WO2017041555A1 - 可吸收封堵器 - Google Patents

可吸收封堵器 Download PDF

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Publication number
WO2017041555A1
WO2017041555A1 PCT/CN2016/085023 CN2016085023W WO2017041555A1 WO 2017041555 A1 WO2017041555 A1 WO 2017041555A1 CN 2016085023 W CN2016085023 W CN 2016085023W WO 2017041555 A1 WO2017041555 A1 WO 2017041555A1
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WIPO (PCT)
Prior art keywords
occluder
polymer
absorbable
copolymer
polylactic acid
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PCT/CN2016/085023
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English (en)
French (fr)
Inventor
向冬
颜莉
陈贤淼
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先健科技(深圳)有限公司
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Publication of WO2017041555A1 publication Critical patent/WO2017041555A1/zh

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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
    • 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
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds

Definitions

  • the present invention relates to cardiovascular medical devices, and more particularly to an absorbable occluder that can be used to occlude intracardiac or intravascular defects.
  • Atrial septal defect ASD
  • ventricular septal defect VSD
  • patent ductus arteriosus PDA
  • interventional therapy for occlusion of heart defects by occluder is the preferred treatment option for patients with cardiac defect indications due to mild trauma, safe operation, and near-term efficacy.
  • occluders are mostly made of a metal alloy material having a shape memory function. After the occluder is implanted in the body, the tissue surrounding the defect grows inward and completes endothelialization, and the occluder will remain in the defect site for life.
  • An occluder made of a metal alloy material has the risk of producing long-term complications including atrioventricular block, valve damage, residual shunt, heart wear, and metal allergy. And the occluder is implanted in the child's childhood, usually expected to have a life span of the patient's life, but the current clinical use history is only 20 years, and the long-term safety needs further follow-up.
  • the material used can be biodegradable polymer materials, such as polylactic acid (PLA), polyglycolic acid (PGA), polyhydroxy fatty acid ester (PHA), polydioxanone (PDO), polycaprolactone (PCL), and the like.
  • the absorbable polymer occluder can be degraded after being completed and absorbed by the body, so that the defect is completely repaired by its own tissue, thereby eliminating the long-term complications caused by the permanent retention of the metal alloy occluder.
  • the composition of the absorbable polymer occluder is usually made of only one polymer, and the absorbable polymer occluder is concentrated and degraded during a certain period of time, and the degradation products thereof will be at that time.
  • the dense release in the segment exceeds the amount that the tissue can absorb, resulting in a severe inflammatory response.
  • the technical problem solved by the present invention is to provide an absorbable polymer occluder which avoids dense release of polymer degradation products in a short time and causes a serious inflammatory reaction.
  • an absorbable occluder comprising a woven mesh, the woven mesh comprising a degradable polymer filament, and the polydispersity coefficient of the degradable polymer filament material is 3-10.
  • the weight average molecular weight ranges from 20,000 Da to 800,000 Da.
  • the total amount of the polymer filaments is 20 to 200.
  • the degradable polymeric filament material is selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxy fatty acid ester (PHA), poly a copolymer of p-dioxanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane or polycarbonate, or at least two of the above polymer monomers.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO poly a copolymer of p-dioxanone
  • PCL polycaprolactone
  • polyamide polyanhydride
  • polyphosphate polyphosphate
  • polyurethane or polycarbonate or at least two of the above polymer monomers.
  • the degradable polymer filament has a diameter ranging from 0.05 mm to 0.50 mm.
  • the degradable polymer material has a crystallinity ranging from 0% to 80%.
  • the occluder further includes a flow blocking membrane secured within the woven mesh by sutures.
  • the flow blocking film material is selected from the group consisting of polyethylene terephthalate (PET), polyethylene (PE), polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid.
