at least a part of the collagen tissue of the heart valve or blood vessel base is decomposed. With this configuration, a novel tubular organ-related lesion model can be provided that simulates a tubular organ lesion such as a heart valve disease in a manner close to an actual lesion. Hereinafter, the preferred embodiment of the tubular organ-associated lesion model of the present invention will be described in detail. Hereinafter, the preferred embodiment of the tubular organ-associated lesion model may be described as the "heart-associated lesion model of the present invention" by focusing on the tubular organ-associated lesion model. However, the preferred embodiment of the heart-associated lesion model of the present invention also applies to the preferred embodiments of other tubular organ-associated lesion models of the present invention, and the present invention is not limited to the heart-associated lesion model.

[0015] Examples of tubular organs include solid organs such as the heart, and hollow organs such as blood vessels, the digestive tract (esophagus, stomach, duodenum, small intestine, large intestine, etc.), and the ureter. In the heart, lesions of the heart valves or the vascular roots connected to the heart are known. Specific examples of the heart valve or vascular roots with lesions that are simulated by the heart valve-related lesion model include the tricuspid valve, pulmonary valve, mitral valve, aortic valve, and aortic root tissue. Among these, the number of patients with diseases related to the mitral valve, aortic valve, and aortic root tissue is large. The heart valve-related lesion model may have only a heart valve or vascular root with a lesion, or may further have other tissues. Examples of other tissues include the left ventricle, left atrium, right atrium, right ventricle, aorta, pulmonary artery, and pulmonary vein. In the heart valve-related lesion model, the heart valve or blood vessel base having the lesion is preferably of biological origin.

[0016] In the tubular organ-associated lesion model of the present invention, the strength of tissues constituting the tubular organ is preferably weakened compared to the respective normal tissues. In particular, in the heart valve-associated lesion model of the present invention, the strength of tissues constituting the heart valve or blood vessel base is preferably weakened compared to the respective normal tissues. In particular, in the tubular organ-related lesion model of the present invention, it is preferable that the strength of collagen tissue among the tissues constituting the tubular organ is weakened compared to the respective normal tissues, and the strength of other tissues is approximately the same as those of the respective normal tissues. Among them, in the heart valve-related lesion model of the present invention, it is preferable that the strength of collagen tissue among the tissues constituting the heart valve or blood vessel base is weakened compared to the respective normal tissues, and the strength of other tissues is approximately the same as those of the respective normal tissues, from the viewpoint of being able to perform expansion without directly damaging the heart valve or blood vessel base tissue. For example, in the case of aortic root tissue, the aorta is composed of a three-layer structure of the intima, media, and adventitia, and each layer is composed of three main types of tissue: collagen, smooth muscle cells, and elastin. Among these, collagen fibers are distributed throughout the tissue, and play a role in binding and supporting the tissue, which is said to be largely responsible for the strength of the tissue. Therefore, when performing aortic root expansion, it is preferable to destroy the collagen fibers in the aortic tissue and weaken the tissue to expand the vascular diameter of the aortic root.

[0017] In the tubular organ-related lesion model of the present invention, at least one of the valve annulus area and other sizes and features of the tubular organ is preferably enlarged compared to the respective normal tissues. Among them, in the heart valve-related lesion model of the present invention, at least one of the valve annulus area and other sizes and features of the heart valve or blood vessel base is preferably enlarged or reduced compared to the respective normal tissues, and is more preferably enlarged. The shape of the expanded portion can be appropriately determined according to the desired cardiac valve-related lesion model. Examples include the AVJ (valve annulus) area, the STJ (commissure part) area, and the intercommissure distance. Among these, it is preferable to expand the valve annulus area. The degree of expansion of the valve annulus area can be appropriately determined according to the desired cardiac valve-related lesion model. For example, the valve annulus area is preferably expanded by 30% or more, more preferably by 50% or more, and particularly preferably by 100% or more, compared to normal tissue. The preferred expansion ranges of the shapes of the other expanded portions are the same. The shape of the portion to be reduced can be appropriately determined according to the desired heart valve-related lesion model. For example, the valve coaptation length cH, the coaptation height eH, etc. can be mentioned. Among these, it is preferable to reduce the valve coaptation length. The degree of reduction of the valve coaptation length can be appropriately determined according to the desired heart valve-related lesion model. For example, the valve coaptation length is preferably reduced by 10% or more, more preferably reduced by 30% or more, and particularly preferably reduced by 50% or more, compared to the normal tissue. The preferable reduction range of the shapes of the other portions to be reduced is similar. The size of these features can be measured by imaging models of heart valve-related lesions using Micro-CT.

