WO2018121169A1 - 一种吻/闭合口加固修复组合件及其制备和使用方法 - Google Patents

一种吻/闭合口加固修复组合件及其制备和使用方法 Download PDF

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Publication number
WO2018121169A1
WO2018121169A1 PCT/CN2017/113789 CN2017113789W WO2018121169A1 WO 2018121169 A1 WO2018121169 A1 WO 2018121169A1 CN 2017113789 W CN2017113789 W CN 2017113789W WO 2018121169 A1 WO2018121169 A1 WO 2018121169A1
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Prior art keywords
repairing
section
kiss
reinforcement
semi
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PCT/CN2017/113789
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English (en)
French (fr)
Inventor
赵博
李学军
王洪权
赵延瑞
费福垒
张晋辉
孙丹丹
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北京博辉瑞进生物科技有限公司
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Application filed by 北京博辉瑞进生物科技有限公司 filed Critical 北京博辉瑞进生物科技有限公司
Priority to EP17886906.1A priority Critical patent/EP3424438B1/en
Priority to US16/090,959 priority patent/US11116504B2/en
Publication of WO2018121169A1 publication Critical patent/WO2018121169A1/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
    • A61B17/068—Surgical staplers, e.g. containing multiple staples or clamps
    • A61B17/072—Surgical staplers, e.g. containing multiple staples or clamps for applying a row of staples in a single action, e.g. the staples being applied simultaneously
    • A61B17/07292—Reinforcements for staple line, e.g. pledgets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/068—Surgical staplers, e.g. containing multiple staples or clamps
    • A61B17/072—Surgical staplers, e.g. containing multiple staples or clamps for applying a row of staples in a single action, e.g. the staples being applied simultaneously
    • A61B17/07207—Surgical staplers, e.g. containing multiple staples or clamps for applying a row of staples in a single action, e.g. the staples being applied simultaneously the staples being applied sequentially
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/04—Surgical instruments, devices or methods, e.g. tourniquets for suturing wounds; Holders or packages for needles or suture materials
    • A61B17/0466—Suture bridges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/04—Surgical instruments, devices or methods, e.g. tourniquets for suturing wounds; Holders or packages for needles or suture materials
    • A61B17/06—Needles ; Sutures; Needle-suture combinations; Holders or packages for needles or suture materials
    • A61B17/06166—Sutures
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/115—Staplers for performing anastomosis in a single operation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B17/11—Surgical instruments, devices or methods, e.g. tourniquets for performing anastomosis; Buttons for anastomosis
    • A61B17/115—Staplers for performing anastomosis in a single operation
    • A61B17/1155—Circular staplers comprising a plurality of staples
    • 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
    • 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
    • A61L31/005—Ingredients of undetermined constitution or reaction products thereof
    • 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
    • A61L31/146—Porous materials, e.g. foams or sponges
    • 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, 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
    • A61B2017/00831—Material properties

Definitions

  • the present invention relates to the technical field of medical devices, and in particular to a kiss/closed mouth reinforcement repair assembly and a method of making and using same.
  • a typical surgical reinforcement device has a jaw structure that typically includes two separate arms with an internal face that is a working surface.
  • the first arm is preferably a staple cartridge arm having a staple cartridge face comprising two or more staple wires, the second arm preferably being an anvil arm having a nail anvil surface.
  • the surgical reinforcement device may or may not have a cutting device with a cutting action.
  • the two stapling arms are positioned to the pre-cut tissue and then tightly locked together.
  • the user operates the stapler through an action procedure, and simultaneously completes the stitching of two or more staple lines onto the tissue and forms a cutting line in the middle of the suture. In this way, the operator can complete the rapid stitching and cutting of the tissue simultaneously.
  • This procedure is much faster than using a surgical scissors/knife in a conventional procedure and then suturing the suture at the incision.
  • the advantage of this kind of surgery is that the bleeding time of the wound is reduced, the time of the whole operation is shortened, and the patient care is obviously improved.
  • the use of bare nails directly means that the staples are in direct contact with the patient's tissue. Because the patient's intact tissue itself prevents the staples from escaping from the combination and compensates for the fracture before healing.
  • the tissue that the patient needs to suture is too fragile to fix the staples in place.
  • the tissue that needs to be anastomotic is very fragile. In extreme cases, the unprotected anastomosis line is prone to full-line tearing.
  • the leakage around the staple also needs to be considered.
  • One known protection measure is the use of reinforcing or reinforcing materials, that is, both the reinforcing material and the patient tissue are used between the arms of the stapler.
  • the reinforcing material is applied to the arms of the surgical stapler in some manner, and then the surgical stapler is used for suturing to protect the patient's tissue.
  • the reinforcing materials used in clinical practice in China are mainly composed of synthetic materials (such as polypropylene materials, polylactic acid materials, etc.).
  • synthetic materials such as polypropylene materials, polylactic acid materials, etc.
  • biodegradable materials show obvious advantages because they do not become permanent foreign bodies, and NEOVEIL, which is made of polylactic acid material, is the most prominent.
  • NEOVEIL which is made of polylactic acid material, is the most prominent.
  • these synthetic materials do not help the wound (nail hole and cut surface) heal.
  • ECM extracellular matrix material
  • the technical problem to be solved by the present invention is to provide a kiss/closed mouth reinforcement repairing assembly which not only provides sufficient strength for the tissue to be treated, prevents tearing of the suture opening, but also has low or near immunogenicity. It has low pathogenicity and high biocompatibility, and retains a large number of beneficial ingredients that promote tissue repair.
  • the technical solution adopted by the present invention is to provide a kiss/closed port reinforcement repairing assembly comprising a reinforcing repairing portion, a protecting portion and a connecting line, wherein the connecting line detachably connects the two ends of the reinforcing and repairing portion, The protection portion is inserted into a space surrounded by the both ends of the reinforcing and repairing portion.
  • the material of the reinforcing and repairing portion is non-immunogenic and in vivo degradable material, has a three-dimensional network porous structure, can strengthen the kiss/closed mouth, is matched with the kiss/closer, or can be non-crossing
  • the collagen fiber is a composition comprising type I, type III, type IV and/or type VI collagen
  • the mucopolysaccharide is a composition comprising chondroitin sulfate and/or hyaluronic acid
  • the growth factor comprises vascular endothelial growth factor
  • the material can be made using mammalian tissue as a raw material, subjected to a risk treatment, immunogen removal and/or sterilization process.
  • the protection part is for facilitating loading the threaded reinforcing repair piece onto the arm of the stapler, protecting the woven mesh structure and adding the insulation material between the connection line and the reinforcement repairing portion, and the protection part is at least partially isolated.
  • the arms and the arms of the closer prevent pull and damage to the connecting wires by the arms of the closer during assembly.
  • the protecting portion is in the form of a flat sheet or a curved sheet, and the length of the protecting portion may be greater than the length of the reinforcing portion, but at least a portion thereof should be The reinforcing and repairing portion encloses a space.
  • the part of the protection part extending out of the space of the reinforcing and repairing part can help to manually withdraw the protection part, and can also protect the connection line by bending to prevent the connection line from being worn.
  • the material of the protection part is synthetic polymer material and ceramic material.
  • the protective portion has a thickness of 50 to 10000 ⁇ m, preferably 100 to 600 ⁇ m or 300 to 350 ⁇ m.
  • the detachable connection portion has at least one hole pair at a corresponding position of the two ends of the reinforcing and repairing portion, and each of the hole pairs includes a wire hole respectively located at two ends of the reinforcing and repairing portion.
  • the single or multiple strands of the connecting wires pass through the wire holes to form a detachable woven mesh structure.
  • the connecting wire material is a medically usable wire
  • the connecting wire is woven into a slip knot
  • the woven mesh structure is woven by wire and knot
  • the slip joint form includes continuous joints and discontinuities.
  • sexual joints the woven mesh structure has a porosity of 75 to 90%.
  • the woven mesh structure is any one of the following woven mesh structures:
  • the first type of the woven mesh structure is divided into a first free section, n first open half sections, a pulling section, a holding section, a locking section, and a first releasing section, which are sequentially divided from a knitting starting end to a knitting end.
  • the rope sleeve surrounded by the first semi-opening section integrally communicates with the two wire holes of the pair of holes, and the open end of the first semi-open section is located at the same end of the reinforcing and repairing portion, the locking segment a sling formed by the first semi-open section; from the woven start end to the woven end, an end of the opening of the first first semi-open section near the knitting start end is connected to the first free section An end of the opening of the nth first semi-open section near the end of the braid is connected to one end of the pulling section, and the other end of the pulling section is connected to one end of the holding section, and the other part of the holding section One end is connected to one end of the locking segment, and the other end of the locking segment is connected to the first release segment;
  • the second woven mesh structure is divided into a second free segment, a second second semi-open segment and a second release segment which are connected in series from the knitting starting end to the knitting end; from the knitting starting end to the knitting end, One end of the opening of the second semi-open section near the starting end of the braid is connected to the second free section, and the opening of the nth second semi-open section is near the end of the braided end and the second a release segment connection, each of the second semi-open segments passing through a wire hole at the same end of the reinforcing repair portion, and each of the second half open segments is surrounded by the second second half open segment
  • the rope sleeve is integrally passed through a rope sleeve surrounded by a front second open section;
  • the third type of woven mesh structure is divided into a third free section, 2n third semi-open sections and a third release section which are connected to each other from the knitting starting end to the knitting end; from the knitting starting end to the knitting end, the first One end of the opening of the third semi-open section near the knitting start end is connected to the third free section, and the opening of the 2nth third semi-open section is near the end of the braided end and the third release a segment connection, wherein the woven mesh structure is knitted in a serpentine manner along the line holes on the reinforcing and repairing portion, and each of the third portions is enclosed from the second third semi-opening portion
  • the rope of the semi-open section is interlaced with the rope sleeve surrounded by the third open half of the previous one.
