WO2015100858A1 - 制备人工心脏瓣膜瓣叶的方法 - Google Patents

制备人工心脏瓣膜瓣叶的方法 Download PDF

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Publication number
WO2015100858A1
WO2015100858A1 PCT/CN2014/073977 CN2014073977W WO2015100858A1 WO 2015100858 A1 WO2015100858 A1 WO 2015100858A1 CN 2014073977 W CN2014073977 W CN 2014073977W WO 2015100858 A1 WO2015100858 A1 WO 2015100858A1
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WIPO (PCT)
Prior art keywords
animal tissue
thickness
tissue membrane
processing
leaflets
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PCT/CN2014/073977
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English (en)
French (fr)
Inventor
钟生平
金昌�
刘静
Original Assignee
金仕生物科技（常熟）有限公司
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Application filed by 金仕生物科技（常熟）有限公司 filed Critical 金仕生物科技（常熟）有限公司
Priority to EP14877472.2A priority Critical patent/EP3090704B1/en
Priority to JP2016544096A priority patent/JP6386564B2/ja
Publication of WO2015100858A1 publication Critical patent/WO2015100858A1/zh
Priority to US15/197,676 priority patent/US10149755B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A61F2/2415—Manufacturing methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
    • A61L27/367—Muscle tissue, e.g. sphincter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
    • A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
    • A61L27/3691—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A61F2240/002—Designing or making customized prostheses
    • A61F2240/004—Using a positive or negative model, e.g. moulds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves

Definitions

  • the invention relates to a method for preparing a prosthetic heart valve leaflet, belonging to the field of medical device technology. Background technique
  • Heart valve disease is currently one of the major types of heart disease that can cause major dysfunction of the heart and ultimately requires replacement of the native heart valve with a prosthetic heart valve.
  • Bioprostheses are a type of artificial heart valve that is currently used.
  • the leaflets of the biological valve are usually made of animal tissue membranes, such as the porcine arterial valve or the pericardium of the cattle, which are sewed onto the valve lobes of the prosthetic heart valve after cross-linking and anti-calcification treatment.
  • the leaflets of each valve need to meet specific criteria, for example, in some cases, different leaflets of the same valve need to maintain a consistent thickness.
  • the thickness of the leaflets is typically 0.3-0.6 mm depending on the size of the valve.
  • the thickness of the bovine pericardium collected from the slaughterhouse is usually 0.1-0.8 mm, and the thickness of each point of each bovine pericardium is not uniform. Therefore, each pericardium can only produce 1-2 qualified leaflets, and the yield is very low.
  • the leaflets of the prosthetic heart valve need to have different thicknesses, and the above treatment method is difficult to satisfy.
  • Patent US Pat. No. 7,141,064 discloses the use of a method of pressurizing during cross-linking to obtain an animal tissue film having a relatively uniform or thin thickness, which can improve the yield.
  • this method tends to straighten the corrugated fibers in the animal tissue membrane (such as the bovine pericardium), reduce its elasticity, and thus affect the bending and stretching effect of the leaflets during heart expansion and contraction, and it is difficult to obtain inconsistent thickness at each point.
  • Leaflets such as the bovine pericardium
  • the invention provides a preparation method of artificial heart valve leaflets, which can conveniently obtain the artificial heart valve leaflets of the required thickness by freezing the animal tissue membrane, thereby improving the yield rate of the animal tissue membrane leaflets, and capable of The original elastic fiber layer of the animal tissue film is retained.
  • the present invention provides a method of preparing a prosthetic heart valve leaflet comprising: freezing an animal tissue membrane to process the animal tissue membrane in a frozen state to a set thickness. It will be understood by those skilled in the art that the animal tissue film is frozen in an unfolded or tiled state, which is more advantageous for the processing.
  • animal tissue membrane was frozen using liquid nitrogen.
  • animal tissue membrane was immersed in liquid nitrogen for the processing.
  • the processing is one or more of grinding, cutting, scraping, milling, and grinding. Further, after the animal tissue film is frozen, or after the animal tissue film in the frozen state is processed to reach a set thickness, the animal tissue film is further formed into a artificial heart valve flap. The desired shape of the leaf.
  • the animal tissue film is placed on a mold corresponding to the thickness distribution of the prosthetic heart valve leaflets, and the animal tissue film is frozen.
  • the animal tissue film in a frozen state is processed to a set thickness to reduce the thickness of the animal tissue film as a whole to a set thickness, or to different parts of the animal tissue film Processed to different thicknesses as needed.
