WO2017041554A1 - 可吸收封堵器 - Google Patents

可吸收封堵器 Download PDF

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Publication number
WO2017041554A1
WO2017041554A1 PCT/CN2016/085020 CN2016085020W WO2017041554A1 WO 2017041554 A1 WO2017041554 A1 WO 2017041554A1 CN 2016085020 W CN2016085020 W CN 2016085020W WO 2017041554 A1 WO2017041554 A1 WO 2017041554A1
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WO
WIPO (PCT)
Prior art keywords
occluder
polymer
degradation
absorbable
woven mesh
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PCT/CN2016/085020
Other languages
English (en)
French (fr)
Inventor
张德元
向冬
陈贤淼
Original Assignee
先健科技(深圳)有限公司
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Publication date
Application filed by 先健科技(深圳)有限公司 filed Critical 先健科技(深圳)有限公司
Priority to EP16843492.6A priority Critical patent/EP3348205B1/en
Priority to US15/741,679 priority patent/US10799245B2/en
Publication of WO2017041554A1 publication Critical patent/WO2017041554A1/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
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12122—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder within the heart
    • 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
    • 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
    • A61L31/041—Mixtures of macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12027—Type of occlusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12027—Type of occlusion
    • A61B17/12031—Type of occlusion complete occlusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12099—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder
    • A61B17/12109—Occluding by internal devices, e.g. balloons or releasable wires characterised by the location of the occluder in a blood vessel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/1214—Coils or wires
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/12—Surgical instruments, devices or methods, e.g. tourniquets for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels, umbilical cord
    • A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
    • A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
    • A61B17/12168—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device having a mesh structure
    • A61B17/12177—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device having a mesh structure comprising additional materials, e.g. thrombogenic, having filaments, having fibers or being coated
    • 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
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • 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
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/148—Materials at least partially resorbable by the body
    • 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 or resorptive
    • 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
    • A61B2017/00606—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
    • A61B2017/00628—T-shaped occluders
    • 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
    • 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
    • A61L2400/00—Materials characterised by their function or physical properties

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 absorbable polymer occluder primarily comprises a woven mesh and a flow blocking film sewn into the woven mesh.
  • the material constituting the woven mesh is usually a polymer material, and the woven mesh generally degrades rapidly in a certain period of time during the degradation process, and releases a large amount of degradation products beyond the content absorbed by the tissue, resulting in severe inflammation. reaction.
  • the technical problem solved by the present invention is to provide an absorbable polymer occluder which avoids dense release of polymer degradation products during a concentrated degradation period and causes a serious inflammatory reaction.
  • the first technical solution adopted by the present invention is: an absorbable occluder comprising a woven mesh, the woven mesh comprising at least two kinds of polymer filaments, the at least two polymer filaments having different concentrated degradation time periods.
  • a second technical solution adopted by the present invention is: an absorbable occluder comprising a woven mesh, the woven mesh comprising a polymer filament comprising at least two types of different concentrated degradation periods polymer.
  • a polymer filament comprising at least two types of different concentrated degradation periods polymer.
  • at least a portion of one such polymer filament may be made from a blend of the at least two polymers having different degradation periods; or a portion thereof may be from the at least two polymers.
  • One portion is made of the other of the at least two polymers, that is, different portions of one polymer filament are made of a polymer having different concentrated degradation periods.
  • the woven mesh comprises 20 to 200 polymer filaments.
  • the polymer fiber material is selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), and polyhydroxy fatty acid ester. (PHA), polydioxanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane or polycarbonate, or at least two of the above polymer monomers Copolymer.
  • the polymer filament has a wire diameter ranging from 0.05 mm to 0.50 mm.
  • the polymer filament material has a weight average molecular weight ranging from 20,000 Da to 800,000 Da.
  • the polymer yarn material has a polydispersity coefficient of 1.2 to 5.
  • the polymer yarn material has a crystallinity ranging from 0% to 80%.
  • the occluder further comprises 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), and polyglycolic acid.