[0018] Examples of the tubular organ-related lesion model of the present invention include a cardiac valve regurgitation model, a tubular organ enlargement model, and aneurysm models of blood vessels, digestive tracts, etc. For example, preferred examples of the tubular organ-related lesion model of the present invention include a mitral valve regurgitation model, an aortic root dilatation model, a left ventricular enlargement model, a right ventricular enlargement model, a left atrium enlargement model, a right atrium enlargement model, and a vascular aneurysm model. Vascular aneurysm models include those in which a portion of a blood vessel is pathologically enlarged. For example, an aortic aneurysm is a blood vessel in which a neuropathy forms in the aorta at the exit of the left ventricle. Since the risk of death due to rupture is extremely high, once the aneurysm reaches a certain size, it becomes a treatment target. Among them, the cardiac valve-related lesion model of the present invention is preferably a cardiac valve regurgitation model. Examples of cardiac valve regurgitation models include an aortic root dilatation model, an aortic valve regurgitation model, a functional mitral valve regurgitation model, a tricuspid valve regurgitation model, and a pulmonary valve regurgitation model. Among these, the aortic root dilatation model, the aortic valve regurgitation model, and the functional mitral valve regurgitation model are the models that are the subject of treatment for many diseases. The cardiac valve-related lesion model of the present invention can be used as a mild cardiac valve regurgitation model with a regurgitation rate of less than 30%, a moderate (moderate) cardiac valve regurgitation model with a regurgitation rate of 30% to less than 50%, or a severe cardiac valve regurgitation model with a regurgitation rate of 50% or more. Among these, a moderate to severe cardiac valve regurgitation model is preferred from the viewpoint of attaching a new medical device and evaluating its performance. The cardiac valve-related lesion model of the present invention preferably has a significantly increased reflux rate compared to the reflux rate of a normal cardiac valve or vascular base (a cardiac valve precursor isolated from an animal or a vascular base precursor connected to the heart), for example, an increase of 30% or more is preferable, and an increase of 50% or more is even more preferable. The reflux rate in the present invention can be calculated by the method described in the Examples below.

[0019] The tubular organ-associated lesion model of the present invention may be one in which at least a portion of the collagen tissue of the tubular organ (such as a heart valve or a blood vessel base) is degraded, and there is no particular limitation on the method for degrading the collagen tissue. Examples of the method for degrading the collagen tissue include application of collagen degrading enzymes such as collagenase and gelatin degrading enzymes. In other words, the tubular organ-associated lesion model of the present invention is preferably formed by applying a collagen-degrading enzyme to tubular organ precursors (such as cardiac valve precursors or vascular base precursors connected to the heart) excised from an animal to degrade the collagen in the tubular organ precursors. The collagen decomposition enzyme is not particularly limited, but among them, collagenase, which is a hydrolase that breaks peptide bonds in collagen molecules, is preferred from the viewpoint of selective hydrolysis. By using such collagenase to decompose collagen, a model can be prepared in which the strength of collagen tissues among the tissues constituting a tubular organ is weakened compared to the respective normal tissues, and the strength of the other tissues is reduced to the same extent compared to the respective normal tissues. The collagen-degrading enzyme is not particularly limited, and any known or commercially available enzyme can be used.

[0020] [Method of producing a tubular organ-associated lesion model] The method for producing a tubular organ-associated lesion model of the present invention is a method for producing a tubular organ-associated lesion model that simulates a lesion relating to a tubular organ containing collagen tissue or the tissue that constitutes a tubular organ, and includes a decomposition step of applying a collagen-degrading enzyme to a tubular organ precursor isolated from an animal to decompose at least a portion of the collagen tissue of the tubular organ precursor. In particular, the tubular organ is preferably a heart valve or a blood vessel root connected to the heart. That is, a preferred embodiment of the present invention is a method for producing a heart valve-related lesion model simulating a lesion relating to a heart valve or a blood vessel root connected to the heart, comprising a decomposition step of applying a collagen decomposition enzyme to a heart valve precursor or a blood vessel root precursor connected to the heart isolated from an animal to decompose at least a part of the collagen tissue of the heart valve precursor or the blood vessel root precursor.