  • processing is to process the animal tissue film in a recess having a depth of the set thickness to reduce the overall thickness of the animal tissue film to the set thickness.
  • animal tissue membrane is a pericardium, decidua or dura mater of a mammal.
  • the processing is performed on the rough surface of the animal tissue film.
  • animal tissue membrane is an animal tissue membrane that has been subjected to cross-linking treatment.
  • the method provided by the invention can easily fix and process the animal tissue membrane while obtaining the artificial heart valve leaflets of the required thickness, and can reduce the damage of the animal tissue membrane and increase the thickness precision of the artificial heart valve leaflets;
  • the method provided by the invention can increase the yield rate of the prosthetic heart valve leaflets, thereby reducing the use cost of the raw materials
  • the method provided by the present invention is capable of retaining the elastic function of the corrugated fibrous layer in the animal tissue membrane (e.g., the pericardium of a mammal), and ensuring the bending and stretching effect of the prosthetic heart valve leaflets during heart expansion and contraction.
  • Figure 1 is a schematic view of the structure of an interventional prosthetic heart valve.
  • Figure 2 is a view of a leaflet that can be used in the interventional prosthetic heart valve of Figure 1 in accordance with one embodiment of the present invention.
  • 3A and 3B are leaflets prepared in accordance with another embodiment of the present invention.
  • FIG. 4 is a flow chart of a method for preparing a prosthetic heart valve leaflet according to the present invention.
  • FIG. 5 is a schematic diagram of a method for preparing a prosthetic heart valve leaflet according to an embodiment of the present invention.
  • FIG. 6 is a schematic view of a method for preparing a prosthetic heart valve leaflet according to another embodiment of the present invention.
  • the invention provides a preparation method of artificial heart valve leaflets, which can conveniently obtain the artificial heart valve leaflets of the required thickness by freezing the animal tissue membrane, thereby improving the yield rate of the animal tissue membrane leaflets, and capable of Preserve the original elasticity of the animal tissue membrane.
  • the animal tissue membrane used contains a certain amount of water, it is usually necessary to pre-freeze the animal tissue membrane, which is more conducive to protecting the structural integrity of the animal tissue membrane.
  • the pre-freezing pretreatment can be carried out directly on the whole animal tissue or on the animal tissue cut into the shape of the leaflet.
  • cold Pre-freezing pretreatment is performed by immersing the animal tissue membrane in a cryoprotectant.
  • the cryoprotectant may be glycerin, dimethyl sulfoxide, ethylene glycol or propylene glycol or the like.
  • the animal tissue film is placed in a freezer (e.g., a container such as a liquid nitrogen tank) and frozen until the animal tissue film is not deformed during processing, so that processing can be performed.
  • a freezer e.g., a container such as a liquid nitrogen tank
  • the animal tissue film is frozen in an unfolded or tiled state.
  • the animal tissue film can also be placed on the mold corresponding to the thickness distribution of the leaflets before freezing; if the central protrusion is used, the mold is recessed around the convex portion, so that the animal tissue film can be attached to the mold during the freezing process.
  • the side of the animal tissue film that is not bonded to the mold can be directly processed into a plane, and the thickness of the portion where the animal tissue film and the middle convex portion of the mold are attached is small, and the circumference and the depression of the mold are combined.
  • the portion where the portion is attached is thick, and the leaflets having the corresponding thickness distribution can be prepared.
  • liquid nitrogen can be used in the present invention, and the temperature is generally about -196 ° C, which allows rapid freezing.
  • one surface of the animal tissue film is processed in a frozen state.
  • the area where the leaflets need to be made can be determined on the animal tissue film first.
  • the above processing is to reduce the thickness of the thicker part of the animal tissue film in the area.
  • the thickness of the area is uniform in the region; or, for some leaflets with a small thickness, the leaf can be further processed to further reduce the thickness of the animal tissue film so as to conform to the set thickness.
  • the set thickness of each part of the leaflets is inconsistent, it can be processed directly according to the set thickness required for each part.
  • the thickness of the animal tissue membrane is processed to a thickness slightly larger than that required for each part of the leaflet, and then the area of the animal tissue membrane is determined to be the leaflet, and the animal tissue in the area is as needed.
  • the film is processed for thickness.
  • the film processing of the animal tissue After the film processing of the animal tissue is completed, it can be processed into a desired shape of the leaflet by mechanical cutting or the like in a frozen state, or can be processed into a shape required for the leaflet by mechanical or laser processing after thawing.