  • PET polyethylene terephthalate
  • PE polyethylene
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO polydioxanone
  • PCL polycaprolactone
  • polyamide polyanhydride
  • polyphosphoric acid a copolymer of at least two of an ester, a polyurethane, or a polycarbonate, or a monomer of the above polymer.
  • 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), polydioxanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane or polycarbonate, or at least two of the above polymer monomers Copolymer.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO polydioxanone
  • PCL polycaprolactone
  • the occluder further includes a locking member, 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 double disc distance of the occluder that is, the waist height is fixed.
  • the locking 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), at least one of polydioxanone (PDO), polycaprolactone (PCL), polyamide, polyanhydride, polyphosphate, polyurethane, polycarbonate, or a monomer of the above polymer At least two copolymers.
  • PLA polylactic acid
  • PGA polyglycolic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • PHA polyhydroxy fatty acid ester
  • PDO polydioxanone
  • PCL polycaprolactone
  • polyamide polyanhydride
  • polyphosphate polyphosphate
  • polyurethane polyurethane
  • polycarbonate or a monomer of the above polymer At least two copolymers.
  • the polymer yarn of the woven mesh of the present invention comprises a high blend of at least two polymers having different concentrated degradation periods.
  • the different polymers included in the present invention are concentrated and degraded in different time periods, thereby avoiding the concentrated degradation of the prior art occluder in a certain period of time during in vivo service, resulting in a serious tissue inflammatory 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 of an occluder according to an embodiment of the present invention.
  • Fig. 3 is a schematic view showing the knitting of the occluder woven net made in the first embodiment of the present invention.
  • Figure 4 is a graph showing the in vitro degradation tendency of two polymer filaments in Example 1 at 37 °C.
  • Figure 5 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Example 1 after implantation of the porcine heart for 2 years.
  • Fig. 6 is a graph showing the in vitro degradation tendency of two polymer filaments in Example 2 at 37 °C.
  • Figure 7 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.
  • Fig. 8 is a graph showing the in vitro degradation tendency of two polymer filaments in Example 3 at 37 °C.
  • Figure 9 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 10 is a graph showing the in vitro degradation tendency of three polymer monofilaments in Example 4 at 37 °C.
  • Figure 11 is a pathological view of the occluder and peripheral myocardial tissue after implantation of the occluder of Example 4 for 2 years.
  • Figure 12 is a graph showing the in vitro degradation tendency of two polymer filaments in Example 5 at 37 °C.
  • Figure 13 is a pathological view of the occluder and peripheral myocardial tissue after implantation of the occluder of Example 5 for 2 years.
  • Figure 14 is a graph showing the in vitro degradation tendency of the blended polymer filaments in Example 6 at 37 °C.
  • Figure 15 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Example 6 after implantation into the porcine heart for 2 years.
  • Figure 16 is a graph showing the in vitro degradation tendency of a single polymer filament in Comparative Example 1 at 37 °C.
  • Figure 17 is a pathological view of the occluder and peripheral myocardial tissue of the occluder of Comparative Example 1 after 2 years of implantation into the porcine heart.
  • 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.
  • a plurality of polymer filaments are divided into a first braided group 111 and a second braided group 112, a plurality of polymer filaments in the first braided group 111, and a plurality of polymer filaments in the second braided group 112.
  • the two braided groups are automatically alternately woven into a well-shaped mesh on the cylindrical mold bar to form a tubular structure, and all the polymer wires at the proximal end of the tubular structure are tightened in the sleeve and melt welded into the plug head 140, far away. All the polymer wires are tightly fixed in the sleeve and melt welded into the head 150 to obtain the network tube as shown in FIG. 3; the network tube structure is heat-set in the mold, and after cooling, the double-disc woven mesh 110 is obtained; A suture 130 made of a polymer sutures the barrier film 120 made of a degradable polymer onto the woven mesh 110.
  • the woven mesh 110 includes a plurality of first woven groups 111 and second woven groups 112 made of a polymer material.
  • 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.
  • 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 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.