  • the kiss/closed mouth reinforcement repair assembly of the present invention has the following advantages over the prior art: the kiss/closed mouth reinforcement repair assembly of the present invention has low or near immunogenicity, and can also avoid many foreign cells.
  • the introduction of the resulting immunopathogenic response has low pathogenicity and high biocompatibility, and retains a large number of beneficial components that promote tissue repair.
  • the invention also provides a preparation method of a kiss/closed mouth reinforcement repairing assembly, which has a high safety and convenient use in a kiss/closed mouth reinforcement repair assembly.
  • the technical solution adopted by the present invention is to provide a method for preparing a kiss/closed mouth reinforcement repairing assembly, which comprises woven the connecting wire on the reinforcing and repairing portion under aseptic conditions, and then assembling
  • the above-mentioned protection portion, that is, the kiss/closed port reinforcement repairing assembly is characterized in that the method for preparing the reinforcing and repairing portion comprises the following steps:
  • Raw material selection and initial treatment select the small intestine submucosal tissue material, remove the lymphoid tissue, rinse with water until the surface is free of stains, screen mesh filtration;
  • the submucosal tissue of the small intestine after the risk treatment in the step (2) is at a concentration of 3 to 6 mol/L, and the volume is the volume of the submucosal tissue of the small intestine after the risk treatment in the step (2).
  • vacuum freeze-drying vacuum-drying the semi-finished product, cutting into a specific shape, and obtaining the dried repairing portion
  • Ethylene oxide sterilization is applied to the reinforcing and repairing part in the step (5).
  • the sterilization conditions are: temperature 35-40 ° C, holding time 3.5 to 4.5 hours, humidity 30 to 70%, epoxy
  • the concentration of ethane is 300-1000 mg/L
  • the sterilization time is 3.5-4.5 hours, and then analyzed in a ventilated analysis chamber.
  • the temperature is controlled between 15 and 25 ° C for 10 to 20 days. Finished product.
  • Sterilization methods can also be performed by radiation sterilization, dry heat sterilization, temperature and humidity sterilization, and/or gas sterilization.
  • the peroxyacetic acid-ethanol solution used in the step (2) has a peroxyacetic acid volume concentration of 0.1 to 5%, an ethanol volume concentration of 5 to 40%, and the peroxyacetic acid-ethanol solution and the porcine small intestine submucosal tissue volume.
  • the ratio is 20 to 40:1, the soaking time is 2 to 4 hours, and the temperature is 10 to 40 °C.
  • the cleaning in the step (3) comprises: ultrasonically cleaning with a PBS solution having a pH of 6-8 and a volume of 20 to 40 times the volume of the small intestinal submucosa after filtering in the step (2). , cleaning temperature 10 ⁇ 40 ° C, each wash for 10 ⁇ 30 minutes, washed several times until the pH of the mixed layer of small intestinal submucosal tissue and PBS solution is 6 ⁇ 8, the small intestinal submucosal tissue after washing with PBS solution, reuse Ultrasonic washing with water for injection was performed at a temperature of 10 to 40 ° C until the detection conductivity of the mixed solution of the intestinal submucosal tissue and water for injection was 0 to 1 ⁇ S/cm.
  • the step (5) vacuum freeze-drying conditions are: pre-freezing to -40 to -50 ° C, holding for 1 to 2 hours; adjusting the temperature to -10 to -20 ° C, holding for 5 to 7 hours; adjusting the temperature -5 ⁇ -4 ° C, heat preservation 1.5 ⁇ 2.5 hours; adjust the product temperature 20 ⁇ 30 ° C, heat preservation 3.5 ⁇ 4.5 hours.
  • the preparation method of the kiss/closed mouth reinforcement repairing assembly prepared by the invention can not only provide sufficient strength for the tissue to be treated, the longitudinal tensile strength can reach more than 24N, and the transverse tensile strength can reach 15N or more. It prevents the kiss/closed mouth tearing, etc., and the assembly and use of the reinforcing material is extremely simple and easy to fall off, ensuring the safety and stability of the surgical procedure.
  • the extracellular matrix remains intact, continuous, and has no cell residue, and can provide a good induction "template” and growth "soil” for cell differentiation and growth, and is a good wound repairing.
  • the kiss/closed mouth repair assembly prepared by the method of the present invention has lower pathogenicity and higher biocompatibility, and retains a number of beneficial components that promote tissue repair.
  • the present invention also provides a simple and easy-to-operate method of using a kiss/closed mouth reinforcement repair assembly that is extremely simple and easy to use and that is not easily detached, thereby ensuring the safety of the surgical procedure. And stability, improving the efficiency of surgery.
  • the method of using the method includes the following steps: the device to be reinforced is matched with the kiss/closed port reinforcement repairing assembly, and the portion to be reinforced of the device to be reinforced is inserted into the space enclosed by the reinforcing and repairing portion, and the device is withdrawn.
  • the protecting portion tightens the connecting line to fasten the reinforcing and repairing portion to the portion to be reinforced of the device to be reinforced, and after pulling/closing/stitching, pull and pull off the connecting line.
  • Figure 1 is a HE stained section of the reinforced repair sheet of the present invention
  • Figure 2 is a SEM photograph of the reinforcing repair sheet of the present invention.
  • Figure 3 is a top plan view showing a first embodiment of the kiss/closed port reinforcement repairing assembly of the present invention
  • FIG. 4 is a top plan view showing a second embodiment of the kiss/closed port reinforcement repairing assembly of the present invention.
  • Figure 5 is a top plan view showing a third embodiment of the kiss/closed port reinforcement repairing assembly of the present invention.
  • Figure 6 is a side elevational view of the kiss/closed mouth reinforcement repair assembly of the present invention.
  • Figure 7 is a schematic view of a surgical reinforcement device stapler
  • Figure 8 is an anvil arm and a staple cartridge of the staple/closed mouth reinforcement repair assembly of the present invention mounted to a surgical reinforcement device stapler Side view of the arm;
  • the present invention provides a kiss/closed mouth reinforcement repair assembly and methods of making and using same, and to assist in understanding various aspects of the present invention, the following embodiments are provided. It is to be noted that the examples are for the purpose of explaining the invention, and the invention is not limited by the examples.
  • Raw materials can be obtained from species such as pigs or cattle, and pigs can be pigs with a genetic homozygosity of 50% or more. The following is an example of pigs.
  • the reinforcing repairing piece is one of the finished products of the reinforcing and repairing part commonly used in the present invention.
  • the reinforcing repair sheet can be prepared as follows:
  • washing process washing with PBS solution with pH value of 6-8, temperature 10 ⁇ 40 °C, the ratio of tissue volume of the small intestine submucosa after solution and (c) treatment is 20-40:1, each time 10 ⁇ 30 Minute; clean 2 to 4 times, check the pH value of 6 ⁇ 8, and then wash with the use of water for injection, the temperature range is 10 ⁇ 40 ° C, the volume ratio of water for injection and submucosal tissue of pig small intestine is 20 ⁇ 40:1, The detection conductivity is terminated below 1 ⁇ S/cm, and the cleaning process needs to be ultrasonically cleaned. In the machine;
  • the mold consists of a needle bottom plate, a cover plate and a heavy object. Different molds need to be selected according to different specifications, and the small intestinal submucosal tissue is laid flat on the needle bottom plate.
  • the product is covered with a non-breathable stainless steel cover. The area of the cover is the final cut size or wider.
  • the weight of the stainless steel plate is 5-10 kg, so that the water overflows from the surrounding area.
  • the small intestine submucosal tissue is superimposed in multiple layers to ensure that the upper and lower layers are tightly adhered together, and a semi-finished reinforcing repair sheet is obtained;
  • Vacuum freeze-drying The process needs to be carried out in a vacuum freeze dryer.
  • the freeze-drying process of the semi-finished product needs to be reconfirmed according to different equipment.
  • the mold is laid flat in the vacuum freeze dryer, and the door of the freeze-drying chamber is closed and opened.
  • Circulating pump for about 1 minute turn on the compressor to cool the freeze-drying box, pre-freeze the product to -45 °C, keep the temperature for about 1-2 hours, turn on the vacuum pump, adjust the product temperature to about -15 °C sublimation, about 5-7 hours later. Adjusting the product temperature to 0 ° C, holding for 2 hours, adjusting the product temperature to 25 ° C, holding for 4 hours, and vacuum freezing and drying to obtain the dried reinforcing sheet;
  • Sterilization analysis The product is sterilized by ethylene oxide.
