WO2023143334A1 - 一种预防吻合口瘘的植入物 - Google Patents

一种预防吻合口瘘的植入物 Download PDF

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Publication number
WO2023143334A1
WO2023143334A1 PCT/CN2023/073021 CN2023073021W WO2023143334A1 WO 2023143334 A1 WO2023143334 A1 WO 2023143334A1 CN 2023073021 W CN2023073021 W CN 2023073021W WO 2023143334 A1 WO2023143334 A1 WO 2023143334A1
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Prior art keywords
implant
digestive tract
fibrinogen
tissue
parts
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PCT/CN2023/073021
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English (en)
French (fr)
Inventor
何红兵
尹荣鑫
周星宇
杨莉
闫侃
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上海松力生物技术有限公司
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Publication of WO2023143334A1 publication Critical patent/WO2023143334A1/zh

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    • 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
    • A61L31/043—Proteins; Polypeptides; Degradation products thereof
    • A61L31/046—Fibrin; Fibrinogen
    • 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
    • A61L31/08—Materials for coatings
    • 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
    • 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
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/406—Antibiotics
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings

Definitions

  • the invention belongs to the technical field of medical devices and relates to an implant for preventing anastomotic leakage.
  • Acute peritoneal (pleurisy) inflammation after gastrointestinal surgery is a serious complication with a high mortality rate between 6-22%, and about 19% of the cases are secondary to anastomotic leakage (AL). has not been effectively reduced.
  • the causes of anastomotic leakage are complex and have many factors. The most important ones are closely related to the anastomotic technique and operation, and are related to local infection of the anastomosis and excessive tension after anastomosis.
  • other risk factors worthy of attention first, frequent and severe cough after surgery, which causes the change of airway pressure to be transmitted to the digestive tract, causing a sharp change in the pressure in the esophagus and gastric cavity to generate a huge shock wave; The pull of gravity, both of which can tear the fragile edematous anastomotic tissue during the healing process and form an anastomotic stoma.
  • Anastomotic leakage may occur within 3 days after the operation, which is an early leakage, and the occurrence rate is about 1-5%; it occurs 4-14 days after operation, which is a mid-term leakage, which has a higher probability of occurrence and more complicated causes, such as anastomotic leakage Local suture infection, tissue cutting necrosis, postoperative pleural effusion not treated in time, pulmonary insufficiency, poor tissue healing ability, severe and frequent coughing, thoracic and gastric dilatation, gastric emptying disorder, and the pulling of the anastomosis by the gravity of the stomach itself Pulling, some are caused by roundworm drilling, etc., the probability of mid-term fistula is about 75-85%; more than 14 days after operation, secondary anastomotic leakage may be caused by local infection around the anastomotic stoma or due to anastomotic fistula The smaller mouth causes later fistula, and the probability of occurrence is about 10-20%.
  • the purpose of the present invention is to address the deficiencies in the prior art and provide an implant for preventing anastomotic leakage.
  • the implant provided by the present invention can increase the local anti-leakage pressure of the anastomotic stoma, reduce local tension, and prevent early
  • the occurrence of anastomotic leakage can also promote the regeneration of anastomotic intestinal wall tissue, thereby effectively preventing the occurrence of anastomotic leakage and anastomotic stricture in the middle and late stages.
  • the present invention provides an implant for preventing anastomotic leakage, the implant has a three-dimensional nano-reticular structure inside, and is prepared from raw materials comprising a fibrinogen complex and a poly(lactic-acid-polycaprolactone) copolymer made.
  • the inventive discovery of the present invention adopts The implant prepared from specific raw materials and having a three-dimensional nano-network structure is degradable and capable of inducing tissue regeneration, which can effectively enhance the leakage pressure resistance of the anastomosis in the early stage of anastomosis and prevent early anastomotic leakage.
  • the above-mentioned implant prepared from specific raw materials and having a three-dimensional nano-network structure degrades, it can effectively induce anastomotic tissue regeneration, thereby preventing anastomotic leakage and anastomosis in the middle (2 weeks to 4 weeks) and late (over 4 weeks) The mouth is narrow.
  • the fibrinogen complex comprises the following components in parts by weight: 0.1-20 parts of fibrinogen, 0.1-10 parts of arginine hydrochloride, 0.01-10 parts of sodium chloride and citrate 1-10 parts of sodium citrate.
  • the fibrinogen in the fibrinogen complex, can be 0.1 part, 0.5 part, 1 part, 1.5 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts copies, 10 copies, 12, 13, 15, 18 or 20 etc.
  • arginine hydrochloride in the fibrinogen complex, can be 0.1 part, 0.5 part, 0.8 part, 1 part, 1.2 part, 1.5 part, 1.8 part, 2 parts, 3 parts, 4 parts, 5 parts parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts etc.
  • sodium chloride in the fibrinogen complex, can be 0.01 part, 0.1 part, 0.2 part, 0.3 part, 0.4 part, 0.5 part, 0.6 part, 0.7 part, 0.8 part, 0.9 part, 1 part, 2 parts parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts or 10 parts etc.
  • sodium citrate in the fibrinogen complex, can be 1 part, 1.2 parts, 1.5 parts, 1.8 parts, 2 parts, 2.2 parts, 2.5 parts, 2.8 parts, 3 parts, 4 parts, 5 parts, 6, 7, 8, 9 or 10 etc.
  • the fibrinogen complex comprises the following components in parts by weight: 3-15 parts of fibrinogen, 0.5-5 parts of arginine hydrochloride, 0.3-5 parts of sodium chloride and citrate 1-10 parts of sodium citrate.
  • the fibrinogen is derived from mammals; the mammals include humans, pigs, cattle, sheep or horses; further preferably, the fibrinogen is derived from pig blood Fibrinogen.
  • the mass ratio of the fibrinogen complex to the poly(lactic acid polycaprolactone) copolymer is (0.31-1.1):1.
  • the mass ratio of the two can be 0.31:1, 0.4:1, 0.45:1, 0.48:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1 or 1.1:1, preferably (0.48-1.1):1.
  • the polylactic acid-polycaprolactone copolymer has a molecular weight of 50,000-300,000.
  • the protein content in the implant is 100-220 mg/g, and the residual protein content is less than 12 mg/g.
  • the protein content is the protein content measured in the test solution prepared by dissolving the sample through sodium hydroxide solution; the residual protein content is the test solution obtained by leaching the sample with water for injection or physiological saline. The resulting protein content.
  • the implant is in the form of a sheet. Since the implant provided by the present invention is prepared from specific raw materials and has a three-dimensional nano-network structure, it presents a very simple sheet structure, which can significantly enhance the anti-leakage pressure of the anastomotic stoma and effectively prevent anastomotic leakage.
  • the implant provided by the invention has a simple appearance and is very convenient to prepare and use.
  • the thickness of the implant is 0.1mm-0.4mm, such as 0.1mm, 0.2mm, 0.25mm, 0.3mm, 0.35mm, 0.38mm, 0.4mm, etc., more preferably 0.2mm-0.38 mm.
  • the porosity of the implant is 40-80%, such as 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, etc. Controlling the porosity of the implant at 40-80% can significantly improve the ability of the implant to resist leakage pressure.
  • the water absorption of the implant is 20-200%, such as 20%, 30%, 40%, 50%, 60%, 80%, 100%, 120%, 150%, 180% , 200%, etc., preferably 50-100%.
