WO2024060481A1 - 替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用 - Google Patents

替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用 Download PDF

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WO2024060481A1
WO2024060481A1 PCT/CN2023/074392 CN2023074392W WO2024060481A1 WO 2024060481 A1 WO2024060481 A1 WO 2024060481A1 CN 2023074392 W CN2023074392 W CN 2023074392W WO 2024060481 A1 WO2024060481 A1 WO 2024060481A1
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adipose tissue
tissue adhesive
adhesion
topological
absorbable sutures
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PCT/CN2023/074392
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English (en)
French (fr)
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黄建永
解文月
田卓灵
袁作楹
万卓
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北京大学
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Publication of WO2024060481A1 publication Critical patent/WO2024060481A1/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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0015—Medicaments; Biocides
    • 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
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/001—Use of materials characterised by their function or physical properties
    • A61L24/0042—Materials 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
    • 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
    • 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
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • 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
    • A61L2300/602—Type of release, e.g. controlled, sustained, slow
    • A61L2300/604—Biodegradation

Definitions

  • the present disclosure relates to a fat tissue adhesive that replaces absorbable sutures, a preparation method and its application, and belongs to the technical field of hydrogel adhesives.
  • Wound closure is critical to medical emergencies and the wound healing process.
  • Layered sutures are usually performed based on the anatomical layers of the tissue, including skin (epidermis) sutures and subcutaneous (subcutaneous tissue such as fat) sutures.
  • Subcutaneous adipose tissue has low toughness and can easily cause additional damage when absorbable sutures are used to close wounds, leading to a high incidence of complications after suturing in obese people.
  • suturing is a time-consuming surgical operation that easily increases the risk of wound infection, making it difficult to achieve ideal results in emergency and minimally invasive surgeries.
  • Bioadhesives have received great attention as potential suture substitutes and auxiliary materials for wound suturing.
  • Bioadhesives can provide mechanical support and hemostatic capabilities while sealing the wound site and preventing leakage to rapidly treat skin wounds and provide an environment that promotes tissue regeneration.
  • Bioadhesives have adjustable physical, chemical and mechanical properties, consistent mechanical strength with biological tissues, adjustable biodegradation rate and tissue healing activity.
  • current bioadhesives are based on short-range forces such as hydrogen bonds and dynamic chemical bonds. They cannot break through the hydrophobic effect on the surface of adipose tissue and thus lose their adhesion effect. They cannot meet the needs of fat suturing of full-thickness open wounds.
  • bioadhesives suitable for subcutaneous adipose tissue is of great clinical value.
  • the main purpose of the present disclosure is to provide an adipose tissue adhesive that replaces absorbable sutures, a preparation method and its application to achieve high-strength adhesion of subcutaneous adipose tissue.
  • the present disclosure provides a fat tissue alternative to absorbable sutures Adhesive.
  • the adipose tissue adhesive includes natural polymers, cross-linking agents and topological small molecules. It uses natural polymers as the main network and uses physical cross-linking to form an adipose tissue adhesive.
  • the adipose tissue adhesive forms accumulated mottled charges at the adhesion interface. These charges cause the adipose tissue adhesive to generate long-distance non-DLVO long-range force at the adhesion interface, breaking through the hydrophobic interaction on the oil surface. , achieving instant adhesion of fat tissue.
  • the adipose tissue adhesive relies on the pioneering effect of the topological small molecules to form topological entanglements at the adhesion interface over time, and the hydrogen bond distribution of the adhesion interface reverses from scatter to cyclic. Transformation, enhanced interface force conduction, increased interface adhesion strength, and achieved strong adhesion to subcutaneous adipose tissue.
  • the maximum fat tissue bonding strength of the fat tissue adhesive is 100kPa.
  • the natural polymer is porcine gelatin, the natural polymer is configured as a solution, and the mass fraction of the natural polymer solution is 10 wt%.
  • the cross-linking agent is a polyphenol substance, and the mass ratio of the cross-linking agent to the natural polymer is 1:1 to 3:1.
  • the topological small molecule provides electrostatic action and topological bonding driving force
  • the mass ratio of the topological small molecule to the natural polymer is 1:2 to 1:8.
  • the present disclosure also provides a method for preparing a fat tissue adhesive that replaces absorbable sutures, including:
  • the cross-linking agent and the natural polymer are fully reacted according to the mass ratio of 1:1 to 3:1, and a tissue adhesive precursor with a cyclic hydrogen bond distribution is obtained after strong physical cross-linking;
  • topological small molecules to the tissue adhesive precursor according to a mass ratio of topological small molecules to natural polymers of 1:2 to 1:8, stir continuously to fully react, and realize the transformation of hydrogen bond distribution from ring to scattered point, that is, Adipose tissue adhesive with strong adhesion to adipose tissue can be obtained.
