Heart valve prosthesis

Abstract

To provide an improved heart valve prosthesis that can be made from human or animal biological tissue and can be manufactured stably and easily. The present invention relates to a heart valve prosthesis obtainable by a method comprising the steps of: a) providing a living tissue of a human or animal, b) shaping the living tissue in a shaping process that imparts to the living tissue the shape and size of a heart valve, and c) fixing and stabilizing the living tissue with a crosslinking agent, thereby retaining the shape imparted to the living tissue in the shaping process, to obtain a heart valve prosthesis, wherein the crosslinking agent comprises at least one compound having a structure according to general formula (I):

Description

[Technical Field]

[0001] The present invention relates to the heart valve prosthesis described in claim 1 and the medical use of the heart valve prosthesis described in claim 13. [Background technology]

[0002] International Publication No. 2004 / 047620 (Patent Document 1) describes a step of fixing tissue with a solution containing phenolic tannins. This international patent application further describes a process of replacing a damaged heart valve by implanting a heart valve bioprosthesis comprising a fixation tissue made of elastin crosslinked with a tannic acid crosslinking agent. The bioprosthesis disclosed in this international patent application has a support material attached to the fixation tissue, in addition to the fixation tissue made of elastin crosslinked with a tannic acid crosslinking agent.

[0003] International Publication No. 2004 / 113431 (Patent Document 2) relates to the use of secoiridoid-containing substances as non-toxic crosslinking agents for crosslinking biomacromolecules such as polypeptides and polysaccharides.

[0004] International Publication No. 2006 / 115733 (Patent Document 3) relates to a method and product for treating connective tissue weakened by the destruction of tissue structure, particularly the degradation of elastin. This therapeutic agent utilizes the specific inherent properties of phenolic compounds to reduce elastin degradation.

[0005] International Publication No. 2008 / 079272 (Patent Document 4) describes a heart valve prosthesis comprising a leaflet portion and an annular stent having annularly spaced commissures. The leaflet portion can be made from animal-derived pericardium.

[0006] International Publication No. 2012 / 068241 (Patent Document 5) describes bioprosthesis tissue and a method for producing the same. These methods include fixing the bioprosthesis implant tissue by heating with 0.1 to 10 wt% glutaraldehyde, covering the fixed tissue with a diamine crosslinking agent, and treating the covered tissue with approximately 0.6 wt% glutaraldehyde.

[0007] Antunes et al. (Antunes, APM et al. "Use of oleuropein as a crosslinking agent for collagen films," J. Leather Sci, (2008) 2(1)) investigated oleuropein, a phenolic compound isolated from olive (Olea europaea L.), as a crosslinking agent for collagen. Various parameters, including oleuropein concentration, enzyme concentration, and culture period, were investigated. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2004 / 047620 [Patent Document 2] International Publication No. 2004 / 113431 [Patent Document 3] International Publication No. 2006 / 115733 [Patent Document 4] International Publication No. 2008 / 079272 [Patent Document 5] International Publication No. 2012 / 068241

[0009] [Non-Patent Document 1] Antunes et al. (Antunes, APM et al. "Use of oleuropein as a crosslinking agent for collagen films," J. Leather Sci, (2008) 2(1)) [Overview of the project] [Problems that the invention aims to solve]

[0010] The object of the present invention is to provide an improved heart valve prosthesis that can be made from human or animal biological tissue, and can be manufactured stably and by a simple method. [Means for solving the problem]

[0011] This objective is achieved by a cardiac prosthesis having the configuration of claim 1. Such a cardiac valve prosthesis can be obtained by a method comprising the steps described below. First, human or animal biological tissue is provided. Next, the biological tissue is molded in a molding step to give the biological tissue the shape and size of a heart valve. Subsequently, the molded biological tissue is fixed and stabilized with a crosslinking agent as defined below. This maintains the shape given to the biological tissue in the molding step. As a result, a cardiac valve prosthesis is obtained.