  • PET polyethylene terephthalate
  • PE polyethylene
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PCL polycaprolactone
  • the suture material is selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxy fatty acid ester (PHA), polydioxane Cyclohexanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane or polycarbonate, or a copolymer of at least two of the above polymer monomers.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO polydioxane Cyclohexanone
  • PCL polycaprolactone
  • a locking member is further disposed between the distal end and the proximal end of the woven mesh, the locking member is a cylindrical structure having a through hole and an internal thread at one end and a through hole at the other end, and the locking member is One end is connected to the distal end, and the other end is detachably connected to the proximal end.
  • the locking member material is selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxy fatty acid ester (PHA), polydioxane Cyclohexanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane or polycarbonate, or a copolymer of at least two of the above polymer monomers.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO polydioxane Cyclohexanone
  • PCL polycaprolactone
  • the polydispersity coefficient is a parameter for characterizing the degree of molecular weight dispersion, and is a ratio of the weight average molecular weight Mw to the number average molecular weight Mn.
  • the present invention defines a narrow molecular weight distribution when the polydispersity coefficient is not more than 3, and a broad molecular weight distribution when it is more than 3.
  • the greater the polydispersity coefficient of the degradable polymer material the longer the degradation cycle of the material.
  • the degradation time of the degradation products of the broad molecular weight distribution degradable polymer material is relatively long, and the polymer is gently degraded during the degradation cycle.
  • the present invention has the following advantages: for an occluder made of a polymer yarn of the same quality, the woven mesh of the present invention comprises a broad molecular weight distribution degradable polymer material, which has a longer degradation cycle. The concentration of degradation products released per unit time period is reduced, thereby avoiding concentrated degradation in a certain period of time, resulting in a serious tissue inflammation reaction.
  • FIG. 1 is a schematic structural view of an occluder according to an embodiment of the present invention.
  • FIG. 2 is a front view of a network management structure of an occluder according to an embodiment of the present invention.
  • Fig. 3 is a graph showing the in vitro degradation tendency of the polymer filaments in Examples 1 to 4 and Comparative Example 1 at 37 °C.
  • Example 4 is a pathological view of the occluder and peripheral myocardial tissue after the occluder of Example 1 was implanted into the porcine heart for 2 years.
  • Figure 5 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Example 2 after implantation of the porcine heart for 2 years.
  • Figure 6 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Example 3 after implantation of the porcine heart for 2 years.
  • Figure 7 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Example 4 after implantation of the porcine heart for 2 years.
  • Fig. 8 is a pathological view of the occluder and peripheral myocardial tissue after the occluder of Comparative Example 1 was implanted into the pig heart for 2 years.
  • the distal end is defined as the end away from the operator during the surgical operation
  • the proximal end is defined as the end close to the operator during the surgical operation.
  • the occluder usually includes two structures of an approximate "work” shape and an approximate "T” shape.
  • the "work” font can be understood as a structure including a double disc and a waist and having a large waist disc.
  • the occluder mainly includes ventricular septal defect (VSD) occluder, atrial septal defect (ASD) occluder, patent ductus arteriosus (PDA) occluder, and patent foramen ovale. (PFO) occluder.
  • VSD ventricular septal defect
  • ASD atrial septal defect
  • PDA patent ductus arteriosus
  • PFO patent foramen ovale.
  • the VSD occluder, the ASD occluder and the PFO occluder have an approximate "work" shape structure of a double disc and a waist
  • the PDA occluder has an approximate "T" shape structure of a single disc and a waist.
  • a double disc occluder 100 includes a woven mesh 110, a baffle film 120 disposed in the woven mesh 110 and sewn on the woven mesh 110, and a locking member 160.
  • the polymer filaments are automatically alternately woven into a well-type grid on a cylindrical mold bar to form a tubular structure, and all the polymer filaments at the proximal end of the tubular structure are tightened in the sleeve and melt welded into the plug head 140, and all the polymer wires at the distal end are assembled. Tightening and fixing in the sleeve and fusion welding into the head 150 to obtain the network tube as shown in FIG.