  • the sterilization conditions are: temperature 40 ° C, holding time 4 hours, humidity 30-70%, ethylene oxide concentration 300-1000 mg/L, sterilization Time 4 hours;
  • Analytical process In the ventilated analysis chamber, the temperature is controlled between 20 ° C and the time is about 14 days, and the finished product of the reinforced repair sheet is obtained.
  • Sterilization methods can also be performed by radiation sterilization, dry heat sterilization, temperature and humidity sterilization, and/or gas sterilization.
  • the degradation time in the body is from 1 to 3 months.
  • the mechanical properties of the reinforced repair sheet include burst strength, stitch retention and/or tensile strength.
  • 1 is a HE-stained section of a reinforced repair sheet; it can be seen from FIG. 1 that after the HE staining, the sample in Example 1 was observed by an optical microscope, and the preparation method provided in the present invention, the retention of the extracellular matrix can be seen. Complete, continuous, no cell residue.
  • the extracellular matrix sheet of the submucosal tissue of the small intestine is obtained after treatment.
  • the collagen fiber is intact, non-destructive, and non-fragmented, and is a porous network structure intertwined. It is proved that the structure can provide a good induction "template” and growth “soil” for cell differentiation and growth, which is a good foundation for wound repair.
  • Example 1 Further, the samples in Example 1 were tested for physical and chemical properties, and the test items were pH, heavy metal content, and ignition residue, suture tensile strength, and tensile strength.
  • pH a sample prepared according to Example 1, according to the method specified in 5.4.1 of GB/T 14233.1-2008, the difference between the pH value of the sample test solution and the blank control solution does not exceed 1;
  • Heavy metal content Prepare samples according to Example 1. Lead and chromium are tested according to the atomic absorption spectrophotometer specified in 5.9.1 of GB/T 14233.1-2008. Mercury and arsenic are in accordance with 5.9.3 of GB/T 14233.1-2008. The specified atomic fluorescence spectrometry test showed that the heavy metal content was less than 0.1 ⁇ g/g.
  • Stitching tensile strength A sample was prepared according to Example 1, and a 3-0 non-absorbable suture was placed at the edge of one end of the repairing piece 2 mm, and the other end of the repairing piece and the suture were respectively fixed on a tensile force meter at 20 mm/ The speed of min was stretched until the stitching point was torn, and the maximum force value was recorded. The results showed that the maximum height of the reinforcing sheet prepared by the method of the present invention was 10 N or more.
  • Tensile strength A sample was prepared in accordance with Example 1, and the sample was cut into a size of 2 cm ⁇ 5 cm, and placed under conditions of a relative humidity of 40% to 60% and a temperature of 22 ° C ⁇ 2 ° C for 2 hours. The two ends of the sample were fixed on the chuck of the tensile testing machine, and were sequentially stretched outward at a speed of 100 mm/min until the sample was broken, and the longitudinal sample and the transverse sample were respectively tested. The final measurement results show that the longitudinal tensile strength can reach more than 24N, and the transverse tensile strength can reach more than 15N.
  • Bacterial endotoxin assay Samples were prepared according to Example 1 and operated according to the method specified in GB/T 14233.2-2005. The results showed that the bacterial endotoxin was less than 2 EU/g.
  • Cell residue examination HE staining was performed for 3 products, 3 fields were selected for each section, and the number of intact cells was divided by 3 under a 400-fold optical microscope. The results showed that the average number of intact cells per field was 0. It is enough to avoid many immune pathogenic reactions caused by the introduction of foreign cells.
  • DNA residue amount A sample was prepared according to Example 1, and the DNA residue amount of the sample provided in Example 3 was measured by a fluorescent staining method according to the method specified in the Pharmacopoeia of the People's Republic of China (2015 Edition 4). The results showed that the residual amount of DNA in the sample was less than 10 pg/g. The various inflammatory reactions caused by the immune response of the receptor to animal-derived DNA are greatly attenuated, or even because the amount of DNA residues has been so low that no obvious inflammatory reaction is found.
  • ⁇ -Gal clearance rate Samples were prepared according to Example 1, according to the method of “Method for evaluating immunogenicity of medical devices, Part 5: Determination of ⁇ -Gal antigen clearance rate in animal-derived medical devices using M86 antibody”, ⁇ -Gal clearance rate is 99.4%
  • IgA Residue Samples were prepared as in Example 1, 10 samples were taken, sampled, leached, and IgA residues were tested using the Porcine Immunoglobulin A (IgA) Quantitative Assay Kit (ELISA). The results showed that the sample of the present invention had an IgA residual of less than 1 ⁇ g/g. Indicates that the sample is immunogenic, or nearly absent.
  • IgA Porcine Immunoglobulin A Quantitative Assay Kit
  • FGF-2 retention Samples were prepared as in Example 1, 10 samples were taken, sampled, leached, and tested for FGF-2 content using the Porcine Basic Fibroblast Growth Factor (FGF2) Assay Kit. The results showed that the average FGF-2 retention amount of the sample of the present invention was 30.8 ng/g ⁇ 17.3 ng/g.
  • FGF2 Porcine Basic Fibroblast Growth Factor
  • VEGF retention Samples were prepared as in Example 1, 10 samples were taken, sampled, leached, and tested for VEGF content using the Porcine Vascular Endothelial Growth Factor (VEGF) kit. The results showed that the average VEGF retention of the sample of the present invention was 99.6 ng/g ⁇ 2.4 ng/g.
  • VEGF Porcine Vascular Endothelial Growth Factor
  • Hyaluronic acid (HA) retention Samples were prepared as in Example 1, 10 samples were taken, sampled, leached, and hyaluronic acid (HA) content was tested using a hyaluronic acid detection kit. The results showed that the hyaluronic acid (HA) retention amount of the sample of the present invention was 332 ⁇ g / g ⁇ 231 ⁇ g / g.
  • the results of the biological test indicate that the reinforced repair sheet of the present invention has low pathogenicity and high biocompatibility, and retains a large number of beneficial ingredients for promoting tissue repair.
  • the biological evaluation of the anastomotic reinforcement repair tablets included cytotoxicity, delayed type hypersensitivity reaction, and intradermal reaction.
  • Cytotoxicity (MTT method): Prepare the sample according to Example 1, sample and extract (the extraction ratio is 6cm2/mL with reference to GB/T16886.12, the extraction medium is complete cell culture medium, and the extraction condition is 37 °C. 24h), according to the test method specified in GB/T16886.5-2003 ("Medical Device Biological Evaluation Part 5 in vitro cytotoxicity test"), the cytotoxicity result is less than or equal to level 1.
  • Delayed type hypersensitivity reaction samples were prepared according to Example 1, and sampled according to the delayed type in GB/T 16886.10-2003 ("Sensitivity and delayed type hypersensitivity test of medical device biological evaluation") The sensitive reaction closed application method was used for the detection.
  • the test sample was selected from the extract solution (the polar extraction medium was selected as physiological saline, the non-polar extraction medium was selected as cottonseed oil, the extraction ratio was 6 cm 2 /mL, and the extraction condition was 37 ° C, 72 h. ), the results showed no delayed hypersensitivity reaction.
  • samples were prepared according to Example 1, sampled, and tested according to the intradermal reaction method in GB/T 16886.10-2003 ("Sensitivity and delayed-type hypersensitivity test of medical device biological evaluation").
  • the polar leaching medium was selected from physiological saline
  • the non-polar leaching medium was selected from cottonseed oil
  • the extraction ratio was 6 cm 2 /mL
  • the extraction condition was 37 ° C, 72 h).
  • the results showed that the difference between the test sample and the solvent control average score was not more than 1.0.
  • the in vitro simulated degradation process of the anastomotic reinforced patch Prepare the sample according to Example 1, and control the sterilization parameters in the ethylene oxide sterilization step so that the sterilization time is 4h, 5h, 6h, 7h, 8h, respectively, and obtain 10mg samples for each sample obtained. Cut into strips), placed in 2 mL of PBS solution containing 0.2 mg/mL proteinase K, placed in a water bath at 56 ° C, photographed every 15 min, and recorded the material degradation process until the material was completely dissolved without solid residue. Results The simulated degradation time of samples in vitro for 4h, 5h, 6h, 7h and 8h was 120min, 90min, 75min, 60min and 45min respectively.
  • Example 1 The angiogenic effects and examination of the reinforced patch.
  • Six samples prepared in Example 1 were taken as the test group; the commercial wound repair material "Bard BARD” patch (BARD) was used as the control group, and six were also taken.
  • the sample prepared in Example 1 was sterilized by low temperature ethylene oxide prior to use, and the BARD was selected to be sterilized and aseptically transported. Twelve samples were implanted subcutaneously into the rat with a 1 ⁇ 1.5 cm block. After 3 weeks, the angiogenic effect of each sample was quantitatively evaluated by microvascular fluorescein spectroscopy.
  • the results of microvascular fluorescein imaging showed that all implants had an angiogenic effect.
  • the blood vessel growth of BARD was significantly lower than that of the self-made patch, and only one of the six implants studied observed vascular enlargement.