[0021] <Disassembly process> In the degradation step, a collagen-degrading enzyme is applied to a tubular organ (such as a cardiac valve precursor or a vascular base precursor connected to the heart) isolated from an animal to degrade at least a portion of the collagen tissue of the tubular organ. There are no particular limitations on the method for applying the collagen-degrading enzyme to the tubular organ precursor, but a preferred method is to immerse the tubular organ precursor in a solution of the collagen-degrading enzyme.

[0022] In the method for producing a tubular organ-related lesion model of the present invention, in the decomposition step, it is preferable to insert an expansion member into the interior of the tubular organ precursor and immerse the tubular organ precursor in a collagenase solution, or to immerse the tubular organ precursor in a collagenase solution and insert an expansion member into the interior of the tubular organ precursor. Among these, in the method for producing a heart valve-related lesion model of the present invention, in the decomposition step, it is preferable to insert an expansion member into the interior of a heart valve precursor or a vascular base precursor and immerse the heart valve precursor or the vascular base precursor in a collagenase solution, or to immerse the heart valve precursor or the vascular base precursor in a collagenase solution and insert an expansion member into the heart valve precursor or the vascular base precursor. In the decomposition step, it is more preferable to insert an expansion member into the tubular organ precursor and immerse the tubular organ precursor in the collagenase solution, from the viewpoint of preventing the collagenase solution from being introduced into the tubular organ precursor and preventing the tubular organ from cracking or fissure. There are no particular limitations on the size or shape of the expansion member, but it is preferable that it is one that does not cause cracks or fissures in the tubular organ such as a heart valve precursor or a vascular base precursor. It is preferable to have a size that can be sealed to fit the inner cavity of the tubular organ, from the viewpoint of preventing the collagenase solution from being introduced into the tubular organ precursor.

[0023] In the method for producing a tubular organ-associated lesion model of the present invention, it is preferable to adjust at least one of the annulus area and other dimensions of the heart valve or blood vessel base by changing the immersion time and the size of the expansion member.

[0024] In the method for producing a tubular organ-related lesion model of the present invention, the size of the expansion member is changed stepwise from small to large to expand the tubular organ precursor (heart valve precursor or vascular base precursor, etc.) stepwise, which is preferable from the viewpoint of expanding the shape of the tubular organ-related lesion model to a desired range without causing tears or cracks. In particular, when trying to expand the shape of the tubular organ-related lesion model to a desired range, even if a tear or crack occurs when an expansion member of that size is inserted into the tubular organ precursor from the beginning, the expansion can be achieved without causing tears or cracks by changing the size of the expansion member stepwise from small to large. FIG. 16 shows a schematic diagram of an example of a method for producing an aortic valve lesion model. It is preferable to use an aortic root tissue extracted from a pig as a tubular organ precursor, insert an expansion member (upper part) and an expansion member (lower part) from both sides of the aortic root tissue to block the lumen (valve ring part), and gradually increase the size of the expansion member inserted into the valve ring part to fill and immerse the outside of the aortic root tissue with a collagen decomposition enzyme solution. It is preferable that the expansion member (upper part) and the expansion member (lower part) have a shape combining a convex part to be inserted into the valve ring part and a flat part, from the viewpoint of stabilizing the flat part when placed on a flat surface and preventing the collagen decomposition enzyme solution from being introduced into the inside of the tubular organ precursor.

[0025] The time for immersion in the collagenase solution is not particularly limited, and can be appropriately set according to the desired performance and shape of the heart valve-related lesion model. For example, in the case of an aortic root dilatation model, an immersion time of less than 9 hours is preferable from the viewpoint of easily producing a mild or moderate heart valve regurgitation model, 4 to 8 hours is more preferable, and 5 to 7 hours is particularly preferable from the viewpoint of easily producing a moderate heart valve regurgitation model. In the case of a functional mitral regurgitation model, from the viewpoint of durability of the functional mitral regurgitation model after immersion, the immersion time is preferably shorter, and more preferably less than 1 hour, whereas from the viewpoint of annular dilation of the functional mitral regurgitation model, the immersion time is preferably 5 minutes or more, and more preferably 15 minutes or more.