  • the cross-linking agent is a polyphenol substance
  • the natural polymer is porcine gelatin
  • the natural polymer is configured as a solution
  • the mass fraction of the natural polymer solution is 10wt%
  • Topological small molecules provide electrostatic interactions and topological adhesion driving forces.
  • the present disclosure also provides an application of a fat tissue adhesive that replaces absorbable sutures in the fields of surgical suturing, 3D printing, biomedicine or environmental engineering.
  • the adipose tissue adhesive as an injectable bioadhesive, has a strong adhesion property with a maximum strength of 100 kPa to the epidermis and subcutaneous adipose tissue, is biocompatible, exhibits biological activity, antibacterial activity, anti-inflammatory activity and antioxidant activity, and can be degraded in vivo or in vitro.
  • the adipose tissue adhesive (GT-N) provided by this disclosure to replace absorbable sutures includes natural polymers, cross-linking agents and topological small molecules. It uses natural polymers as the main network and uses physical cross-linking to form fat. Tissue adhesive. The adipose tissue adhesive forms accumulated mottled charges at the adhesion interface. These charges enable the adipose tissue adhesive to generate long-distance non-DLVO long-range force at the adhesion interface, breaking through the hydrophobic effect on the oil surface and realizing adipose tissue instant adhesion.
  • the adipose tissue adhesive (GT-N) provided by this disclosure to replace absorbable sutures includes natural polymers, cross-linking agents and topological small molecules. It uses natural polymers as the main network and uses physical cross-linking to form fat. Tissue adhesive. This adipose tissue adhesive relies on the pioneering role of the topological small molecules to form topological entanglements at the adhesion interface over time. The hydrogen bond distribution of the adhesion interface reverses from scattered to cyclic, strengthening the interface. Through force conduction, the interface adhesion strength increases, achieving high-strength adhesion to subcutaneous fat tissue. The maximum strength of fat tissue bonding of this fat tissue adhesive is 100kPa.
  • the adipose tissue adhesive (GT-N) provided by the present disclosure to replace absorbable sutures is a bioadhesive suitable for high-strength bonding of subcutaneous fat in obesity-type full-thickness wounds (such as caesarean section surgery). .
  • This bioadhesive is physically cross-linked by natural polymers, natural polyphenols and active small molecules. It can achieve high-strength adhesion to subcutaneous fat tissue with a strength of up to 100kPa. It is expected to replace absorbable sutures for subcutaneous fat. Closure solves the problem of bioadhesives being difficult to adhere to oily tissue.
  • the adipose tissue adhesive (GT-N) provided by this disclosure to replace absorbable sutures is different from existing adhesion methods.
  • the adhesive interface formed by this adipose tissue adhesive will gradually strengthen over time and can Maintain stable and effective wound closure in high-salt environments or physiological pH changes.
  • the adipose tissue adhesive (GT-N) provided by the present disclosure to replace absorbable sutures, operates It is easy to operate and can be injected into affected areas of various shapes to achieve instant closure, which further improves the efficiency of wound treatment in first aid, reduces surgical costs and the degree of wound infection, has clinical promotion value, and can effectively close deep full-thickness wound in vitro models and fat resection. Wounds, has a bright future in fat-related surgeries.
  • the adipose tissue adhesive (GT-N) provided by the present disclosure to replace absorbable sutures has good adhesion properties to the epidermis and other tissues.
  • GT-N adipose tissue adhesive
  • the mixture also provided a fluid seal against fluid-filled perforated stomachs (1 cm wide holes), further demonstrating that the adhesive could be used to adhere to dynamic and deformable tissues.
  • the adipose tissue adhesive (GT-N) provided by this disclosure to replace absorbable sutures has good biocompatibility, does not produce cytotoxic by-products, has no cytotoxicity, and has antibacterial, anti-inflammatory and other biological properties. Activity, it has potential applications in the fields of surgical suturing, 3D printing, biomedicine or environmental engineering.
  • Figure 1 is a schematic diagram of an adipose tissue adhesive that replaces absorbable sutures provided by an embodiment of the present disclosure to achieve high-strength adhesion to subcutaneous adipose tissue.
  • Figure 2 is a schematic diagram of an adhesion strength test of an adipose tissue adhesive that replaces absorbable sutures according to Embodiment 1 of the present disclosure, where a is the change in adhesion strength of adipose tissue over time, and b is the adhesion strength test with maximum adhesion.