  • the suture 130 sutures the baffle film 120 made of a degradable polymer onto the woven mesh 110.
  • One end of the locking member 160 is connected to the sealing head 150, and the other end is detachably connected to the plug 140. When the other end of the locking member 160 is matched with the plug 140, the double disc distance of the occluder 110 is fixed, and the waist height is fixed.
  • the double disc structure of the plug 110 is shaped.
  • the material of the locking member 160 may be selected from a degradable polymer material, such as selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polyhydroxy fatty acid ester (PHA), and poly-pair. a copolymer of dioxetane (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane, polycarbonate, or a monomer of at least two of the above polymers .
  • the structure of the locking member 160 and the connection manner with the woven mesh 110 are not limited thereto, and the general structure and connection manner in the art may be adopted as long as the waist height of the locking occluder can be a predetermined value (ie, the depth to be blocked). Yes, no longer repeat them.
  • the ratio of the residual mass of the polymer to the initial mass during the degradation of the polymer is defined as the mass retention of the polymer.
  • the mass retention rate drops to 5% or less, it is completely degraded.
  • the polymer mass retention rate drops faster during a certain period of time, and the polymer is said to be concentrated and degraded during this period of time.
  • the mass retention rate of the polymer in the present invention is decreased by 5% or more every two months, it can be considered that the polymer is concentratedly degraded within the two months; if the mass retention rate is less than 5%, it is called a gentle degradation of the polymer.
  • the reduced quality during polymer degradation is considered to be the amount of degradation product released.
  • the mechanical properties of the degradable polymer filaments were tested using a universal testing machine to obtain the elastic modulus and elongation at break of the polymer filaments.
  • the test and test conditions were GB/T228. -2010, original gauge length 10mm, tensile speed 1mm/min. If the polymer filament has a certain elastic modulus (not less than 1GPa) and elongation at break (not less than 20%) after 6 months of degradation, it can be judged that 6 occluders composed of the polymer filament The frame structure remained stable after the month.
  • the polymer filaments subjected to in vitro degradation experiments were sampled and weighed every 2 months.
  • the test results were accurate to one millionth of a gram, and the relationship between the mass drop of the polymer filaments and time was obtained, that is, the mass retention rate changed with time.
  • the trend curve, the time interval in which the polymer is concentrated and degraded is the concentrated degradation period of the polymer.
  • the degradable occluder prepared in different examples was implanted into the heart of the pig, and the pigs in the animal experiment were followed up. Two years after the implantation, the pig was sacrificed, and the occluder and the surrounding myocardial tissue were taken out for pathological section analysis to obtain a pathological map of the occluder and the surrounding myocardial tissue.
  • the overall mass of the occluder woven mesh is 0.726 g.
  • the woven mesh comprises 96 poly(L-lactic acid) (PLLA) filaments having a weight average molecular weight of 100,000 Da and a polydispersity of 6.02, a wire diameter of 0.15 mm and a crystallinity of 50%.
  • the in vitro degradation test of PLLA filaments showed that the elastic modulus measured after 6 months of degradation was 2.66 GPa and the elongation at break was 70%, which indicates that the occluder made of PLLA wire of this example can be guaranteed to be implanted 6 It has a stable frame structure within a month to achieve complete endothelial climbing; the change trend of PLLA silk mass retention rate with time is shown in curve 1 of Figure 3, and its degradation period is about 4 ⁇ 5 years, and the polymer quality is retained.
  • the rate of decline every 2 months in the 6th to 56th months is less than 5%, indicating that the degradation products are released gently in the 6th to 56th months; after the occluder of this embodiment is implanted into the heart of the pig for 2 years, Pathological analysis of the occluder and peripheral myocardial tissue, the pathological map shown in Figure 4, no significant inflammation and foreign body reaction.
  • the overall mass of the occluder woven mesh is 0.726 g.
