WO2019184555A1 - 一种封堵装置及其制备方法 - Google Patents

一种封堵装置及其制备方法 Download PDF

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Publication number
WO2019184555A1
WO2019184555A1 PCT/CN2019/071340 CN2019071340W WO2019184555A1 WO 2019184555 A1 WO2019184555 A1 WO 2019184555A1 CN 2019071340 W CN2019071340 W CN 2019071340W WO 2019184555 A1 WO2019184555 A1 WO 2019184555A1
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WIPO (PCT)
Prior art keywords
waist
occlusion device
barb
skeleton
waist portion
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PCT/CN2019/071340
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English (en)
French (fr)
Inventor
康亚红
张国艺
高晨光
陆威
姜洪焱
Original Assignee
上海微创医疗器械（集团）有限公司
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Priority to EP19774921.1A priority Critical patent/EP3777702A4/en
Publication of WO2019184555A1 publication Critical patent/WO2019184555A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00004—(bio)absorbable, (bio)resorbable, resorptive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00526—Methods of manufacturing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00575—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00575—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
    • A61B2017/00579—Barbed implements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00575—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
    • A61B2017/00597—Implements comprising a membrane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00575—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
    • A61B2017/00606—Implements H-shaped in cross-section, i.e. with occluders on both sides of the opening
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00575—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect for closure at remote site, e.g. closing atrial septum defects
    • A61B2017/00623—Introducing or retrieving devices therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/0057—Implements for plugging an opening in the wall of a hollow or tubular organ, e.g. for sealing a vessel puncture or closing a cardiac septal defect
    • A61B2017/00646—Type of implements
    • A61B2017/0065—Type of implements the implement being an adhesive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00876—Material properties magnetic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00898—Material properties expandable upon contact with fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00902—Material properties transparent or translucent
    • A61B2017/00915—Material properties transparent or translucent for radioactive radiation
    • A61B2017/0092—Material properties transparent or translucent for radioactive radiation for X-rays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00942—Material properties hydrophilic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00831—Material properties
    • A61B2017/00951—Material properties adhesive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B90/00—Instruments, implements or accessories specially adapted for surgery or diagnosis and not covered by any of the groups A61B1/00 - A61B50/00, e.g. for luxation treatment or for protecting wound edges
    • A61B90/39—Markers, e.g. radio-opaque or breast lesions markers
    • A61B2090/3966—Radiopaque markers visible in an X-ray image

Definitions

  • the invention relates to a medical occlusion device and a preparation method thereof, in particular to a self-expanding cardiac septal defect occlusion device and a preparation method thereof.
  • transcatheter percutaneous transluminal occlusion devices for the treatment of atrial septal defect (ASD), patent foramen ovale (PFO), ventricular septal defect (VSD) and arteries
  • Heart disease such as catheter patency (PDA) is becoming an increasingly important method and is becoming widely accepted.
  • Nitinol heart interval occluder has good elastic memory. After entering the human body, it can immediately return to the required structural shape, close to the defect site, and the residual shunt is small, achieving excellent sealing effect, but such occluder is not degradable, and is permanently retained in the body after being placed. There are potential risks; the other type of occluder is mainly made of biodegradable materials, mostly in the research stage, mainly made of biodegradable materials. Due to its nature and characteristics, it is made into a seal.
  • occluder Throughout the current implantable occluder, whether it is the use of non-degradable alloy materials or degradable polymer materials, from material selection to shape design, a wide variety, a wide variety.
  • the common features of these occluders are: a double disc-shaped design, through a thin neck connection, double disc surface internal and external seams to fill the flow film, and then clamped in the defect, using the double disc surface with a baffle to block blood flow Pass through to achieve the occluder effect.
  • these occluders also have some problems.
  • the edge of the defect site is required to have a certain distance from the coronary sinus, superior vena cava, inferior vena cava, pulmonary vein, and atrioventricular valve.
  • the space in which the plug is opened can meet the basic requirements of interventional occluder treatment, which leads to the inability of some patients to adopt interventional treatment; in addition, these occluders have larger structures and more materials, whether it is Nitinol or Degradable materials have a greater impact on the complications brought about by the later stage, and a larger delivery catheter is needed during the delivery process, which has great damage to the blood vessels; and the defect parts of different patients have different shapes and are placed in a fixed shape.
  • the plugging device will result in the failure to completely block the defect and have a large residual shunt.
  • a occlusion device and a preparation method thereof which are used for sealing a defect of a heart interval, have good structural stability, are not easy to rebound or shift, and are small and can be widely applied. Interventional treatment of various cardiac septal defect sites, small volume, low material usage, excellent biocompatibility, and rapid closure of the defect site, as well as filling irregularly shaped tissue defects.
  • the technical solution adopted by the present invention to solve the above technical problems is to provide a occlusion device including a skeleton and a flow blocking film, wherein the skeleton includes a waist portion and a barb connected to at least one end of the waist portion, the waist portion Coated with a solid dry gel attached to at least one end of the waist and/or the inside of the barb.
  • the solid dry gel is made of a degradable material.
  • the degradable material of the solid dry gel is selected from a block copolymer or a crosslinked copolymer composed of at least one aliphatic polymer and at least one water-soluble polymer, or by at least one parent A block copolymer or crosslinked copolymer composed of a polymer and at least one aliphatic polymer or water-soluble polymer.
  • the aliphatic polymer is selected from the group consisting of polylactic acid or a copolymer thereof or polycaprolactone or a copolymer thereof;
  • the water-soluble polymer is selected from polyacrylic acid or polyethylene glycol;
  • the amphiphilic polymer is selected Self-polymerizing N-isopropylacrylamide or a copolymer thereof.
  • the degradable material from which the solid dry gel is made has a weight average molecular weight ranging from 10 4 to 10 6 Da.
  • the skeleton and/or the flow blocking film are made of a degradable material.
  • the skeleton is selected from the group consisting of a degradable magnesium alloy, a degradable zinc alloy or a copolymer and/or a blend of one or more of the following materials: polylactic acid, polyglycolic acid, polycaprolactone, a polydioxanone, a polyamino acid;
  • the barrier film is selected from the group consisting of copolymers and/or blends of one or more of the following materials: polylactic acid, polyglycolic acid, polycaprolactone, poly Dioxanone, polyamino acid.
  • the waist portion is a mesh tubular hollow structure or a hollow tubular structure.
  • the axial length of the waist portion ranges from 3.5 mm to 5.5 mm; and the inner diameter of the waist portion ranges from 2 to 60 mm.
  • the barb extends away from the waist in a radial direction of the skeleton from a joint with the waist, and has at least one inner bent structure extending toward the waist.
  • the barb has a plurality of inner bending structures including at least one semi-arc-shaped bending structure and/or at least one hook-shaped bending structure.
  • the barbs are evenly or unevenly arranged along the circumference, the semicircle or the three quarters of the circumference of the end face of the waist.
  • the two ends of the waist are provided with barbs, and the magnetic poles attracted to each other are respectively disposed on the barbs at the symmetrical positions of the proximal end and the distal end of the waist.
  • the present invention also provides a method for preparing the above-mentioned occlusion device, comprising the steps of: forming the waist portion of the skeleton by wire woven or laser cutting of a tube; forming the bottom at least one end of the waist by heat setting a hook; a flow blocking film is fixed to at least one end of the waist and/or the inside of the barb; a solid dry gel is applied to the waist.
  • the waist portion is formed by wire weaving, and the barb is formed by heat setting a wire which is reserved at both ends of the waist portion.