[0012] The term "biological tissue" encompasses connective tissue, muscle tissue, nerve tissue, epithelial tissue, fascial tissue, peritoneal tissue, and myocardial tissue. While these tissues also contain fluid components, they can be considered solid biological tissues. The term "biological tissue" explicitly excludes fluid biological tissues such as blood and lymph.

[0013] In one embodiment, the term “living tissue” does not include natural heart valve tissue.

[0014] In one embodiment, the animal tissue is derived from a rodent or a non-human mammal.

[0015] In the prior art, crosslinking agents were used simply to reduce the biodegradability of the biological tissue used. However, the method used to manufacture the heart valve prosthesis described in the claims utilizes a molding process to impart a desired shape and size, i.e., the shape and size of a heart valve, to the biological tissue. The crosslinking agent then maintains this predetermined shape. The prior art does not suggest that crosslinking agents can be used to maintain a predetermined shape. Rather, for example, International Publication No. 2004 / 047620 discloses a bioprosthesis having tissue fixed with a crosslinking agent on the one hand, and a support material attached to the fixed tissue on the other hand. Thus, the prior art teaches that the crosslinking agent used can be used to alter the chemical structure of the treated biological tissue. However, the prior art does not teach that the use of a crosslinking agent can maintain a predetermined shape of the biological tissue.

[0016] In contrast, the heart valve prosthesis according to the claims of the present invention is a self-contained heart valve prosthesis that does not require, nor includes, further support materials or support structures. Rather, no additional support materials or support structures exist. The heart valve prosthesis can be implanted in the form of a heart valve prosthesis combination including the heart valve prosthesis and a carrier (e.g., a stent) connected to the heart valve prosthesis. To connect the heart valve prosthesis to the carrier, the heart valve prosthesis can be sutured to the carrier. However, the carrier is not necessary to structurally support the heart valve prosthesis. Rather, the carrier is there to keep the heart valve prosthesis in place after implantation and to allow the heart valve prosthesis to function properly.

[0017] In one embodiment, the molding process is a process of applying positive or negative pressure to biological tissue. For example, the biological tissue may be inserted into a mold and molded by applying pressure, for example, by a suction process, to form the shape of the mold.

[0018] In one embodiment, the forming step is a deep drawing process, for example, a deep drawing process using an individually formed mold (last).

[0019] In one embodiment, the crosslinking agent not only maintains a predetermined shape of the biological tissue but also helps to stabilize the structure of the extracellular matrix of the biological tissue, and the extracellular matrix includes glycosaminoglycans, collagen, and elastin.

[0020] The crosslinking agent has at least one secoiridoid corresponding to the following general formula (I) or has a secoiridoid.

[0021]

Chemical formula

[0022]

Chemical formula

[0023]

Chemical formula

[0024] R 2 If this corresponds to formula (III), then residue R 2 The bond between the adjacent heterocyclic compound is retained R 2 The conservative R is bonded to the hetero ring of 2 The bond extends away from the oxygen atom, resulting in the structure shown in formula (VI) below.

[0025] [ka]

[0026] In one embodiment, the residues of the structure according to formula (I) have a structure according to the following formula (IV).

[0027] [ka]

[0028] In one embodiment, 2 It has a structure that conforms to general formula (III) and a structure that conforms to the following formula (V).

[0029] [ka] By combining the latter two embodiments, the following structure conforming to general formula (VII) can be obtained.

[0030] [ka]

[0031] In one embodiment, 5 , R 6 , R 7 , R 8 , and R 9At least two of them show OH.

[0032] In one embodiment, 5 , R 6 , and R 9 H indicates a stable R 7 and R 8 This indicates OH.

[0033] In one embodiment, 1 and R 3 This indicates CH3.

[0034] In one embodiment, 2 This represents OH. Furthermore, the crosslinking agent has or is equivalent to one of the following general formulas (VIII) to (IX).

[0035] [ka]

[0036] In one embodiment, 1 , R 3 This represents CH3 in equations (VIII) and (IX).