  • the woven mesh consisted of 96 PLLA filaments having a weight average molecular weight of 100,000 Da and a polydispersity factor of 5.12, a crystallinity of 50% and a wire diameter of 0.15 mm.
  • the in vitro degradation test of PLLA filaments showed that the elastic modulus measured after 6 months of degradation was 2.86 GPa and the elongation at break was 66%, which indicates that the occluder made of PLLA wire of this example can be ensured in implantation.
  • the woven mesh comprises 200 polylactic acid-glycolic acid copolymer (PLGA) filaments having a weight average molecular weight of 50,000 Da and a polydispersity factor of 10, a wire diameter of 0.50 mm, and a crystallinity of 80. %.
  • PLGA polylactic acid-glycolic acid copolymer
  • the in vitro degradation test of PLGA wire showed that the elastic modulus measured after 6 months of degradation was 3.01 GPa and the elongation at break was 75%, which indicates that the occluder made of PLGA wire of this example can be guaranteed to be implanted 6 It has a stable frame structure within a month to achieve complete endothelial climbing; PLGA filaments decrease by less than 5% every 2 months in the 6th to 54th months, and the PLGA silk mass retention rate changes with time. As shown by curve 3 in Figure 3, The degradation products were released gently in the 6th to 54th months. After the occluder of this embodiment was implanted into the heart of the pig for 2 years, the occluder and the surrounding myocardial tissue were analyzed by pathological section. The pathological map is shown in Figure 6. No obvious inflammation and foreign body reaction.
  • the woven mesh comprises 20 non-crystalline polyhydroxy fatty acid ester (PHA) filaments having a weight average molecular weight of 800,000 Da and a polydispersity coefficient of 3, and a wire diameter of 0.05 mm.