  • the burst strength of the implant is 10N-100N, such as 20N, 30N, 40N, 50N, 60N, 70N, 80N, 90N, etc., preferably 20N-80N.
  • the tensile strength of the implant is 0.5MPa-5MPa, such as 0.5MPa, 1.0MPa, 1.5MPa, 2.0MPa, 2.5MPa, 3.0MPa, 3.5MPa, 4.0MPa, 4.5MPa, 5.0 MPa and the like are preferably 1.0 to 4.0 MPa.
  • the elongation at break of the implant is 60-200%, such as 60%, 70%, 80%, 90%, 100%, 120%, 140%, 160%, 180%, 200% or the like, preferably 70% to 160%.
  • the implant is prepared by electrospinning.
  • the solution containing the fibrinogen complex and the solution containing polylactide polycaprolactone are mixed and then added to the same capacity tube of the electrospinning machine for electrospinning.
  • the compound containing fibrinogen when preparing the implant, the compound containing fibrinogen
  • the solution of the compound and the solution containing polycaprolactone polylactic acid were respectively added into two different capacity tubes of the electrospinning machine, and the electrospinning was carried out simultaneously.
  • the fibrinogen complex used to prepare the implant is in solution.
  • the solvent of the solution is selected from one or more of pure water, water for injection, saline solution, buffer; the saline solution is selected from sodium chloride solution, potassium chloride solution; the buffer is selected from phosphate buffered saline solution, Tris-HC1 buffer, glycine buffer, D-Hank's solution.
  • the fibrinogen complex is an aqueous solution with a concentration of 8-36g%, preferably 8-29g% (g%, ie g/100ml).
  • the solution containing poly(lactic-acid-polycaprolactone) is a poly(lactic-acid-polycaprolactone) copolymer with a concentration of 5-10% by mass volume, preferably 5- 8% dissolved in one or more mixed solvents of hexafluoroisopropanol, chloroform, dimethylformamide, tetrahydrofuran and acetone.
  • the solution containing polylactide-polycaprolactone uses hexafluoroisopropanol as a solvent; after the product is prepared, it should be ensured that the residual amount of hexafluoroisopropanol is less than 0.55 mg/g.
  • the voltage difference of the electrospinning is 15kv-140kv, preferably 40kv-60kv; the electrospinning distance is 10mm-60mm or 10-50cm; the spinning solution advancing speed It is 2-399ml/h, preferably 40-60ml/h, or 401-960mL/h.
  • the implant when preparing the implant, it is necessary to remove the residual organic solvent in the implant obtained by electrospinning, and then sterilize.
  • Said disinfection can adopt methods such as ethylene oxide, gamma rays or electron beams.
  • the surface of the implant is coated with drugs having antibacterial and/or anti-inflammatory effects.
  • the medicine can be gentamicin, penicillin, streptomycin, metronidazole and the like.
  • the implant is implanted at the anastomosis when a stapler is used to perform anastomosis of the digestive tract.
  • an opening is provided in the center of the implant, through which the connecting rod between the staple cartridge and the nail abutment seat of the stapler can pass.
  • the implant is mated to a staple cartridge of the stapler.
  • the stapler is a tubular stapler
  • the implant is in the shape of a disc with an open center.
  • the present invention provides a method for implanting said implant.
  • the using method includes the following steps: placing the implant between the staple cartridge and the staple abutment seat of the stapler.
  • the method further includes: using a stapler to implant the implant at an anastomosis of the digestive tract.
  • the alimentary canal in the present invention may refer to the esophagus, stomach, small intestine, large intestine, colorectum, etc.
  • the present invention provides the use of the implant in the preparation of materials for repairing tissue defects in the body.
  • the implant is used to prepare a repair material for anastomotic stoma after digestive tract surgery.
  • the digestive tract is preferably selected from the group consisting of esophagus, stomach, small intestine, large intestine and colorectum.
  • the present invention provides the use of the implant in in situ inducing regeneration of digestive tract tissue.
  • the digestive tract is preferably selected from the group consisting of esophagus, stomach, small intestine, large intestine and colorectum.
  • the digestive tract tissue is the tissue at the anastomosis after digestive tract surgery.
  • the digestive tract tissue is selected from the group consisting of mucosal layer, muscularis submucosa, muscularis layer, and adventitia layer, and their corresponding extracellular matrix.
  • the implant provided by the present invention can induce the regeneration of anastomotic intestinal wall tissue (comprising mucosal layer, submucosal muscle layer, muscle layer and adventitia layer and corresponding extracellular matrix) in situ in the early stage after implantation, avoiding Local scar formation can be prevented, which can prevent the occurrence of early anastomotic leakage, and then lay a solid foundation for preventing adverse reactions such as anastomotic leakage and intestinal scar contraction in the middle and late stages.
  • anastomotic intestinal wall tissue comprising mucosal layer, submucosal muscle layer, muscle layer and adventitia layer and corresponding extracellular matrix
  • the present invention provides the use of the implant in promoting capillary proliferation and/or regeneration of digestive tract tissue.
  • the digestive tract is preferably selected from the group consisting of esophagus, stomach, small intestine, large intestine and colorectum.
  • the digestive tract tissue is the tissue at the anastomosis after digestive tract surgery.
  • the digestive tract tissue is selected from the group consisting of mucosal layer, muscularis submucosa, muscularis layer, and adventitia layer, and their corresponding extracellular matrix.
  • the implant of the present invention can promote the healing of the anastomotic stoma by promoting the capillary proliferation of the anastomotic stoma tissue and the regeneration of the intestinal wall tissue of the anastomotic stoma, thereby effectively preventing the occurrence of anastomotic stoma leakage and anastomotic stoma stenosis in the middle and late stages.
  • the present invention provides the use of a hydrophilic electrospun biocomposite scaffold material in the preparation of materials for promoting the proliferation of capillaries in digestive tract tissue and/or promoting the regeneration of digestive tract tissue
  • the composite scaffold material is made of
  • the aqueous solution of fibrinogen, L-arginine or its hydrochloride is blended with P(LLA-CL) solution, and is prepared by electrospinning technology; wherein, the fibrinogen and L-arginine or The mass ratio of its hydrochloride is 1.2:1 ⁇ 12.5:1;
  • the aqueous solution of the fibrinogen, L-arginine or its hydrochloride wherein the solvent is selected from one or more of pure water, water for injection, saline solution, buffer; the saline solution is selected from chlorine Sodium chloride solution, potassium chloride solution;
  • the buffer is selected from phosphate buffer, Tris-HCl buffer, glycine buffer, D-Hank's solution.
  • the digestive tract tissue is the tissue at the anastomosis after digestive tract surgery; the digestive tract is preferably selected from the group consisting of esophagus, stomach, small intestine, large intestine and colorectum.
  • the digestive tract tissue is selected from the group consisting of mucosal layer, muscularis submucosa, muscularis layer, and adventitia layer, and their corresponding extracellular matrix.
  • the fibrinogen is mammalian-derived fibrinogen.
  • the mammal is a human, porcine, bovine, ovine or equine.
  • the mass ratio of polylactic acid and polycaprolactone in the P(LLA-CL) is 20:80 ⁇ 95:5.
  • the solvent in the P(LLA-CL) solution is selected from hexafluoroiso One or more of propanol, chloroform, dimethylformamide, tetrahydrofuran, chloroform or acetone.
  • the mass ratio of fibrinogen:P(LLA-CL) 0.2:1 to 2.1:1.