  • the animal tissue film is formed into a shape as described in the leaflet in a conventional manner prior to freezing, and then frozen, and then processed as needed in a frozen state to reduce the thickness of the thicker portion of the animal tissue film in the region. Its thickness is uniform; or, for some leaflets with a smaller thickness, It can be further processed to further reduce the thickness of the animal tissue film so that it conforms to a smaller set thickness, and can also be directly processed according to the required thickness of each part.
  • the above processing in the frozen state may be selected from any other method capable of partially or collectively reducing the thickness of the tissue, such as grinding, cutting, scraping, milling, grinding, or the like, and the above methods may be used in combination.
  • the animal tissue film is fixed in a fixture and placed in liquid nitrogen for freezing, and then the frozen animal tissue film with the fixture is processed; of course, it can be frozen and then fixed, and then processed.
  • the machining can be carried out on equipment fixed to grinding (such as grinding machines), milling (such as milling machines) or cutting (such as planers), or by manual grinding tools, grinding tools, or scrapers.
  • the animal tissue membrane used is any animal tissue membrane that can be used for artificial heart valve leaflets, such as the pericardium (or pericardium) of mammalian cattle and horses.
  • the animal tissue film usually has a rough surface and a relatively smooth surface, the rough surface is often a surface connected to other tissues in the living body, and the portion close to the smooth surface is often the tissue coated inside the animal tissue film, usually It is a corrugated elastic fiber layer composed of collagen or the like.
  • the rough surface of the animal tissue film can be selected to be processed, which facilitates retention of the elastic fiber layer and smoothing of the rough surface.
  • the different parts of the leaflets may have different thicknesses for facilitating connection with the leaflet fixation member, improving the durability of the leaflets, or supporting the leaflets to prevent collapse thereof.
  • animal tissue membranes can be processed in accordance with the above needs.
  • the position where the leaflet and the valve frame need to be sutured can retain a large thickness; or the thickness structure and mechanical characteristics of the human physiological valve can be simulated to be processed into a thickness structure having the same or similar thickness distribution as the human physiological valve.
  • the processed tissue or leaflets to be processed in a frozen state can be directly immersed in liquid nitrogen and can be fixed by a fixture; or the frozen tissue or leaflets can be placed in liquid nitrogen.
  • the refrigerating device or the surface of the device that is cooled by liquid nitrogen is beneficial to maintain its frozen state while being easy to process.
  • the animal tissue film when the required set thickness is the same, the animal tissue film can be placed in the concave mold during processing, the concave mold has a groove of a desired thickness and shape, and the depth of the groove is the desired setting.
  • the thickness is uniform, and the processing tool with a working surface slightly larger than the width of the die (such as a manual scraper or a grinding tool) is used to perform the limit by using the surface of the die, so that the processing tool can be moved along the outer surface of the die to obtain a uniform thickness.
  • Animal tissue membrane. Machining with a die is easier to operate and is beneficial Obtain a more uniform thickness of the animal tissue membrane.
  • FIG. 1 is a schematic view showing the structure of an artificially inserted valve.
  • the valve includes a cylindrical frame 100, a leaflet structure 200 having three leaflets, and a suture skirt 300.
  • the leaflet structure 200 is disposed inside the cylindrical frame 100, wherein each leaflet has a shape as shown in Fig. 2 and is fixed to the cylindrical frame 100 by a suture.
  • the stitching skirt 300 is circumferentially disposed between the cylindrical frame 100 and the leaflet structure 200.
  • the preparation process of the leaflet 20 is as shown in FIG. 4, and the pericardial piece 1 (the thickness of which is between 0.3 and 0.8 mm) of the collected bovine leaf is pretreated before freezing, and then placed In the basket 2, the pericardium sheet 1 may be a cross-linked pericardium sheet, which is advantageous for improving the stability of the tissue of the pericardial sheet.
  • the basket 2 is then placed in a liquid nitrogen tank 3 for freezing.
  • the frozen pericardial sheet 1 is taken out from the liquid nitrogen tank 3 and the basket 2 and fixed on the surface 31 of the liquid nitrogen refrigeration apparatus. Since the surface serves as a reference plane for thickness measurement during processing, it is required to be flattened, and the pericardium sheet 1 is fixed. Smooth facing down.
  • the rough surface of the fixed pericardium sheet 1 is ground by grinding, and the thickness of the pericardial sheet 1 is polished to 0.25 mm to make the thickness uniform. Then remove the polished carton piece 1 and clean it to remove the scraped debris and residue. Then, it is thawed, and then the appropriate area is selected according to the size of the leaflet to be processed into the desired leaflet shape, and finally the leaflet 20 is obtained.