  • PHA polyhydroxy fatty acid ester
  • the overall mass of the occluder woven mesh is 0.726 g.
  • the woven mesh comprises 96 degradable polymer PLLA filaments having a weight average molecular weight of 100,000 Da and a polydispersity factor of 1.49, a crystallinity of 50% and a wire diameter of 0.15 mm.
  • the in vitro degradation test of PLLA filaments showed that the elastic modulus measured after 6 months of degradation was 3.08 GPa and the elongation at break was 63%, respectively.
  • the occluder made of this comparative ratio PLLA wire can ensure 6 implants.

Abstract

一种可吸收封堵器（100），包括编织网（110），所述编织网（110）包括一种可降解高分子丝，所述高分子丝材料的多分散系数为3～10，重均分子量范围为20,000Da～800,000Da。该可吸收封堵器（100）可以避免组成编织网（110）的高分子丝的降解产物在某一时间段内集中释放导致严重的组织炎症反应。

Description

可吸收封堵器
【技术领域】
本发明涉及心血管医疗器械，尤其涉及一种可用于封堵心脏内或血管内缺损的可吸收封堵器。
【背景技术】
房间隔缺损(ASD)，室间隔缺损(VSD)，动脉导管未闭(PDA)是几种常见的先天性心脏缺损。通过封堵器封堵心脏缺损的介入治疗方法由于创伤轻微、手术安全、近中期疗效确切，是具有心脏缺损适应症的患者的首选治疗方案。
目前，封堵器大多由具有形状记忆功能的金属合金材料制成。封堵器植入体内后，缺损周围的组织向内生长并完成内皮化，封堵器将终身存在于缺损部位。由金属合金材料制成的封堵器，具有产生包括房室传导阻滞、瓣膜损伤、残余分流、心脏磨穿、金属过敏等远期并发症的风险。且封堵器在患者处于儿童期植入，通常被期望使用寿命为患者的一生，但目前临床使用历史只有20年，更远期的安全性需要进一步随访。
可吸收聚合物封堵器作为新一代的封堵器，采用的材料可为生物可降解高分子材料，如聚乳酸 (PLA)、聚乙醇酸(PGA)、聚羟基脂肪酸脂(PHA)、聚二氧环己酮(PDO)、聚己内酯(PCL)等。可吸收聚合物封堵器在完成内皮化后可发生降解而被机体吸收，使缺损完全由自身组织修复，从而消除金属合金封堵器永久存留体内造成的远期并发症。目前，组成可吸收聚合物封堵器通常仅由一种聚合物制成，该可吸收聚合物封堵器在降解过程中，通常在某个时间段内集中降解，其降解产物会在该时间段内密集释放，超出组织能吸收的含量，从而导致严重的炎症反应。
【发明内容】
本发明所解决的技术问题在于，提供一种可吸收聚合物封堵器，避免聚合物降解产物在短时间内密集释放而导致严重的炎症反应。
本发明采用的技术方案如下：一种可吸收封堵器，包括编织网，所述编织网包括一种可降解高分子丝，所述可降解高分子丝材料的多分散系数为3~10，重均分子量范围为20,000Da~800,000Da。
在其中一个实施例中，所述高分子丝总数量为20~200根。
在其中一个实施例中，所述可降解高分子丝材料选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚羟基脂肪酸脂(PHA)、聚对二氧环己酮(PDO)、聚己内酯(PCL)、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或至少两种上述聚合物单体的共聚物。
在其中一个实施例中，所述可降解高分子丝丝径范围为0.05mm~0.50mm。
在其中一个实施例中，所述可降解高分子丝材料结晶度范围为0%~80%。
在其中一个实施例中，所述封堵器还包括阻流膜，所述阻流膜是通过缝合线固定在所述编织网内。