  • the heat setting comprises bending the wire into a direction close to the waist to overpressure so that the barb has an inwardly directed prestress.
  • applying the solid dry gel to the waist comprises: resting the waist in a sol, and then forming a solid xerogel at the waist by lyophilization; or spraying a sol onto the waist, It is then obtained by solvent evaporation drying; or the sol is sprayed onto a wire or tube and then dried by solvent evaporation to obtain the wire or the tube for forming the waist.
  • the flow blocking film is fixed to at least one end of the waist and/or the inside of the barb by stitching, heat fusion or cementation.
  • the present invention Compared with the prior art, the present invention has the following beneficial effects: the present invention provides a occlusion device and a preparation method thereof, and the occlusion device adopts a structure which has a smaller size and can be used for a smaller diameter delivery sheath.
  • the damage to the vessel wall is smaller, and it can also be applied to the interventional closure of younger people.
  • the amount of material is reduced, the complication rate after implantation is reduced, and the cost is saved.
  • With the solid dry gel The characteristics of swelling after being exposed to blood in the body can fill irregular tissue defects, and can be applied to the narrow edge of the defect site and the complicated shape of the defect site, thereby broadening the application range of the interventional treatment of the cardiac septal defect.
  • FIG. 1 is a schematic view showing the overall structure of a occlusion device in a released state according to an embodiment of the present invention
  • FIG. 2 is a front view of the occlusion device in a released state according to an embodiment of the present invention
  • FIG. 3 is a top view of the occlusion device in a released state according to an embodiment of the present invention.
  • FIG. 4 is a schematic view of the occlusion device released from the catheter according to an embodiment of the present invention.
  • FIG. 5 is a schematic view of a occlusion device for sealing a cardiac septal defect portion according to an embodiment of the present invention.
  • proximal and distal are used as orientation words, wherein “proximal” means one end near the operator during surgery; “distal” means away from the operator One end.
  • proximal means one end near the operator during surgery; “distal” means away from the operator One end.
  • distal means away from the operator One end.
  • the term “or” is generally used in its meaning including “and/or” unless the context clearly dictates otherwise.
  • FIG. 1 is a schematic view showing the overall structure of the occlusion device 8 in a released state according to an embodiment of the present invention
  • FIG. 2 is a front view showing the occlusion device 8 in a released state according to an embodiment of the present invention
  • FIG. 3 is a occlusion device according to an embodiment of the present invention. 8 top view in the released state.
  • the present invention provides a occlusion device 8 comprising a skeleton, a flow blocking membrane and a solid xerogel as a filling medium for the defect site.
  • the occlusion device 8 has good structural stability, is not easy to rebound or shift, has the characteristics of small volume, small amount of material, and excellent biocompatibility, and the rapid expansion of the solid dry gel after contact with blood can quickly seal the defect.
  • the site and operation are simple, and it can fill irregular tissue defects.
  • it also solves the problems that the occluder in the prior art is difficult to adapt to the delivery of the fine blood vessels due to its large volume and difficulty in transporting in the delivery sheath, and cannot be applied to patients with narrow edges of the defect portion and complicated shapes of the defect portion.
  • the skeleton comprises a waist portion 1 and a proximal barb 2 or a distal barb 5 which is connected to at least one end of the waist portion 1 and functions as a fixed occlusion device 8.
  • a baffle is fixed on the skeleton.
  • the choke membrane includes a proximal obstruction membrane 3 and a distal obstruction membrane 4, respectively fixed to the proximal and distal or proximal barbs 2 of the waist 1 and The inside of the distal barb 5 (i.e., the side of the barb that faces the central axis of the waist 1); in another embodiment, the baffle includes only the proximal obstruction membrane 3 or only the distal obstruction membrane 4. In this embodiment, the solid dry gel is coated on the waist portion 1.
  • the solid dry gel contacts the blood to rapidly absorb water and expand and fill the defect cavity 11 to achieve the sealing effect;
  • the solid dry gel, coated on the waist structure does not mean that the remaining part may not be applied with a solid xerogel, for example, a barb or a baffle film may also be coated with a solid xerogel.
  • the skeleton, solid dry gel, and the flow blocking film are preferably made of a degradable material.
  • the skeleton is made of a degradable material.
  • the degradable material constituting the skeleton requires better mechanical properties and a controlled degradation cycle, and should meet certain strength requirements and maintain a stable shape in a short period of time without rebounding.
  • the degradable material constituting the skeleton may be selected from copolymers and/or blends of one or more of the following materials: polylactic acid (PLA: Poly-lactide Acid), polyglycolic acid (PGA) : Poly-glycolide), polycaprolactone (PCL: Poly-caprolactone), polydioxanone (PDO: Poly-dioxanone), polyamino acid (PAA: Polyamino acid), preferably, for example, polylactic acid-caprolactone copolymerization
  • Degradable polymer materials such as polylactic acid-glycolic acid copolymer, polylactic acid-caprolactone-glycolic acid copolymer, and degradable metal or alloy materials such as degrading
  • the solid dry gel is a kind of dry gel formed after water loss, and can rapidly absorb water and expand into a hydrogel having a significantly increased volume when it is contacted with water again, and has good biocompatibility and tissue adhesion.
  • the solid xerogel is preferably made of a degradable material selected from the group consisting of at least one aliphatic polymer and at least one water soluble polymer, or at least one A block copolymer or crosslinked copolymer of an amphiphilic polymer and at least one aliphatic polymer or water soluble polymer.
  • the aliphatic polymer is selected from the group consisting of polylactic acid (PLA) or a copolymer thereof or polycaprolactone (PCL) or a copolymer thereof;
  • the water-soluble polymer is selected from the group consisting of polyacrylic acid (PAA) or polyethylene.
  • Alcohol (PEG) the amphiphilic polymer is selected from the group consisting of poly N-isopropyl acrylamide (PNIPAAm) or a copolymer thereof.
  • the block copolymer or crosslinked copolymer formed includes PEG-PLGA-PEG, PLGA-PEG-PLGA, PCLA-PEG-PCLA or Dex-PCL-HEMA, and the like.
  • the degradable material constituting the solid dry gel has a weight average molecular weight ranging from 10 4 to 10 6 Da.
  • the degradation cycle and mechanical properties of the degradable solid dry gel can be controlled according to the molecular weight of the polymer, the polymer ratio, etc., and can be controlled to be slowly degraded after completion of endothelialization at about 6 months.
  • the solid dry gel can be formed by standing a skeleton (including the waist 1) in a sol and then forming a solid gel by lyophilization; or spraying the sol onto the waist 1 by a spraying device, and then evaporating by a solvent Drying gives a solid dry gel; or alternatively, the sol is first sprayed onto a wire or tube used to prepare the skeleton (including the waist 1) by a spraying apparatus, and then the wire or tube is made into a skeleton.
  • the skeleton includes a waist portion 1 and a proximal barb 2 or a distal end that is coupled to the at least one end of the waist portion 1 (for example, the occlusion device 8 for the patent ductus arteriosus is provided with a barb at one end) to act as a fixed occlusion device 8.
  • Barbs 5 The skeleton may be a mesh tubular hollow structure. For example, a monofilament prepared by using a degradable material is woven into a mesh tube structure, and a mesh tube of a specific length is taken as a waist portion 1 according to a position to be implanted, and the monofilaments at both ends or one end of the waist portion 1 are heat-set to obtain a barb.
  • Barbs are optionally provided at one or both ends of the waist 1 according to the patient site to be blocked.
  • the barbs 5 are usually placed at the waist 1 remote.