  • PDO dioxetane
  • PCL polycaprolactone
  • polyamide polyanhydride
  • polyphosphate polyphosphate
  • polyurethane polyurethane
  • polycarbonate or monomers of at least two of the above polymers Things.
  • 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 present invention defines that the ratio of the residual mass of the polymer to the initial mass during polymer degradation is the mass retention of the polymer.
  • 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 is decreased by 5% or more every two months, it is considered that the polymer is concentratedly degraded within the two months; if the mass retention rate is less than 5%, it is referred to as a gentle degradation of the polymer.
  • the total time period during which the polymer is concentrated and degraded is referred to as the concentrated degradation period of the polymer, and the reduced quality during the degradation of the polymer is regarded as the release amount of the degradation product.
  • the different polymer filaments are immersed in a phosphate buffered saline solution at 37 ° C. In vitro degradation experiments were performed.
  • 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 quality of the occluder woven mesh is 0.726 g.
  • the first weave group consisted of 36 mutually arranged poly-L-lactic acid (PLLA) wires having a diameter of 0.50 mm and 36 PLLA wires having a diameter of 0.15 mm arranged in parallel with each other.
  • the PLLA filament in the first braided group has a molecular weight of 100,000 Da, a molecular weight distribution coefficient of 1.50, and a crystallinity of 48%.
  • the PLLA filament in the second braided group has a molecular weight of 100,000 Da, a molecular weight distribution coefficient of 1.49, and a crystallinity of 49%.
  • the in vitro degradation experiments of the two wires were carried out. After 6 months of degradation, the elastic moduli of the two wires were 3.89 GPa and 3.08 GPa, respectively, and the elongation at break were 72% and 63%, respectively.
  • the occluder made of polymer silk can ensure a stable frame structure within 6 months of implantation, and the endothelium can be completely covered; the change rate of the mass retention rate of the two wires with time is shown in Fig. 4 respectively.
  • the complete degradation time of the PLLA wire with a wire diameter of 0.50 mm is 4 to 5 years, and the degradation time period is from 20 months to 38 months, and the PLLA filament degradation cycle with a wire diameter of 0.15 mm.
  • the concentrated degradation time period is from June to October.
  • the two kinds of filaments are concentrated and degraded in completely different time periods, so that the degradation products can be prevented from being densely released at the same time period; after the occluder of the embodiment is implanted into the heart of the pig for 2 years, the occluder and the peripheral myocardial tissue are performed.
  • Pathological section analysis the pathological map shown in Figure 5, no significant inflammation and foreign body reaction.
  • the first braided group comprises 48 polyhydroxyalkanoate (PHA) filaments having a molecular weight of 800,000 Da
  • the second braided group comprises 48 polycaprolactones (PCL) having a molecular weight of 100,000 Da. wire.
  • the PHA filament of the first braided group has a molecular weight distribution coefficient of 4.80, a wire diameter of 0.05 mm, and a crystallinity of 30%
  • the PCL filament of the second braided group has a molecular weight distribution coefficient of 1.90, a wire diameter of 0.15 mm, and a crystallinity of 50. %.
  • the in vitro degradation experiments were carried out on the two filaments.
  • the elastic moduli of the two filaments were 4.39 GPa and 3.28 GPa, respectively, and the elongation at break were 84% and 65%, respectively.
  • the occluder made of polymer silk has a stable frame structure within 6 months of implantation, and the endothelial climbing can be completed completely; the change rate of the mass retention rate of the two wires with time is shown in curve 1 of Fig. 6, respectively. 2, the degradation cycle of PHA silk is 4 to 5 years, the period of concentrated degradation is from 18 months to 38 months, the degradation period of PCL silk is 2 to 3 years, and the period of concentrated degradation is from June to October.
  • the two filaments are concentrated and degraded in different time periods, so that the degradation products can be prevented from being densely released at the same time.
  • the occluder of this embodiment was implanted into the heart of the pig for 2 years, the occluder and peripheral myocardial tissue were analyzed by pathological section. The pathological map is shown in Fig. 7, and there is no obvious inflammation and foreign body reaction.