在其中一个实施例中，所述阻流膜材料选自聚对苯二甲酸乙二醇酯（PET）、聚乙烯(PE)、聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚羟基脂肪酸脂(PHA)、聚对二氧环己酮(PDO)、聚己内酯(PCL)、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或上述聚合物单体中的至少两种的共聚物。
在其中一个实施例中，所述缝合线材料选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚羟基脂肪酸脂(PHA)、聚对二氧环己酮(PDO)、聚己内酯(PCL)、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或上述聚合物单体中的至少两种的共聚物。
在其中一个实施例中，所述编织网远端和近端之间还设置有锁定件，所述锁定件为一端带通孔和内螺纹，另一端无通孔的圆柱体结构，锁定件的一端与远端相连，另一端可拆卸地与近端相连，当锁定件的另一端与近端吻合时，封堵器的双盘距离即腰高得以固定。
在其中一个实施例中，所述锁定件材料选自聚乳酸(PLA)、聚乙醇酸(PGA)、聚乳酸-羟基乙酸共聚物(PLGA)、聚羟基脂肪酸脂(PHA)、聚对二氧环己酮(PDO)、聚己内酯(PCL)、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或上述聚合物单体中的至少两种的共聚物。
多分散系数是表征分子量分散程度的参数，为重均分子量Mw与数均分子量Mn的比值，多分散系数越大，分子量分布越宽。本发明定义多分散系数不大于3时为窄分子量分布，大于3时为宽分子量分布。可降解高分子材料的多分散系数越大，材料的降解周期越长。相比分子量比较集中的窄分子量分布的高分子材料，宽分子量分布的可降解高分子材料降解产物的释放时间相对较长，聚合物在降解周期内平缓降解。
本发明与现有技术相比，具备以下优点：对于采用相同质量的高分子丝制作的封堵器，本发明的编织网包括宽分子量分布的可降解高分子材料，具有更长的降解周期，降低了单位时间段内的降解产物释放浓度，从而避免在某一时间段内集中降解，造成严重的组织炎症反应。
【附图说明】
图1为本发明一实施方式制作的封堵器的结构示意图。
图2为本发明一实施方式制作的封堵器的网管结构主视图。
图3为37℃条件下实施例1~4、对比例1中的高分子丝的体外降解趋势图。
图4为实施例1的封堵器植入猪心脏2年后封堵器与周边心肌组织的病理图。
图5为实施例2的封堵器植入猪心脏2年后封堵器与周边心肌组织的病理图。
图6为实施例3的封堵器植入猪心脏2年后封堵器与周边心肌组织的病理图。
图7为实施例4的封堵器植入猪心脏2年后封堵器与周边心肌组织的病理图。
图8为对比例1的封堵器植入猪心脏2年后封堵器与周边心肌组织的病理图。
【具体实施方式】
为了对本发明的技术特征、目的和效果有更加清楚的理解，现对照附图详细说明本发明的具体实施方式，但是本发明保护的范围并不局限于此。
在介入医疗领域，定义远端为手术操作时远离操作人员的一端，定义近端为手术操作时靠近操作人员的一端。
按形状分，封堵器通常包括近似“工”字型和近似“T”字型两种结构。所述“工”字型可以理解为包括双盘和一腰部且呈腰小盘大的结构。按适用的心脏缺损部位分类，封堵器主要包括室间隔缺损（VSD）封堵器、房间隔缺损（ASD）封堵器、动脉导管未闭（PDA）封堵器，和卵圆孔未闭（PFO）封堵器。其中，VSD封堵器、ASD封堵器和PFO封堵器具有双盘和一腰部的近似“工”字型结构，PDA封堵器具有单盘和一腰部的近似“T”字型结构。
以下以 “工”字型双盘封堵器为例，详细说明本发明提供的封堵器的结构和材质，但是本发明的封堵器并不限于此结构。