  • a degradable tubular (rod-like) material is laser-cut to form a web-shaped hollow structure (similar to a cut stent-like) of the waist 1 and further heat-treated, finished, etc., at the waist 1 Barbs are formed at either ends or at one end.
  • the waist portion 1 of the skeleton may also be a hollow tubular material, which is made of a degradable tube material, and has no hollow structure on its outer surface.
  • the waist portion 1 mainly serves to connect the proximal barbs 2 or/and the distal barbs 5 so that the occlusion device 8 can be attached to the defect portion and maintain the relative position, and can also be the choke membranes 3, 4 and the solid state.
  • the xerogel provides support.
  • the structure of the waist portion 1 has a certain flexibility, and can be appropriately bent to adhere to a wall when encountering a hole having a complicated shape and structure.
  • the length of the waist portion 1 is equivalent to the thickness of the defect portion (for example, a heart gap) of about 3.5 to 5.5 mm, preferably 4 mm;
  • the inner diameter of the waist structure can be designed to be 2-60 mm, and the size is mainly based on the defect portion. Depending on the size, it is significantly larger than the diameter of the heart septum so that it can fit snugly against the inner wall of the notch and can be adapted to different patients by making various types of occlusion devices.
  • the proximal barbs 2 and distal barbs 5 extend away from the waist in a radial direction of the skeleton from a junction with the waist, and have at least one inner bent structure extending toward the waist. Specifically, it can be designed into different shapes: for example, the barb has only one inner bending structure, can be directly clamped and hooked on the tissue wall of the defect portion, and has small volume and small space; for example, the proximal barb 2 and the far
  • the end barb 5 has a plurality of inner bending structures, for example including at least one semi-circular bending structure and at least one hook-shaped bending structure, so that the barbs can be clamped on the tissue wall and form a barb similar
  • the structure effectively prevents the displacement of the occlusion device 8.
  • the proximal barb 2 and the distal barb 5 can be formed by a heat setting method.
  • proximal barb 2 and the distal barb 5 can be hooked on the tissue wall to fix the occlusion device 8.
  • one of the following treatment schemes may be preferred: Scheme a: symmetrical position at the proximal and distal ends of the waist The proximal barbs 2 and the distal barbs 5 are respectively provided with mutually attracting magnetic poles, so that the barbs at both ends are attracted to each other, so that the fixing device 8 is more firmly fixed; scheme b: the proximal barbs 2 and When the distal barb 5 is heat-treated, the barb is over-pressed to have an inward-facing pre-stress, which refers to a pre-stress toward the center of the waist, which can significantly enhance the effect of the clamping.
  • proximal or inferior barbs 2 or distal barbs 5 can be designed, depending on the edge of the defect, from the coronary sinus, superior vena cava, inferior vena cava, pulmonary vein, and atrioventricular valve
  • the barbs may be of different distributions, such as the barbs being evenly or unevenly arranged along the circumference, half circumference or three quarters of the circumference of the end face of the waist 1.
  • the barbs are evenly arranged within the aforementioned range.
  • the proximal barb 2 or the distal barb 5 can be designed to be unilaterally distributed, ie, inverted.
  • the hook is distributed on the side away from the vein or valve to avoid contact with the vein or valve during insertion and withdrawal, resulting in an acute reaction.
  • the baffle is fixed to at least one end of the waist or the inner side of the barb, and may be fixed to one end or both ends of the waist, or may be fixed to the inner side of the proximal or distal barb.
  • the baffle film is fixed to at least one end of the waist or the inside of the barb by suture stitching, or is fixed to at least one end of the waist or the inside of the barb by heat fusion or cementation. Its function is mainly to prevent blood flow, including the proximal obstruction membrane 3 fixed to the inner side of the lumbar 1 or the inner side of the proximal barb 2, and the distal obstruction fixed to the distal end of the lumbar 1 or the inner side of the distal barb 5 Membrane 4.
  • the flow blocking film is prepared using a degradable material, and a copolymer and/or a blend of one or more of the following materials may be selected: polylactic acid (PLA: Poly-lactide Acid), polyglycolic acid (PGA: Poly-glycolide), polycaprolactone (PCL: Poly-caprolactone), polydioxanone (PDO: Poly-dioxanone), polyamino acid (PAA: Polyamino acid).
  • PLA Poly-lactide Acid
  • PGA Poly-glycolide
  • PCL Poly-caprolactone
  • PDO Poly-dioxanone
  • PAA Polyamino acid
  • the flow-blocking film may be a degradable polymer material such as a polylactic acid-caprolactone copolymer, a polylactic acid-glycolic acid copolymer, or a polylactic acid-caprolactone-glycolic acid copolymer.
  • the degradable material constituting the flow-blocking film has a weight average molecular weight ranging from 10 5 to 10 6 Da and a distribution width of 1-3.
  • the development marker can be added or affixed to the occlusion device 8 in a variety of ways.
  • a plurality of the developing wires and the monofilament may be mixed and woven into a net-tube skeleton; or the developing material may be sutured.
  • the patch is placed at the position of a suitable occluding device 8; or the developing point is engraved on the skeleton; or an appropriate amount of the developing material and the degradable material may be blended and extruded to form the occluding device 8. All of the above solutions can achieve the fixation of the developing marker, and can be used to determine whether the occlusion device 8 is accurately placed at the heart defect site and whether displacement occurs in the later stage.
  • the developing material used for the above development marker may be selected from non-metallic substances such as diatrizoic acid, sodium iodide, iohexol, iodixanol, iodophor, barium sulfate, diatrizoate, bismuth subcarbonate, Titanium oxide, zirconium oxide, etc.; metal materials such as gold, ruthenium, osmium, molybdenum, tungsten, platinum, rhodium, and the like may also be selected.
  • non-metallic substances such as diatrizoic acid, sodium iodide, iohexol, iodixanol, iodophor, barium sulfate, diatrizoate, bismuth subcarbonate, Titanium oxide, zirconium oxide, etc.
  • metal materials such as gold, ruthenium, osmium, molybdenum, tungsten, platinum, rhodium, and the
  • the developing material may also be a biodegradable material such as iron, gold, ruthenium, osmium, molybdenum or the like; or a non-biodegradable material such as diatrizoate, iopromide or iodobenzene hexaol.
  • a biodegradable material such as iron, gold, ruthenium, osmium, molybdenum or the like
  • a non-biodegradable material such as diatrizoate, iopromide or iodobenzene hexaol.
  • the respective constituent structures of the occlusion device 8 are preferably made of a degradable material, have good biocompatibility, and part of the structure of the occlusion device 8 can be various embodiments according to actual needs. Choose the right solution, freely combine and match, and make a complete occlusion device8.
  • a multi-hook plugging device 8 is made by using a braided mesh tube as an example for sealing a central atrial septal defect.
  • a braided mesh tube as an example for sealing a central atrial septal defect.
  • the occlusion device 8 in this embodiment includes a skeleton, a flow blocking film, and a development marker, wherein the skeleton includes a waist portion 1, and a proximal barb 2 that is respectively coupled to both ends of the waist portion 1 and functions as a fixed occlusion device 8 and Remote barb 5.
  • a monofilament is woven into a web-shaped waist portion 1, and the ends of the monofilaments are reserved at both ends of the waist portion 1 for making the barbs 2, 5.
  • a developing wire made of a degradable material is used as a developing mark, and a plurality of developing wires are symmetrically placed on the axis of the waist 1 and mixed with the degradable wire.
  • the developing wire can be used to determine whether the blocking device 8 is at a heart defect site. Accurate placement and displacement in the later stages.