  • the results of vascular volume studies showed that BARD implants were much lower than the experimental group.
  • the results of histological studies were also consistent with the results of microvascular fluorescein angiography and gelatin ink perfusion.
  • the experimental group had significant fibrovascular stenosis and showed significant functional reconstruction evidence; while the control BARD implants only observed very small amounts. Fibrovascular growth.
  • the first woven mesh structure is divided into a first free segment 1311, a plurality of first half open segments 1312 connected to each other, a pulling segment 1313, a retaining segment 1314, a locking segment 1315 and a first release from a knitting starting end to a knitting end.
  • the number of the first semi-open segments 1312 may be the same as the number of the hole pairs 111, and the first half of the first semi-open segment 1312 is connected to the two wire holes of the hole pair 111, the first half
  • the open end of the open section 1312 is located at the same end of the reinforcing repair portion 11, and the locking section 1315 passes through the sleeve of the first semi-open section 1312; from the knitting start end to the braided end, the first first half open section 1312 One end of the opening near the knitting start end is connected to the first free section 1311, and one end of the opening of the last first half open section 1312 near the knitting end is connected to one end of the pulling section 1313, and the other end of the pulling section 1313 and the holding section 1314 One end of the holding section 1314 is connected to one end of the locking section 1315, and the other end of the locking section 1315 is connected to the first releasing section 1316.
  • the protective portion 12 is inserted into the space surrounded by the two ends of the reinforcing and repairing portion 11, and the kiss/closed port is repaired and repaired by the connecting wire 13 in a loose state.
  • the assembly, and then the loosened kiss/closed mouth reinforcement repair assembly is placed over the anvil arm 21 and/or the staple cartridge arm 22 of the stapler 2, And the woven mesh structure and the protection portion 12 conforming to the woven mesh structure are on the non-working surface of the anvil arm 21 and/or the staple cartridge arm 22, and the protection portion 12 is withdrawn; then in the first free segment 1311, the holding section 1314 and the first releasing section 1316 are not moved, the tensioning pulling section 1313 is fastened to the anvil arm 21 and/or the magazine arm 22 to make the first
  • the release section 1316 is located near the handle 23 of the stapler 2, and the kiss/close/stitching operation is performed using the stapler 2 with the reinforcing repair function; after the kiss/close/stitch is completed, the first release section 1316 is pulled and the connection is made. Line 13 is pulled away.
  • the second woven mesh structure is divided into a second free segment 1321, a n second second open segment 1322, a second release segment 1323, and a second half open segment 1322 which are sequentially connected in series from a knitting start end to a braided end.
  • each of the second semi-open sections 1322 passes through the line hole at the same end of the reinforcing repair portion 11, and from the second second half open section
  • the holster surrounded by each of the second semi-open sections 1322 integrally passes through a sling surrounded by the first second half of the open section 1322.
  • the protective portion 12 is inserted into the space surrounded by the two ends of the reinforcing and repairing portion 11, and the kiss/closed port is repaired and fixed in a loose state.
  • the assembly fits the loosened kiss/closed mouth reinforcement repair assembly over the anvil arm 21 and/or the staple cartridge arm 22 of the stapler 2 and conforms the woven mesh structure to the woven mesh structure
  • the protection portion 12 is on the non-working surface of the anvil arm 21 and/or the staple cartridge arm 22, and the protection portion 12 is withdrawn; then, in the case where the second free segment 1321 and the second release portion 1323 are not moved, the tension is tightened.
  • a loop encased by the nth second half open section 1322 secures the kiss/closed mouth reinforcement repair assembly to the anvil arm 21 and/or the staple cartridge arm 22 such that the second release section 1323 is in the stapler 2 The vicinity of the handle 23, and then the stapler 2 with the reinforcing repair function is used for the kiss/close/stitching operation; after the kiss/close/stitching is completed, the second release section 1323 is pulled to pull the connecting line 13 away.