  • a is the change in adhesion strength of adipose tissue over time
  • b is the adhesion strength test with maximum adhesion.
  • c is the stability test of samples with maximum adhesion strength after 24 hours of treatment in different water environments
  • d is the adhesion of GT-N adipose tissue adhesive to In vitro model of deep full-thickness wounds.
  • Figure 3 is a graph showing the results of testing an adipose tissue adhesive that replaces absorbable sutures according to Example 2 of the present disclosure, where a is the relationship between the viscosity of GT-N adipose tissue adhesive and the shear rate, and b is Fourier transform infrared spectrum (FTIR) of GT-N adipose tissue adhesive, c is the swelling rate of GT-N adipose tissue adhesive in deionized water over time.
  • FTIR Fourier transform infrared spectrum
  • Figure 4 is a pair of adipose tissue adhesives replacing absorbable sutures according to Embodiment 3 of the present disclosure.
  • a schematic diagram of the adhesion strength test where a is a schematic diagram of a fat tissue lap shear test, and b is the optimization of the adhesion strength of GT-N tissue adhesive with different proportions of cross-linking agents and topological molecules over time; c is the typical load-displacement curve of the maximum adhesion strength, d is the adhesion strength to pig skin at different times, and e is the adhesion strength of GT-N tissue adhesive to other tissues.
  • Figure 5 is a schematic diagram of the adhesion performance test of adipose tissue adhesive that replaces absorbable sutures according to Example 4 of the present disclosure, where a is a photo of GT-N tissue adhesive adhering to chicken hearts and livers, b is the in vitro adhesive performance of GT-N tissue adhesive, and c is a picture of isolated pig stomach tissue using a gel patch to stop leakage.
  • Figure 6 is a schematic diagram of cell activity testing of adipose tissue adhesive that replaces absorbable sutures according to Example 5 of the present disclosure, where a is L929 cells cultured in GT-N tissue adhesive extract for 1 day and 3 Days and 5 days later, fluorescent images of living and dead staining; b is the CCK8 cell activity test results.
  • Figure 7 is a schematic diagram of the antibacterial activity and in vivo degradation test of adipose tissue adhesive that replaces absorbable sutures according to Example 6 of the present disclosure, where a is the antibacterial activity of GT-N tissue adhesive, and b is the Mouse subcutaneous implantation model for in vivo degradation test: cross-sectional area of tissue sections 1 week and 1 month after GT and GT-N tissue adhesives were implanted subcutaneously in mice.
  • Embodiments of the present disclosure provide an adipose tissue adhesive that replaces absorbable sutures, a preparation method and an application thereof.
  • the adipose tissue adhesive includes natural polymers, cross-linking agents and topological small molecules. It uses natural polymers as the main network and uses physical cross-linking to form the adipose tissue adhesive.
  • the fat tissue adhesive forms aggregated mottled charges at the adhesion interface. These charges enable the fat tissue adhesive to generate long-range non-DLVO long-range forces at the adhesion interface, breaking through the hydrophobic effect of the oil surface and achieving instantaneous adhesion of the fat tissue.
  • the adipose tissue adhesive relies on the prior knowledge of the topological small molecules.
  • the driving effect leads to the formation of topological entanglements at the adhesion interface over time, and the hydrogen bond distribution at the adhesion interface reverses from scattered to ring-like, which enhances the interface force conduction, increases the interface adhesion strength, and achieves contact with subcutaneous adipose tissue. strong adhesion.
  • Figure 1 is a schematic diagram of the adipose tissue adhesive provided by an embodiment of the present disclosure to replace absorbable sutures to achieve high-strength adhesion to subcutaneous adipose tissue.
  • the adipose tissue adhesive has the greatest adhesion to adipose tissue.
  • the strength is 100kPa.
  • the natural polymer is porcine gelatin, the natural polymer is configured as a solution, and the mass fraction of the natural polymer solution is 10 wt%.
  • the cross-linking agent is a polyphenol substance, and the mass ratio of the cross-linking agent to the natural polymer is 1:1 to 3:1.
  • the cross-linking agent The mass ratio to the natural polymer may be 1:1.
  • the topological small molecule provides electrostatic interaction and topological adhesion driving force
  • the mass ratio of the topological small molecule to the natural polymer is 1:2 to 1:8.
  • the The mass ratio of the topological small molecule to the natural polymer may be 1:4.
  • the adipose tissue adhesive that replaces absorbable sutures has potential applications in the fields of surgical suturing, 3D printing, biomedicine or environmental engineering.