  • the monofilament of the waist 1 and the barbs 2, 5 can be obtained by a method of stretching, weaving, heat setting, etc. by using a degradable polymer material.
  • a monofilament polylactic acid (PLLA) monofilament is used to woven into a network tube structure.
  • the length of the mesh tube structure is about 4 mm as the waist portion 1 (the wall portion of the defect portion of the central type atrial septal defect is usually about 4 mm), and the monofilaments reserved at both ends of the waist portion 1 are heat-set and finished.
  • the barb structure can be obtained by using two monofilaments or a plurality of monofilaments to form a barb, and the position of the waist 1 is divided into a proximal barb 2 and a distal barb 5, the barb 2, 5 from the junction with the waist 1 extending away from the waist 1 in the radial direction of the occluding device 8, and having an inward prestress by bending inwardly (ie, toward the waist)
  • the barbs 2, 5 are clamped and clamped on the tissue wall, and are hooked in the tissue wall, which is stable and firm, and ensures zero displacement of the plugging device 8.
  • applying the solid dry gel to the waist 1 includes: resting the skeleton in the sol, and then forming the skeleton carrying the solid dry gel by lyophilization; or spraying the sol through a spraying device The waist 1 is then dried by solvent evaporation to obtain a skeleton carrying a solid dry gel.
  • the sol is selected from a liquid degradable material, preferably a block copolymer or a crosslinked copolymer composed of at least one aliphatic polymer and at least one water soluble polymer, or from at least one amphiphilic polymer a block copolymer or a crosslinked copolymer composed of at least one aliphatic polymer or a water-soluble polymer, such as a PLA block copolymer (for example, PLA Pluronic® F127), and further, for example, PEG-PLGA-PEG, PLGA-PEG - PLGA, PCLA-PEG-PCLA or Dex-PCL-HEMA.
  • the sol preferably uses the above-described degradable material having a weight average molecular weight of from 10 4 to 10 6 Da.
  • the choke membrane includes a proximal obstruction membrane 3 at the proximal end of the skeleton and a distal obstruction membrane 4 at the distal end of the skeleton, and is fixed to both ends of the waist 1 or the inside of the barbs 2, 5, respectively.
  • a baffle film is sutured and fixed at both ends of the waist 1 by using a degradable suture to ensure that the choke film can be tightly sealed.
  • the order of applying the solid dry gel to the waist 1 and the fixed blocking film 3, 4 may be interchanged before and after, and depending on the coating position of the solid solid gel or the fixed position of the choke film, These two steps can also be carried out before or after the step of making the waist 1 of the skeleton, or before or after the step of making the barbs 2, 5, which is not limited in the present invention. Further, the solid dry gel is not limited to being applied only to the waist portion 1, and may be additionally applied to the barbs 2, 5 or the baffles 3, 4.
  • the defect portion of the heart tissue is blocked by the catheter and placed into the occlusion device 8, see FIGS. 4 and 5.
  • the distal barb 5 is first pushed out from the delivery catheter 10, and the distal barb 5 is opened and hooked at the distal end.
  • the wall of the defect-free tissue 9 As shown in Fig.
  • the delivery catheter 10 is withdrawn, the waist 1 and the proximal barb 2 are pushed out, and the proximal barb 2 is opened and hooked at the proximal end of the defect wall 9
  • the waist portion 1 of the occluding device 8 in the released state is much larger than the inner diameter of the defect cavity 11
  • the waist portion 1 is pressed and abuts against the deflated tissue wall 9 of the defect cavity 11, and the occlusion is blocked.
  • the device 8 is imported.
  • the dry gel on the skeleton absorbs water after contact with the blood, and a preliminary swelling occurs to form a hydrogel.
  • the hydrogel after absorbing water is gradually formed. The expansion fills the defect cavity 11. Complete the blockage.
  • the occlusion device of the present invention has the following effects and advantages as compared with the prior art:
  • the skeleton of the occlusion device of the present invention comprises a waist portion and a barb connected to the waist portion, and is designed to eliminate the huge double-disc structure adopted by the occluder in the prior art, and is instead a small-sized barb structure. , to achieve the fixation of the occlusion device at the defect site.
  • the structural stability of the barb is good, and the rebound deformation is not easy to occur, and the position of the skeleton can be well fixed to avoid displacement.
  • the waist-coated solid dry gel adheres to the tissue wall after contact with the blood, which provides a stronger guarantee for the displacement of the late plugging device.
  • the occlusion device of the present invention can be more widely used in the venous sinus, superior vena cava, and inferior vena cava due to the significant reduction of the space required for anchoring the occlusion device on both sides of the defect tissue wall.
  • Closer patients such as veins, pulmonary veins, and atrioventricular valves have broadened the range of applications for minimally invasive interventional procedures for cardiac septal defect.
  • the occlusion device of the present invention significantly reduces the outer diameter and the overall volume compared to the prior art occluder having a large double disc structure, so that a smaller diameter delivery catheter can be used to deliver the occlusion.
  • Device which can reduce the damage to the blood vessel wall during delivery and reduce vascular inflammation; in addition, the smaller diameter delivery catheter can be applied to the younger patients with cardiac septal defect, further broadening the micro-trauma interventional treatment The range of applications for cardiac septal defect.
  • the occlusion device of the present invention can save about 50% of the amount of framing material compared with the occluder of the prior art which adopts a huge double disc structure, and the cost is greatly saved.
  • the occlusion device uses a more flexible degradable material, including polycaprolactone (PCL), polyglycolic acid (PGA), polylactic acid (PLA), polydioxane Ketones (PDO), polyamino acids (PAA) or copolymers and/or blends of the foregoing or degradable zinc alloys, degradable magnesium alloys, etc., and polycaprolactone (PCL), polyglycolic acid (PGA), polylactic acid (PLA), polydioxanone (PDO), polyamino acid (PAA) or copolymers and/or blends of the foregoing, which have good deformability
  • the solid dry gel can be filled with irregular tissue defects after being exposed to blood, and the effect of effective sealing can be achieved, so that the microtrauma intervention can be applied.
  • the occlusion device can be entirely made of a degradable material, including a degradable skeleton and a baffle material, and a degradable solid xerogel material, after completion of endothelialization at the defect site,
  • the occlusion device will gradually degrade and disappear, which significantly improves its safety for human body; in addition, due to the small size and less material used in the occlusion device of the present invention, the amount of degradation products generated during the degradation process of the occlusion device is also greatly increased. Reduced, thereby reducing the incidence of related complications.