  • Example 2
  • the present embodiment provides a method for preparing a prosthetic heart valve leaflet, which can be used for the interventional valve as described in the embodiment 1, and can also be applied to other biological valves using the animal pericardial membrane as the leaflet.
  • the method for preparing the leaflet 20 can still be as shown in FIG. 4, and the bovine pericardium sheet is cut into the shape of the leaflet; the pericardial sheet 1 having the leaflet shape with the thickness of each part being larger than the final required thickness is selected, Performing pre-freezing pretreatment; then placing the leaflet sheet 1 having a leaflet shape into the female mold shown in Fig. 6, placing the pericardial sheet 1 smoothly downward when placed; the shape of the groove in the concave mold
  • the leaflets have the same shape, and the depth of the groove is the set thickness of the leaflets; then the carpel piece 1 is placed in the basket 2 together with the die, and the basket 2 is placed in the liquid nitrogen tank 3 for freezing.
  • the frozen die is taken out together with the pericardium sheet 1, and the female mold is fixed to the surface 31 of the liquid nitrogen refrigeration apparatus.
  • the processing is performed by scraping, and the working surface of the scraper used is larger than the width of the groove, and the pericardial sheet 1 having the shape of the leaflet is scraped layer by layer until the thickness of the pericardium sheet 1 is equal to the concave
  • the depth of the groove ie the set thickness of the leaflets
  • the edge of the die can play a limiting role, which is beneficial to control the thickness precision of the final leaflet and improve the uniformity of its thickness.
  • This embodiment provides a method for fabricating leaflets of different thicknesses.
  • the leaflet structure of different thickness can refer to the leaflet in the patent US20130116676.
  • the outer periphery of the leaflet is thicker relative to the center, so as to increase the strength when suturing the valve frame, and the center portion can be strengthened.