  • the equilibrium contact angle of the hydrophilic electrospun biocomposite scaffold material is less than 55°.
  • the total volume shrinkage rate is not greater than 20%; the porosity is not lower than 30%.
  • the aqueous solution of fibrinogen, L-arginine or its hydrochloride is further loaded with antibacterial substances, and the antibacterial substances are selected from the group consisting of penicillins, cephalosporins, and carbapenicases. Alkenes, aminoglycosides, tetracyclines, macrolides, glycosides, sulfonamides, quinolones, nimidazoles, lincoamines, fosfomycin, chloramphenicol, p-colistin B, One or more of bacitracins.
  • the penicillins are selected from penicillins, ampicillin, carbenicillin; the cephalosporins are selected from cephalexin, cefuroxime sodium, ceftriaxone, cefpirome; the carbapenicase The alkene is thiamycin; the aminoglycoside is selected from gentamycin, streptomycin, kanamycin; the tetracycline is selected from tetracycline, aureomycin; the macrolide is selected from Erythromycin, azithromycin; the glycosides are vancomycin; the sulfonamides are selected from sulfadiazine and trimethoprim; the quinolones are selected from pipemidic acid and ciprofloxacin; the nimidazoles selected from metronidazole and tinidazole; the lincoamines selected from lincomycin and clindamycin.
  • the release amount of the antibacterial substance is no less than 30% of the total loaded amount.
  • the present invention has the following beneficial effects: (1) the implant provided by the present invention does not need to use any chemical or biological cross-linking agent for cross-linking and fixing, and does not contain biologically active factors and living cells; (2) ) The implantation provided by the present invention is induced through in situ colorectal tissue (including but not limited to: serosa, smooth muscle layer, submucosa and mucosal layer, and corresponding capillaries and cell matrix) regeneration, increase the local anti-leakage pressure of the anastomotic stoma, reduce the local tension, and then prevent the occurrence of early anastomotic leakage; (3) the implant of the present invention can also promote the anastomotic tissue capillary The proliferation of blood vessels and the regeneration of the intestinal wall tissue of the anastomosis promote the healing of the anastomosis, which can effectively prevent the occurrence of anastomotic leakage and anastomotic stricture in the middle and late stages.
  • in situ colorectal tissue including
  • Figure 1 is a broken-line relationship between the pressure in the small intestine lumen and the outer diameter of the small intestine after anastomosis.
  • Fig. 2 is a schematic diagram of the change of anastomotic leakage pressure on day 0, day 14, day 28 and day 56 of colorectal anastomotic operation.
  • Figure 3 is a schematic diagram showing the healing of the anastomotic intestinal wall tissue in the test group and the control group by HE staining at 8 weeks after operation.
  • Fig. 4 is a schematic diagram of the intestinal wall tissue healing of the anastomosis in the Masson staining test group and the control group at 8 weeks after operation.
  • the part raw material source that adopts is as follows:
  • Polylactic acid-polycaprolactone the molecular weight is 50,000-300,000 Daltons, purchased from Purac Company in the Netherlands;
  • Fibrinogen complex (pig source): produced by Shanghai Songli Biotechnology Co., Ltd. in accordance with the production process approved by the relevant state departments.
  • This embodiment provides a disc-shaped implant (with a hole in the middle) with a diameter of 2.9 cm, which is specifically prepared by the following method:
  • step (3) Mix the solution obtained in step (1) and step (2) and add it into the same capacity tube of the electrospinning machine, so that the mass ratio of the fibrinogen complex to the poly(lactic acid polycaprolactone) copolymer is 0.56: 1.
  • electrospinning electrospinning machine model: NS1WS 500Elmarco Czech Republic
  • the voltage difference of spinning is 50kv
  • the spinning distance is 40cm
  • the spinning solution propulsion speed is 50ml/h;
  • Residual organic solvent in the implant obtained by electrospinning is removed, and then sterilized by electron beam.
  • this embodiment specifically provides 6 kinds of implants with different thicknesses; the thicknesses of the 6 kinds of implants are respectively 0.01mm, 0.1mm, 0.2mm, 0.38mm, 0.8mm and 1.2mm, The corresponding porosity is in the range of 40%-80%, the water absorption is in the range of 50%-100%, and the bursting strength is in the range of 20-80N.
  • the disc-shaped implant with a diameter of 2.9 cm (open hole in the middle)
  • the specific preparation method is the same as that in Embodiment 1.
  • This embodiment specifically provides 5 kinds of implants with different porosities; the porosities of the 5 kinds of implants are respectively 10%, 20%, 40%, 80% and 95%, and the corresponding thickness is between 0.2mm-0.38mm. In the range of mm, the water absorption rate is in the range of 50%-100%, and the bursting strength is in the range of 20N-80N.
  • This embodiment provides a disc-shaped implant with a diameter of 2.9 cm (with a hole in the middle), and the specific preparation method is the same as that in Embodiment 1.
  • This embodiment specifically provides 6 kinds of implants with different water absorption rates; the water absorption rates of the 6 kinds of implants are respectively 10%, 20%, 50%, 100%, 200% and 300%, and the corresponding thickness is 0.2 In the range of mm-0.38mm, the porosity is in the range of 40%-80%, and the bursting strength is in the range of 20N-80N.
  • Example 1 The plants provided in Example 1 were tested for Performance Test 1, and the results are shown in Table 1.
  • the implant provided by the present invention when used, the local anti-leakage pressure of the anastomotic stoma can be increased, the local tension can be reduced, and the occurrence of anastomotic leak can be prevented; and the implant provided by the present invention has a thickness of 0.01 In the range of mm-0.8mm, the average leakage pressure is above 4.03KPa, which is higher than the standard requirements of 5.2.3 Pressure Test in YY/T0245-2008 General Technical Conditions for Anastomotic (Sewing) Staplers (not less than 3.6KPa) ; and when the thickness of the implant is 0.1-0.4mm, especially 0.2-0.38mm, the average leakage pressure is much higher than the standard requirement The pressure value is 3.6KPa.
  • Example 2 The plants provided in Example 2 were tested for performance test 1, and the results are shown in Table 2.
  • Example 3 The plants provided in Example 3 were tested for Performance Test 1, and the results are shown in Table 3.
  • the leakage pressure mean value is not less than 3.80KPa, higher than YY/T0245-2008 anastomotic (suture) stapler general technology 5.2.3 Standard requirements for pressure resistance test in the conditions (not less than 3.6KPa); and when the water absorption is in the range of 50-100%, it is much higher than the pressure value 3.6KPa required by the standard.
  • the first group is the normal control group
  • the second group is the group without implants
  • the third group Group is to add implant group
  • described implant is the implant that embodiment 1-4 provides;
  • the small intestines of the second and third groups were cut from the middle into two sections of equal length, and then anastomosed with a tubular stapler (CN-CS29, Jiangsu Chennuo Medical Instrument Co., Ltd.). into things.
  • CN-CS29 Jiangsu Chennuo Medical Instrument Co., Ltd.
  • the leak pressure of the anastomosis is 4.0 ⁇ 1.05KPa, which is 22% of the intestinal wall rupture pressure (18.0 ⁇ 1.33KPa) of the normal control group;
  • the mouth leakage pressure was 7.0 ⁇ 1.17KPa, which was 38% of the intestinal wall rupture force of the normal control group and increased by more than 42% compared with the group without implants.