[0026] Other conditions for the decomposition step are not particularly limited. The concentration of the collagen decomposition enzyme solution and the enzyme concentration are not particularly limited and can be appropriately set according to the performance and shape of the desired cardiac valve-related lesion model. For example, 0.1% and 125 Unit / ml can be exemplified, but the present invention is not limited to this embodiment. The temperature of the collagen-degrading enzyme solution is not particularly limited and can be, for example, 35° C. to 37° C., but the present invention is not limited to this embodiment.

[0027] [Simulation test equipment for tubular organ-related lesions] The tubular organ-associated lesion simulation test device of the present invention is a tubular organ-associated lesion simulation test device in which the tubular organ-associated lesion model of the present invention is incorporated into the tubular organ-associated portion of a circulation simulator. In particular, it is preferable that the tubular organ is a heart valve or a blood vessel base connected to the heart. That is, a preferable embodiment of the present invention is a simulation test device for heart valve-related lesions, in which the heart valve-related lesion model of the present invention is incorporated into a heart valve-related portion of a pulsatile circulation simulator. There is no particular limitation on the circulation simulator such as the pulsatile circulation simulator, and a known one may be used, or a heart may be artificially imitated and manufactured by combining a pump, etc. In addition, the pulsatile circulation simulator does not need to imitate all the functions of the heart, and for example, when the heart valve or blood vessel base is the aortic base or mitral valve, it may imitate the functions of the left ventricle and the left atrium and omit the functions of the right ventricle and the right atrium. The pulsation of the pulsatile circulation simulator, for example the pulse rate and flow rate, can be set as appropriate. There is no particular limitation on the method for incorporating the tubular organ valve-related lesion model of the present invention into the tubular organ-related portion of the circulation simulator.

[0028] [Testing methods for medical devices] The medical device testing method of the present invention is a method for testing a medical device using the tubular organ-related lesion model of the present invention or the tubular organ-related lesion simulation test device of the present invention, in which a specific medical device is brought into contact with the tubular organ-related lesion model to perform characteristic testing of the medical device outside the human body. Thus, the tubular organ-related lesion model of the present invention is useful as an evaluation model to replace humans in the development of new treatments for tubular organ diseases such as heart valve disease. In the method for testing a medical device of the present invention, it is preferable to carry out a reflux suppression performance test of the medical device outside the human body by contacting a tubular organ-related lesion model with medical devices of different shapes or sizes and carrying out a circulatory flow test. Among these, it is more preferable to carry out a reflux suppression performance test of the medical device outside the human body by contacting a tubular organ-related lesion model with medical devices of different shapes or sizes and carrying out a pulsatile flow test. EXAMPLES

[0029] The present invention will be described in more detail below with reference to examples and comparative examples. The materials, amounts used, ratios, processing contents, processing procedures, etc. shown in the following examples can be appropriately changed without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be interpreted as being limited by the specific examples shown below.

[0030] [Examples 1-4] <Creation of aortic lesion model> An aortic lesion model (aortic root dilatation model) was prepared according to the following procedure. The aortic root excised from a pig heart was used as a vascular root precursor to be connected to the heart excised from an animal. A photograph of the aortic root used as a vascular root precursor is shown in Figure 1. The outer diameter of the valve annulus was 24 mm. The vascular root precursor was immersed in a collagenase solution (SIGMA C0130-1G Collagenase from Clostridium histolyticum, for general use, Type I) to decompose the collagen in the aortic tissue. The immersion conditions were 0.1% concentration, 125 U / ml enzyme concentration, and 35°C temperature, and the immersion time was 3 hours (Example 1), 6 hours (Example 2), 9 hours (Example 3), or 12 hours (Example 4).