  • the adipose tissue adhesive has strong adhesion properties with a maximum strength of 100kPa to epidermal and subcutaneous adipose tissue, is biocompatible, and exhibits biological activity, antibacterial activity, and anti-inflammatory activity. and antioxidant activity, able to be degraded in vivo or in vitro.
  • the preparation method of the adipose tissue adhesive that replaces absorbable sutures includes: fully reacting the cross-linking agent and the natural polymer according to the mass ratio of 1:1 to 3:1, strong physical After cross-linking, a tissue adhesive precursor with a cyclic hydrogen bond distribution is obtained; topological small molecules are added to the tissue adhesive precursor according to the mass ratio of topological small molecules to natural polymers of 1:2 to 1:8, and continue Stir and react thoroughly to realize the transformation of hydrogen bond distribution from ring to scattered point, and then you can obtain an adipose tissue adhesive that strongly adheres to adipose tissue.
  • the cross-linking agent is a polyphenol substance
  • the natural polymer is porcine gelatin
  • the natural polymer is configured as a solution
  • the mass fraction of the natural polymer solution is 10wt%
  • the topology is small Molecules provide electrostatic interactions and topological adhesion driving forces.
  • the preparation method of the fat tissue adhesive that replaces the absorbable sutures is to dissolve natural polymers in deionized water to obtain a polymer solution with a mass fraction of 10%; then prepare a high-concentration crosslinker aqueous solution, and the crosslinker and the polymer are fully reacted in a mass ratio of 1:1; after physical crosslinking, an adhesive precursor with a cyclic hydrogen bond distribution is obtained; topological small molecules are added to the precursor, the mass ratio of the polymer to the topological molecule is 4:1, and stirring is continued until sufficient reaction occurs; this process interrupts the cyclic hydrogen bonds, and changes the hydrogen bond distribution type from cyclic to scattered points, thereby obtaining an adhesive with strong fat tissue adhesion.
  • fresh pig fat tissue with epidermis (10mm ⁇ 15mm) or other adhesion test tissue was prepared.
  • a small amount of tissue adhesive was injected and applied between two pieces of fat tissue, followed by pressing for 5 seconds.
  • the adhesion strength was measured at different times using a universal tensile testing machine.
  • the strain rate of the universal tensile testing machine was 5mm/min, and all group tests were repeated 3 times.
  • the in vitro model of deep full-thickness wounds uses isolated pig tissue with in vitro epidermis and subcutaneous fat.
  • a scalpel is used to cut a wound of about 2cm into the tissue.
  • the depth of the wound penetrates from the epidermis to the subcutaneous fat part, and then the tissue is bonded.
  • inject the agent into the subcutaneous fat tissue section press gently on the wound section, and wait for the wound to close.
  • Figure 2 is a schematic diagram of adhesion strength testing of adipose tissue adhesives that replace absorbable sutures according to Embodiment 1 of the present disclosure, where a is the change in adhesion strength of adipose tissue over time.
  • b is the long-term underwater stability test of the sample with the maximum adhesion strength
  • c is the stability test of the sample with the maximum adhesion strength after 24 hours of treatment in different water environments
  • d is the GT-N adipose tissue In vitro model of adhesive adhesion to deep full-thickness wounds.
  • Figure 3 is a graph showing the results of testing a fat tissue adhesive that replaces absorbable sutures according to Example 2 of the present disclosure, where a is the viscosity and shear of GT-N fat tissue adhesive rate, b is the Fourier transform infrared spectrum (FTIR) of GT-N adipose tissue adhesive, and c is the swelling rate of GT-N adipose tissue adhesive in deionized water over time.
  • FTIR Fourier transform infrared spectrum
  • Figure 4 is a schematic diagram of testing the adhesion strength of adipose tissue adhesive that replaces absorbable sutures according to Embodiment 3 of the present disclosure, where a is a schematic diagram of the adipose tissue lap shear test, and b is the optimization of the adhesion strength of GT-N tissue adhesive with different proportions of cross-linking agent and topological molecules over time; c is the typical load-displacement curve of the maximum adhesion strength, and d is the adhesion strength to pig skin at different times. Adhesion strength, e is the adhesion strength of GT-N tissue adhesive to other tissues.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • tissue injury model To construct an isolated pig stomach tissue injury model, first make a 1cm diameter model on the isolated pig stomach. hole, and continuously pour water into the inside to ensure a steady flow of water flowing out of the hole on the surface of the pig's stomach. The injectable tissue adhesive is then injected onto the gauze, using the gauze as a backing to spread the tissue adhesive evenly on the gauze surface. The gauze loaded with tissue adhesive was pressed against the pig stomach injury to seal and stop leakage. After stopping the pressing, it was observed that the gauze adhered to the pig stomach injury and prevented water from flowing out from the damaged area. Tear off the gauze at the damaged part of the tissue, and observe that the water inside the pig's stomach gradually overflows, and at the same time, the tissue is slightly deformed by the adhesive.