[0037] In one embodiment, the crosslinking agent has a compound corresponding to the following formula (X) or (XI), or the crosslinking agent itself corresponds to these formulas.

[0038] [ka]

[0039] A crosslinking agent having a structure corresponding to formula (X) exists in equilibrium with a structure corresponding to the following formula (XII).

[0040] [ka]

[0041] A crosslinking agent having a structure corresponding to formula (XI) exists in equilibrium with a structure corresponding to the following formula (XIII).

[0042] [ka]

[0043] In one embodiment, the crosslinking agent comprises at least one compound according to formula (VI), formula (X), formula (XI), formula (XII), formula (XIII) or a derivative thereof, or is a compound according to formula (VI), formula (X), formula (XI), formula (XII), formula (XIII) or a derivative thereof.

[0044] In one embodiment, the term “derivative” refers to a compound that can be derived from a particular compound by a naturally occurring biotransformation process. That is, these derivatives would be formed in the body of a human or animal by enzymatic activity or non-enzymatic biochemical transformation or maturation process. Specific examples of derivatives of compounds following formulas (VI), (X), (XI), (XII), or (XIII) are the compounds corresponding to formulas (XIV) to (XXII) below.

[0045] [ka]

[0046] [ka]

[0047] [ka]

[0048] All of these derivatives, particularly those having structures according to formulas (XI), (XIII), (XIX), (XX), (XXI), or (XXII), are especially suitable for crosslinking human or animal tissues.

[0049] Compounds that can be derived from compounds having a structure according to formula (I) by biochemical methods similar to those used for the specific derivatives described above are also included in the subject matter described in the claims and form part of the present invention.

[0050] In one embodiment, 10 , R 11 , R 12 , R 13 At least two of them show OH.

[0051] In one embodiment, 10 , R 11 , R 12 , R 13 Each of these represents OH.

[0052] In one embodiment, 5 , R 6 , and R 9 H indicates a stable R 7 and R 8 This indicates OH, and residue R 1 and R 3 This indicates CH3, and the retained R 2 This corresponds to formula (III), and residue R 10 , R 11 , R 12 , R 13 This represents an OH group. Furthermore, this compound has a structure corresponding to the following general formula (XXIII).

[0053] [ka]

[0054] In one embodiment, 5 , R 6 , and R 9 H indicates a stable R 7 and R 8 This indicates OH, and residue R 1 and R 3 This indicates CH3, and the retained R 2 This corresponds to formula (V), and residue R 10 , R 11 , R 12 , R13 The OH group represents an OH group, and the residues in the structure according to formula (I) have a structure according to formula (IV). The compound then has a structure corresponding to the following general formula (XXIV).

[0055] [ka]

[0056] In one embodiment, the biological tissue that is held in a predetermined shape is cardiac tissue.

[0057] In one embodiment, the biological tissue that is held in a predetermined shape is myocardial tissue.

[0058] In one embodiment, the biological tissue that is held in a predetermined shape is pericardial tissue.

[0059] In one embodiment, the heart valve prosthesis is an aortic valve prosthesis, a pulmonary valve prosthesis, a mitral valve prosthesis, or a tricuspid valve prosthesis.

[0060] In one embodiment, the shape of the heart valve, i.e., the shape to be given to the biological tissue, is defined by performing the steps described below. First, a three-dimensional image of the individual diseased heart valve is obtained by an appropriate imaging method, such as magnetic resonance imaging (MRI), computed tomography (CT), (three-dimensional) ultrasound, or three-dimensional rotational angiography. Second, three-dimensional reconstruction of the imaging data is performed while correcting the disease (so-called virtual valvular surgery). Third, a digital three-dimensional mold of the required heart valve prosthesis is created. Fourth, a mold of the "real" heart valve is created based on the digital three-dimensional mold. This can be achieved, for example, by an appropriate technique such as three-dimensional printing or injection molding.