[0031] As the expansion member to be inserted inside the vascular root precursor, expansion members of different sizes were prepared according to the shape of the aortic root. The shape of one example of the expansion member is shown in Figure 2. A first-stage expansion member with a low expansion ratio was inserted into the vascular base precursor, and the vascular base precursor was immersed in a collagenase solution. Then, expansion members with gradually increasing expansion ratios were inserted into the vascular base precursor in multiple stages, and finally, an expansion member with the size shown in Fig. 2 was inserted as shown in Fig. 3 and left for 1 hour to produce the aortic base expansion models of Examples 1 to 4. In this specification, "expansion" and "expansion ratio" are synonymous with "expansion" and "expansion ratio". Furthermore, when expansion members of different sizes are inserted into the interior of the vascular base precursor without being divided into multiple stages, for example, when an expansion member of the size shown in Figure 2 is inserted from the beginning, it may not fit in or a tear may occur in the portion of the vascular base precursor being expanded. Alternatively, the vascular base precursor may be immersed in a collagenase solution and then an expansion member may be inserted into the interior of the vascular base precursor. However, in this case as well, if the expansion is not carried out in a stepwise manner, tears may occur in the expanded portion of the vascular base precursor.

[0032] <Creating a simulation test device for heart valve-related lesions> The aortic root dilation models prepared in Examples 1 to 4 were incorporated into the heart valve-related portion of the pulsatile circulation simulator to create a simulation test device for the heart valve-related lesions of Examples 1 to 4. A cylindrical aortic blood vessel was connected to the left ventricular outlet of the model and sutured to the tissue around the aortic valve. The pulsatile circulation simulator used is shown in Figure 4. With this configuration, the pulsatile circulation simulator can obtain flow waveforms over time using an ultrasonic flowmeter, and can measure left ventricular pressure and aortic pressure using a pressure transducer. Note that P1 represents left ventricular pressure, P2 represents aortic pressure, and Q represents aortic valve flow rate.

[0033] <Reflux rate evaluation> In order to evaluate the pulsation performance of the aortic root according to differences in immersion time in collagenase, the reflux rate of the aortic root dilation models prepared in Examples 1 to 4 was measured. Here, the regurgitation rate is the ratio of the regurgitation volume (the sum of the dynamic regurgitation volume: regulation and the static regurgitation volume: leakage) to the inflow volume (aortic valve output: forward flow) of the obtained flow waveform, and is defined by the following equation 1.

number

[0034] <Shape evaluation> To evaluate whether the aortic root dilation model was sufficiently dilated, the closed shape of the model was imaged using a Micro-CT (TDM1300-IS (Yamato Scientific Co., Ltd.)). The imaging method was to apply an air pressure of 80 mmHg from the aortic side to observe the valve shape, and each part was measured using volume rendering software (Mimics Research (Materialize Co., Ltd.)) based on the captured CT data. The aortic root shape of the aortic root dilation model of Example 2 was compared with that of a normal root model (aortic root excised from a pig heart) before immersion. The measurement items were the valve annulus area (AVJ) and valve coaptation length (cH; also called coaptation length) in the schematic diagram of the cross section of the aortic root shown in FIG. As shown in FIG. 8, the aortic root dilation model of Example 2 (after dilation) had a significantly increased valve annulus area (AVJ) compared with the normal root model (before dilation). Furthermore, as shown in FIG. 9, compared with the normal root model (before dilation), the aortic root dilation model of Example 2 (after dilation) had a significantly reduced valve coaptation length (cH) as shown in FIG. From the above, it was found that according to the present invention, an aortic lesion model (aortic root dilatation model) with deteriorated valve coaptation performance could be produced. By contacting a newly developed medical device (e.g., annuloplasty ring) with such an aortic lesion model and performing a pulsatile flow test, it is possible to test the reflux inhibition performance of the medical device outside the human body, making the aortic lesion model of the present invention highly applicable industrially.

[0035] [Examples 11-13] <Creating a mitral regurgitation model> A mitral regurgitation model (functional mitral regurgitation model) was prepared according to the following procedure. A porcine mitral valve was extracted from a porcine heart, leaving the left atrium, and used as a heart valve precursor extracted from an animal. The size of the anterior leaflet of the porcine mitral valve was measured and recorded. The heart valve precursor (porcine mitral valve) from the left atrium to the valve annulus was immersed in collagenase solution C0130-1G similar to that in Example 1 to decompose collagen in the mitral valve and tissues adjacent to the mitral valve. The immersion conditions were a concentration of 0.1%, an enzyme concentration of 125 U / ml, and a temperature of 37° C., for 10 minutes (Example 11), 30 minutes (Example 12), or 60 minutes (Example 13), as shown in FIG.