  • Figure 5 is a schematic diagram of the adhesion performance test of adipose tissue adhesive that replaces absorbable sutures according to Example 4 of the present disclosure, where a is the GT-N tissue adhesive adhering to the chicken heart. and photos on the liver, b is the in vitro adhesive performance of GT-N tissue adhesive, c is a picture of isolated pig stomach tissue using a gel patch to stop leakage.
  • Figure 6 is a schematic diagram of cell activity testing of adipose tissue adhesive that replaces absorbable sutures according to Example 5 of the present disclosure, where a is the expression of L929 cells in GT-N tissue adhesive extract Fluorescence images of live and dead staining after 1, 3 and 5 days of culture; b is the CCK8 cell activity test results.
  • PBS phosphate buffered saline
  • Figure 7 is a schematic diagram of the antibacterial activity and in vivo degradation test of adipose tissue adhesive that replaces absorbable sutures according to Example 6 of the present disclosure, where a is the antibacterial activity of GT-N tissue adhesive.
  • Activity, b is the in vivo degradation test through the rat subcutaneous implantation model: the cross-sectional area of tissue sections of GT and GT-N tissue adhesives after 1 week and 1 month of subcutaneous implantation in mice.

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Abstract

本公开提供了一种替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用，属于水凝胶粘合剂技术领域。该脂肪组织粘合剂包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。利用本公开，能够实现对皮下脂肪组织的高强粘附，强度高达100kPa，有望代替可吸收缝合线用于皮下脂肪闭合，解决了生物粘合剂难以粘附油脂组织的难题。不同于现有粘附手段，该水凝胶形成的粘附界面会随时间逐渐增强，并能在高盐环境或生理性pH值变化下保持伤口闭合的稳定有效性。该水凝胶操作简便，可注射至各种形状的患处实现瞬时闭合，进一步提高了急救中伤口处理效率，降低手术成本和伤口感染程度，具有临床推广价值。

Description

替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用 技术领域
本公开涉及一种替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用，属于水凝胶粘合剂技术领域。
背景技术
伤口缝合对于医用急救和创伤愈合过程至关重要。通常根据组织的解剖层次进行分层缝合，包括皮肤(表皮)缝合和皮下(脂肪等皮下组织)缝合。皮下脂肪组织韧性较低，在使用可吸收缝合线闭合伤口时易造成额外损伤，导致肥胖人群缝合术后并发症的高发。且缝合是一个耗时的外科操作易增加伤口感染风险，难以在急诊和微创手术中发挥理想效果。