  • the ribs support the valve leaflets when the leaflets are thin. It may also have a similar thickness distribution to the human physiological valve as shown in Fig. 3B, that is, the central portion of the leaflet is thinner, and the outer peripheral portion is gradually thickened relative to the central portion.
  • the method for preparing the leaflet 20 can still be as shown in FIG. 4, and the bovine pericardial sheet 1 is cut into a shape of a leaflet; the pericardial sheet 1 having a leaflet shape in which the thickness of each part is greater than the final required thickness is selected, Pre-freezing pretreatment; then placing the leaflet sheet 1 having a leaflet shape into the concave mold shown in Fig.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Transplantation (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Vascular Medicine (AREA)
  • Botany (AREA)
  • Cardiology (AREA)
  • Molecular Biology (AREA)
  • Manufacturing & Machinery (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Prostheses (AREA)
  • Materials For Medical Uses (AREA)

Abstract

一种制备人工心脏瓣膜瓣叶的方法，包括将动物组织膜冷冻，对冷冻状态下的动物组织膜进行加工以使其达到设定厚度。该方法通过冷冻动物组织膜再进行加工，能够方便地获得所需厚度的人工心脏瓣膜瓣叶，提高动物组织膜瓣叶的产出率。

Description

制备人工心脏瓣膜瓣叶的方法
技术领域
本发明涉及一种制备人工心脏瓣膜瓣叶的方法， 属于医疗器械技术领 域。 背景技术
心脏瓣膜疾病目前是心脏病的主要种类之一， 可以导致心脏重大功能障 碍， 并且最终需要用人工心脏瓣膜替换自体心脏瓣膜。 生物瓣膜是一类目前 常用的人工心脏瓣膜。 生物瓣膜的瓣叶通常采用动物组织膜制成， 例如猪动 脉瓣膜或牛的心包，经过交联和抗钙化处理后缝制到人工心脏瓣膜的瓣架上。
为满足瓣膜的功能， 每个瓣膜的瓣叶需要符合特定指标， 例如在一些情 况下， 同一瓣膜的不同瓣叶需要保持一致的厚度。对于外科植入的生物瓣膜， 根据瓣膜尺寸的差别，其对瓣叶厚度的要求通常为 0.3-0.6mm。而目前从屠宰 厂采集的牛心包厚度通常为 0.1-0.8mm， 并且每片牛心包各点的厚度也不一 致。 因此每片心包往往只能够制取 1-2片合格的瓣叶， 产出成品率很低。 而 对于经皮介入的生物瓣膜， 为了提高经血管的可输送性， 需要降低介入瓣膜 的预装直径， 这使得要求采用的动物组织膜更薄， 往往要低于 0.25mm， 因此 可用于经皮介入的生物瓣膜的动物组织膜很少， 产出成品率更低。
另一些情况下， 为了满足特定功能， 人工心脏瓣膜的瓣叶各点需要具有 不同的厚度， 而上述的处理方法很难满足。
因此， 需要对动物组织膜进行加工， 以满足对瓣膜瓣叶厚度的要求。 专 利 US7141064中公开了采用在交联过程中加压的方法获得厚度较均匀或较薄 的动物组织膜， 能够提高成品率。 然而此方法容易使动物组织膜 （如牛的心 包） 中的波纹状纤维变直， 降低其弹性， 进而影响瓣叶在心脏扩张和收缩时 的弯曲舒展的效果， 并且难以获得各点厚度不一致的瓣叶。 专利 US2013110097, US20130116676和 US20130310929中公开了采用激光去除， 刮削，研磨等方法对交联或半交联状态的组织进行处理使其厚度均匀或减小， 并且能够获得各点厚度不同的瓣叶结构。 但人工心脏瓣膜采用的动物组织膜 多为软体组织， 采用上述方法加工时容易变形或起皱， 不易操作， 并且加工 后难以去除组织的残留碎屑。 发明内容