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Abstract

一种封堵装置及其制备方法，包括骨架和阻流膜（3,4），其中，骨架包括腰部（1）和与腰部（1）的至少一端连接的倒钩（4,5），腰部（1）涂覆有固态干凝胶，阻流膜（3,4）固定在腰部（1）的至少一端和/或倒钩（4,5）的内侧。该封堵装置所采用的结构使其具有更小的尺寸，能够使用于更小直径的输送鞘中，减少了材料用量，降低了植入后的并发症率，也节约了成本；借助固态干凝胶接触血液后膨胀的特性，能够填充不规则形状的组织缺损，可以应用于缺损部位边缘较窄以及缺损部位形状复杂的情况，拓宽了介入治疗心脏间隔缺损的应用范围。

Description

一种封堵装置及其制备方法 技术领域
本发明涉及一种医用封堵装置及其制备方法，尤其涉及一种自膨胀心脏间隔缺损封堵装置及其制备方法。
 背景技术
随着植入性医疗器械和介入心脏病学的不断发展，经导管经皮置入封堵器治疗房间隔缺损（ASD）、卵圆孔未闭（PFO）、室间隔缺损（VSD）及动脉导管未闭（PDA）等心脏病成为越来越重要的方法，并且逐渐广为接受。
关于封堵器的研究，科研领域和临床领域积累了丰富的经验，尤其是镍钛合金封堵器，已临床应用十多年，镍钛合金心脏间隔封堵器具有良好的弹性记忆性，置入到人体后，可以立刻恢复到所要求的结构形状，很好贴紧缺损部位，残余分流小，达到极佳的封堵效果，但是这类封堵器不可降解，置入后永久留存体内，存在潜在的风险；另一类封堵器主要是采用生物可降解材料制成，多为研究阶段，主要是采用生物可降解材料制作而成，由于其本身的性质及特点，导致所制成封堵器的两个封堵单元之间收缩回弹力不足，并不能紧贴缺损部位的两侧而影响封堵器效果，因此这类封堵器中需要设计一些锁定机构来保持两个盘面之间的稳定距离，但是目前这些锁定部件存在一些问题和缺陷，并且制备工艺复杂，成本高。
纵观当下的植入性封堵器，无论是采用不可降解的合金材料还是可降解的高分子材料，从材料的选择到形状的设计，种类繁多，各式各样。这些封堵器共同的特点是：采用双盘状的设计，通过一个细颈部连接，双盘面内外缝补阻流膜，然后夹持在缺损部位，利用带阻流膜的双盘面来阻挡血流的通过，从而达到封堵器效果。但是这些封堵器也存在一些问题，例如，由于存在较大的双盘面，要求缺损部位边缘距离冠状静脉窦、上腔静脉、下腔静脉、肺静脉以及房室瓣膜有一定的距离，存在足够封堵器撑开的空间，才能满足介入封堵器治疗的基本要求，这就导致部分患者无法采用介入治疗；另外，这些封堵器结构较大，材料用量较多，无论是镍钛合金材料还是可降解材料，对后期带来的并发症影响更大，并且，输送过程中需要更大的输送导管，对血管损伤大；还有不同患者的缺损部位的形状各异，置入固定形状的封堵器，会导致无法完全封堵缺损部位，存在较大的残余分流等问题。
 技术问题
为解决上述技术问题，需要提供一种封堵装置及其制备方法，所述封堵装置用于封堵心脏间隔的缺损，其结构稳定性好，不易回弹或移位，小巧而能够广泛应用于各类心脏间隔缺损部位的介入治疗，体积小、材料用量少、具备优良的生物相容性，并且可以快速封堵缺损部位，以及填充不规则形状的组织缺损。
 技术解决方案
本发明为解决上述技术问题而采用的技术方案是提供一种封堵装置，包括骨架和阻流膜，其中，所述骨架包括腰部和与所述腰部的至少一端连接的倒钩，所述腰部涂覆有固态干凝胶，所述阻流膜固定在所述腰部的至少一端和/或所述倒钩的内侧。
进一步地，所述固态干凝胶由可降解材料制成。
进一步地，制成所述固态干凝胶的可降解材料选自由至少一种脂肪族聚合物与至少一种水溶性聚合物组成的嵌段共聚物或交联共聚物，或者由至少一种双亲性聚合物与至少一种脂肪族聚合物或水溶性聚合物组成的嵌段共聚物或交联共聚物。
进一步地，所述脂肪族聚合物选自聚乳酸或其共聚物或者聚己内酯或其共聚物；所述水溶性聚合物选自聚丙烯酸或聚乙二醇；所述双亲性聚合物选自聚N-异丙基丙烯酰胺或其共聚物。
进一步地，制成所述固态干凝胶的可降解材料的重均分子量的范围为10 4-10 6Da。
进一步地，所述骨架和/或所述阻流膜由可降解材料制成。
进一步地，所述骨架选自可降解镁合金、可降解锌合金或者下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸、聚乙醇酸、聚己内酯、聚二氧环己酮、聚氨基酸；所述阻流膜选自下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸、聚乙醇酸、聚己内酯、聚二氧环己酮、聚氨基酸。
进一步地，所述腰部为网管状镂空结构或者中空管状结构。
进一步地，所述腰部的轴向长度的范围为3.5mm～5.5mm；所述腰部的内径的范围为2～60mm。
进一步地，所述倒钩自与所述腰部的连接处沿所述骨架的径向远离所述腰部延伸，且具有至少一个向所述腰部延伸的内弯折结构。
进一步地，所述倒钩具有多个内弯折结构，包括至少一个半圆弧型弯折结构和/或至少一个钩型弯折结构。
进一步地，所述倒钩沿着所述腰部的端面的圆周、半圆周或四分之三圆周均匀或不均匀排布。
进一步地，所述腰部的两端均设置有倒钩，在所述腰部的近端和远端的对称位置的倒钩上分别设置有相互吸引的磁极。
本发明还提供了一种上述封堵装置的制备方法，包括如下步骤：通过丝材编织或者管材激光切割形成所述骨架的所述腰部；通过热定型在所述腰部的至少一端形成所述倒钩；在所述腰部的至少一端和/或所述倒钩的内侧固定阻流膜；将固态干凝胶涂覆于所述腰部。
进一步地，所述腰部通过丝材编织形成，所述倒钩通过将所述腰部的两端预留出的丝材热定型形成。
进一步地，所述热定型包括：将所述丝材向靠近所述腰部的方向弯折过压使所述倒钩具有向内侧的预应力。
进一步地，将固态干凝胶涂覆于所述腰部包括：将所述腰部静置在溶胶中，然后通过冻干在所述腰部形成固态干凝胶；或者将溶胶喷涂到所述腰部上，然后通过溶剂挥发干燥得到；或者将溶胶喷涂到丝材或者管材上，然后通过溶剂挥发干燥得到用于形成所述腰部的所述丝材或者所述管材。
进一步地，所述阻流膜通过缝合、热熔或者胶结固定在所述腰部的至少一端和/或所述倒钩的内侧。
 有益效果
本发明对比现有技术有如下的有益效果：本发明提供了封堵装置及其制备方法，所述封堵装置所采用的结构使其具有更小的尺寸，能够使用于更小直径的输送鞘中，对血管壁损伤更小，也可以适用于年龄更小的人群的介入封堵，同时，减少了材料用量，降低了植入后的并发症率，也节约了成本；借助固态干凝胶置入体内接触血液后膨胀的特性，能够填充不规则形状的组织缺损，可以应用于缺损部位边缘较窄以及缺损部位形状复杂的情况，拓宽了介入治疗心脏间隔缺损的应用范围。
 附图说明
图1为本发明实施例中封堵装置释放状态下的整体结构示意图；
图2为本发明实施例中封堵装置释放状态下的主视图；
图3为本发明实施例中封堵装置释放状态下的俯视图；