  • the first knitting group includes 10 PLLA wires having a crystallinity of 80%
  • the second knitting group includes 10 PLGA wires having a crystallinity of 20%.
  • the first weave group and the second weave group had a wire diameter of 0.25 mm, and molecular weight and molecular weight distribution coefficients of 200,000 Da and 1.69, respectively.
  • the in vitro degradation experiments of the two wires were carried out. After 6 months of degradation, the elastic moduli of the two wires were 3.56 GPa and 2.65 GPa, respectively, and the elongation at break were 76% and 60%, respectively.
  • the occluder made of polymer silk has a stable frame structure within 6 months of implantation, and the endothelium can be completely covered; the change rate of the mass retention rate of the two wires with time is shown in curve 1 of Fig. 8, respectively.
  • the complete degradation time of the PLLA filament is 4 to 5 years, and the concentrated degradation time period is from the 20th to the 34th month.
  • the complete degradation time of PLGA silk is 2 to 3 years, and the concentrated degradation time period is from August to 22nd.
  • the two filaments are concentrated and degraded in different time periods, so that the degradation products can be prevented from being released intensively at the same time.
  • the first braided group comprises 96 poly-L-lactic acid (PLLA) filaments
  • the second braided group comprises 48 poly-polylactic acid (PDLLA) filaments and 48 polylactic acid-glycolic acid copolymers.
  • PLGA silk.
  • the PLLA filament has a molecular weight of 300,000 Da, a molecular weight distribution coefficient of 1.60, a wire diameter of 0.15 mm, a crystallinity of 50%, a PDLLA amorphous polymer, a molecular weight of 200,000 Da, a molecular weight distribution coefficient of 1.80, and a wire diameter of 0.15 mm.
  • amorphous polymer having a molecular weight of 20,000 Da, a molecular weight distribution coefficient of 1.80, and a wire diameter of 0.15 mm.
  • the in vitro degradation experiments were carried out on the three kinds of filaments. After 6 months of degradation, the elastic modulus of PLLA, PDLLA and PLGA filaments were 4.20 GPa, 3.14 GPa and 1.16 GPa, respectively, and the elongation at break was 80% and 55, respectively.
  • the complete degradation time of PLLA filament is 4 ⁇ 5 years, and the concentrated degradation time period is 18th to 36th.
  • the complete degradation time of PDLLA silk is 2 ⁇ 3 years, and the concentrated degradation time period is from October to 22nd.
  • the complete degradation time of PLGA silk is 1 ⁇ 2 years, and the concentrated degradation time period is from June to July.
  • the three kinds of filaments are concentrated and degraded in different time periods, so that the dense release of degradation products of the occluder in the same period of time can be avoided.
  • the first weave group comprises 48 hydrophilically treated PLLA wires
  • the second weave group comprises 56 surface untreated PLLA wires.
  • the PLLA filaments in both braided groups have a molecular weight of 300,000 Da, a molecular weight distribution coefficient of 1.60, a wire diameter of 0.15 mm, and a crystallinity of 50%.
  • PLLA filaments with hydrophilic surface treatment are more likely to degrade after contact with water, while PLLA filaments without hydrophilic treatment have a relatively slow degradation rate.
  • the in vitro degradation experiments were carried out on the two filaments.
  • the elastic moduli of the two filaments were 4.20 GPa and 2.97 GPa, respectively, and the elongation at break were 80% and 58%, respectively.
  • the occluder made of polymer silk has a stable frame structure within 6 months of implantation, and the endothelial climbing can be completed completely; the change rate of the mass retention rate of the two wires with time is shown in curve 1 of Fig. 12, respectively. 2, the non-hydrophilic polymer filament degradation time is 4 to 5 years, the concentrated degradation period is from 18 months to 36 months, and the surface treated with hydrophilic treatment has a degradation time of 2 to 3 years. The concentrated degradation time period is from June to October.