如图1所示，本发明一实施方式提供的双盘封堵器100包括编织网110、设置与编织网110内且缝合在编织网110上的阻流膜120以及锁定件160。在圆柱形模棒上将高分子丝自动交替编织成井型网格，形成管状结构，将管状结构近端所有高分子丝收紧在套管内并熔融焊接成栓头140，远端所有高分子丝收紧固定在套管内并熔融焊接成封头150，得到如图2所示的网管；将网管结构置于模具中热定型，冷却之后得到双盘编织网110；采用可降解聚合物制成的缝合线130将可降解聚合物制成的阻流膜120缝合在编织网110上。锁定件160的一端与封头150相连，另一端可拆卸地与栓头140相连，当锁定件160的另一端与栓头140吻合时，封堵器110的双盘距离即腰高得以固定，封堵器110的双盘结构得以定型。锁定件160的材质可选用可降解高分子材料，如选自聚乳酸(PLA)，聚乙醇酸(PGA)，聚乳酸-羟基乙酸共聚物(PLGA)，聚羟基脂肪酸脂(PHA)，聚对二氧环己酮(PDO)，聚己内酯(PCL)，聚酰胺，聚酸酐、聚磷酸酯、聚氨酯、聚碳酸酯中的一种，或至少两种上述聚合物的单体的共聚物。锁定件160的结构及与编织网110的连接方式并不限于此，可采用本领域通用结构及连接方式，只要能在锁定封堵器的腰高至预定值（即待封堵缺损的深度）即可，不再赘述。
本发明中定义聚合物降解过程中，聚合物的剩余质量与初始质量的比值为聚合物的质量保留率。当质量保留率下降到5%及以下时，为完全降解。聚合物质量保留率在某段时间内下降较快，则称聚合物在该段时间内集中降解。本发明中聚合物质量保留率每2个月下降5%及以上时，可视为聚合物在该2月内集中降解；若质量保留率低于5%以下，则称为聚合物平缓降解。聚合物降解过程中减少的质量视为降解产物的释放量。
本发明为了考察不同分子量分布高分子丝的降解周期、集中降解时间和降解产物的释放情况，以及高分子丝降解6个月后的力学性能，将不同的高分子丝浸泡在37℃的磷酸缓冲盐溶液中进行体外降解实验。
高分子丝体外降解实验进行6个月后，使用万能试验机对可降解高分子丝进行力学性能测试得到高分子丝的弹性模量和断裂伸长率，测试标准和测试条件分别为GB/T228-2010，原始标距10mm，拉伸速度1mm/min。若高分子丝降解6个月后仍具有一定的弹性模量（不低于1GPa）和断裂伸长率（不低于20%），可判断由该种高分子丝构成的封堵器6个月后仍保持稳定的框架结构。
每隔2个月对进行体外降解实验的高分子丝取样称重，测试结果精确到百万分之一克，得到高分子丝的质量下降与时间的关系曲线，即质量保留率随时间变化的趋势曲线，聚合物集中降解的时间区间为聚合物的集中降解时间段。
本发明为了考察封堵器降解的释放产物对炎症异物反应的影响，将不同实施例制作的可降解封堵器植入到猪的心脏内，对动物实验的猪进行随访观察。待植入2年后将猪处死，取出封堵器和周边的心肌组织，做病理切片分析，得到封堵器和周边心肌组织的病理图。
实施例1
本实施例提供的封堵器中，封堵器编织网的整体质量为0.726g。编织网包括96根重均分子量为100,000Da，多分散系数为6.02的聚左旋乳酸（PLLA）丝，丝径为0.15mm，结晶度为50%。对PLLA丝进行体外降解实验，经6个月降解后测得的弹性模量为2.66GPa，断裂伸长率为70%，这说明本实施例PLLA丝制作的封堵器可保证在植入6个月内具有稳定的框架结构，从而实现内皮爬覆完全；PLLA丝质量保留率随时间延长的变化趋势如图3的曲线1所示，其降解周期约为4~5年，聚合物质量保留率在第6~56个月中每2个月的下降值均小于5%，说明降解产物在第6~56个月平缓释放；将本实施的封堵器植入猪的心脏2年后，对封堵器与周边心肌组织进行病理切片分析，其病理图如图4所示，无明显炎症和异物反应。
实施例2
本实施例提供的封堵器中，封堵器编织网的整体质量为0.726g。编织网包括96根重均分子量为100,000Da，多分散系数为5.12的PLLA丝，结晶度为50%，丝径为0.15mm。对PLLA丝进行体外降解实验，经6个月降解后测得的弹性模量为2.86GPa，断裂伸长率为66%，可这说明本实施例PLLA丝制作的封堵器可保证在植入6个月内具有稳定的框架结构，从而实现内皮爬覆完全；PLLA丝质量保留率随时间延长的变化趋势如图3的曲线2所示，降解周期为4~5年，聚合物质量保留率在第6~52个月中的每2个月的下降值均小于5%，说明降解产物在第6~52个月平缓释放；将本实施例的封堵器植入猪的心脏2年后，对封堵器与周边心肌组织进行病理切片分析，其病理图如图5所示，无明显炎症和异物反应。
实施例3
本实施例提供的封堵器中，编织网包括200根重均分子量为50,000Da，多分散系数为10的聚乳酸-羟基乙酸共聚物（PLGA）丝，丝径为0.50mm，结晶度为80%。对PLGA丝进行体外降解实验，经6个月降解后测得的弹性模量为3.01GPa，断裂伸长率为75%，这说明本实施例PLGA丝制作的封堵器可保证在植入6个月内具有稳定的框架结构，从而实现内皮爬覆完全；PLGA丝在第6~54个月中每2个月的下降值均小于5%，PLGA丝质量保留率随时间延长的变化趋势如图3的曲线3所示, 降解产物在第6~54个月平缓释放；将本实施的封堵器植入猪的心脏2年后，对封堵器与周边心肌组织进行病理切片分析，其病理图如图6所示，无明显炎症和异物反应。