  • the third woven mesh structure is divided into a third free segment 1331, 2n third semi-open segments 1332 and a third release segment 1333 which are interconnected, and the number of the third semi-open segments 1332 can be divided into three. It is twice the number of the hole pairs 111; from the knitting start end to the knitting end, the end of the first third half open section 1332 near the knitting start end is connected to the third free section 1331, the 2nd third half One end of the opening of the open section 1332 near the end of the braid is connected to the third release section 1333, and the braided mesh structure is knitted in a serpentine manner along the line holes on the reinforcing repair portion 11, and from the second third Starting from the semi-open section, the ropes surrounding each of the third semi-open sections 1332 The loops enclosed by the former third half open section 1332 are interlaced.
  • the protective portion 12 is inserted into the space surrounded by the both ends of the reinforcing and repairing portion 11, and the kiss/closed port is repaired and fixed in a loose state.
  • the assembly fits the loosened kiss/closed mouth reinforcement repair assembly over the anvil arm 21 and/or the staple cartridge arm 22 of the stapler 2 and conforms the woven mesh structure to the woven mesh structure
  • the protection portion 12 is on the non-working surface of the anvil arm 21 and/or the staple cartridge arm 22, withdrawing the protection portion 12; then, in the case where the third free segment 1331 and the third release segment 1333 are stationary, the tension is tightened.
  • the ferrule enclosed by the 2nth third semi-open section 1332 secures the kiss/closed port reinforcement repair assembly to the anvil arm 21 and/or the staple cartridge arm 22 such that the third release section 1333 is in the stapler 2
  • the handle 23 is in the vicinity, and the stapler 2 with the reinforcing repair function is used to perform the kiss/close/stitching operation; after the kiss/close/stitch is completed, the third release section 1333 is pulled to pull the connecting line 13 away.
  • the stapler commonly used in surgery is used as the cable life, and the commonly used staples are titanium, magnesium, aluminum or other absorbable materials, but can also be applied to the kiss/closer as a linear kiss/closer or ring. Kiss/closer and other types of kiss/closers.
  • the woven mesh structure in the embodiment of the present invention and the accompanying drawings is only an example, but in actual operation, the actual length, the fastening strength, and the matching kiss according to the kiss/closed port reinforcement repair assembly are required.
  • Closed/stitched device features extend the woven mesh structure to more line holes or pairs of holes on each side.

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Abstract

吻/闭合口加固修复组合件，包括加固修复部（11）、保护部（12）和连接线（13），连接线（13）将加固修复部（11）的两端可拆卸连接，保护部（12）穿插于加固修复部（11）的两端围合成的空间内，同时也提供了吻/闭合口加固修复组合件的制备和使用方法。吻/闭合口加固修复组合件不仅能够为待处理组织提供足够的强度，防止缝合口撕裂，而且免疫原性很低或近无，具有较低的致病性和高的生物相容性，且保留了大量的促进组织修复的有益成分。

Description

一种吻/闭合口加固修复组合件及其制备和使用方法 技术领域
本发明涉及医疗器械的技术领域，具体地是一种吻/闭合口加固修复组合件及其制备和使用方法。
背景技术
外科加固装置因其可以在同一时间快速的切割和与密闭病人体内的组织器官，相比于常规手术的先用手术刀/剪切开，在很大程度上减少了此类手术过程的风险，并缩短了手术时间，因而在外科手术上有非常广泛的应用。一般外科加固装置有一个颌式结构，通常包括两个分开的臂，内部的面为工作面。第一条臂优选为钉仓臂，具有钉仓面，包括两条或多条钉线，第二条臂优选为钉砧臂，具有钉砧面。外科加固装置可以带有或不带具有切割作用的切割装置。
在典型的吻合器手术中，两个吻合臂定位到预切组织然后紧紧的锁在一起。使用者通过一个动作过程操作吻合器，同步完成了将两条或两条以上钉线缝合到组织上并在缝合线的中间位置形成一条切割线。以这种方式，操作者可是同步完成对组织的快速缝合和切割。此过程比常规手术中使用手术剪/刀切割，然后再用缝合线的在切口处缝合的过程要快得多。此种手术好处就是：创口出血时间减少，整个手术的时间缩短，因而病人护理得到明显提高。
在某些手术中，直接使用裸钉，就是吻合钉直接与病人的组织接触是行得通的。因为在愈合之前，病人完整的组织本身就可以防止吻合钉从组合中脱离，并补偿裂缝。然而，对另外一些手术，病人需要缝合的组织实在是太脆弱了，难以把吻合钉固定在相应的位置。比如，肺部的手术，一些发生特殊病变的肺组织，需要吻合的组织是很脆弱的，极端情况下，未经保护的吻合线容易发生全线撕裂。随着在病变的肺组织手术中使用外科加固设备的日益广泛，采取措施保护脆弱的组织免于被吻合钉撕裂或在外科缝合过程中被撕裂已经变得越来越重要。再者，当吻合器被用到的时候，吻合钉周围的渗漏问题也需要考虑解决。
一种已知的保护措施是使用增强或加固材料，就是加固材料与病人组织都在吻合器的两臂之间使用。通常的情况下，第一步，加固材料以某种方式应用于外科缝合器的臂上，然后外科缝合器再用于缝合以保护病人的组织。
国内临床上用到的加固材料以合成材料(如聚丙烯材料、聚乳酸材料等)为主。然而生物可降解的材料因其不会成为永久异物，而表现出明显的优势，其中以聚乳酸材料材质的奈维(NEOVEIL)最为突出。然而这些合成材料无法帮助创面(钉孔和与切面)愈合。
现代医用植入材料的发展方向是可降解、具有主动诱导组织再生的生物材料。近来兴起的一系列由动物组织或器官通过脱细胞并去除免疫致病原而得到的植入材料，如脱细胞心包，脱细胞真皮基质等，具有可降解、低免疫原、本身和降解物产物均有良好的生物相容性等优势。研究发现细胞外基质材料(ECM)能够为组织修复提供良好的微环境，具有诱导细胞分化、促进细胞生长的作用。
发明内容