  • the two filaments are concentrated and degraded in different time periods, so that the intensive release of the degradation products of the occluder during the same period of time can be avoided.
  • the occluder provided in this embodiment comprises 92 braided yarns obtained by melt-blending and blending PLLA particles and PLGA particles at a mass ratio of 1:1, and the wire diameter is 0.15 mm.
  • the PLLA particles selected therein have a weight average molecular weight of 500,000 Da, a molecular weight distribution coefficient of 1.60, and a crystallinity of 50%.
  • the amorphous polymer PLGA particles selected had a weight average molecular weight of 200,000 Da and a molecular weight distribution coefficient of 2.70.
  • the elastic modulus of the mixed yarn was 3.21 GPa and the elongation at break was 67%, indicating that the occluder made of the mixed yarn of the present embodiment has a stable frame structure within 6 months of implantation.
  • the endothelium can be completely covered; the change rate of the mass retention rate of the mixed silk with time is shown in Fig. 14.
  • the degradation time of the mixed filament polymer filament is 4 to 5 years, and the mixed filament is in the 8th month of the degradation cycle. It is gently degraded within 52 months, which can avoid the dense release of degradation products in the same period of time during the service of the occluder.
  • the occluder of the present embodiment was implanted into the heart of the pig for 2 years, the occluder and the surrounding myocardial tissue were subjected to pathological section analysis, and the pathological map thereof is shown in Fig. 15, and there was no obvious inflammation and foreign body reaction.
  • the occluder provided by the present comparative example has an overall mass of 0.726 g, including 96 PLLA wires having a diameter of 0.15 mm, wherein 48 pieces are arranged in parallel to each other to form a first weave group, and 48 pieces are arranged in parallel with each other. Second weave group.
  • the PLLA filament has a molecular weight of 100,000 Da, a molecular weight distribution coefficient of 1.49, and a crystallinity of 49%.
  • the in vitro degradation test of PLLA filaments showed that the elastic modulus of PLLA filaments was 3.08 GPa and the elongation at break was 63% after 6 months of degradation, indicating that the occluder made in this comparative example was implanted for 6 months.
  • the internal frame has a stable frame structure, and the endothelium can be completely covered.
  • the change rate of the mass retention rate of the polymer filament with time is shown in Fig. 16.
  • the degradation period of the polymer filament is 2 to 3 years, and the polymer filament is in the first From June to December, the degradation is concentrated, and the degradation products are densely released during this period.
  • the occluder of this comparative example was implanted into the heart of the pig for 2 years, the occluder and peripheral myocardial tissue were analyzed by pathological section.
  • the pathological map is shown in Figure 17, and the occluder was implanted for 2 years after inflammation and foreign body. The reaction is more serious.
  • Example 1 The experimental results of Examples 1, 6 and Comparative Example 1 show that the polymer yarn prepared by blending at least two polymers having different concentrated degradation periods or at least two polymers having different concentrated degradation periods are used.
  • the silk braided occluder woven mesh on the basis of ensuring a stable frame structure in the early stage of implantation (6 months), the polymer constituting the polymer filament releases the degradation products in different concentrated degradation time periods, thereby avoiding sealing
  • the plug release densely releases degradation products during the same period of service during service, resulting in a serious inflammatory response.