[0036] As an expansion member to be inserted inside the heart valve precursor, expansion members (sizers) of different sizes were prepared according to the shape of the mitral valve annulus. The shape of one example of an expansion member is shown in Figure 11. The shape of the expansion member is composed of an upper curve (circle symbol 1) with a width equivalent to the intercommissural distance x shown in Figure 11 and with rounded corners, a semicircle (circle symbol 2) with the intercommissural distance of each individual as a diameter R (x / 2), and a line segment (circle symbol 3) connecting the upper curve (circle symbol 1) and the semicircle (circle symbol 2). After inserting a first-stage expansion member with a low expansion ratio into the heart valve precursor and immersing the left atrium to the annulus of the heart valve precursor in a collagenase solution, expansion members with gradually increasing expansion ratios were inserted into the annulus of the heart valve precursor in multiple stages, and finally, an expansion member with the size shown in Figure 11 was inserted as shown in Figure 12 and left for a predetermined time to create the functional mitral regurgitation models of Examples 11 to 13. In order to forcibly create a disease model from a normal porcine mitral valve, the goal was to expand three sizes (increase the intercommissural distance x by 6 mm) from the normal porcine mitral valve. Furthermore, if expansion members of different sizes are inserted into the annulus of a cardiac valve precursor without being separated into multiple stages, for example, if an expansion member of the size shown in Figure 11 is inserted from the beginning, it will not fit or tears will form in the part of the annulus being expanded. Alternatively, the heart valve precursor can be immersed in a collagenase solution before inserting an expansion member into the annulus of the heart valve precursor; however, in this case too, if the expansion is not carried out in a stepwise manner, tears may form in the annulus.

[0037] <Creating a simulation test device for heart valve-related lesions> The functional mitral regurgitation model prepared in Examples 11 to 13 was incorporated into the heart valve-related portion of the pulsatile circulation simulator to prepare a simulation test device for the heart valve-related lesions of Examples 11 to 13. The expanded mitral valve model was sutured to the annular suture sheet shown in Figure 13 and attached to the pulsatile circulation simulator. The annular suture sheet used should be one that is appropriate for the size of the anterior leaflet of the measured porcine mitral valve. The pulsatile circulation simulator used is shown in Figure 14. With this configuration, the pulsatile circulation simulator can obtain the flow waveform over time using an ultrasonic flowmeter, and can measure the left ventricular pressure and aortic pressure using a pressure transducer. Note that P1 represents left ventricular pressure, P2 represents aortic pressure, and Q represents flow rate.

[0038] <Evaluation of functional mitral regurgitation model> The mitral regurgitation rate was measured for the functional mitral regurgitation models prepared in Examples 11 to 13. The mitral regurgitation rate is the ratio of the mitral regurgitation amount (the amount of regurgitation associated with the closing behavior of the mitral valve during early left ventricular contraction: Regurgitation, and the amount of leakage when the mitral valve is closed: Leakage) to the obtained mitral inflow amount (the amount of flow from the left atrium to the left ventricle when the mitral valve opens during left ventricular diastole: Forward flow). The mitral regurgitation rate can be calculated using a formula similar to Formula 1 above. Next, the annulus area expansion rate was measured in the functional mitral regurgitation models of Examples 11 to 13. The obtained results are shown in FIG. In Example 11, in which the immersion time was 10 minutes, the annular area increased by 18.1% before and after annular dilation, and the mitral regurgitation rate, which was 12.7% in the normal model, increased to 16.7%. In case 12, where the immersion time was 30 minutes, the annular area increased by 50.2% and the mitral regurgitation rate increased from 16.5% to 24.4%. In Example 13, where the immersion time was 60 minutes, the valve annulus area increased by 52.2%, and the mitral regurgitation rate increased from 15.5% to 20.5%. Note that, although Example 12, where the immersion time was 30 minutes, and Example 13, where the immersion time was 60 minutes, had a similar effect of expanding the valve annulus area by about 50%, Example 12, where the immersion time was shorter, is preferable from the viewpoint of the durability of the porcine mitral valve tissue after immersion. From the above results, it was found that in Examples 11 to 13, a mitral regurgitation rate of less than 30% occurred, and therefore these can be used as models of mild functional mitral regurgitation. Furthermore, by gradually increasing the size of the expansion device with an immersion time of 30 minutes, it was found that this could be used as a model of severe functional mitral regurgitation with a regurgitation rate of 60%. Furthermore, it was found that the functional mitral regurgitation models of Examples 11 to 13 can also be used as lesion models for quantitatively evaluating mitral regurgitation volume by applying an artificial mitral valve. By contacting such a functional mitral regurgitation model with a medical device based on a new idea or a medical device of a different shape or size and performing a pulsatile flow test, the regurgitation suppression performance test of the medical device can be performed outside the human body, so that the functional mitral regurgitation model of the present invention has high industrial applicability.