本发明提供一种人工心脏瓣膜瓣叶的制备方法， 通过冷冻动物组织膜 再进行加工， 能够方便地获得所需厚度的人工心脏瓣膜瓣叶， 提高动物组织 膜瓣叶的产出率， 并且能够保留动物组织膜原有的弹性纤维层。
本发明提供一种制备人工心脏瓣膜瓣叶的方法， 其包括， 将动物组织膜 冷冻， 对冷冻状态下的动物组织膜进行加工以使其达到设定厚度。 本领域技 术人员可以理解， 所述动物组织膜在展开或平铺的状态下冷冻， 更有利于所 述加工的进行。
进一歩地， 使用液氮将所述动物组织膜冷冻。
进一歩地， 将所述动物组织膜浸泡在液氮中进行所述加工。
进一歩地， 所述加工为磨削、 切削、 刮削、 铣削和研磨中的一种或几种。 进一歩地， 在将所述动物组织膜冷冻之前， 或者对所述冷冻状态下的动 物组织膜进行加工以使其达到设定厚度之后， 还包括将所述动物组织膜制成 人工心脏瓣膜瓣叶所需形状。
进一歩地， 将所述动物组织膜置于与人工心脏瓣膜瓣叶厚度分布对应的 模具上， 再将所述动物组织膜冷冻。
进一歩地， 在将所述动物组织膜冷冻之前， 还包括使用冷冻保护剂对其 进行预处理。
进一歩地， 所述对冷冻状态下的动物组织膜进行加工以使其达到设定厚 度为将所述动物组织膜的厚度整体降低至一设定厚度， 或者将所述动物组织 膜的不同部位按需加工成不同厚度。
进一歩地， 所述加工为将所述动物组织膜置于深度为所述设定厚度的凹 模内进行加工以将所述动物组织膜的整体厚度降低至所述设定厚度。
进一歩地， 所述动物组织膜为哺乳动物的心包、 膈膜或硬脑膜。
进一歩地， 所述加工是对所述动物组织膜的粗糙面进行的。
进一歩地， 所述动物组织膜为经过交联处理后的动物组织膜。 本发明方案的实施， 至少具有以下优势：
1、 本发明提供的方法在获得所需厚度的人工心脏瓣膜瓣叶的同时， 对动物组织膜容易固定和加工， 而且能够减少动物组织膜的损坏， 增加了 人工心脏瓣膜瓣叶的厚度精度；
2、 本发明提供的方法能够提高人工心脏瓣膜瓣叶的产出率， 进而降 低原材料的使用成本；
3、 本发明提供的方法能够保留动物组织膜 （如哺乳动物的心包） 中 波纹状纤维层的弹性功能， 保证人工心脏瓣膜瓣叶在心脏扩张和收缩时的 弯曲舒展效果。 附图说明
图 1为一种介入人工心脏瓣膜的结构示意图。
图 2 为本发明一个实施例制备的可用于图 1中介入人工心脏瓣膜的 瓣叶。
图 3A和图 3B为本发明另一实施例制备的瓣叶。
图 4为本发明提供的人工心脏瓣膜瓣叶制备方法的流程图。
图 5为本发明一实施例提供的人工心脏瓣膜瓣叶制备方法的示意图。 图 6 为本发明另一实施例提供的人工心脏瓣膜瓣叶制备方法的示意 图。 具体实施方式 以下参照本发明实施例的附图来更充分地描述本发明。 然而， 本发明可 以许多不同形式来体现， 不应理解为限于本文陈述的实施例。
本发明提供一种人工心脏瓣膜瓣叶的制备方法， 通过冷冻动物组织膜 再进行加工， 能够方便地获得所需厚度的人工心脏瓣膜瓣叶， 提高动物组织 膜瓣叶的产出率， 并且能够保留动物组织膜原有的弹性。
冷冻前预处理：
因采用的动物组织膜中含一定的水， 通常需要对该动物组织膜进行冷 冻前预处理， 更有利于保护动物组织膜的结构完整性。 冷冻前预处理可以 直接对整片动物组织进行， 也可以对裁制成瓣叶形状的动物组织进行。 冷 冻前预处理为将该动物组织膜浸入冷冻保护剂中处理。 所述冷冻保护剂可 以为甘油、 二甲基亚砜、 乙二醇或丙二醇等物质。
冷冻：
进行冷冻前预处理之后， 将动物组织膜置于冷冻装置 （如液氮罐等容 器） 中进行冷冻， 直至该动物组织膜在加工时不变形， 从而能够进行加工 为止。 为了更有利于所述加工的进行， 所述动物组织膜在展开或平铺的状 态下冷冻。 也可以将动物组织膜在冷冻前平铺置于与瓣叶厚度分布对应的 模具上； 如采用中心凸起， 四周相对凸起部凹陷的模具， 可使得动物组织 膜在冷冻过程中与模具贴合， 后续加工时， 可以直接将动物组织膜不与模 具贴合的一面加工成平面， 并使得所述动物组织膜与模具的中间凸起部位 贴合的部位厚度较小， 四周与模具的凹陷部位贴合的部位厚度较大， 能够 制备具有相应厚度分布的瓣叶。
本发明中可使用商购的液氮， 温度一般在 -196°C左右， 可实现快速冷 冻。
加工：