[0061] To perform the molding process, biological tissue is inserted into a heart valve mold and molded using an appropriate molding technique, such as deep drawing. Once the biological tissue has reached the desired shape within the heart valve mold, a crosslinking agent is added to the molded biological tissue. The addition of the crosslinking agent causes the biological tissue to crosslink, allowing it to stably maintain the shape it has acquired within the heart valve mold. As a result, a human artificial heart valve, or heart valve prosthesis, made from biological tissue is completed. Due to the chemical crosslinking of the biological tissue, the molded biological tissue maintains its acquired shape even after the crosslinking agent and mold are removed. This artificial heart valve can then be implanted into an individual.

[0062] In one embodiment, the crosslinking agent is used in a concentration of 0.01-10% (v / v) or (w / w), particularly 0.02-9%, particularly 0.03-8%, particularly 0.04-7%, particularly 0.05-6%, particularly 0.06-5%, particularly 0.07-4%, particularly 0.07-4%, particularly 0.08-3%, particularly 0.09-2%, particularly 0.1-1%, particularly 0.2-0.9%, particularly 0.3-0.8%, particularly 0.4-0.7%, and particularly 0.5-0.6% of the total volume of the treatment solution.

[0063] In one embodiment, the crosslinking agent is kept in contact with the molded biological tissue for a period of time ranging from 1 to 72 hours, particularly 2 to 48 hours, particularly 3 to 36 hours, particularly 4 to 24 hours, particularly 5 to 20 hours, particularly 6 to 15 hours, and particularly 8 to 12 hours.

[0064] In one embodiment, during the culture period using the crosslinking agent for the molded biological tissue, the temperature is kept within the range of 15°C to 40°C, particularly 20°C to 38°C, particularly 22°C to 37°C, particularly 25°C to 35°C, and particularly 27°C to 30°C.

[0065] In one embodiment, the treatment solution containing the crosslinking agent also contains a buffer capable of buffering the treatment solution at a pH value of approximately 5. Particularly suitable pH values ​​for the treatment solution are in the pH range of pH 4 to pH 6, particularly pH 4.5 to pH 5.5, particularly pH 4.7 to pH 5.2, and particularly pH 4.8 to pH 5.0. Citrate buffer is a particularly suitable buffer.

[0066] In one embodiment, the molded biological tissue and processing solution are stirred in a shaker, such as an oscillating shaker, for at least part of the molding process. For example, stirring is performed over time periods ranging from 5 minutes to 2 hours, particularly from 10 minutes to 1.5 hours, particularly from 20 minutes to 1 hour, and particularly from 30 minutes to 45 minutes. Stirring is typically performed at the start of the crosslinking process. Appropriate stirring speeds are in the range of 10 revolutions per minute (rpm) to 500 rpm, particularly from 20 rpm to 450 rpm, particularly from 30 rpm to 400 rpm, particularly from 40 rpm to 350 rpm, particularly from 50 rpm to 300 rpm, particularly from 60 rpm to 250 rpm, particularly from 70 rpm to 200 rpm, particularly from 80 rpm to 150 rpm, and particularly from 90 rpm to 100 rpm.

[0067] In one embodiment, the biological tissue being molded originates from the same individual to which the heart valve prosthesis will later be implanted. In other words, the heart valve prosthesis is an autologous heart valve prosthesis.

[0068] In one embodiment, biological tissue is excised from a human or animal body before the molding process and before the biological tissue is crosslinked. Such excision is typically performed by conventional surgical methods.

[0069] In one embodiment, the present invention relates to a cardiac valve prosthesis combination comprising a cardiac valve prosthesis and a carrier (e.g., a stent) as described above.

[0070] In one embodiment, the present invention relates to a medical method for treating heart disease caused by a damaged heart valve in a human or animal requiring treatment, by replacing the damaged or diseased heart valve with a heart valve prosthesis as described above.