  • Figure 1 is a broken-line relationship between the pressure in the small intestine lumen and the outer diameter of the small intestine after anastomosis. It can be seen from Figure 1 that placing an implant in the anastomosis can effectively protect the diameter of the anastomosis from changing with the diameter of the intestinal cavity. The increase of the pressure increases rapidly, so that the distance between the staple gaps is relatively constant, the leakage pressure of the anastomosis is increased, and the occurrence of early anastomotic leakage is prevented.
  • Each group is divided into 4 time points (0 day, 14 day, 28 day and 56 day after operation), and 6 pigs are dissected at each time point to measure the leakage pressure of the anastomotic stoma.
  • the rupture force of intestinal segment after colorectal anastomosis was used as normal control.
  • Figure 2 shows the changes in the leakage pressure of the anastomotic stoma on day 0, 14, 28 and 56 days after the colorectal anastomotic stoma operation. It can be seen from Figure 2 that on the 56th day after the operation, the anastomotic leakage pressure in the test group had returned to the normal intestinal wall level, while that in the control group had only reached about 80% of the normal intestinal wall level.
  • HE staining results From Figure 3, it can be seen that the test group (anastomotic stoma loaded with implant group; A: ⁇ 20, C: ⁇ 40) and the control group (anastomotic stoma without implant group; B: ⁇ 20, D: ⁇ 40) Histological regeneration of intestinal wall. Among them, the mucosal layer, submucosa, muscular layer, and adventitia in the test group were intact, and the place marked with "asterisk" was the place where non-absorbable sutures passed; the mucosal layer in the control group was intact, but the submucosa and muscular layer were intact. The layer is absent at the site of the anastomosis, which is filled by a disorderly array of fibrous tissue.
  • test group anastomotic stoma loading implant group; A: ⁇ 20, C: ⁇ 40
  • control group anastomotic stoma loading implant group; B: ⁇
  • Histological regeneration of intestinal wall From Figure 4, it can be seen that the test group (anastomotic stoma loading implant group; A: ⁇ 20, C: ⁇ 40) and control group (anastomotic stoma loading implant group; B: ⁇ ) at the 8th week after operation 20, D: ⁇ 40) Histological regeneration of intestinal wall.
  • the test group showed that the mucosal layer, submucosal muscle layer, muscle layer and adventitia layer were intact, and the space between the submucosa muscle layer and the muscle layer was similar to normal tissue, filled with collagen-based cell matrix and adipose tissue; and The control group lacked intact submucosa and muscularis submucosa, which was filled with bluish scar tissue.
  • the implant provided by the present invention can increase the local anti-leakage pressure of the anastomotic stoma and reduce the local tension in the early stage after implantation, thereby preventing the occurrence of anastomotic leakage, and at the same time, it can also be induced by in situ
  • the regeneration of anastomotic intestinal wall tissue can avoid local scar formation, so that it can effectively prevent anastomotic leakage and intestinal leakage in the middle and late stage. Adverse reactions such as scar shrinkage have laid a solid foundation.