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Abstract

一种可吸收封堵器（100），包括编织网（110），编织网（110）包括至少两种具有不同集中降解时间段的高分子丝，或包括一种由至少两种具有不同集中降解时间段的聚合物共混制成的高分子丝。可吸收封堵器（100）可以避免组成编织网（110）的高分子丝在同一时间段内集中降解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。可吸收聚合物封堵器主要包括编织网和缝合于编织网内的阻流膜。目前，组成编织网的材料通常为一种聚合物材料，该种编织网在降解过程中整体会在某个时间段降解较快，大量释放降解产物，超出组织能吸收的含量，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集中降解时间段内密集释放而导致严重的炎症反应。
本发明采用的第一种技术方案为：一种可吸收封堵器，包括编织网，所述编织网包括至少两种高分子丝，该至少两种高分子丝具有不同集中降解时间段。
本发明采用的第二种技术方案是：一种可吸收封堵器，包括编织网，所述编织网包括一种高分子丝，该种高分子丝包括至少两种具有不同集中降解时间段的聚合物。举例而言，一根该种高分子丝的至少部分可以是由所述至少两种具有不同降解时间段的聚合物的共混物制成；也可以是其中一部分由该至少两种聚合物中的一种制成，另一部分由该至少两种聚合物中的其他种制成，即一根高分子丝的不同部分由具有不同集中降解时间段的聚合物制成。
对于前述任一技术方案，在其中一个实施例中，所述编织网包括20~200根高分子丝。
对于前述任一技术方案，在其中一个实施例中，所述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，或上述聚合物单体中的至少两种的共聚物。
对于前述任一技术方案，在其中一个实施例中，所述高分子丝的丝径范围为0.05mm~0.50mm。
对于前述任一技术方案，在其中一个实施例中，所述高分子丝材料重均分子量范围为20,000Da~800,000Da。
对于前述任一技术方案，在其中一个实施例中，所述高分子丝材料多分散系数为1.2~5。
对于前述任一技术方案，在其中一个实施例中，所述高分子丝材料结晶度范围为0%~80%。
对于前述任一技术方案，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。
对于前述任一技术方案，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，或上述聚合物的单体中的至少两种的共聚物。
对于前述任一技术方案，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。
对于前述任一技术方案，在其中一个实施例中，所述封堵器还包括锁定件，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。
对于前述任一技术方案，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、聚碳酸酯中的至少一种，或上述聚合物的单体中至少两种的共聚物。
与现有技术相比，对于采用相同质量的高分子丝制作的封堵器，本发明的编织网的高分子丝包括由至少两种具有不同集中降解时间段的聚合物共混制成的高分子丝或包括至少两种具有不同集中降解时间段的高分子丝。本发明包括的不同聚合物在不同的时间段集中降解，从而避免了现有技术的封堵器在体内服役过程中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主视图。
图3为本发明实施例1制作的封堵器编织网的编织示意图。
图4为37℃条件下实施例1中两种高分子丝的体外降解趋势图。
图5为实施例1的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图6为37℃条件下实施例2中两种高分子丝体外降解趋势图。
图7为实施例2的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图8为37℃条件下实施例3中两种高分子丝体外降解趋势图。
图9为实施例3的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图10为37℃条件下实施例4中三种高分子单丝体外降解趋势图。
图11为实施例4的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图12为37℃条件下实施例5中两种高分子丝体外降解趋势图。
图13为实施例5的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图14为37℃条件下实施例6中共混高分子丝体外降解趋势图。
图15为实施例6的封堵器植入猪心脏2年后封堵器和周边心肌组织的病理图。
图16为37℃条件下对比例1中单一高分子丝体外降解趋势图。