Claims

1. A tubular organ lesion model simulating a lesion of a tubular organ containing collagen tissue or a tissue constituting the tubular organ, comprising: A tubular organ-associated lesion model, in which at least a portion of the collagen tissue of the tubular organ is degraded and the strength of the tissues constituting the tubular organ is weakened compared to that of each normal tissue.

2. The tubular organ-associated lesion model according to claim 1 , wherein the tubular organ is a heart valve or a blood vessel root connected to the heart.

3. The tubular organ-associated lesion model according to claim 1, wherein the strength of collagen tissue among the tissues constituting the tubular organ is weakened compared to that of the respective normal tissues, and the strength of the other tissues is approximately the same as that of the respective normal tissues.

4. A tubular organ lesion model simulating a lesion of a tubular organ containing collagen tissue or a tissue constituting the tubular organ, comprising: A tubular organ-associated lesion model, in which at least a portion of the collagen tissue of the tubular organ is degraded and at least one of the valve annulus area and other sizes or characteristics of the tubular organ is expanded compared to the respective normal tissue.

5. A tubular organ lesion model simulating a lesion relating to a tubular organ containing collagen tissue or a tissue constituting said tubular organ, comprising: A tubular organ-associated lesion model in which at least a portion of the collagen tissue of the tubular organ is degraded, and a collagen-degrading enzyme is applied to a tubular organ precursor removed from an animal to degrade the collagen of the tubular organ precursor.

6. A tubular organ lesion model simulating a lesion in a tubular organ containing collagen tissue or a tissue constituting the tubular organ, comprising: A tubular organ-associated lesion model, which is a mitral valve regurgitation model, an aortic root dilatation model, a left ventricular enlargement model, a right ventricular enlargement model, a left atrial enlargement model, a right atrial enlargement model or a vascular aneurysm model, in which at least a portion of the collagen tissue of the tubular organ is degraded.

7. A simulation test device for tubular organ-related lesions, comprising a tubular organ-related lesion model according to any one of claims 1 to 6 incorporated in a tubular organ-related portion of a circulation simulator.

8. A method for testing a medical device using the tubular organ-associated lesion model according to any one of claims 1 to 6 or the tubular organ-associated lesion simulation test device according to claim 7, A method for testing a medical device, comprising contacting a specific medical device with the tubular organ-associated lesion model, thereby performing a characteristic test of the medical device outside the human body.

9. The method for testing a medical device according to claim 8, further comprising the step of contacting medical devices of different shapes or sizes with the tubular organ-related lesion model and conducting a circulatory flow test to test the reflux suppression performance of the medical device outside the human body.

10. A method for producing a tubular organ lesion model that simulates a lesion in a tubular organ containing collagen tissue or a tissue constituting the tubular organ, comprising: A method for producing a tubular organ-associated lesion model, comprising a decomposition step of applying a collagen-decomposing enzyme to a tubular organ precursor isolated from an animal to decompose at least a portion of the collagen tissue of the tubular organ precursor.

11. The method for producing a tubular organ-associated lesion model according to claim 10, wherein the tubular organ is a heart valve or a blood vessel root connected to the heart.

12. In the decomposition step, an expansion member is inserted into the inside of the tubular organ precursor, and the tubular organ precursor is immersed in the solution of the collagen decomposition enzyme, or The method for producing a tubular organ-associated lesion model according to claim 10 or 11, comprising immersing the tubular organ precursor in a solution of collagen degrading enzyme and inserting an expansion member into the inside of the tubular organ precursor.

13. The method for producing a tubular organ-associated lesion model according to claim 12, wherein the size of the expansion member is changed stepwise from small to large to expand the tubular organ precursor stepwise.

14. The method for manufacturing a tubular organ-associated lesion model according to claim 13, further comprising adjusting at least one of the valve annulus area and other dimensions or features of the tubular organ by changing the immersion time and the size of the expansion member.

Images