近年来生物粘合剂作为具有潜力的缝合线替代品和辅助材料，在伤口缝合时受到了极大的关注。生物粘合剂可以提供机械支持和止血能力，同时密封伤口部位和防止泄漏，以快速处理皮肤伤口，并提供促进组织再生的环境。
生物粘合剂具有可调节的物化、力学特性，与生物组织的一致的力学强度，可调节的生物降解率以及促组织愈合活性。但目前生物粘合剂均基于氢键及动态化学键等短程力作用，无法突破脂肪组织表面的疏水作用从而失去粘附效果，不能满足全层开放性伤口脂肪缝合的需求。
因此，开发适用于皮下脂肪组织的生物粘合剂具有重大临床价值。
发明内容
有鉴于此，本公开的主要目的在于提供一种替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用，以实现皮下脂肪组织的高强粘附。
为达到上述目的，本公开提供了一种替代可吸收缝合线的脂肪组织 粘合剂，该脂肪组织粘合剂包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。
上述方案中，该脂肪组织粘合剂在粘附界面形成聚集的斑驳电荷，这些电荷使得该脂肪组织粘合剂在粘附界面处产生长距离的非DLVO长程力，突破了油脂表面的疏水作用，实现脂肪组织的瞬时黏附。
上述方案中，该脂肪组织粘合剂依赖于所述拓扑小分子的先驱作用，随着时间变化在粘附界面处形成拓扑缠结，粘附界面的氢键分布由散点状向环状逆转变，增强界面力传导，界面粘附强度增加，实现与皮下脂肪组织的强粘附。
上述方案中，该脂肪组织粘合剂的脂肪组织粘接最大强度为100kPa。
上述方案中，所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％。
上述方案中，所述交联剂为多酚类物质，所述交联剂与所述天然高分子的质量比为1∶1～3∶1。
上述方案中，所述拓扑小分子提供静电作用与拓扑粘接驱动力，所述拓扑小分子与所述天然高分子的质量比为1∶2～1∶8。
为达到上述另一个目的，本公开还提供了一种替代可吸收缝合线的脂肪组织粘合剂的制备方法，包括：
将交联剂与天然高分子按照质量比1∶1～3∶1充分反应，强物理交联后得到具有环状氢键分布的组织粘合剂前驱体；
按照拓扑小分子与天然高分子质量比为1∶2～1∶8向组织粘合剂前驱体中加入拓扑小分子，持续搅拌充分反应，实现氢键分布由环状向散点状转变，即可得到对脂肪组织强粘附的脂肪组织粘合剂。
上述方案中，所述交联剂为多酚类物质；所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％；所述拓扑小分子提供静电作用与拓扑粘接驱动力。
为达到上述再一个目的，本公开还提供了一种替代可吸收缝合线的脂肪组织粘合剂在外科手术缝合、3D打印、生物医学或环境工程领域的应用。
上述方案中，所述脂肪组织粘合剂作为注入式生物粘合剂，对表皮及皮下脂肪组织具有最大强度为100kPa的强粘附性能，并具有生物相容性，表现出生物活性、抗菌活性、抗炎活性及抗氧化活性，能够在体内或体外降解。
从上述技术方案可以看出，本公开提供的替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用，具有以下有益效果：
1、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。该脂肪组织粘合剂在粘附界面形成聚集的斑驳电荷，这些电荷使得该脂肪组织粘合剂在粘附界面处产生长距离的非DLVO长程力，突破了油脂表面的疏水作用，实现脂肪组织的瞬时黏附。
2、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。该脂肪组织粘合剂依赖于所述拓扑小分子的先驱作用，随着时间变化在粘附界面处形成拓扑缠结，粘附界面的氢键分布由散点状向环状逆转变，增强界面力传导，界面粘附强度增加，实现了与皮下脂肪组织的高强粘附，该脂肪组织粘合剂的脂肪组织粘接最大强度为100kPa。
3、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，是一种适用于肥胖型全层伤口(例如剖妇产手术)皮下脂肪高强粘接的生物粘合剂。该生物粘合剂由天然高分子、天然多酚类物质以及活性小分子物理交联而成，能够实现对皮下脂肪组织的高强粘附，强度高达100kPa，有望代替可吸收缝合线用于皮下脂肪闭合，解决了生物粘合剂难以粘附油脂组织的难题。
4、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，不同于现有粘附手段，该脂肪组织粘合剂形成的粘附界面会随时间逐渐增强，并能在高盐环境或生理性pH值变化下保持伤口闭合的稳定有效性。