图17为对比例1的封堵器植入猪心脏2年后封堵器和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、设于编织网110内且缝合在编织网110上的阻流膜120、以及锁定件160。如图2所示，将多根高分子丝分成第一编织组111和第二编织组112，第一编织组111内的多根高分子丝和第二编织组112内的多根高分子丝皆相互平行排列，该两编织组在圆柱形模棒上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3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。也就是说，编织网110包括多根由高分子材料制成的第一编织组111和第二编织组112。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、聚碳酸酯中的至少一种，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，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。聚合物集中降解的总时间段称为该聚合物的集中降解时间段，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，封堵器编织网整体质量为0.726g。第一编织组包括36根相互排列的直径为0.50mm的聚左旋乳酸（PLLA）丝和36根相互平行排列的直径为0.15mm的PLLA丝。其中第一编织组中PLLA丝分子量为100,000Da，分子量分布系数为1.50，结晶度为48%；第二编织组中PLLA丝的分子量为100,000Da，分子量分布系数为1.49，结晶度为49%。对两种丝进行体外降解实验，经6个月降解后测得两种丝的弹性模量分别为3.89GPa和3.08GPa，断裂伸长率分别为72%和63%，这说明本实施例两种高分子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，可以实现内皮爬覆完全；两种丝的质量保留率随时间延长的变化趋势分别如图4中曲线1，2所示，丝径为0.50mm的PLLA丝完全降解时间即降解周期为4~5年，集中降解时间段为第20月到~第38月，丝径为0.15mm的PLLA丝降解周期为2~3年，集中降解时间段为第6月~第20月。两种丝在完全不同的时间段集中降解，从而可以避免降解产物在同一时间段密集释放；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2
本实施例提供的封堵器中，第一编织组包括48根分子量为800,000Da的聚羟基脂肪酸脂(PHA)丝，第二编织组包括48根分子量为100,000Da的聚己内酯(PCL)丝。第一编织组的PHA丝的分子量分布系数为4.80，丝径为0.05mm，结晶度为30%；第二编织组的PCL丝的分子量分布系数为1.90，丝径为0.15mm，结晶度为50%。对两种丝进行体外降解实验，经6个月降解后测得两种丝的弹性模量分别为4.39GPa和3.28GPa，断裂伸长率分别为84%和65%，这说明本实施例两种高分子丝制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；两种丝的质量保留率随时间延长的变化趋势分别如图6中曲线1，2所示，PHA丝降解周期为4～5年，集中降解时间段为第18月~第38月，PCL丝降解周期为2～3年，集中降解时间段为第6月~第20月，两种丝在不同时间段内集中降解，从而可以避免降解产物在同一时间段密集释放。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7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，第一编织组包括10根结晶度为80%的PLLA丝，第二编织组包括10根丝结晶度为20%的PLGA丝。第一编织组和第二编织组的丝径均为0.25mm、分子量和分子量分布系数分别为200,000Da和1.69。对两种丝进行体外降解实验，经6个月降解后测得两种丝的弹性模量分别为3.56GPa和2.65GPa，断裂伸长率分别为76%和60%，这说明本实施例两种高分子丝制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；两种丝的质量保留率随时间延长的变化趋势分别如图8中曲线1，2所示，PLLA丝完全降解时间为4～5年，集中降解时间段为第20月~第34月。PLGA丝完全降解时间为2～3年，集中降解时间段为第8月~第22月，两种丝在不同时间段内集中降解，从而可以避免降解产物在同一时间段密集释放。将采用本实施例的两种高分子丝制作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9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，第一编织组包括96根聚左旋乳酸(PLLA)丝，第二编织组包括48根聚消旋乳酸（PDLLA）丝和48根聚乳酸-羟基乙酸共聚物(PLGA)丝。PLLA丝分子量为300,000Da，分子量分布系数为1.60，丝径为0.15mm，结晶度为50%，PDLLA为非结晶聚合物，分子量为200,000Da，分子量分布系数为1.80，丝径为0.15mm，PLGA为非结晶型聚合物，分子量为20,000Da，分子量分布系数为1.80，丝径为0.15mm。对三种丝进行体外降解实验，经6个月降解后测得PLLA丝、PDLLA丝、PLGA丝的弹性模量分别为4.20GPa、3.14GPa和1.16GPa，断裂伸长率分别为80%、55%，和39%，这说明本实施例三种高分子丝制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；三种高分子丝的质量保留率随时间延长的变化趋势分别如图10中曲线1，2，3所示，PLLA丝完全降解时间为4~5年，集中降解时间段为第18月~第36月， PDLLA丝完全降解时间为2~3年，集中降解时间段为第10月~第22月。PLGA丝完全降解时间为1~2年，集中降解时间段为第6月~第14月。三种丝在不同时间段内集中降解，从而可以避免封堵器在同一时间段内降解产物密集释放。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11所示，无明显炎症和异物反应。
实施例5