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Abstract

本发明提供了一种预防吻合口瘘的植入物，所述植入物内部具有三维纳米网状结构，由包含纤维蛋白原复合物和聚乳酸聚己内酯共聚物的原料制备而成。本发明提供的植入物可以增加吻合口局部的抗泄漏压力，降低局部张力，原位诱导吻合口肠壁组织的再生，进而可以预防早期吻合口瘘的发生；同时还可以促进吻合口组织毛细血管的增殖以及促进吻合口肠壁组织的再生，促进吻合口愈合，从而可以有效的预防中期和晚期吻合口瘘和吻合口狭窄的发生。

Description

一种预防吻合口瘘的植入物 技术领域
本发明属于医疗器械技术领域，涉及一种预防吻合口瘘的植入物。
背景技术
消化道手术后的急性腹膜(胸膜)炎是严重的并发症，死亡率高，在6-22％之间，其中大约19％的病例是继发于吻合口瘘(AL)，目前对于发病率并未获得有效降低。
发生吻合口瘘的原因很复杂，有多方面的因素，最主要的是与吻合技术和手术操作密切相关，并与吻合口局部感染和吻合后张力过大等有关。另外值得重视的其他危险因素：一是术后频繁剧烈的咳嗽，引起呼吸道压力的变化传导到消化道，致食管和胃腔内压力急剧变化产生巨大的冲击波；二是大口吞咽过量饮食致使胃自身重力的牵拉，两者均可使愈合过程中脆弱水肿的吻合口组织撕裂而形成吻合口。吻合口瘘可能在手术后3天内出现，为早期瘘，发生概率在1-5％左右；在术后4-14天发生，为中期瘘，发生概率较大，发生原因较为复杂，如吻合口局部缝线感染、组织切割坏死、术后胸腔积液未及时处理、肺膨胀不全、组织愈合能力欠佳、剧烈频繁的咳嗽、胸胃扩张、胃排空障碍、胃自身重力对吻合口的牵拉，个别因蛔虫钻孔所致等，中期瘘发生概率约为75-85％；术后14天以上，可能会由于吻合口周围的局部感染所引起的继发性吻合口瘘或由于吻合瘘口较小引起后期瘘，发生概率为10-20％左右。早期诊断和治疗可以减少吻合口瘘的发生，但由于目前诊断方法缺乏特异性，因而对于吻合口瘘最好的治疗方法还是预防。目前常用的预防手段主要包括机械肠准备和/或口服抗生素、采用手术吻合器、进行漏气试验、引外流、经肛管手术，在上述预防方法中，依据目前的研究，没有足够证据证实机械肠准备和/或 口服抗生素与降低吻合口瘘的发生有直接关系，漏气试验并不能降低吻合口瘘的发生；而采用手术吻合器仅在有结肠切除手术中优于手缝吻合；外引流和经肛管手术在一定程度上可以降低吻合口瘘的发生，但是结肠手术无需引外流，反而会增加成本。
发明内容
本发明的目的在于针对现有技术存在的不足，提供一种预防吻合口瘘的植入物，本发明提供的植入物可以增加吻合口局部的抗泄漏压力，降低局部张力，进而可以预防早期吻合口瘘的发生，同时还可以通过促进吻合口肠壁组织的再生，从而可以有效的预防中期和晚期吻合口瘘和吻合口狭窄的发生。
为达此目的，本发明采用以下技术方案：
第一方面，本发明提供一种预防吻合口瘘的植入物，所述植入物内部具有三维纳米网状结构，由包含纤维蛋白原复合物和聚乳酸聚己内酯共聚物的原料制备而成。
现有技术在实施空腔脏器吻合时，吻合口间隙应该尽量清除诸如脂肪等组织，同时也尽量减少各种异物在吻合间隙的留存，以有利于吻合口愈合；本发明创造性的发现，采用由特定的原料制备而成且具有三维纳米网状结构的植入物，可降解并且能够诱导组织再生，可以在吻合初期有效地增强吻合口的抗泄漏压力的能力，预防早期吻合口瘘。随着上述由特定原料制备且具有三维纳米网状结构植入物降解，可以有效地诱导吻合口组织再生，从而预防中期(2周-4周)和晚期(4周以上)吻合口瘘和吻合口狭窄。
在一些实施方式中，所述纤维蛋白原复合物包含如下重量份数的组分：纤维蛋白原0.1-20份，精氨酸盐酸盐0.1-10份，氯化钠0.01-10份和枸橼酸钠1-10份。
例如，所述纤维蛋白原复合物中，纤维蛋白原可以是0.1份、0.5份、1份、1.5份、2份、3份、4份、5份、6份、7份、8份、9份、10份、 12份、13份、15份、18份或20份等。
例如，所述纤维蛋白原复合物中，精氨酸盐酸盐可以是0.1份、0.5份、0.8份、1份、1.2份、1.5份、1.8份、2份、3份、4份、5份、6份、7份、8份、9份或10份等。
例如，所述纤维蛋白原复合物中，氯化钠可以是0.01份、0.1份、0.2份、0.3份、0.4份、0.5份、0.6份、0.7份、0.8份、0.9份、1份、2份、3份、4份、5份、6份、7份、8份、9份或10份等。
例如，所述纤维蛋白原复合物中，枸橼酸钠可以是1份、1.2份、1.5份、1.8份、2份、2.2份、2.5份、2.8份、3份、4份、5份、6份、7份、8份、9份或10份等。
在一些实施方式中，所述纤维蛋白原复合物包含如下重量份数的组分：纤维蛋白原3-15份，精氨酸盐酸盐0.5-5份，氯化钠0.3-5份和枸橼酸钠1-10份。
在一些实施方式中，所述纤维蛋白原是来源于哺乳动物的纤维蛋白原；所述哺乳动物包括人、猪、牛、羊或马；进一步优选地，所述纤维蛋白原为猪血来源的纤维蛋白原。
在一些实施方式中，所述纤维蛋白原复合物与聚乳酸聚己内酯共聚物的质量比为(0.31-1.1)：1。具体地，二者的质量比可以是0.31:1，0.4:1，0.45：1，0.48：1，0.5:1，0.6:1，0.7：1，0.8：1，0.9：1，1：1或1.1：1，优选为(0.48-1.1):1。
在一些实施方式中，所述聚乳酸-聚己内酯共聚物的分子量为5万-30万。
在一些实施方式中，所述植入物中蛋白质含量为100-220mg/g，且残留蛋白含量小于12mg/g。其中，蛋白质含量是将样品经过氢氧化钠溶液溶解后，制得的供试液中测得的蛋白质含量；残余蛋白含量是将样品经过注射用水或者生理盐水浸提后得到的供试液中测得的蛋白质含量。
在一些实施方式中，所述植入物呈片状。由于本发明提供的植入物由特定的原料制备而成，且具有三维纳米网状结构，因此呈现极为简单的片状结构，就能够明显增强吻合口抗泄漏压力，有效预防吻合口瘘。本发明提供的植入物外形简单，制备和使用都非常简便。
在一些实施方式中，所述植入物的厚度为0.1mm-0.4mm，例如0.1mm、0.2mm、0.25mm、0.3mm、0.35mm、0.38mm、0.4mm等，进一步优选为0.2mm-0.38mm。
在一些实施方式中，所述植入物的孔隙率为40-80％，例如40％、45％、50％、55％、60％、65％、70％、75％、80％等。将植入物的孔隙率控制在40-80％，可以显著提高植入物的抗泄漏压力的能力。
在一些实施方式中，所述植入物的吸水性为20-200％，例如20％、30％、40％、50％、60％、80％、100％、120％、150％、180％、200％等，优选为50-100％。
在一些实施方式中，所述植入物的顶破强度为10N-100N，例如20N、30N、40N、50N、60N、70N、80N、90N等，优选为20N-80N。
在一些实施方式中，所述植入物的拉伸强度为0.5MPa-5MPa,例如0.5MPa、1.0MPa、1.5MPa、2.0MPa、2.5MPa、3.0MPa、3.5MPa、4.0MPa、4.5MPa、5.0MPa等，优选为1.0～4.0MPa。
在一些实施方式中，所述植入物的断裂伸长率为60-200％，例如60％、70％、80％、90％、100％、120％、140％、160％、180％、200％等，优选为70％～160％。
在一些实施方式中，所述植入物采用静电纺丝方法制备而成。
在一些实施方式中，制备所述植入物时，将含有纤维蛋白原复合物的溶液与含有聚乳酸聚己内酯的溶液混匀后加入静电纺丝机的同一容量管中，进行静电纺丝。