本发明所要解决的技术问题是：提供一种吻/闭合口加固修复组合件，其不仅能够为待处理组织提供足够的强度，防止缝合口撕裂，而且免疫原性很低或近无，具有较低的致病性和高的生物相容性，且保留了大量的促进组织修复的有益成分。
本发明所采取的技术方案是：提供一种吻/闭合口加固修复组合件包括加固修复部、保护部和连接线，所述连接线将所述加固修复部的两端可拆卸连接，所述保护部穿插于加固修复部的两端围合成的空间内。
吻/闭合口为胃吻/闭合口，食道吻/闭合口，十二指肠吻/闭合口，小肠吻/闭合口，肺切除术后残端闭合口，支气管残端吻/闭合口，胆道吻/闭合口，胰腺切除术后残端闭合口，结直肠吻/闭合口，血管吻/闭合口。
作为优选，所述加固修复部的材料为无免疫原性且可体内降解的材料，具有三维网状多孔结构，能够加固吻/闭合口，与吻/闭合器配套使用，也可以为包含非交联型胶原纤维、粘多糖、生长因子和糖蛋白的片状除抗原动物源细胞外基质材料。其中，胶原纤维为包含I型、III型、IV型和/或VI型胶原的组合物，粘多糖为包含硫酸软骨素和/或透明质酸的组合物，生长因子为包含血管内皮生长因子、成纤维细胞生长因子和/或转化生长因子的组合物，除抗原动物源细胞外基质材料是除抗原粘膜下层基质材料、心包基质材料或真皮基质材料或除抗原小肠粘膜下层基质材料，细胞外基质材料可以是采用哺乳动物组织为原料，经风险处理、免疫原去除和/或灭菌工艺制成。
保护部是为了方便将穿了线的加固修复片加载到吻合器的臂上，对编织网状结构给予保护而在连接线和加固修复部之间添加的隔离材料，并且保护部至少部分隔离连接线和闭合器的臂，防止在组装过程中闭合器的臂对连接线的拉扯和损伤。作为优选，保护部为平面片状或曲面片状，保护部的长度可以大于加固修复部的长度，但是其至少一部分应当位 于所述加固修复部围成空间中。保护部伸出加固修复部围成空间的部分可以有助于手动撤出该保护部，也可以经弯折保护连接线，防止连接线发生磨损，保护部的材料为合成高分子材料、陶瓷材料、金属材料、特卫强纸、医用合成纸中的一种或多种组合。作为优选，所述的保护部的厚度是50～10000微米，优选100～600微米或300～350微米。
所述可拆卸连接具体是指：所述加固修复部的两端沿边缘的对应位置处设有至少一个孔对，每个所述孔对均包括分别位于所述加固修复部两端的线孔，单股或多股的所述连接线穿过所述线孔形成可拆卸的编织网状结构。作为优选，所述连接线材料为医疗可用线，连接线编织成活结，以活结形式编织的编织网状结构，编织网状结构以线、结方式编织制成，活结形式包括连续活节和间断性活节，编织网状结构的孔隙率为75～90％。
作为优选，所述编织网状结构为以下编织网状结构中的任一种：
第一种所述编织网状结构由编织起始端到编织末端依次分为第一自由段、互相连接的n个第一半开放段、拉动段、保持段、锁定段、第一释放段，每个所述第一半开放段所围成的绳套整体连通所述孔对的两个线孔，所述第一半开放段的开口端位于所述加固修复部的同一端，所述锁定段穿过所述第一半开放段围成的绳套；由编织起始端到编织末端，第一个所述第一半开放段的开口处靠近编织起始端的一端与所述第一自由段连接，第n个所述第一半开放段的开口处靠近编织末端的一端与所述拉动段的一端连接，所述拉动段的另一端与所述保持段的一端连接，所述保持段的另一端与所述锁定段的一端连接，所述锁定段的另一端与所述第一释放段连接；
第二种所述编织网状结构由编织起始端到编织末端依次分为第二自由段、互相串接的n个第二半开放段、第二释放段；由编织起始端到编织末端，第一个所述第二半开放段的开口处靠近编织起始端的一端与所述第二自由段连接，第n个所述第二半开放段的开口处靠近编织末端的一端与所述第二释放段连接，每个所述第二半开放段均穿过位于所述加固修复部同一端的线孔，且从第二个第二半开放段起，每个所述第二半开放段所围成的绳套整体穿过其前一个第二半开放段所围成的绳套；
第三种所述编织网状结构由编织起始端到编织末端依次分为第三自由段、互相连接的2n个第三半开放段、第三释放段；由编织起始端到编织末端，第一个所述第三半开放段的开口处靠近编织起始端的一端与所述第三自由段连接，第2n个所述第三半开放段的开口处靠近编织末端的一端与所述第三释放段连接，所述编织网状结构的编织方式为沿着所述加固修复部上的线孔依次进行蛇形编织，且从第二个第三半开放段起，围成每个所述第三半开放段的绳线与其前一个所述第三半开放段所围成的绳套交织。
本发明的吻/闭合口加固修复组合件，与现有技术相比具有以下优点：本发明吻/闭合口加固修复组合件免疫原性很低或近无，也能够避免很多的因外源细胞引入而导致的免疫致病反应，具有较低的致病性和高的生物相容性，且保留了大量的促进组织修复的有益成分。
本发明的还提供了一种吻/闭合口加固修复组合件的制备方法，该制备方法获得的一种吻/闭合口加固修复组合件安全性高、使用方便。
本发明所采取的技术方案是：提供一种吻/闭合口加固修复组合件的制备方法，该制备方法包括在无菌条件下，将所述连接线编织在所述加固修复部上，再组装上所述保护部，即得所述吻/闭合口加固修复组合件，其特征在于：所述加固修复部的制备方法包括以下步骤：
(1)原料选择与初处理：选取小肠粘膜下层组织材料，剔除淋巴组织，用水冲洗至表面无污渍，筛网过滤；
(2)风险处理：用过氧乙酸-乙醇溶液浸泡步骤(1)筛网过滤后的小肠粘膜下层组织，筛网过滤；
(3)免疫原去除：将所述步骤(2)风险处理后的小肠粘膜下层组织与浓度为3～6mol/L、体积为所述步骤(2)风险处理后的小肠粘膜下层组织体积20～30倍的氯化钠溶液混合，于-25～-20℃冷冻，0.5～1.5小时后取出，置于35～40℃同浓度氯化钠溶液中融化，反复冷冻-融化3～5次后，清洗去除氯化钠，筛网过滤；
(4)固定：选择带有针底板、盖板与重物的特定模具，将步骤(3)免疫原去除后的小肠粘膜下层组织平铺于带针底板上，盖上盖板，重物挤压，让水分溢出，得半成品；
(5)真空冷冻干燥：对半成品进行真空冷冻干燥，切割成特定形状，得干燥的所述加固修复部；
(6)灭菌解析：对步骤(5)中的加固修复部采用环氧乙烷灭菌，灭菌条件：温度35-40℃，保温时间3.5～4.5小时，湿度30～70％，环氧乙烷的浓度为300～1000mg/L，灭菌时间3.5～4.5小时，再在通风的解析室中解析，温度控制在15～25℃之间，时间10～20天，得所述加固修复部的成品。
灭菌方式还可以采用辐射灭菌、干热灭菌、温湿灭菌和/或气体灭菌。
作为优选，所属步骤(2)使用的过氧乙酸-乙醇溶液中过氧乙酸体积浓度0.1～5％、乙醇体积浓度5～40％，所述过氧乙酸-乙醇溶液与猪小肠粘膜下层组织体积比例为20～40:1，浸泡时间2～4小时、温度10～40℃。
作为优选，所述步骤(3)中的清洗具体包括：用pH值为6～8、体积为所述步骤(2)筛网过滤后的小肠粘膜下层组织体积20～40倍的PBS溶液超声清洗，清洗温度10～40℃、每次清洗10～30分钟，多次清洗直至小肠粘膜下层组织和PBS溶液的混合溶液pH值为6～8，得到PBS溶液清洗后的小肠粘膜下层组织，再用注射用水超声清洗，在温度10～40℃清洗，直至小肠粘膜下层组织和注射用水的混合溶液的检测电导率为0～1μS/cm。
作为优选，所述步骤(5)真空冷冻干燥条件依次为：预冻至-40～-50℃，保温1～2小时；调节温度至-10～-20℃，保温5～7小时；调节温度-5～-4℃，保温1.5～2.5小时；调节产品温度20～30℃，保温3.5～4.5小时。
本发明制备的吻/闭合口加固修复组合件的制备方法，与现有技术相比，不仅能够为待处理组织提供足够强度，纵向抗张强度可达24N以上，横向抗张强度可达15N以上，防止了吻/闭合口撕裂等，而且加固材料的组装及使用也极其简单易行且不易脱落，保证了外科手术过程的安全性和稳定性。本发明中提供的制备方法脱细胞处理后，细胞外基质的保留完整、连续，无细胞残留，能够为细胞的分化、生长提供良好的诱导“模板”和生长“土壤”，是创伤修复的良好基础，本发明方法制备的吻/闭合口加固修复组合件具有较低的致病性和较高生物相容性，且保留了大量促进组织修复的有益成分。
本发明还提供了一种简单易于操作的吻/闭合口加固修复组合件的使用方法，该吻/闭合口加固修复组合件的使用极其简单易行且不易脱落，保证了外科手术过程的安全性和稳定性，提高了外科手术的效率。所述使用方法包括以下步骤：取与所述吻/闭合口加固修复组合件相配合的待加固装置，将待加固装置的待加固部位穿插于所述加固修复部围成的空间，撤出所述保护部，拉紧连接线使所述加固修复部紧固在待加固装置的待加固部位，完成吻/闭/缝合后，牵拉并抽离连接线。
附图说明
图1是本发明加固修复片的HE染色切片；
图2是本发明加固修复片的SEM照片；
图3是本发明吻/闭合口加固修复组合件的第一种实施方式俯视示意图；
图4是本发明吻/闭合口加固修复组合件的第二种实施方式俯视示意图；
图5是本发明吻/闭合口加固修复组合件的第三种实施方式俯视示意图；
图6是本发明吻/闭合口加固修复组合件的侧视示意图；
图7是一种外科加固装置吻合器的示意图；
图8是本发明吻/闭合口加固修复组合件安装到外科加固装置吻合器的钉砧臂和钉仓 臂侧视图；
其中，11.加固修复部，12.保护部，13.连接线，111.孔对，1311.第一自由段，1312.第一半开放段，1313.拉动段，1314.保持段，1315.锁定段，1316.第一释放段，1321.第二自由段，1322.第二半开放段，1323.第二释放段，1331.第三自由段，1332.第三半开放段，1333.第三释放段，2.吻合器，21.钉砧臂，22.钉仓臂，23.把手。
具体实施方式
本发明提供一种吻/闭合口加固修复组合件及其制备和使用方法，为了帮助理解本发明的各个方面，提供以下实施例。需要说明的是，实施例是为了解释本发明，本发明并不为这些实施例所限制。原料的可以从猪或牛等物种获取，其中猪可以是基因纯合率50％以上的猪。下文以猪为例进行说明。
实施例1：
加固修复片的制备
需要说明的是，加固修复片为本发明常用的加固修复部的成品之一。
加固修复片可以按如下述方法制备：
(a)原料选择与初处理：选择中国近交系五指山小型猪作为动物来源，动物品种的确定采用专利ZL200510008994.2所规定的方法，取新鲜屠宰的中国近交系五指山小型猪的小肠组织清洗洁净，分离出小肠粘膜下层组织，将小肠粘膜下层组织分割成规定尺寸，剔除淋巴组织，用自来水冲洗1～3次，再用纯化水冲洗至表面无污渍，将冲洗后的小肠粘膜下层组织静置，筛网过滤。
(b)风险处理：采用过氧乙酸－乙醇溶液浸泡(a)筛网过滤好的小肠粘膜下层组织，该过程可在不锈钢桶中进行，过氧乙酸浓度采用0.1～5％，乙醇浓度采用5～40％，灭活时间2～4小时，溶液与小肠粘膜下层组织体积比为20～40：1，温度范围为10～40℃，筛网过滤；