本实施例提供的封堵器中，第一编织组包括48根表面经过亲水处理的PLLA丝，第二编织组包括56根表面未处理的PLLA丝。两编织组中的PLLA丝分子量均为300,000Da，分子量分布系数为1.60，丝径为0.15mm，结晶度为50%。其中，表面经亲水处理的PLLA丝，与水接触后更容易发生降解，而未经亲水处理的PLLA丝，降解速率相对较慢。对两种丝进行体外降解实验，经6个月降解后测得两种丝的弹性模量分别为4.20GPa和2.97GPa，断裂伸长率分别为80%和58%，这说明本实施例两种高分子丝制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；两种丝的质量保留率随时间延长的变化趋势分别如图12中曲线1，2所示，未亲水处理的高分子丝降解时间为4～5年，集中降解时间段为第18月~第36个月，表面经过亲水处理的高分子丝降解时间为2～3年，集中降解时间段为第6月~第20月。两种丝在不同时间段内集中降解，从而可以避免封堵器在服役过程中降解产物在同一时间段内密集释放。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13所示，无明显炎症和异物反应。
实施例6
本实施例提供的封堵器中，包括92根由PLLA颗粒与PLGA颗粒按质量比为1:1熔融共混后抽丝而成的编织丝，丝径为0.15mm。其中选用的PLLA颗粒重均分子量为500,000Da，分子量分布系数为1.60，结晶度为50%。选用的非晶聚合物PLGA颗粒重均分子量为200,000Da，分子量分布系数为2.70。经6个月降解后测得该混合丝的弹性模量为3.21GPa，断裂伸长率为67%，说明本实施例混合丝制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；混合丝的质量保留率随时间延长的变化趋势如图14所示，混合丝的高分子丝降解时间为4~5年，混合丝在降解周期第8月~第52月内平缓降解，从而可以避免封堵器在服役过程中降解产物在同一时间段内密集释放。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15所示，无明显炎症和异物反应。
对比例1
本对比例提供的封堵器，封堵器编织网整体质量为0.726g，包括96根直径为0.15mm的PLLA丝，其中48根相互平行排列组成第一编织组，另外48根相互平行排列组成第二编织组。PLLA丝分子量为100,000Da，分子量分布系数为1.49，结晶度为49%。对PLLA丝进行体外降解实验，经6个月降解后测得PLLA丝的弹性模量为3.08GPa，断裂伸长率为63%，这说明本对比例制作的封堵器在植入6个月内具有稳定的框架结构，可以实现内皮爬覆完全；高分子丝的质量保留率随时间延长的变化趋势如图16所示，该高分子丝降解周期为2~3年，高分子丝在第6月~第20月集中降解，降解产物在该时间段密集释放。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17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、6和对比例1的实验结果表明：采用由至少两种具有不同集中降解时间段的聚合物共混制成的高分子丝或采用至少两种具有不同集中降解时间段的高分子丝编织封堵器编织网，在保证植入早期（6个月）内具有稳定的框架结构的基础上，组成高分子丝的聚合物在不同集中降解时间段内释放降解产物，从而可以避免封堵器在服役过程中同一时间段内密集释放降解产物，产生严重的炎症反应。

Claims (10)

  1. 一种可吸收封堵器，包括编织网，其特征在于，所述编织网包括至少两种高分子丝，所述至少两种高分子丝具有不同集中降解时间段。
  2. 一种可吸收封堵器，包括编织网，其特征在于，所述编织网包括一种高分子丝，该种高分子丝包括至少两种具有不同集中降解时间段的聚合物。
  3. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述编织网包括20~200根高分子丝。
  4. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述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。
  5. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述高分子丝的丝径范围为0.05mm~0.50mm。
  6. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述高分子丝的重均分子量范围为20,000Da~800,000Da。
  7. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述高分子丝的多分散系数为1.2~5。
  8. 根据权利要求1或2所述的可吸收封堵器，其特征在于，所述高分子丝的结晶度范围为0%~80%。
  9. 根据权利要求1或2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。
  10. 根据权利要求1或2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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US20180214159A1 (en) 2018-08-02
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US10799245B2 (en) 2020-10-13

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