在一些实施方式中，制备所述植入物时，将含有纤维蛋白原复合 物的溶液和含有聚乳酸聚己内酯的溶液分别加入到静电纺丝机的两个不同的容量管中，同时进行静电纺丝。
在一些实施方式中，制备所述植入物时采用的纤维蛋白原复合物为溶液形式。该溶液的溶剂选自纯水、注射用水、盐溶液、缓冲液中的一种或多种；所述盐溶液选自氯化钠溶液、氯化钾溶液；所述缓冲液选自磷酸盐缓冲液、Tris-HC1缓冲液、甘氨酸缓冲液、D-Hank's液。作为一种具体实施方式，制备所述植入物时，纤维蛋白原复合物为浓度8-36g％、优选为8-29g％(g％，即g/100ml)的水溶液。
在一些实施方式中，制备所述植入物时，所述含有聚乳酸聚己内酯的溶液是将聚乳酸聚己内酯共聚物以质量体积百分浓度5-10％、优选为5-8％溶解在六氟异丙醇、三氯甲烷、二甲基甲酰胺、四氢呋喃和丙酮中的一种或两种以上的混合溶剂中。作为一种具体实施方式，所述含有聚乳酸聚己内酯的溶液以六氟异丙醇为溶剂；制备得到产品后，应确保六氟异丙醇的残留量小于0.55mg/g。
在一些实施方式中，制备所述植入物时，所述静电纺丝的电压差为15kv-140kv、优选为40kv-60kv；电纺距离为10mm-60mm或10～50cm；纺丝液推进速度为2-399ml/h、优选为40-60ml/h，或为401-960mL/h。
在一些实施方式中，制备所述植入物时，还需将静电纺丝所得植入物中残留的有机溶剂去除，再进行消毒。所述消毒可以采用环氧乙烷、γ射线或电子束等方式。
在一些实施方式中，所述植入物表面涂覆具有抗菌和/或消炎作用的药物。所述药物可以采用庆大霉素、青霉素、链霉素、甲硝唑等。
在一些实施方式中，所述植入物是利用吻合器进行消化道吻合术时被植入于吻合口处。
在一些实施方式中，所述植入物的中心设有开口，吻合器的钉仓与抵钉座之间的连接杆可在其中穿过。
在一些实施方式中，所述植入物与所述吻合器的钉仓匹配。
在一些实施方式中，所述吻合器为管型吻合器，所述植入物呈中心开口的圆片状。
第二方面，本发明提供所述植入物的植入方法。
具体而言，所述使用方法包括如下步骤：将所述植入物置于吻合器的钉仓与抵钉座之间。
在一些实施方式中，所述方法还包括：利用吻合器将所述植入物植入于消化道的吻合口处。
本发明所述消化道可以指食道、胃、小肠、大肠、结直肠等。
第三方面，本发明提供所述植入物植入物在制备修复机体组织缺损的材料中的用途。
在一些实施方式中，所述植入物用于制备消化道手术后吻合口的修复材料。所述消化道优选选自食道、胃、小肠、大肠和结直肠。
第四方面，本发明提供所述植入物植入物在原位诱导消化道组织再生中的用途。所述消化道优选选自食道、胃、小肠、大肠和结直肠。
在一些实施方式中，所述消化道组织为消化道手术后吻合口处组织。
在一些实施方式中，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
本发明提供的植入物在植入后早期，可以通过原位诱导吻合口肠壁组织(包括粘膜层，粘膜下肌层，肌层和外膜层及相应的细胞外基质)的再生，避免了局部瘢痕形成，可以预防早期吻合口瘘的发生，继而为预防中期和晚期吻合口瘘和肠道瘢痕收缩等不良反应奠定了坚实的基础。
第五方面，本发明提供所述植入物植入物在促进消化道组织毛细血管增殖和/或促进消化道组织再生中的用途。所述消化道优选选自食道、胃、小肠、大肠和结直肠。
在一些实施方式中，所述消化道组织为消化道手术后吻合口处组织。
在一些实施方式中，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
本发明的植入物可以通过促进吻合口组织毛细血管的增殖以及促进吻合口肠壁组织的再生，促进吻合口愈合，从而可以有效的预防中期和晚期吻合口瘘和吻合口狭窄的发生。
第六方面，本发明提供一种亲水性静电纺生物复合支架材料在制备用于促进消化道组织毛细血管增殖和/或促进消化道组织再生的材料中的用途，所述复合支架材料是由纤维蛋白原、L-精氨酸或其盐酸盐的水溶液与P(LLA-CL)溶液共混，采用静电纺技术制备而得到的；其中，所述纤维蛋白原与L-精氨酸或其盐酸盐的质量比为1.2:1～12.5:1；
所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液，其中的溶剂选自纯水、注射用水、盐溶液、缓冲液中的一种或多种；所述盐溶液选自氯化钠溶液、氯化钾溶液；所述缓冲液选自磷酸盐缓冲液、Tris-HCl缓冲液、甘氨酸缓冲液、D-Hank’s液。
在一些实施方式中，所述消化道组织为消化道手术后吻合口处组织；所述消化道优选选自食道、胃、小肠、大肠和结直肠。
在一些实施方式中，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
在一些实施方式中，所述纤维蛋白原是来源于哺乳动物的纤维蛋白原。
在一些实施方式中，所述哺乳动物为人、猪、牛、羊或马。
在一些实施方式中，所述P(LLA-CL)中聚乳酸和聚己内酯的质量比为20:80～95:5。
在一些实施方式中，所述的P(LLA-CL)溶液中的溶剂选自六氟异 丙醇、三氯甲烷、二甲基甲酰胺、四氢呋喃、氯仿或丙酮中的一种或者多种。
在一些实施方式中，所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液与P(LLA-CL)溶液共混后，其中纤维蛋白原:P(LLA-CL)的质量比为0.2:1～2.1:1。
在一些实施方式中，所述亲水性静电纺生物复合支架材料的平衡接触角小于55°。
在一些实施方式中，所述亲水性静电纺生物复合支架材料与水溶液接触后，总体积皱缩率不大于20％；孔隙率不低于30％。
在一些实施方式中，所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液中，还进一步加载有抗菌物质，所述抗菌物质选自青霉素类、头孢菌素类、碳青酶烯类、氨基糖甙类、四环素类、大环内脂类、糖甙类、磺胺类、喹诺酮类、硝咪唑类、林克胺类、磷霉素、氯霉素、对粘菌素B、杆菌肽中的一种或多种。
在一些实施方式中，所述青霉素类选自青霉素、氨苄西林、羧苄西林；所述头孢菌素类选自头孢氨苄、头孢呋辛钠、头孢曲松、头孢匹罗；所述碳青酶烯类为硫霉素；所述氨基糖甙类选自庆大霉素、链霉素、卡那霉素；所述四环素类选自四环素、金霉素；所述大环内脂类选自红霉素、阿奇霉素；所述糖甙类为万古霉素；所述磺胺类选自磺胺嘧啶、甲氧苄啶；所述喹诺酮类选自吡哌酸、环丙沙星；所述硝咪唑类选自甲硝唑、替硝唑；所述林克胺类选自林可霉素、克林霉素。
在一些实施方式中，在该支架材料植入体内后15分钟内，所述抗菌物质的释放量不低于总加载量的30％。
与现有技术相比，本发明具有以下有益效果：(1)本发明提供的植入物无需采用任何化学或生物交联剂进行交联固定，也不含有生物活性因子和活细胞；(2)本发明提供的植入经过原位诱导结直肠组织(包括但不限于：浆膜，平滑肌层，粘膜下层和粘膜层，及相应 的毛细血管和细胞基质)再生，增加吻合口局部的抗泄漏压力，降低局部张力，进而可以预防早期吻合口瘘的发生；(3)本发明的植入物同时还可以通过促进吻合口组织毛细血管的增殖以及促进吻合口肠壁组织的再生，促进吻合口愈合，从而可以有效的预防中期和晚期吻合口瘘和吻合口狭窄的发生。
附图说明
图1为吻合后小肠腔内压力与小肠外直径的折线关系图。
图2为结直肠吻合口手术0天、14天、28天和56天，吻合口泄露压力的变化情况示意图。
图3为术后8周，HE染色示意试验组和对照组吻合口肠壁组织愈合情况示意图。
图4为术后8周，Masson染色试验试验组和对照吻合口肠壁组织愈合情况示意图。
具体实施方式
下面结合附图并通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述具体实施方式仅仅是帮助理解本发明，不应视为对本发明的具体限制。