将动物组织膜冷冻后， 在冷冻状态下对动物组织膜的一个表面进行加 工。 可以先在动物组织膜上确定需要制成瓣叶的区域， 当瓣叶各部位实际 所需的厚度 （即设定厚度） 一致时， 上述加工为减小该区域动物组织膜较 厚部位的厚度使得其在该区域的厚度均匀一致； 或者， 对于一些设定厚度 较小的瓣叶， 可再进行加工， 进一歩整体减小动物组织膜的厚度使得其符 合设定厚度。 当瓣叶各部位的设定厚度不一致时， 可以直接按各部位所要 求的设定厚度进行加工。 或者， 对动物组织膜整体的厚度加工至稍大于瓣 叶各部位所要求的设定厚度， 然后再在动物组织膜上确定需要制成瓣叶的 区域， 并根据需要对该区域内的动物组织膜进行厚度加工。
对该动物组织膜加工完成后可以在冷冻状态下通过机械切割等方式 加工成瓣叶所需形状， 也可以在解冻后通过机械或激光等方式加工成瓣叶 所需的形状。
或者， 在冷冻之前先按常规方式将该动物组织膜制成瓣叶所述的形状， 然后进行冷冻， 之后在冷冻状态下根据需要进行加工， 减小该区域动物组织 膜较厚部位的厚度使得其厚度均匀； 或者， 对于一些设定厚度较小的瓣叶， 可再进行加工， 进一歩整体减小动物组织膜的厚度使得其符合更小的设定 厚度， 也可以直接按各部位所要求的设定厚度进行加工。
其中在冷冻状态下的上述加工可以选自磨削、 切削、 刮削、 铣削、 研磨 等其他任意能够部分或整体减小组织厚度的方法， 也可以将上述方法组合使 用。 比如将动物组织膜固定在工装夹具内一起放入液氮进行冷冻， 然后将带 有工装夹具的冷冻后的动物组织膜进行加工； 当然也可以先冷冻再行固定， 然后进行加工。所述加工可以为固定在磨削 (如磨床)、铣削 (如铣床)或切削 (如 刨床)设备上进行加工， 或者采用手动的磨削工具、 研磨工具、 或刮刀等对其 进行加工。
本发明中， 所使用的动物组织膜为可用于人工心脏瓣膜瓣叶的任意动物 组织膜， 如哺乳动物牛、 马的心包 （或称心包片） 等。 所述动物组织膜通常 具有一个粗糙表面和一个相对光滑的表面， 粗糙表面往往是与生物体内其它 组织相连的表面， 而与光滑表面相接近部分往往是该动物组织膜内部包覆的 组织， 通常为由胶原蛋白等构成的波纹状弹性纤维层。在具体的实施方式中， 可选择对动物组织膜的粗糙面进行加工， 这样加工后利于保留弹性纤维层， 并使得粗糙面变得光滑平整。
在一些情况下， 瓣叶不同部位可具有不同厚度， 便于与瓣叶固定件进行 连接固定， 提高瓣叶的耐久性， 或对瓣叶进行支撑防止其坍塌等。 本发明中 可根据上述需求对动物组织膜进行加工。 比如瓣叶与瓣架需要缝合连接的部 位可保留较大的厚度； 或者模拟人体生理瓣膜的厚度结构和力学特点， 将其 加工成与人体生理瓣膜具有相同或相似厚度分布的厚度结构。
本发明中， 所述在冷冻状态下加工， 所需要加工的组织或瓣叶可以直接 浸泡在液氮中， 并可以通过工装夹具进行固定； 或将冷冻后的组织或瓣叶置 于采用液氮制冷的装置内或置于采用液氮制冷的装置表面， 有利于维持其冷 冻状态， 同时易于加工操作。
本发明中， 当需要的设定厚度一致时， 加工时可将动物组织膜置于凹模 内， 所述凹模具有所需厚度和形状的凹槽， 凹槽的深度为与所需的设定厚度 一致， 采用工作表面稍大于凹模宽度的加工工具 （如手动刮刀或研磨工具） 进行加工， 利用凹模表面进行限位， 这样可以使加工工具沿着凹模外表面运 动， 获得厚度一致的动物组织膜。 使用凹模进行加工更易于操作， 且有利于 获得厚度更均匀一致的动物组织膜。
以下结合附图对本发明的具体实施方式进行说明。 实施例 1
本实施例提供了一种人工心脏瓣膜瓣叶的制备方法。 图 1为一种人工介 入瓣膜的结构示意图。 该瓣膜包括圆柱形框架 100、 具有 3个瓣叶的瓣叶结 构 200以及缝合裙 300。 瓣叶结构 200设置在圆柱形框架 100的内部， 其中 各瓣叶具有如图 2所示的形状， 并通过缝合线固定在圆柱形框架 100上。 缝 合裙 300沿周向设置在圆柱形框架 100和瓣叶结构 200之间。
其中， 瓣叶 20的制备流程如图 4所示， 将采集的作为瓣叶用的牛的心包 片 1 (其厚度在 0.3-0.8mm之间）在进行冷冻前的预处理， 然后将其放入提篮 2 内， 上述心包片 1可为经交联的心包片， 有利于提高心包片的组织的稳定 性。 然后将提篮 2放入液氮罐 3内冷冻。 将冷冻后的心包片 1从液氮罐 3和 提篮内 2取出固定在液氮制冷设备的表面 31， 由于该表面作为加工时厚度测 量的基准平面， 因此要求其平整， 固定时使心包片 1光滑面向下。
如图 5所示采用磨削的方式对固定的心包片 1粗糙表面进行打磨， 直致 将心包片 1厚度打磨到 0.25mm， 以使其厚度均匀一致。然后取下打磨后的心 包片 1， 进行清洗， 去除打磨后的碎屑和残渣。 然后解冻， 再根据瓣叶的尺 寸选取合适的区域加工成所需的瓣叶形状， 最终获得瓣叶 20。 实施例 2
本实施例提供了一种人工心脏瓣膜瓣叶的制备方法， 其可用于如实施 1 中描述的介入瓣膜，也可以应用于其它采用动物心包片膜作瓣叶的生物瓣膜。