5、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，操 作简便，可注射至各种形状的患处实现瞬时闭合，进一步提高了急救中伤口处理效率，降低手术成本和伤口感染程度，具有临床推广价值，可以有效闭合深层全层创面离体模型和脂肪切除创面，在脂肪相关外科手术中前景广阔。
6、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，对表皮及其他组织具有良好的粘附性能，除了密封液体泄漏的离体猪胃以外，该脂肪组织粘合剂还可以对充满液体的穿孔胃(1厘米宽的孔)提供流体密封，进一步表明，该粘合剂可以用于粘附动态和可变形的组织上。
7、本公开提供的替代可吸收缝合线的脂肪组织粘合剂(GT-N)，具有良好的生物相容性，不产生细胞毒性副产物，无细胞毒性，且具有抗菌、抗炎等生物活性，在在外科手术缝合、3D打印、生物医学或环境工程等领域都有潜在的应用前景。
附图说明
为了更进一步说明本公开的内容，以下结合附图对本公开做详细描述，其中：
图1是本公开实施例提供的替代可吸收缝合线的脂肪组织粘合剂实现与皮下脂肪组织的高强粘附的示意图。
图2是依照本公开实施例1的对替代可吸收缝合线的脂肪组织粘合剂进行粘附强度测试的示意图，其中，a是脂肪组织的粘附强度随时间的变化，b是具有最大粘附强度的样品的长期水下稳定性测试，c是具有最大粘附强度的样品在不同的水环境中经过24小时处理后的稳定性测试，d是GT-N脂肪组织粘合剂粘附在深层全厚度伤口的体外模型。
图3是依照本公开实施例2对替代可吸收缝合线的脂肪组织粘合剂进行测试的结果图，其中，a是GT-N脂肪组织粘合剂的粘度与剪切率的关系，b是GT-N脂肪组织粘合剂的傅里叶变换红外光谱(FTIR)，c是GT-N脂肪组织粘合剂在去离子水中随时间变化的溶胀率。
图4是依照本公开实施例3对替代可吸收缝合线的脂肪组织粘合剂 的粘附强度进行试验的示意图，其中，a是脂肪组织搭接剪切试验示意图，b是不同比例的交联剂与拓扑分子对GT-N组织粘合剂的粘附强度随时间的优化；c是最大粘附强度的典型负载-位移曲线，d是不同的时间下对猪皮肤的粘附强度，e是GT-N组织粘合剂对其他组织的粘附强度。
图5是依照本公开实施例4对替代可吸收缝合线的脂肪组织粘合剂进行粘合性能测试的示意图，其中，a是GT-N组织粘合剂粘附在鸡心和肝脏上的照片，b是GT-N组织粘合剂的体外粘合性能，c是采用凝胶贴片贴住漏液的离体猪胃组织止漏图片。
图6是依照本公开实施例5对替代可吸收缝合线的脂肪组织粘合剂进行细胞活性测试的示意图，其中，a是L929细胞在GT-N组织粘合剂提取物中培养1天、3天和5天后，活体和死体染色的荧光图像；b是CCK8细胞活性测试结果。
图7是依照本公开实施例6对替代可吸收缝合线的脂肪组织粘合剂进行抗菌活性及体内降解试验的示意图，其中，a是GT-N组织粘合剂的抗菌活性，b是通过大鼠皮下植入模型进行体内降解试验：GT和GT-N组织粘合剂在小鼠皮下植入1周和1个月后的组织切片的截面面积。
具体实施方式
为使本公开的目的、技术方案和优点更加清楚明白，以下结合具体实施例，并参照附图，对本公开进一步详细说明。
本公开实施例提供了一种替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用。该脂肪组织粘合剂包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。
在本公开实施例中，该脂肪组织粘合剂在粘附界面形成聚集的斑驳电荷，这些电荷使得该脂肪组织粘合剂在粘附界面处产生长距离的非DLVO长程力，突破了油脂表面的疏水作用，实现脂肪组织的瞬时黏附。
在本公开实施例中，该脂肪组织粘合剂依赖于所述拓扑小分子的先 驱作用，随着时间变化在粘附界面处形成拓扑缠结，粘附界面的氢键分布由散点状向环状逆转变，增强界面力传导，界面粘附强度增加，实现与皮下脂肪组织的强粘附。
如图1所示，图1是本公开实施例提供的替代可吸收缝合线的脂肪组织粘合剂实现与皮下脂肪组织的高强粘附的示意图，该脂肪组织粘合剂的脂肪组织粘接最大强度为100kPa。
在本公开实施例中，所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％。
在本公开实施例中，所述交联剂为多酚类物质，所述交联剂与所述天然高分子的质量比为1∶1～3∶1，可选地，所述交联剂与所述天然高分子的质量比可以为1∶1。
在本公开实施例中，所述拓扑小分子提供静电作用与拓扑粘接驱动力，所述拓扑小分子与所述天然高分子的质量比为1∶2～1∶8，可选地，所述拓扑小分子与所述天然高分子的质量比可以为1∶4。
在本公开实施例中，所述的替代可吸收缝合线的脂肪组织粘合剂在外科手术缝合、3D打印、生物医学或环境工程等领域都有潜在的应用前景。所述脂肪组织粘合剂作为注入式生物粘合剂，对表皮及皮下脂肪组织具有最大强度为100kPa的强粘附性能，并具有生物相容性，表现出生物活性、抗菌活性、抗炎活性及抗氧化活性，能够在体内或体外降解。