本发明实施例中，采用的部分原料来源如下：
聚乳酸-聚己内酯：分子量为5万-30万道尔顿，购自荷兰Purac公司；
纤维蛋白原复合物(猪源)：上海松力生物技术有限公司按照国家有关部门批准的生产工艺生产。
实施例1
本实施例提供直径为2.9cm的圆片形植入物(中间开孔)，具体采用如下方法制备而成：
(1)将纤维蛋白原复合物以浓度15g％溶解于生理盐水中；
(2)将聚乳酸聚己内酯共聚物以质量浓度百分比8％溶解在六 氟异丙醇溶剂中；
(3)将步骤(1)和步骤(2)所得溶液混匀后加入静电纺丝机的同一容量管中，使得纤维蛋白原复合物与聚乳酸聚己内酯共聚物的质量比为0.56：1，进行静电纺丝(静电纺机型号：NS1WS 500Elmarco捷克)制备；纺丝的电压差为50kv，纺丝距离40cm，纺丝液推进速度为50ml/h；
(4)将静电纺丝所得植入物中残留的有机溶剂去除，再用电子束进行灭菌。
通过调整静电纺丝参数，本实施例具体提供了6种不同厚度的植入物；所述6种植入物的厚度分别为0.01mm、0.1mm、0.2mm、0.38mm、0.8mm和1.2mm，相应的孔隙率在40％-80％的范围内，吸水率在50％-100％的范围内，顶破强度在20-80N的范围内。
实施例2
本实施例直径为2.9cm的圆片形植入物(中间开孔)，具体制备方法同实施例1。
本实施例具体提供了5种不同孔隙率的植入物；所述5种植入物的孔隙率分别为10％、20％、40％、80％和95％，相应的厚度在0.2mm-0.38mm的范围内，吸水率在50％-100％的范围内，顶破强度在20N-80N的范围内。
实施例3
本实施例提供直径为2.9cm的圆片形植入物(中间开孔)，具体制备方法同实施例1。
本实施例具体提供了6种不同吸水率的植入物；所述6种植入物的吸水率分别为10％、20％、50％、100％、200％和300％，相应的厚度在0.2mm-0.38mm的范围内，孔隙率在40％-80％的范围内，顶破强度在20N-80N的范围内。
性能测试1
1、测试方法：
取体重100-150kg猪的新鲜小肠，截取长度为10cm的新鲜小肠，每段从中部剪断为等长两段；采用管型吻合器(CN-CS29，江苏臣诺医疗器械有限公司)进行吻合，在吻合器钉座与抵钉座之间的远近端小肠壁间放置实施例提供的植入物(植入物贴附在吻合口处)；
然后，夹闭一端，另一端连接气体加压装置及灵敏度为0.01KPa，精度为0.02％的压力表，将整段肠道完全浸入生理盐水溶液中，缓慢持续加压，直至生理盐水溶液中出现气泡为止，此时压力定义为吻合口泄漏压力，记录相应泄漏压力。
2、测试结果
1)对实施例1提供的植物进行性能测试1的测试，结果见表1。
表1
由表1可知，采用本发明提供的植入物时，可以增加吻合口局部的抗泄漏压力，降低局部张力，进而可以预防吻合口瘘的发生；并且，本发明提供的植入物厚度在0.01mm-0.8mm的范围内时，泄漏压力均值在4.03KPa以上，高于YY/T0245-2008吻(缝)合器通用技术条件中5.2.3耐压检验的标准要求(不低于3.6KPa)；且当植入物的厚度为0.1-0.4mm、尤其是0.2-0.38mm时，泄漏压力均值远高于标准要求 的压力值3.6KPa。
2)对实施例2提供的植物进行性能测试1的测试，结果见表2。
表2
由表2可知，当本发明提供的植入物的孔隙率在20-80％的范围内时，泄漏压力均值不低于6.63KPa，远高于YY/T0245-2008吻(缝)合器通用技术条件中5.2.3耐压检验的标准要求(不低于3.6KPa)；且孔隙率在40-80％的范围内时，泄漏压力均值不低于6.63KPa，远高于标准要求的压力值3.6KPa。
3)对实施例3提供的植物进行性能测试1的测试，结果见表3。
表3
由表3可知，当本发明提供的植入物的吸水率在20-200％的范围内时，泄漏压力均值不低于3.80KPa，高于YY/T0245-2008吻(缝)合器通用技术条件中5.2.3耐压检验的标准要求(不低于3.6KPa)；且吸水率在50-100％范围内时，远高于标准要求的压力值3.6KPa。
性能测试2
取6只体重100-150kg猪的新鲜小肠，各截取长度为10cm的新鲜小肠6段，平均分为三个组，第一组正常对照组，第二组为不加植入物组，第三组为加植入物组，所述植入物为实施例1-4提供的植入物；
第二组和第三组的小肠从中部剪断为等长两段，然后采用管型吻合器(CN-CS29，江苏臣诺医疗器械有限公司)对进行吻合，第三组在吻合口处设置植入物。
对每组肠道分别进行如下测试：夹闭一端，另一端连接气体加压装置及灵敏度为0.01KPa，精度为0.02％的压力表，将肠道完全浸入生理盐水溶液中，缓慢加压，并测定1、5、10、15、20、25KPa压力下的中段肠道外径(mm)，直至生理盐水溶液中出现气泡为止，定义为肠道破裂力(KPa)，记录出现肠道外径以及相应的肠壁破裂压力，测试结果见表4和图1：
表4
由表4可知，小肠吻合口不放置植入物，吻合口泄漏压力为4.0±1.05KPa，是正常对照组肠壁破裂压力(18.0±1.33KPa)的22％；而放置植入物组，吻合口泄漏压力为7.0±1.17KPa，是正常对照组肠壁破裂力的38％，比不放置植入物组提高42％以上。
图1为进行吻合后小肠腔内压力与小肠外直径的折线关系图，由图1可知，肠道行吻合术时在吻合口内放置植入物，可以有效地保护吻合口处的直径不随肠腔内压力的增加而快速增加，这样便于吻合钉间隙的距离相对恒定，提高吻合口泄漏压力，预防早期吻合口瘘的发生。
性能测试3
取体重40-60kg的猪48头，采用管型吻合器(CN-CS29，江苏臣诺医疗器械有限公司)进行结直肠吻合术，分为加实施例1-4提供的植入物组(n＝24)和不加植入物组(n＝24)；
每组各分为4个时间点(术后0天，14天，28天和56天)，每个时间点取6头猪进行解剖，测定吻合口泄漏压力，同随机测定12头猪未进行结直肠吻合术肠段的破裂力作为正常对照。
测试结果见表5：
表5
由表5可知，术后当时(即术后0天)测定吻合口泄漏压力，加植入物组相较于不加植入物组的泄漏压力提高了35％左右；术后14天，加植入物组的泄漏压力达到正常成年猪直肠肠壁的破裂压力的80％左右，而不加植入物的为56％。
图2为结直肠吻合口手术后0天、14天、28天和56天，吻合口泄露压力的变化情况。由图2可知，在术后第56天，试验组吻合口泄漏压力已经恢复到正常肠壁水平，而对照组仅仅达到正常肠壁水平的80％左右。
性能测试4
按照性能测试3的方法进行手术。分别于术后2周、4周和8周，经过全身麻醉后取每组动物直结肠吻合口样品。其中每组6只动物随机选择2只，进行相关的组织学分析。10％中性福尔马林中固定至少48小时，进行HE/Masson染色，在光镜下观察组织学改变情况。采用KF-PRO-020数字切片扫描仪(KFBIO，中国宁波)扫描病理切片，K-Viewer软件(KFBIO，中国宁波)对病理切片进行相关分析。
HE染色结果：由图3可知术后第8周试验组(吻合口加载植入物组；A:×20，C:×40)和对照组(吻合口不加载植入物组；B:×20，D:×40)的肠壁组织学再生情况。其中，试验组粘膜层、粘膜下肌层、肌层和外膜层完整，其中“星号”标示处为不可吸收缝合线穿过处；对照组的粘膜层完整，但是粘膜下肌层和肌层在吻合口部位缺如，该部位被无序排列的纤维样组织所填充。
Masson染色结果：由图4可知术后第8周试验组(吻合口加载植入物组；A:×20，C:×40)和对照组(吻合口不加载植入物组；B:×20，D:×40)的肠壁组织学再生情况。其中，试验组示粘膜层、粘膜下肌层、肌层和外膜层完整外，粘膜下肌层和肌层间与正常组织相似，由胶原蛋白为主的细胞基质和脂肪组织所填充；而对照组在粘膜层下缺乏完整的粘膜下肌层和肌层，其中被蓝色的瘢痕组织所填充。