图4为本发明实施例中封堵装置从导管释放后的示意图；
图5为本发明实施例中封堵装置封堵心脏间隔缺损部位的示意图。
图中：
1腰部 2 近端倒钩 3 近端阻流膜
4 远端阻流膜 5 远端倒钩 8 封堵装置
9缺孔组织壁 10 输送导管 11缺损空腔
本发明的最佳实施方式
在此处键入本发明的最佳实施方式描述段落。
 本发明的实施方式
下面结合附图和实施例对本发明作进一步的描述。
为了更加清楚地描述本发明的结构特征，采用“近端”、“远端”作为方位词，其中“近端”表示在手术过程中靠近操作者的一端；“远端”表示远离操作者的一端。术语“或”通常是以包括“和/或”的含义而进行使用的，除非内容另外明确指出外。
图1为本发明实施例中封堵装置8释放状态下的整体结构示意图；图2为本发明实施例中封堵装置8释放状态下的主视图；图3为本发明实施例中封堵装置8释放状态下的俯视图。
本发明提供一种封堵装置8，包括骨架、阻流膜和作为缺损部位填充介质的固态干凝胶。这套封堵装置8结构稳定性好，不易回弹或移位，具有体积小、材料用量少、生物相容性优良的特点，并且固态干凝胶接触血液后迅速膨胀可以快速封堵缺损部位、操作简单，能够填充不规则形状的组织缺损。同时，还解决了现有技术中的封堵器由于体积大、在输送鞘中输送困难，难以适应细血管输送，无法应用于缺损部位边缘较窄以及缺损部位形状复杂的患者等问题。
请参见图1、图2和图3，本发明提供的封堵装置8，包括骨架、固态干凝胶和阻流膜3、4。其中，骨架包括腰部1以及与腰部1的至少一端连接、起固定封堵装置8作用的近端倒钩2或远端倒钩5。骨架上固定有阻流膜，在一实施例中，阻流膜包括近端阻流膜3和远端阻流膜4，分别固定在腰部1的近端和远端或近端倒钩2和远端倒钩5的内侧（即倒钩的朝向腰部1中心轴的一侧）；在另一实施例中，阻流膜仅包括近端阻流膜3或者仅包括远端阻流膜4。本实施例中，固态干凝胶涂覆在腰部1上，当封堵装置8成功置入后，固态干凝胶与血液接触而快速吸水膨胀并填满缺损空腔11达到封堵的效果；这里，固态干凝胶，涂覆在腰部结构上不代表其余部位不可以施加固态干凝胶，例如，倒钩或阻流膜上也可以涂覆固态干凝胶。骨架、固态干凝胶、阻流膜优选由可降解材料制成。
优选地，所述骨架由可降解材料制成。构成所述骨架的所述可降解材料需要较好的力学性能和可控降解周期，应满足一定的强度要求和短期内保持稳定的形状、不发生回弹的要求。较佳地，构成所述骨架的可降解材料可选择下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸（PLA: Poly-lactide Acid）、聚乙醇酸（PGA: Poly-glycolide）、聚己内酯（PCL: Poly-caprolactone）、聚二氧环己酮（PDO: Poly-dioxanone）、聚氨基酸（PAA：Polyamino acid），优选例如聚乳酸-己内酯共聚物、聚乳酸-羟基乙酸共聚物、聚乳酸-己内酯-乙醇酸共聚物等可降解高分子材料，也可选择可降解镁合金、可降解锌合金等可降解金属或合金材料。优选地，构成所述骨架的所述可降解材料的重均分子量的范围为10 5-10 6Da，分布宽度为1-3。
所述固态干凝胶是一类失水后形成的干凝胶、当再次接触水后能够快速吸水膨胀为体积显著增大的水凝胶，具有良好的生物相容性和组织粘附性。固态干凝胶优选由可降解材料制成，所述可降解材料选自由至少一种脂肪族聚合物和至少一种水溶性聚合物组成的嵌段共聚物或交联共聚物，或者由至少一种双亲性聚合物与至少一种脂肪族聚合物或水溶性聚合物组成的嵌段共聚物或交联共聚物。优选地，所述脂肪族聚合物选自聚乳酸（PLA）或其共聚物或者聚己内酯（PCL）或其共聚物；所述水溶性聚合物选自聚丙烯酸（PAA）或聚乙二醇（PEG）；所述双亲性聚合物选自聚N-异丙基丙烯酰胺（PNIPAAm）或其共聚物。所形成的嵌段共聚物或交联共聚物包括PEG-PLGA-PEG、PLGA-PEG-PLGA、PCLA-PEG-PCLA或Dex-PCL-HEMA等。优选地，构成所述固态干凝胶的可降解材料的重均分子量的范围为10 4-10 6Da。特别地，所述可降解固态干凝胶的降解周期和力学性能可根据聚合物的分子量、聚合物配比等来调控，可控制在6个月左右、在完成内皮化后缓慢发生降解。
特别地，所述固态干凝胶可通过将骨架（包括腰部1）静置在溶胶中，然后通过冻干形成固态凝胶；或者，通过喷涂设备将溶胶喷涂到腰部1上，然后通过溶剂挥发干燥得到固态干凝胶；再或者，先通过喷涂设备将溶胶喷涂到用于制备骨架（包括腰部1）的丝材或者管材上，然后再将所述丝材或者管材制成骨架。
所述骨架包括腰部1，以及与腰部1的至少一端（例如用于动脉导管未闭的封堵装置8为一端设有倒钩）连接起固定封堵装置8作用的近端倒钩2或远端倒钩5。所述骨架可以为网管状镂空结构。例如，采用可降解材料制备的单丝编织成网管结构，根据需要植入的位置取特定长度的网管作为腰部1，腰部1的两端或其中一端的单丝经过热定形得到倒钩。根据需要封堵的病患部位，选择在腰部1的一端或两端设置倒钩，例如，用于治疗动脉导管未闭（PDA）的封堵装置8中通常将倒钩5设置在腰部1的远端。在另外一个实施例中，采用可降解的管状（棒状）材料经过激光切割形成网管状镂空结构（类似于切割支架状）的腰部1，并可以进一步采取热处理、精加工等步骤，在腰部1的两端或一端形成倒钩。所述骨架的腰部1也可以是中空管状物，采用可降解管材制作而成，其外表没有镂空结构。
所述腰部1主要是起连接近端倒钩2或/和远端倒钩5而使封堵装置8贴合缺损部位并保持相对位置的作用，同时也能够为阻流膜3、4和固态干凝胶提供支撑。所述腰部1的结构具有一定的柔韧性，可以满足在遇到形状结构复杂的缺孔时能够适当地弯折以贴壁。
优选地，所述腰部1的长度和缺损部位（例如心脏间隔缺口）的厚度相当，约为3.5~5.5mm，优选4 mm；腰部结构的内径可设计为2-60mm，其大小主要根据缺损部位的尺寸而定，但显著大于心脏间隔缺口的直径，以便于撑开后可以与缺口内壁紧贴，通过制作多种型号的封堵装置来适应不同患者。
所述近端倒钩2和远端倒钩5自与所述腰部的连接处沿所述骨架的径向远离所述腰部延伸，具有至少一个向所述腰部延伸的内弯折结构。具体可设计成不同形状：例如，倒钩只具有一个内弯折结构，可以直接夹持并钩挂在缺损部位组织壁上，体积小、占用空间小；又例如，近端倒钩2和远端倒钩5具有多个内弯折结构，例如包括至少一个半圆弧型弯折结构和至少一个钩型弯折结构，如此倒钩可以夹持在组织壁上，并形成一种类似倒刺结构，有效防止封堵装置8位移。近端倒钩2和远端倒钩5可以通过热定型的方法形成。
请参见图4、图5，在封堵装置8经输送导管10导入并撑开后，近端倒钩2和远端倒钩5能够钩挂在组织壁上以固定封堵装置8。为了让倒钩2、5实现更好的固定效果，保证夹紧达到零位移，可优选采用以下几种处理方案中的一种：方案a：在所述腰部的近端和远端的对称位置的近端倒钩2和远端倒钩5上分别添加有相互吸引的磁极，使两端的倒钩相互吸引，使封堵装置8的固定更加牢固；方案b：在将近端倒钩2和远端倒钩5热处理定形时，对倒钩过压使其具有向内侧的预应力，所述向内侧的预应力是指朝向腰部的中心的预应力，可显著增强夹持固定的效果。