[0071] In one embodiment, the present invention relates to the medical use of the previously described heart valve prosthesis in the treatment of heart disease caused by a impaired heart valve. Such heart disease is, for example, heart valve insufficiency or stenosis.

[0072] In one embodiment, the heart valve prosthesis is implanted into the same human or animal body from which the biological tissue used to manufacture the heart valve prosthesis was obtained. In other words, the heart valve prosthesis is an autologous heart valve prosthesis.

[0073] In one embodiment, the present invention relates to a medical method for producing a heart valve prosthesis for an individual human or animal in need of treatment. The method includes the steps of providing human or animal biological tissue, shaping the biological tissue in a molding process to give the biological tissue a desired shape and size of a heart valve, and maintaining the shape given to the biological tissue in the molding process by contacting the molded biological tissue with a crosslinking agent to fix and stabilize the biological tissue. These steps result in a heart valve prosthesis. In one embodiment, the crosslinking agent includes, or consists solely of, a compound having a structure according to the general formula (I) described above. Thereafter, each residue of formula (I) has a compound as described above.

[0074] All embodiments of the described heart valve prostheses, methods, and applications can be combined in any desired manner and substituted for the described applications and other methods, and vice versa. [Brief explanation of the drawing]

[0075] Further detailed embodiments of the present invention will be described by exemplary embodiments and accompanying drawings. [Figure 1] This diagram shows a comparison of two types of crosslinking agents used for crosslinking molded biological tissues. [Modes for carrying out the invention]

[0076] In vitro tests were conducted to determine whether different crosslinking agents have different effects on crosslinking biological tissues. For the in vitro tests, human and animal biological tissues were used and molded using a deep drawing process to give the biological tissues the shape and size of a heart valve, specifically a pulmonary valve.

[0077] Subsequently, the molded biological tissue was fixed and stabilized by the addition of two different crosslinking agents. Glutaraldehyde (GA) was used in one case, and a compound having the structure of formula (X) was used in the other. The latter compound will be referred to as compound X below. The final concentration of GA was selected to be in the range of 0.2–0.625% in the treatment solution. The final concentration of compound X was selected to be in the range of 0.05% in the treatment solution. Culturing was carried out at temperatures in the range of 20°C to 40°C for a duration of 20 minutes (GA) or 24 hours (compound X). The treatment solution containing the crosslinking agent was buffered with citrate buffer in the range of pH 4.8–5.0. Within the first 30 minutes of the crosslinking process, the molded biological tissue and treatment solution were stirred with a 100 rpm oscillating shaker.

[0078] Subsequently, tensile tests were conducted. Both GA and compound X were able to crosslink molded biological tissue, but compound X was found to be more suitable for the crosslinking process because it stabilized the structure of the molded biological tissue more effectively.

[0079] As can be seen in Figure 1, the biological tissue treated with compound X (curve 1) showed 1.5 times greater stress resistance than the biological tissue crosslinked with GA (curve 2) (9.5 MPa vs. 6.7 MPa). At the same time, the maximum strain achieved was 10% higher when crosslinked with GA than when crosslinked with compound X (57% vs. 51%). However, in order for the heart valve to function properly, not only high strain resistance but also higher stress resistance and sufficient high strain resistance are considered important. Therefore, we decided to conduct further characteristic tests only on the molded biological tissue crosslinked with compound X.

[0080] Examination of the shrinkage temperature using differential scanning calorimeter (DSC) confirmed that the biological tissue was sufficiently cross-linked. Subsequent cytotoxicity and biocompatibility tests revealed no associated cytotoxicity and confirmed high biocompatibility. Furthermore, no necrosis was observed when the cross-linked biological tissue was placed in fibroblast culture medium.

[0081] Subsequently, in vivo studies were conducted to evaluate the stability of cross-linked biological tissue over a long period in a real-world environment.

[0082] In the initial preclinical trials, we successfully demonstrated the general feasibility and safety of heart valve replacement.