其中， 瓣叶 20制备方法仍可以如图 4所示， 将牛的心包片剪裁为瓣叶形 状； 挑选各部位厚度均大于最终需求的设定厚度的具有瓣叶形状的心包片 1， 对其进行冷冻前的预处理； 然后将该具有瓣叶形状的心包片 1放入图 6所示 的凹模内， 放入时使心包片 1光滑面向下； 所述凹模中的凹槽形状与瓣叶外 形相同， 凹槽的深度为瓣叶的设定厚度； 然后将该心包片 1连同凹模一同放 入提篮 2内， 将提篮 2放入液氮罐 3内冷冻。 将冷冻后的凹模连同该心包片 1取出， 将凹模固定于液氮制冷设备的表面 31。 如图 6所示， 采用刮削的方式进行加工， 使用的刮刀工作表面的尺寸大 于凹槽的宽度， 逐层对该具有瓣叶形状的心包片 1进行刮削， 直至该心包片 1 的厚度等于凹槽深度 （即瓣叶的设定厚度） ， 获得瓣叶。 因为刮刀尺寸较 大， 这样凹模边缘可以起到限位作用， 有利于控制最终的瓣叶的厚度精度， 提高其厚度的均匀性。 加工完成后将获得的瓣叶取下， 进行清洗， 去除打磨 后的碎屑和残渣， 然后解冻。 实施例 3
本实施例提供了一种不同厚度瓣叶的制作方法。 不同厚度的瓣叶结构可 以参照专利 US20130116676中的瓣叶， 如图 3A所示， 其瓣叶外周相对中心 部位较厚， 以便于增加与瓣架缝合时的强度， 另外其中心部位还可以设置加 强筋,当瓣叶较薄时对瓣叶起支撑作用。 也可以如图 3B所示与人体生理瓣膜 具有类似厚度分布， 即瓣叶的中心部位较薄， 外周相对中心部位逐渐增厚。
其中， 瓣叶 20的制备方法仍可以如图 4所示， 将牛的心包片 1剪裁为瓣 叶形状； 挑选各部位厚度均大于最终需求的设定厚度的具有瓣叶形状的心包 片 1， 对其进行冷冻前的预处理； 然后将该具有瓣叶形状的心包片 1放入图 6 所示的凹模内， 放入时使心包片 1光滑面向下； 所述凹模中的凹槽形状与瓣 叶外形相同， 凹槽的深度可以为瓣叶最薄处的设定厚度； 然后将该心包片 1 连同凹模一同放入提篮 2内， 将提篮 2放入液氮罐 3内冷冻。 将冷冻后的凹 模连同该心包片 1取出， 将凹模固定于液氮制冷设备的表面 31。
如图 6所示采用刮削方式进行加工， 或如图 5所示采用磨削的方式进行 加工。 刮削或磨削时可以采用较小的刀头或磨头， 利于局部减小厚度， 边加 工边对各部位进行测量，直到各部位均加工到所需的设定厚度，获得瓣叶 20。 加工完成后取下瓣叶 20， 进行清洗， 去除刮削或打磨后的碎屑和残渣， 然后 解冻。
最后应说明的是： 以上各实施例仅用以说明本发明的技术方案， 而非 对其限制； 尽管参照前述各实施例对本发明进行了详细的说明， 本领域的 普通技术人员应当理解： 其依然可以对前述各实施例所记载的技术方案进 行修改， 或者对其中部分或者全部技术特征进行等同替换； 而这些修改或 者替换， 并不使相应技术方案的本质脱离本发明各实施例技术方案的范 围。

Claims

权 利 要 求 书
1、 一种制备人工心脏瓣膜瓣叶的方法， 其包括， 将动物组织膜冷冻， 对 冷冻状态下的所述动物组织膜进行加工以使其达到设定厚度。
2、根据权利要求 1所述的方法，其中，使用液氮将所述动物组织膜冷冻。
3、 根据权利要求 2所述的方法， 其中， 将所述动物组织膜浸泡在液氮中 进行所述加工。
4、 根据权利要求 1所述的方法， 其中， 所述加工为磨削、 切削、 刮削、 铣削和研磨中的一种或几种。
5、 根据权利要求 1所述的方法， 其中， 在将所述动物组织膜冷冻之前， 或者对所述冷冻状态下的动物组织膜进行加工以使其达到设定厚度之后， 还 包括将所述动物组织膜制成人工心脏瓣膜瓣叶所需形状。
6、 根据权利要求 1所述的方法， 其中， 将所述动物组织膜置于与人工心 脏瓣膜瓣叶厚度分布对应的模具上， 再将所述动物组织膜冷冻。
7、 根据权利要求 1所述的方法， 其中， 在将所述动物组织膜冷冻之前， 还包括使用冷冻保护剂对其进行预处理。
8、 根据权利要求 1所述的方法， 其中， 所述对冷冻状态下的动物组织膜 进行加工以使其达到设定厚度为将所述动物组织膜的厚度整体降低至一设定 厚度， 或者将所述动物组织膜的不同部位按需加工成不同厚度。
9、 根据权利要求 8所述的方法， 其中， 所述加工为将所述动物组织膜置 于深度为所述设定厚度的凹模内进行加工以将所述动物组织膜的整体厚度降 低至所述设定厚度。
10、 根据权利要求 1所述的方法， 其中， 所述动物组织膜为哺乳动物的 心包、 膈膜或硬脑膜。
11、 根据权利要求 1或 10所述的方法， 其中， 所述加工是对所述动物组 织膜的粗糙面进行的。
12、 根据权利要求 1所述的方法， 其中， 所述动物组织膜为经过交联 处理后的动物组织膜。
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