(c)免疫原去除：采用4mol/L浓度的氯化钠溶液，其与(b)处理后的小肠粘膜下层组织体积比为20～30:1，于-20℃冷冻，约1小时后取出，置于37℃同浓度氯化钠溶液中融化；反复冷冻-融化3～5次后，用纯水放置于超声波中清洗，把氯化钠清洗干净，筛网过滤；
(d)清洗过程：采用pH值为6～8的PBS溶液清洗，温度10～40℃，溶液与(c)处理后的小肠粘膜下层组织体积比例为20～40：1，每次10～30分钟；清洗2～4次，检测pH值为6～8，再用采用的注射用水清洗，温度范围为10～40℃，注射用水与猪小肠粘膜下层组织材料体积比为20～40：1，检测电导率为1μS/cm以下终止，清洗过程需在超声波清洗 机中进行；
(e)固定：该步骤在模具上进行，模具由带针底板、盖板与重物三部分组成，需要根据不同的规格尺寸选择不同的模具，将小肠粘膜下层组织平铺于带针底板上，产品上面覆盖有不透气的不锈钢盖板，盖板的面积为最终裁剪的尺寸或更宽，不锈钢板上压5～10公斤的重物，让水分从四周溢出，将多层半挤压好的小肠粘膜下层组织多层叠加，确保上下层之间紧紧粘住，得半成品的加固修复片；
(f)真空冷冻干燥：该过程需要在真空冷冻干燥机中进行，半成品的冷冻干燥工艺需要根据不同的设备重新确认，将模具平铺于真空冷冻干燥机中，关闭冻干室的门，打开循环泵约1分钟，开启压缩机对冻干箱致冷，将产品预冻至-45℃，保温约1～2小时，开启真空泵，调节产品温度约-15℃升华，约5～7小时后，调节产品温度0℃，保温2小时，调节产品温度25℃，保温4小时，真空冷冻干燥完成，得干燥的所述加固修复片；
(g)成型：干燥的产品取出后，切割成固定的形状；将连接线组装或缝制到干燥产品上，添加合适大小的特卫强纸为保险，采用双层特卫强包装袋包装，该过程需要无菌转运与操作；
(h)灭菌解析：产品采用环氧乙烷灭菌，灭菌条件：温度40℃，保温时间4小时，湿度30～70％，环氧乙烷的浓度为300～1000mg/L，灭菌时间4小时；解析过程：通风的解析室中，温度控制在20℃之间，时间约14天，得所述加固修复片的成品。
灭菌方式还可以采用辐射灭菌、干热灭菌、温湿灭菌和/或气体灭菌。
实施例2：
本发明加固修复片的效果验证实验
优选在体内降解时间为1～3个月。加固修复片的力学性能包括破裂强度、缝合保持力和/或抗张强度。图1是加固修复片的HE染色切片；从图1可以看到HE染色后，通过光学显微镜对实施例1中的样品进行观察，可以看到本发明中提供的制备方法，细胞外基质的保留完整、连续，无细胞残留。
通过扫描电子显微镜对样品进行观察，可以看到处理后得到小肠粘膜下层组织的细胞外基质片，胶原蛋白纤维完整、未发生破坏、无断裂，是一种相互交错的多孔网络状结构，研究已证明该结构能够为细胞的分化、生长提供良好的诱导“模板”和生长“土壤”，是创伤修复的良好基础。
进一步对实施例1中的样品进行理化性能检测，检测项目为酸碱度、重金属含量和炽灼残渣，缝合抗拉强度，抗张强度。
a.酸碱度：按照实施例1制备样品，依据GB/T 14233.1-2008中5.4.1规定的方法进行，样品检验液与空白对照液的PH值之差不超过1；
b.重金属含量：按照实施例1制备样品，铅、铬按GB/T 14233.1-2008中5.9.1规定的原子吸收分光光度计法试验，汞、砷按GB/T 14233.1-2008中5.9.3规定的原子荧光光谱法试验，检测结果显示，重金属含量低于0.1μg/g。
c.炽灼残渣：按照实施例1制备样品，按照《中华人民共和国药典》(2015年版四部)0841规定的方法测定，炽灼残渣为1.0％。
d.缝合抗拉强度：按照实施例1制备样品，用3-0非吸收缝合线在修复片一端边缘2毫米处，将修复片的另一端和缝合线分别固定在拉力仪上，以20mm/min的速度进行拉伸，直到缝合点被撕裂，记录最大力值，结果显示，本发明方法制备的加固修复片最大值可达10N以上。
e.抗张强度：按照实施例1制备样品，将样品裁剪成2cm×5cm尺寸，在相对湿度为40％-60％，温度为22℃±2℃的条件下放置2小时后进行试验。将试样两端固定在拉伸试验机的夹头上，以100mm/min的速度依次向外拉伸直到试样断裂，纵向试样和横向试样分别进行试验。最后的测定结果显示纵向抗张强度可达24N以上，横向抗张强度可达15N以上。
对加固修复片进行了生物化学检测。
a.细菌内毒素测定：按照实施例1制备样品，按GB/T 14233.2-2005规定的方法进行操作，结果显示细菌内毒素小于2EU/g。b.细胞残留检查:取3个产品分别进行HE染色，每个切片选3个视野，在400倍光学显微镜下观察完整细胞数量除以3，结果显示，平均每个视野完整细胞数量为0。足以避免很多的因外源细胞引入而导致的免疫致病反应。
c.DNA残留量：按照实施例1制备样品，依据《中华人民共和国药典》(2015版四部)3407规定的方法测定)，采用荧光染色法检测实施例3所提供的样品的DNA残留量。结果显示，样品中的DNA残留量小于10pg/g。大大减弱受体对动物源DNA的免疫反应而造成的各种炎症反应，甚或由于DNA残留量已经低至如此而无明显的炎症反应发现。
d.α-Gal清除率：按照实施例1制备样品，根据“医疗器械免疫原性评价方法第5部分：用M86抗体测定动物源性医疗器械中α-Gal抗原清除率”的方法检测，α-Gal清除率为99.4％
d.IgA残留量：按照实施例1制备样品，取10个样品，取样，浸提，用猪免疫球蛋白A(IgA)定量检测试剂盒(ELISA)测试IgA残留量。结果显示，本发明样品的IgA残留小于1μg/g。表示样品的免疫原性很低，或近无。
e.FGF-2保留量：按照实施例1制备样品，取10个样品，取样，浸提，用猪碱性成纤维细胞生长因子(FGF2)检测试剂盒测试FGF-2含量。结果显示，本发明样品的FGF-2保留量平均值为30.8ng/g±17.3ng/g。
f.VEGF保留量：按照实施例1制备样品，取10个样品，取样，浸提，用猪血管内皮细胞生长因子(VEGF)试剂盒测试VEGF含量。结果显示，本发明样品的VEGF保留量平均值为99.6ng/g±2.4ng/g。
g.透明质酸(HA)保留量：按照实施例1制备样品，取10个样品，取样，浸提，用透明质酸检测试剂盒测试透明质酸(HA)含量。结果显示，本发明样品的透明质酸(HA)保留量平均值为332μg/g±231μg/g。
h.硫酸氨基聚糖(sGAGs)保留量：按照实施例1制备样品，取10个样品，取样，浸提，用Biocolor硫酸氨基聚糖检测试剂盒测试硫酸氨基聚糖(sGAGs)含量。结果显示，本发明样品的硫酸氨基聚糖(sGAGs)含量平均值为7442μg/g±6393μg/g。
生物学检测的结果表明本发明的加固修复片具有较低的致病性和高的生物相容性，且保留了大量的促进组织修复的有益成分。
对吻合口加固修复片的生物学评价，检测项目包括细胞毒性、迟发型超敏反应、皮内反应。
a.细胞毒性(MTT法)：按照实施例1制备样品，取样，浸提(浸提比例参考GB/T16886.12选择6cm2/mL，浸提介质为细胞完全培养基，浸提条件37℃，24h)，按照GB/T16886.5-2003(《医疗器械生物学评价第5部分体外细胞毒性试验》)中规定的试验方法检测，细胞毒性结果小于或等于1级。
b.迟发型超敏反应：按照实施例1制备样品，取样，按照GB/T16886.10-2003(《医疗器械生物学评价第十部分刺激与迟发型超敏反应试验》)中的迟发型超敏反应封闭敷贴法进行检测，试验样品选用浸提液(极性浸提介质选生理盐水，非极性浸提介质选棉籽油，浸提比例选择6cm2/mL，浸提条件37℃，72h)，结果显示无迟发型超敏反应。
c.刺激：按照实施例1制备样品，取样，按照GB/T16886.10-2003(《医疗器械生物学评价第十部分刺激与迟发型超敏反应试验》)中的皮内反应法进行检测，极性浸提介质选生理盐水，非极性浸提介质选棉籽油，浸提比例选择6cm2/mL，浸提条件37℃，72h)，结果显示试验样品与溶剂对照综合平均记分之差不大于1.0。
吻合口加固修复片的体外模拟降解过程。按照实施例1制备样品，在环氧乙烷灭菌步骤控制灭菌参数使灭菌时间分别4h、5h、6h、7h、8h，获得的样品各组取10mg样品(裁 剪为长条状)，置于2mL含0.2mg/mL蛋白酶K的PBS溶液中，并置于56℃水浴，每隔15min拍照，并记录材料降解过程，直至材料全部溶解无固体体残留。结果灭菌4h、5h、6h、7h、8h的样品体外模拟降解时间分别为120min、90min、75min、60min、45min。
加固修复片的血管生成效应及检查。取实施例1中制备的样品6个，为试验组；选用商用伤口修补材料“巴德BARD”补片(BARD)为对照组，也取6个。实施例1中制备的样品使用前经低温环氧乙烷灭菌，BARD选用已灭菌且无菌转运的类型。12个样品分别取1×1.5cm的块植入大鼠的皮下，3周后用微血管荧光造影的方法定量评估每个样品的血管生成效应。其中三个BARD和三个自制植入体，用明胶墨汁灌注法，通过计算样品中血管的直径、密度、面积等，定量检测样品中的血管容量。另外三个BARD和自制植入体，用切片和H&E染色法进行组织学研究，以表征细胞生长情况。
微血管荧光造影的结果表明所有的植入体均有血管生成效应。BARD的血管生长情况明显低于自制补片，在所研究的6个植入体中仅有一块儿观察到血管长入。血管容量的研究结果显示BARD植入体远远低于实验组。组织学研究的结果也与微血管荧光造影和明胶墨汁灌注的结果一致，实验组有明显的纤维血管长入，表现出显著的功能重建证据效应；而对照组BARD植入体仅观察到极微量的纤维血管长入。
结合附图进一步分别说明本发明的三种编织网状结构吻/闭合口加固修复组合件中及其使用方法。
实施例3：
第一种编织网状结构由编织起始端到编织末端依次分为第一自由段1311、互相连接的多个第一半开放段1312、拉动段1313、保持段1314、锁定段1315和第一释放段1316，第一半开放段1312的数量可与所述孔对111的数量相同，每个第一半开放段1312所围成的绳套整体连通孔对111的两个线孔，第一半开放段1312的开口端位于加固修复部11的同一端，锁定段1315穿过第一半开放段1312围成的绳套；由编织起始端到编织末端，第一个第一半开放段1312的开口处靠近编织起始端的一端与第一自由段1311连接，最后一个第一半开放段1312的开口处靠近编织末端的一端与拉动段1313的一端连接，拉动段1313的另一端与保持段1314的一端连接，保持段1314的另一端与锁定段1315的一端连接，锁定段1315的另一端与第一释放段1316连接。