根据缺损部位边缘的情况，可设计数量不等、大小不定的近端倒钩2或远端倒钩5,根据缺损部位边缘距离冠状静脉窦、上腔静脉、下腔静脉、肺静脉以及房室瓣膜的距离不同，倒钩可采用不同分布，如所述倒钩沿着所述腰部1的端面的圆周、半圆周或四分之三圆周均匀或不均匀排布。优选地，倒钩在前述范围内均匀排布。
特别地，缺损部位边缘距离冠状静脉窦、上腔静脉、下腔静脉、肺静脉或房室瓣膜等较近时，可将近端倒钩2或远端倒钩5设计成单侧分布，即倒钩分布在远离静脉或瓣膜的一侧，避免置入、回撤过程中与静脉或瓣膜接触，造成急性反应。
阻流膜固定在腰部的至少一端或倒钩的内侧，可以是固定在腰部的一端或两端，也可以是固定在近端或远端倒钩的内侧。优选地，所述阻流膜通过缝线缝合固定在腰部的至少一端或倒钩的内侧，或者通过热熔或胶结的方式固定在腰部的至少一端或倒钩的内侧。其作用主要是防止血流通过，包括固定在腰部1近端或者近端倒钩2内侧的近端阻流膜3，及固定在腰部1远端或者远端倒钩5内侧的远端阻流膜4。优选地，阻流膜采用可降解材料制备而成，可选择下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸（PLA: Poly-lactide Acid）、聚乙醇酸（PGA: Poly-glycolide）、聚己内酯（PCL: Poly-caprolactone）、聚二氧环己酮（PDO: Poly-dioxanone）、聚氨基酸（PAA：Polyamino acid）。例如，阻流膜可采用聚乳酸-己内酯共聚物、聚乳酸-羟基乙酸共聚物、聚乳酸-己内酯-乙醇酸共聚物等可降解高分子材料。优选地，构成所述阻流膜的可降解材料的重均分子量的范围为10 5-10 6Da，分布宽度为1-3。
为了在植入过程中以及术后准确地定位封堵装置8，可采用多种方式将显影标记物加入或固定到封堵装置8上。在本发明的一个实施例中，采用单丝编织形成骨架的网管形腰部及倒钩时，可将几根显影丝和单丝进行混编后编织成网管状骨架；或者采用缝线将显影材料缝补在合适的封堵装置8的位点上；或者将显影点雕刻在骨架上；又或者可将适量的显影材料与可降解材料共混挤出后制成封堵装置8。以上所有的方案均可实现显影标记物的固定，可用于判断封堵装置8是否在心脏缺损部位准确放置和后期是否发生位移。
上述显影标记物所采用的显影材料可选择非金属物质，如泛影酸、碘化钠、碘海醇、碘克沙醇、碘佛醇、硫酸钡、泛影葡胺、碱式碳酸铋、氧化钛、氧化锆等；也可选择金属物质，如金、铼、铱、钼、钨、铂、铑等。显影材料也可以是生物可降解材料，如铁、金、铼、铱、钼等；也可选择不可生物降解材料，如泛影葡胺、碘普罗胺和碘苯六醇等。
所述封堵装置8的各个组成结构优选均由可降解材料制作而成，具有良好的生物相容性，且所述封堵装置8中的部分组成结构可根据实际需求从多种实施方案中选择合适的方案，进行自由组合搭配，制作成一套完整的封堵装置8。
实施例1
下面以编织网管制作多钩封堵装置8为例，用于封堵中央型房间隔缺损，具体示意图请参阅图1、图2、图3、图4和图5。
本实施例中的封堵装置8包括骨架、阻流膜及显影标记物，其中骨架包括腰部1，以及分别与腰部1的两端连接并起固定封堵装置8作用的近端倒钩2和远端倒钩5。
本实施例中,采用单丝编织成网管形的腰部1，所述单丝的端部预留在所述腰部1的两端，用以制作倒钩2、5。采用可降解材料制成的显影丝作为显影标记物，将几根显影丝以腰部1的轴为中心对称放置与可降解丝进行混编，显影丝可用于判断封堵装置8是否在心脏缺损部位准确放置和后期是否发生位移。
制作腰部1和倒钩2、5的单丝可以采用可降解高分子材料，通过拉伸、编织、热定形等方法得到，本实施例中，采用左旋聚乳酸（PLLA）单丝编织成网管结构。所述网管结构的长度约4 mm作为腰部1（通常情况下中央型房间隔缺损的缺损部位壁厚约为4mm），所述腰部1的两端预留出的单丝通过热定形、精加工等方式得到倒钩结构，可以采用两根单丝或多根单丝制作成一个倒钩，相对于所述腰部1的位置分为近端倒钩2和远端倒钩5，所述倒钩2、5自与腰部1的连接处沿所述封堵装置8的径向远离所述腰部1延伸，并且通过向内（即向腰部方向）弯折过压而具有向内侧的预应力，封堵使用时，所述倒钩2、5撑开后夹持在组织壁上，并钩挂在组织壁内，稳定牢固，确保封堵装置8零位移。
完成骨架结构制作后，将固态干凝胶涂覆于腰部1，包括：将骨架静置在溶胶中，然后通过冻干形成载有固态干凝胶的骨架；或者，通过喷涂设备将溶胶喷涂到腰部1上，然后通过溶剂挥发干燥得到载有固态干凝胶的骨架。所述溶胶选用液态的可降解材料，优选为由至少一种脂肪族聚合物和至少一种水溶性聚合物组成的嵌段共聚物或交联共聚物，或者由至少一种双亲性聚合物与至少一种脂肪族聚合物或水溶性聚合物组成的嵌段共聚物或交联共聚物，例如PLA嵌段共聚物（例如，PLA Pluronic® F127），又例如PEG-PLGA-PEG、PLGA-PEG-PLGA、PCLA-PEG-PCLA或Dex-PCL-HEMA等。所述溶胶优选采用重均分子量为10 4-10 6Da的上述可降解材料。
阻流膜包括位于骨架近端的近端阻流膜3和位于骨架远端的远端阻流膜4，并分别固定在腰部1的两端或倒钩2、5的内侧。本实施例中采用可降解缝合线将阻流膜缝合固定在腰部1的两端，以确保阻流膜能够封堵严密。
将固态干凝胶涂覆于腰部1与固定阻流膜3、4这两个步骤的顺序可以前后互换，并且，根据不同的固态干凝胶的涂覆位置或阻流膜的固定位置，这个两个步骤也可以在制作骨架的腰部1的步骤之前或者之后进行，或者制作倒钩2、5的步骤之前或者之后进行，本发明对此不作限制。此外，固态干凝胶不限于仅涂覆在腰部1，也可以额外涂覆于倒钩2、5上或阻流膜3、4上。
在完成以上实施例中的封堵装置8的制作后，通过导管输送并置入封堵装置8对心脏组织的缺损部位进行封堵，具体参见图4和图5。首先，将封堵装置8压握在输送导管10中，并输送至心脏的缺损部位后，由输送导管10中先推出远端倒钩5，远端倒钩5撑开并钩挂在远端的缺孔组织壁9上，如图5所示，然后回撤输送导管10，推出腰部1以及近端倒钩2，近端倒钩2撑开并钩挂在近端的缺孔组织壁9上，由于封堵装置8的腰部1在释放状态下的内径远大于缺损空腔11的内径，从而腰部1会被挤压而紧贴在缺损空腔11的缺孔组织壁9上，封堵装置8导入完毕。同时，在置入封堵装置8的过程中，骨架上的干凝胶与血液接触后吸水，会发生初步溶胀形成水凝胶，待封堵装置8完成导入后，吸水后的水凝胶逐步膨胀填满缺损空腔11。完成封堵。
综上，本发明的封堵装置与现有技术相比，具有以下效果和优势：