由上述实验测试结果可知，本发明提供的植入物在植入后早期，可以增加吻合口局部的抗泄漏压力，降低局部张力，进而可以预防吻合口瘘的发生，同时还可以通过原位诱导吻合口肠壁组织(包括粘膜层，粘膜下肌层，肌层和外膜层及相应的细胞外基质)的再生，避免了局部瘢痕形成，从而可以有效的预防中期和晚期吻合口瘘和肠道瘢痕收缩等不良反应奠定了坚实的基础。
虽然，上文中已经用一般性说明、具体实施方式及试验，对本发 明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。

Claims (25)

  1. 一种预防吻合口瘘的植入物，其特征在于，所述植入物内部具有三维纳米网状结构，由包含纤维蛋白原复合物和聚乳酸聚己内酯共聚物的原料制备而成。
  2. 根据权利要求1所述的植入物，其特征在于，所述纤维蛋白原复合物包含如下重量份数的组分：纤维蛋白原0.1-20份，精氨酸盐酸盐0.1-10份，氯化钠0.01-10份和枸橼酸钠1-10份；
    优选地，所述纤维蛋白原复合物包含如下重量份数的组分：纤维蛋白原3-15份，精氨酸盐酸盐0.5-5份，氯化钠0.3-5份和枸橼酸钠1-10份；
    更优选地，所述纤维蛋白原为猪血来源的纤维蛋白原。
  3. 根据权利要求1或2所述的植入物，其特征在于，所述植入物中，纤维蛋白原复合物与聚乳酸聚己内酯共聚物的质量比为(0.31-1.1)：1；
    优选地，所述聚乳酸聚己内酯共聚物的分子量为5万-30万。
  4. 根据权利要求1所述的植入物，其特征在于，所述植入物呈片状，厚度为0.1mm-0.4mm、优选为0.2mm-0.38mm；
    优选地，所述植入物的孔隙率为40-80％；和/或，所述植入物的吸水性为20-200％、优选为50-100％。
  5. 根据权利要求1-4任意一项所述的植入物，其特征在于，所述植入物采用静电纺丝方法制备而成。
  6. 根据权利要求5所述的植入物，其特征在于，制备所述植入物时，将含有纤维蛋白原复合物的溶液和含有聚乳酸聚己内酯的溶液混匀后加入静电纺丝机的同一容量管中，进行静电纺丝；或者，将含有纤维蛋白原复合物的溶液和含有聚乳酸聚己内酯的溶液分别加入到静电纺丝机的两个不同的容量管中，同时进行静电纺丝；
    优选地，所述含有聚乳酸聚己内酯的溶液是将聚乳酸聚己内酯共聚物以质量浓度百分比5-10％溶解在六氟异丙醇、三氯甲烷、二甲基甲酰胺、四氢呋喃和丙酮中的一种或两种以上的混合溶剂中。
  7. 根据权利要求1-6任意一项所述的植入物，其特征在于，所述植入物表面涂覆具有抗菌和/或消炎作用的药物。
  8. 根据权利要求1所述的植入物，其特征在于，所述植入物是利用吻合器进行消化道吻合术时被植入于吻合口处；
    优选地，所述植入物的中心设有开口，吻合器的钉仓与抵钉座之间的连接杆可在其中穿过；
    优选地，所述植入物与所述吻合器的钉仓匹配；
    优选地，所述吻合器为管型吻合器，所述植入物呈中心开口的圆片状。
  9. 权利要求1-8任意一项所述植入物的植入方法，其特征在于，包括如下步骤：将所述植入物置于吻合器的钉仓与抵钉座之间；
    优选还包括：利用吻合器将所述植入物植入于消化道的吻合口处；所述消化道优选选自食道、胃、小肠、大肠和结直肠。
  10. 权利要求1-8任意一项所述植入物在制备修复机体组织缺损的材料中的用途；
    优选地，所述植入物用于制备消化道手术后吻合口的修复材料；所述消化道优选选自食道、胃、小肠、大肠和结直肠。
  11. 权利要求1-8任意一项所述植入物在原位诱导消化道组织再生中的用途；
    优选地，所述消化道组织为消化道手术后吻合口处组织；所述消化道优选选自食道、胃、小肠、大肠和结直肠；
    优选地，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
  12. 权利要求1-8任意一项所述植入物在促进消化道组织毛细血 管增殖和/或促进消化道组织再生中的用途；
    优选地，所述消化道组织为消化道手术后吻合口处组织；所述消化道优选选自食道、胃、小肠、大肠和结直肠；
    优选地，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
  13. 一种亲水性静电纺生物复合支架材料在制备用于促进消化道组织毛细血管增殖和/或促进消化道组织再生的材料中的用途，其特征在于，所述复合支架材料是由纤维蛋白原、L-精氨酸或其盐酸盐的水溶液与P(LLA-CL)溶液共混，采用静电纺技术制备而得到的；其中，所述纤维蛋白原与L-精氨酸或其盐酸盐的质量比为1.2:1～12.5:1；
    所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液，其中的溶剂选自纯水、注射用水、盐溶液、缓冲液中的一种或多种；所述盐溶液选自氯化钠溶液、氯化钾溶液；所述缓冲液选自磷酸盐缓冲液、Tris-HCl缓冲液、甘氨酸缓冲液、D-Hank’s液。
  14. 根据权利要求13所述的用途，其特征在于，所述消化道组织为消化道手术后吻合口处组织；所述消化道优选选自食道、胃、小肠、大肠和结直肠。
  15. 根据权利要求13所述的用途，其特征在于，所述消化道组织选自粘膜层、粘膜下肌层、肌层和外膜层，以及各自相应的细胞外基质。
  16. 根据权利要求13-15任一项所述的用途，其特征在于，所述纤维蛋白原是来源于哺乳动物的纤维蛋白原。
  17. 根据权利要求16所述的用途，其特征在于，所述哺乳动物为人、猪、牛、羊或马。
  18. 根据权利要求13-15任一项所述的用途，其特征在于，所述P(LLA-CL)中聚乳酸和聚己内酯的质量比为20:80～95:5。
  19. 根据权利要求13-15任一项所述的用途，其特征在于，所述的 P(LLA-CL)溶液中的溶剂选自六氟异丙醇、三氯甲烷、二甲基甲酰胺、四氢呋喃、氯仿或丙酮中的一种或者多种。
  20. 根据权利要求13-15任一项所述的用途，其特征在于，所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液与P(LLA-CL)溶液共混后，其中纤维蛋白原:P(LLA-CL)的质量比为0.2:1～2.1:1。
  21. 根据权利要求13-15任一项所述的用途，其特征在于，所述亲水性静电纺生物复合支架材料的平衡接触角小于55°。
  22. 根据权利要求13-15任一项所述的用途，其特征在于，所述亲水性静电纺生物复合支架材料与水溶液接触后，总体积皱缩率不大于20％；孔隙率不低于30％。
  23. 根据权利要求13-15任一项所述的用途，其特征在于，所述纤维蛋白原、L-精氨酸或其盐酸盐的水溶液中，还进一步加载有抗菌物质，所述抗菌物质选自青霉素类、头孢菌素类、碳青酶烯类、氨基糖甙类、四环素类、大环内脂类、糖甙类、磺胺类、喹诺酮类、硝咪唑类、林克胺类、磷霉素、氯霉素、对粘菌素B、杆菌肽中的一种或多种。
  24. 根据权利要求23所述的用途，其特征在于，所述青霉素类选自青霉素、氨苄西林、羧苄西林；所述头孢菌素类选自头孢氨苄、头孢呋辛钠、头孢曲松、头孢匹罗；所述碳青酶烯类为硫霉素；所述氨基糖甙类选自庆大霉素、链霉素、卡那霉素；所述四环素类选自四环素、金霉素；所述大环内脂类选自红霉素、阿奇霉素；所述糖甙类为万古霉素；所述磺胺类选自磺胺嘧啶、甲氧苄啶；所述喹诺酮类选自吡哌酸、环丙沙星；所述硝咪唑类选自甲硝唑、替硝唑；所述林克胺类选自林可霉素、克林霉素。
  25. 根据权利要求23所述的用途，其特征在于，在该支架材料植入体内后15分钟内，所述抗菌物质的释放量不低于总加载量的30％。
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