连接线13按照上述第一种编织网状结构进行编织后，将保护部12穿插入加固修复部11的两端围合成的空间内，成为连接线13处于偏松散状态的吻/闭合口加固修复组合件，然后将偏松散的吻/闭合口加固修复组合件套在吻合器2的钉砧臂21和/或钉仓臂22上， 且使编织网状结构和与编织网状结构相贴合的保护部12处在钉砧臂21和/或钉仓臂22的非工作面上，撤出保护部12；然后在第一自由段1311、保持段1314和第一释放段1316不动的情况下，拉紧拉动段1313使吻/闭合口加固修复组合件紧固在钉砧臂21和/或钉仓臂22上，使第一释放段1316处于吻合器2的把手23附近，进而使用附有加固修复功能的吻合器2进行吻/闭/缝合操作；在完成吻/闭/缝合后，牵拉第一释放段1316，将连接线13抽离。
实施例4：
第二种编织网状结构由编织起始端到编织末端依次分为第二自由段1321、互相串接的n个第二半开放段1322、第二释放段1323，第二半开放段1322的数量可与孔对111的数量相同；由编织起始端到编织末端，第一个第二半开放段1322的开口处靠近编织起始端的一端与第二自由段1321连接，第n个第二半开放段1322的开口处靠近编织末端的一端与第二释放段1323连接，每个第二半开放段1322均穿过位于加固修复部11同一端的线孔，且从第二个第二半开放段起，每个第二半开放段1322所围成的绳套整体穿过其前一个第二半开放段1322所围成的绳套。
连接线13按照上述第二种编织网状结构进行编织后，将保护部12穿插入加固修复部11的两端围合成的空间内，成为连接线13处于偏松散状态的吻/闭合口加固修复组合件，然后将偏松散的吻/闭合口加固修复组合件套在吻合器2的钉砧臂21和/或钉仓臂22上，且使编织网状结构和与编织网状结构相贴合的保护部12处在钉砧臂21和/或钉仓臂22的非工作面上，撤出保护部12；然后在第二自由段1321和第二释放段1323不动的情况下，拉紧第n个第二半开放段1322所围成的绳套使吻/闭合口加固修复组合件紧固在钉砧臂21和/或钉仓臂22上，使第二释放段1323处于吻合器2的把手23附近，进而使用附有加固修复功能的吻合器2进行吻/闭/缝合操作；在完成吻/闭/缝合后，牵拉第二释放段1323，将连接线13抽离。
实施例5：
第三种编织网状结构由编织起始端到编织末端依次分为第三自由段1331、互相连接的2n个第三半开放段1332、第三释放段1333，第三半开放段1332的数量可为孔对111的数量的两倍；由编织起始端到编织末端，第一个第三半开放段1332的开口处靠近编织起始端的一端与第三自由段1331连接，第2n个第三半开放段1332的开口处靠近编织末端的一端与第三释放段1333连接，编织网状结构的编织方式为沿着加固修复部11上的线孔依次进行蛇形编织，且从第二个第三半开放段起，围成每个第三半开放段1332的绳线与其 前一个第三半开放段1332所围成的绳套交织。
连接线13按照上述第三种编织网状结构进行编织后，将保护部12穿插入加固修复部11的两端围合成的空间内，成为连接线13处于偏松散状态的吻/闭合口加固修复组合件，然后将偏松散的吻/闭合口加固修复组合件套在吻合器2的钉砧臂21和/或钉仓臂22上，且使编织网状结构和与编织网状结构相贴合的保护部12处在钉砧臂21和/或钉仓臂22的非工作面上，撤出保护部12；然后在第三自由段1331和第三释放段1333不动的情况下，拉紧第2n个第三半开放段1332所围成的绳套使吻/闭合口加固修复组合件紧固在钉砧臂21和/或钉仓臂22上，使第三释放段1333处于吻合器2的把手23附近，进而使用附有加固修复功能的吻合器2进行吻/闭/缝合操作；在完成吻/闭/缝合后，牵拉第三释放段1333，将连接线13抽离。、
本发明实施例中运用了外科手术中常用的吻合器作为索命，常用缝钉为钛、镁、铝或其他可吸收材质，但是也可以运用于吻/闭合器为线性吻/闭合器或环形吻/闭合器等其他类型的吻/闭合器。
需要说明的是，本发明实施例及附图中的编织网状结构仅作为示例，但是实际操作中需根据吻/闭合口加固修复组合件的实际长度、紧固强度以及与之相配合的吻/闭/缝合装置特点将该编织网状结构扩展到每侧更多个线孔或孔对的情况。
以上就本发明较佳的实施例作了说明，但不能理解为是对权利要求的限制。本发明不仅局限于以上实施例，其具体结构允许有变化，凡在本发明独立要求的保护范围内所作的各种变化均在本发明的保护范围内。

Claims (10)

  1. 一种吻/闭合口加固修复组合件，其特征在于：该吻/闭合口加固修复组合件包括加固修复部、保护部和连接线，所述连接线将所述加固修复部的两端可拆卸连接，所述保护部穿插于加固修复部的两端围合成的空间内。
  2. 根据权利要求1所述的一种吻/闭合口加固修复组合件，其特征在于：所述加固修复部的材料为无免疫原性且可体内降解的材料，所述保护部的材料为合成高分子材料、陶瓷材料、金属材料、特卫强纸、医用合成纸中的一种或多种组合，所述连接线材料为医疗可用线。
  3. 根据权利要求1所述的一种吻/闭合口加固修复组合件，其特征在于：所述保护部为平面片状或曲面片状，所述保护部的厚度为50～10000微米，所述保护部的长度大于所述加固修复部的长度。
  4. 根据权利要求1所述的一种吻/闭合口加固修复组合件，其特征在于：所述可拆卸连接具体是指：所述加固修复部的两端沿边缘的对应位置处设有至少一个孔对，每个所述孔对均包括分别位于所述加固修复部两端的线孔，单股或多股的所述连接线穿过所述线孔形成可拆卸的编织网状结构。
  5. 根据权利要求4所述的一种吻/闭合口加固修复组合件，其特征在于：所述编织网状结构为以下编织网状结构中的任一种：
    第一种所述编织网状结构由编织起始端到编织末端依次分为第一自由段、互相连接的n个第一半开放段、拉动段、保持段、锁定段、第一释放段，每个所述第一半开放段所围成的绳套整体连通所述孔对的两个线孔，所述第一半开放段的开口端位于所述加固修复部的同一端，所述锁定段穿过所述第一半开放段围成的绳套；由编织起始端到编织末端，第一个所述第一半开放段的开口处靠近编织起始端的一端与所述第一自由段连接，第n个所述第一半开放段的开口处靠近编织末端的一端与所述拉动段的一端连接，所述拉动段的另一端与所述保持段的一端连接，所述保持段的另一端与所述锁定段的一端连接，所述锁定段的另一端与所述第一释放段连接；
    第二种所述编织网状结构由编织起始端到编织末端依次分为第二自由段、互相串接的n个第二半开放段、第二释放段；由编织起始端到编织末端，第一个所述第二半开放段的开口处靠近编织起始端的一端与所述第二自由段连接，第n个所述第二半开放段的开口处靠近编织末端的一端与所述第二释放段连接，每个所述第二半开放段均穿过位于所述加固 修复部同一端的线孔，且从第二个第二半开放段起，每个所述第二半开放段所围成的绳套整体穿过其前一个第二半开放段所围成的绳套；
    第三种所述编织网状结构由编织起始端到编织末端依次分为第三自由段、互相连接的2n个第三半开放段、第三释放段；由编织起始端到编织末端，第一个所述第三半开放段的开口处靠近编织起始端的一端与所述第三自由段连接，第2n个所述第三半开放段的开口处靠近编织末端的一端与所述第三释放段连接，所述编织网状结构的编织方式为沿着所述加固修复部上的线孔依次进行蛇形编织，且从第二个第三半开放段起，围成每个所述第三半开放段的绳线与其前一个所述第三半开放段所围成的绳套交织。
  6. 权利要求1所述的一种吻/闭合口加固修复组合件的制备方法，该制备方法包括在无菌条件下，将所述连接线编织在所述加固修复部上，再组装上所述保护部，即得所述吻/闭合口加固修复组合件，其特征在于：所述加固修复部的制备方法包括以下步骤：
    (1)原料选择与初处理：选取小肠粘膜下层组织材料，剔除淋巴组织，用水冲洗至表面无污渍，筛网过滤；
    (2)风险处理：用过氧乙酸-乙醇溶液浸泡步骤(1)筛网过滤后的小肠粘膜下层组织，筛网过滤；
    (3)免疫原去除：将所述步骤(2)风险处理后的小肠粘膜下层组织与浓度为3～6mol/L、体积为所述步骤(2)风险处理后的小肠粘膜下层组织体积20～30倍的氯化钠溶液混合，于-25～-20℃冷冻，0.5～1.5小时后取出，置于35～40℃同浓度氯化钠溶液中融化，反复冷冻-融化3～5次后，清洗去除氯化钠；
    (4)固定：选择带有针底板、盖板与重物的特定模具，将步骤(3)免疫原去除后的小肠粘膜下层组织平铺于带针底板上，盖上盖板，重物挤压，让水分溢出，得半成品；
    (5)真空冷冻干燥：对半成品进行真空冷冻干燥，切割成特定形状，得干燥的所述加固修复部；
    (6)灭菌解析：对步骤(5)中的加固修复部进行灭菌，灭菌条件：温度35～40℃，保温时间3.5～4.5小时，湿度30～70％，环氧乙烷的浓度为300～1000mg/L，灭菌时间3.5～4.5小时，再在通风的解析室中解析，温度控制在15～25℃之间，时间10～20天，得所述加固修复部的成品。
  7. 根据权利要求6所述的一种吻/闭合口加固修复组合件的制备方法，其特征在于：所属步骤(2)使用的过氧乙酸-乙醇溶液中过氧乙酸体积浓度0.1～5％、乙醇体积浓度5～40％，所述过氧乙酸-乙醇溶液与猪小肠粘膜下层组织体积比例为20～40:1，浸泡时间2～4 小时、温度10～40℃。
  8. 根据权利要求6所述的一种吻/闭合口加固修复组合件的制备方法，其特征在于：所述步骤(3)中的清洗去除氯化钠具体包括：用pH值为6～8、体积为所述步骤(2)筛网过滤后的小肠粘膜下层组织体积20～40倍的PBS溶液超声清洗，清洗温度10～40℃、每次清洗10～30分钟，多次清洗直至小肠粘膜下层组织和PBS溶液的混合溶液pH值为6～8，得到PBS溶液清洗后的小肠粘膜下层组织，再用注射用水超声清洗，在温度10～40℃清洗，直至小肠粘膜下层组织和注射用水的混合溶液的检测电导率为0～1μS/cm。
  9. 根据权利要求6所述的一种吻/闭合口加固修复组合件的制备方法，其特征在于：所述步骤(5)真空冷冻干燥条件依次为：预冻至-40～-50℃，保温1～2小时；调节温度至-10～-20℃，保温5～7小时；调节温度-5～-4℃，保温1.5～2.5小时；调节产品温度20～30℃，保温3.5～4.5小时。
  10. 权利要求1-5任一权利要求所述的一种吻/闭合口加固修复组合件的使用方法，其特征在于：该使用方法包括以下步骤：取与所述吻/闭合口加固修复组合件相配合的待加固装置，将待加固装置的待加固部位穿插于所述加固修复部围成的空间，撤出所述保护部，拉紧连接线使所述加固修复部紧固在待加固装置的待加固部位，完成吻/闭/缝合后，牵拉并抽离连接线。
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US11116504B2 (en) 2021-09-14
CN106725679A (zh) 2017-05-31
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