实施例4
本实施例提供的封堵器中，编织网包括20根重均分子量为800,000Da，多分散系数为3的非结晶聚羟基脂肪酸脂(PHA)丝，丝径为0.05mm。对丝进行体外降解实验，经6个月降解后测得的弹性模量为3.54GPa，断裂伸长率为82%，这说明本实施例 PHA丝制作的封堵器可保证在植入6个月内具有稳定的框架结构，从而实现内皮爬覆完全；PHA丝在第6~64个月中每2个月的下降值均小于5%，PHA丝质量保留率随时间延长的变化趋势如图3的曲线4所示，降解产物在第6~64个月平缓释放；将本实施的封堵器植入猪的心脏2年后，对封堵器与周边心肌组织进行病理切片分析，其病理图如图7所示，无明显炎症和异物反应。
对比例1
本实施例提供的封堵器中，封堵器编织网的整体质量为0.726g。编织网包括96根重均分子量为100,000Da，多分散系数为1.49的可降解高分子PLLA丝，结晶度为50%，丝径为0.15mm。对PLLA丝进行体外降解实验，经6个月降解后测得的弹性模量为3.08GPa，断裂伸长率分别为63%，本对比例PLLA丝制作的封堵器可保证在植入6个月内具有稳定的框架结构，从而实现内皮爬覆完全；PLLA丝的质量保留率随时间延长的变化趋势如图3的曲线5所示，降解周期为2~3年，高分子丝在第6~20个月集中降解，降解产物在该时间段内集中释放；将本对比例的封堵器植入猪的心脏2年后，对封堵器与周边心肌组织进行病理切片分析，其病理图如图8所示，封堵器植入2年后炎症和异物反应比较严重。
实施例1~2和对比例1的实验结果表明：针对质量相同的封堵器，采用宽分子量分布的高分子丝制成的封堵器，在保证植入早期（6个月）内具有稳定的框架结构的基础上，能够延长封堵器的降解周期，从而可以避免降解产物集中释放，产生严重的炎症反应。

Claims (7)

  1. 一种可吸收封堵器，包括编织网，所述编织网包括一种可降解高分子丝，其特征在于，所述可降解高分子丝材料的多分散系数为3~10，重均分子量范围为20,000Da~800,000Da。
  2. 根据权利要求1所述的可吸收封堵器，其特征在于，所述可降解高分子丝总数量为20~200根。
  3. 根据权利要求1所述的可吸收封堵器，其特征在于，所述可降解高分子丝材料选自聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物、聚羟基脂肪酸脂、聚对二氧环己酮、聚己内酯、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或上述聚合物单体中的至少两种的共聚物。
  4. 根据权利要求1所述的可吸收封堵器，其特征在于，所述可降解高分子丝的丝径范围为0.05mm~0.50mm。
  5. 根据权利要求1或3所述的可吸收封堵器，其特征在于，所述可降解高分子丝材料的结晶度范围为0%~80%。
  6. 根据权利要求1所述的可吸收封堵器，其特征在于，所述封堵器还包括阻流膜，所述阻流膜通过缝合线固定在所述编织网内，所述阻流膜材料选自聚对苯二甲酸乙二醇酯、聚乙烯、聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物、聚羟基脂肪酸脂、聚对二氧环己酮、聚己内酯、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯、或聚碳酸酯中，或上述聚合物的单体中的至少两种的共聚物，所述缝合线材料选自聚乳酸、聚乙醇酸、聚乳酸-羟基乙酸共聚物、聚羟基脂肪酸脂、聚对二氧环己酮、聚己内酯、聚酰胺、聚酸酐、聚磷酸酯、聚氨酯或聚碳酸酯，或上述聚合物单体中的至少两种的共聚物。
  7. 根据权利要求1所述的可吸收封堵器，其特征在于，所述封堵器还包括锁定件，所述锁定件的一端与远端相连，另一端可拆卸地与近端相连，当锁定件的另一端与近端吻合时，封堵器的腰高得以固定。
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