1）本发明的封堵装置的骨架包括腰部和与腰部连接的倒钩，设计上摒弃了现有技术中的封堵器采用的巨大的双盘状结构，取而代之的是结构小巧的倒钩结构，实现封堵装置在缺损部位的固定。所述倒钩的结构稳定性好，不易发生回弹变形，可以很好地固定骨架的位置，避免发生位移。而腰部涂覆的固态干凝胶在接触血液膨胀后与组织壁粘结，为后期封堵装置不发生位移提供了更强有力的保障。同时，由于显著减少了在缺损组织壁两侧所需的用于锚定封堵装置的空间，本发明的封堵装置可以更广泛应用于缺孔部位距离冠状静脉窦、上腔静脉、下腔静脉、肺静脉以及房室瓣膜等较近的患者，拓宽了微创伤介入治疗心脏间隔缺损的应用范围。
2）本发明的封堵装置与现有技术中采用巨大的双盘状结构的封堵器相比，显著缩小了外径和整体的体积，从而可以采用直径更小的输送导管来输送封堵装置，这样可以减少在输送过程中对血管壁造成的损伤，降低血管炎症；另外，直径更小的输送导管可以应用于年纪更小的心脏间隔缺损患病人群，进一步拓宽了微创伤介入治疗心脏间隔缺损的应用范围。
3）本发明的封堵装置与现有技术中采用巨大的双盘状结构的封堵器相比，可以节省约50%的骨架材料用量，大大节约了成本。
4）根据本发明的优选实施例，封堵装置采用柔韧性更好的可降解材料，包括聚己内酯（PCL）、聚乙醇酸（PGA）、聚乳酸（PLA）、聚二氧环己酮（PDO）、聚氨基酸（PAA）或前述的共聚物和/或共混物或者可降解锌合金、可降解镁合金等制作而成的骨架，以及聚己内酯（PCL）、聚乙醇酸（PGA）、聚乳酸（PLA）、聚二氧环己酮（PDO）、聚氨基酸（PAA）或前述的共聚物和/或共混物制作而成的阻流膜，具有较好的形变能力，可以在缺损部位复杂、左右缺口不齐的情况下，通过固态干凝胶接触血液后膨胀能够填充不规则形状的组织缺损，到达有效封堵的效果，从而可以将微创伤介入治疗应用于缺口复杂的患者。5）根据本发明的优选实施例，封堵装置可全部采用可降解材料制作完成，包括可降解的骨架和阻流膜材料以及可降解的固态干凝胶材料，在缺损部位完成内皮化后，封堵装置会逐步降解消失，显著提高了其用于人体的安全性；此外，由于本发明的封堵装置体积小、用料少，在封堵装置的降解过程中产生的降解产物量也大大降低，从而降低了相关并发症的发生率。
6）现有的可降解封堵器大多需要复杂的锁件结构，制作工艺复杂，而本发明的封堵装置结构简单，制作工艺简便，封堵性能优异。
虽然本发明已以较佳实施例揭示如上，然其并非用以限定本发明，任何本领域技术人员，在不脱离本发明的精神和范围内，当可作些许的修改和完善，因此本发明的保护范围当以权利要求书所界定的为准。
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Claims (18)

  1. 一种封堵装置，包括骨架和阻流膜，其特征在于，所述骨架包括腰部和与所述腰部的至少一端连接的倒钩，所述腰部涂覆有固态干凝胶，所述阻流膜固定在所述腰部的至少一端和/或所述倒钩的内侧。
  2. 如权利要求1所述的封堵装置，其特征在于，所述固态干凝胶由可降解材料制成。
  3. 如权利要求2所述的封堵装置，其特征在于，制成所述固态干凝胶的可降解材料选自由至少一种脂肪族聚合物与至少一种水溶性聚合物组成的嵌段共聚物或交联共聚物，或者由至少一种双亲性聚合物与至少一种脂肪族聚合物或水溶性聚合物组成的嵌段共聚物或交联共聚物。
  4. 如权利要求3所述的封堵装置，其特征在于，所述脂肪族聚合物选自聚乳酸或其共聚物或者聚己内酯或其共聚物；所述水溶性聚合物选自聚丙烯酸或聚乙二醇；所述双亲性聚合物选自聚N-异丙基丙烯酰胺或其共聚物。
  5. 如权利要求3所述的封堵装置，其特征在于，制成所述固态干凝胶的可降解材料的重均分子量的范围为10 4-10 6Da。
  6. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述骨架和/或所述阻流膜由可降解材料制成。
  7. 如权利要求6所述的封堵装置，其特征在于，所述骨架选自可降解镁合金、可降解锌合金或者下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸、聚乙醇酸、聚己内酯、聚二氧环己酮、聚氨基酸；所述阻流膜选自下述材料中的一种或者多种的共聚物和/或共混物：聚乳酸、聚乙醇酸、聚己内酯、聚二氧环己酮、聚氨基酸。
  8. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述腰部为网管状镂空结构或者中空管状结构。
  9. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述腰部的轴向长度的范围为3.5mm～5.5mm；所述腰部的内径的范围为2～60mm。
  10. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述倒钩自与所述腰部的连接处沿所述骨架的径向远离所述腰部延伸，且具有至少一个向所述腰部延伸的内弯折结构。
  11. 如利要求10所述的封堵装置，其特征在于，所述倒钩具有多个内弯折结构，包括至少一个半圆弧型弯折结构和/或至少一个钩型弯折结构。
  12. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述倒钩沿着所述腰部的端面的圆周、半圆周或四分之三圆周均匀或不均匀排布。
  13. 如权利要求1-5任一项所述的封堵装置，其特征在于，所述腰部的两端均设置有倒钩，在所述腰部的近端和远端的对称位置的倒钩上分别设置有相互吸引的磁极。
  14. 一种如权利要求1-13任一项所述的封堵装置的制备方法，其特征在于，包括如下步骤：
    通过丝材编织或者管材激光切割形成所述骨架的所述腰部；
    通过热定型在所述腰部的至少一端形成所述倒钩；
    在所述腰部的至少一端和/或所述倒钩的内侧固定阻流膜；
    将固态干凝胶涂覆于所述腰部。
  15. 如权利要求14所述的制备方法，其特征在于，所述腰部通过丝材编织形成，所述倒钩通过将所述腰部的两端预留出的丝材热定型形成。
  16. 如权利要求15所述的制备方法，其特征在于，所述热定型包括：将所述丝材向靠近所述腰部的方向弯折过压使所述倒钩具有向内侧的预应力。
  17. 如权利要求14所述的制备方法，其特征在于，将固态干凝胶涂覆于所述腰部包括：将所述腰部静置在溶胶中，然后通过冻干在所述腰部形成固态干凝胶；或者将溶胶喷涂到所述腰部上，然后通过溶剂挥发干燥得到；或者将溶胶喷涂到丝材或者管材上，然后通过溶剂挥发干燥得到用于形成所述腰部的所述丝材或者所述管材。
  18. 如权利要求14所述的制备方法，其特征在于，所述阻流膜通过缝合、热熔或者胶结固定在所述腰部的至少一端和/或所述倒钩的内侧。
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