[0083] In a second preclinical study, the long-term stability of the manufactured heart valve prostheses was confirmed. Using an animal model (sheep), sufficiently high stability of the cross-linking tissue was demonstrated over a period of 1.5 years. Furthermore, no heart failure with more than 20% regurgitation was observed. In addition, no heart valve stenosis was observed.

[0084] Furthermore, the fabricated heart valve prostheses underwent various histological examinations. The thickness, length, and structure of the fabricated heart valve prostheses were consistent with those of the replaced natural heart valve. No thrombi were observed throughout the prosthesis or at the apical hinge. The endothelium of the heart valve prosthesis was confirmed to be complete and precisely localized. Proper and localized neointimal formation was observed, and its extent was sufficient.

[0085] Analysis of foreign body reactions and other inflammatory responses in M1 (CD80), M2 (CD163) macrophages, T cells (CD3), and B cells (CD79a) revealed an increase in M2 macrophages. This can be considered an indication of an immune response that favors differentiation into myofibroblasts.

[0086] No related neovascularization was observed. The heart valve prosthesis was in complete contact with the pulmonary artery wall. No calcification was observed. Furthermore, there were no signs of necrosis of the pulmonary artery wall.

[0087] In other words, the heart valve prosthesis produced by shaping biological tissue and crosslinking it with crosslinkable compound X integrated appropriately with the surrounding biological tissue, resulting in a heart valve prosthesis that provided stable function over the long term. Furthermore, this disclosure includes the following details regarding the manner of implementation. [Aspect 1] It is a heart valve prosthesis, a) A step of providing human or animal biological tissue, b) A process of shaping the biological tissue to give it the shape and size of a heart valve, c) A step of obtaining a heart valve prosthesis by fixing and stabilizing the biological tissue with a crosslinking agent, thereby maintaining the shape given to the biological tissue during the molding process, In a heart valve prosthesis that can be obtained by a method including, The aforementioned crosslinking agent is general formula (I): [ka] It comprises at least one compound, salt, or derivative having a structure according to the following, In the formula, R 1 and R 3 These are H or CH, independently of each other and independently of other residues in the compound. 3 Show, R 4 It is independent of other residues in the compound, H or general formula (II): [ka] This shows a residue having a structure that follows the following: In the formula, R 5 ,R 6 ,R 7 ,R 8 ,R 9 These components, independently of each other and independently of other residues in the compound, represent either H or OH. R 2 This is independent of other residues in the compound, and is either H, OH, or general formula (III): [ka] This shows a residue having a structure that follows the following: In the formula, R10 ,R 11 ,R 12 ,R 13 These represent H or OH independently of each other and independently of other residues in the compound. Heart valve prosthesis. [Aspect 2] In the heart valve prosthesis described in Embodiment 1, a residue having a structure according to formula (I) is defined as formula (IV):

change

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Claims

1. It is a heart valve prosthesis, a) A step of providing human or animal biological tissue, b) A process of shaping the biological tissue in which the biological tissue is given the shape and size of a heart valve, c) A step of obtaining a heart valve prosthesis by fixing and stabilizing the biological tissue with a crosslinking agent, thereby maintaining the shape given to the biological tissue during the molding process, In a heart valve prosthesis that can be obtained by a method including, The aforementioned crosslinking agent is given by formula (X): 【Chemistry 1】 A compound or salt having a structure according to the above, Heart valve prosthesis.

2. A heart valve prosthesis according to claim 1, characterized in that the biological tissue is connective tissue, fascial tissue, peritoneal tissue, or cardiac tissue.

3. A heart valve prosthesis according to claim 2, characterized in that the biological tissue is pericardial tissue.

4. A heart valve prosthesis according to any one of claims 1 to 3, for use in treating a heart disease caused by a defective heart valve.

5. A heart valve prosthesis according to any one of claims 1 to 3 for the use described in claim 4, wherein the same living tissue of the same biological origin as the human or animal to which the heart valve prosthesis is implanted is used in the manufacture of the heart valve prosthesis.