在本公开实施例中，所述的替代可吸收缝合线的脂肪组织粘合剂的制备方法，包括：将交联剂与天然高分子按照质量比1∶1～3∶1充分反应，强物理交联后得到具有环状氢键分布的组织粘合剂前驱体；按照拓扑小分子与天然高分子质量比为1∶2～1∶8向组织粘合剂前驱体中加入拓扑小分子，持续搅拌充分反应，实现氢键分布由环状向散点状转变，即可得到对脂肪组织强粘附的脂肪组织粘合剂。其中，所述交联剂为多酚类物质；所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％；所述拓扑小分子提供静电作用与拓扑粘接驱动力。
在本公开的一个实施例中，所述的替代可吸收缝合线的脂肪组织粘合剂的制备方法，是将天然高分子溶于去离子水中，得到质量分数10％的高分子溶液；接着配置高浓度交联剂水溶液，交联剂与高分子按质量比1∶1充分反应；物理交联后得到环状氢键分布的粘合剂前驱体；向前驱体中加入拓扑小分子，高分子与拓扑分子质量比为4∶1，持续搅拌直至充分反应；这一过程中断了环状氢键，使氢键分布类型由环状向散点状转变，即可得到具有强脂肪组织粘接的粘合剂。
在本公开实施例中，图中所述所有粘附试验均按照美国测试与材料协会(ASTM)剪切搭接测试方法进行。
以下结合附图和实施例对本公开进行详细说明。
实施例1：
首先制备新鲜带有表皮的猪脂肪组织(10mm×15mm)或其他粘附测试组织。在两块脂肪组织之间注射涂抹少量组织粘合剂，随后按压5秒，用万能拉伸试验机在不同时间进行测量粘附强度，万能拉伸试验机的应变速率为5mm/min，所有组别试验重复3次。
深层全层伤口的体外模型中使用具有体外表皮与皮下脂肪的猪的离体组织，首先用手术刀将组织切开2cm左右的伤口，伤口深度从表皮贯穿至皮下脂肪部分，随后将组织粘合剂注射至皮下脂肪组织断面，对其伤口断面后轻轻按压，等待伤口闭合。
如图2所示，图2是依照本公开实施例1的对替代可吸收缝合线的脂肪组织粘合剂进行粘附强度测试的示意图，其中，a是脂肪组织的粘附强度随时间的变化，b是具有最大粘附强度的样品的长期水下稳定性测试，c是具有最大粘附强度的样品在不同的水环境中经过24小时处理后的稳定性测试，d是GT-N脂肪组织粘合剂粘附在深层全厚度伤口的体外模型。
实施例2：
称取0.5g的GT-N组织粘合剂，并将其置于50ml水溶液中孵育， 整个过程在37℃水浴摇床中进行，并在不同的时间点采集组织粘合剂的质量。膨胀率(％)＝(Ws-Wd)/Wd×100％，其中Ws和Wd是水凝胶在膨胀状态和原始状态的重量。在37℃的流变仪上使用直径为20毫米的平行板进行复合粘度测量(0.5Hz)和频率扫描(0.1-100Hz)。将GT-N组织粘合剂冻干后测试傅里叶变换红外光谱(FTIR)光谱。
如图3所示，图3是依照本公开实施例2对替代可吸收缝合线的脂肪组织粘合剂进行测试的结果图，其中，a是GT-N脂肪组织粘合剂的粘度与剪切率的关系，b是GT-N脂肪组织粘合剂的傅里叶变换红外光谱(FTIR)，c是GT-N脂肪组织粘合剂在去离子水中随时间变化的溶胀率。
实施例3：
交联剂与拓扑分子的质量比优化试验，将天然高分子溶于去离子水中，得到质量分数10％的高分子溶液。配置高浓度交联剂水溶液，与高分子按质量比1∶1充分反应。物理交联后得到环状氢键分布的粘合剂前驱体。向前驱体中加入拓扑小分子，拓扑分子与交联剂的质量比分别为1∶2，1∶4，1∶6，1∶8，持续搅拌直至充分反应，分别得到GT-N8-1、GT-N6-1、GT-N4-1、GT-N2-1组织粘合剂。制备新鲜带有表皮的猪脂肪组织(10mm×15mm)，按照美国测试与材料协会(ASTM)剪切搭接测试方法对上述四种组织粘合剂的粘附强度进行测试。
如图4所示，图4是依照本公开实施例3对替代可吸收缝合线的脂肪组织粘合剂的粘附强度进行试验的示意图，其中，a是脂肪组织搭接剪切试验示意图，b是不同比例的交联剂与拓扑分子对GT-N组织粘合剂的粘附强度随时间的优化；c是最大粘附强度的典型负载-位移曲线，d是不同的时间下对猪皮肤的粘附强度，e是GT-N组织粘合剂对其他组织的粘附强度。
实施例4：
构建离体猪胃组织损伤模型，首先在离体猪胃上制一个直径为1cm 的孔，并向内部不断灌注水，保证有源源不断的水流从猪胃表面的孔中流出。随后将可注射组织粘合剂注射到纱布上，已纱布为衬底，使组织粘合剂均匀的铺展在纱布表面。将负载组织粘合剂的纱布按压在猪胃损伤处用于密封止漏，停止按压后可以观察到纱布粘附于猪胃损伤处，并阻止了水从破损处流出。撕下组织破损处的纱布，观察到猪胃内部的水逐渐溢出，同时组织受到粘合剂牵拉发生轻微的变形。
如图5所示，图5是依照本公开实施例4对替代可吸收缝合线的脂肪组织粘合剂进行粘合性能测试的示意图，其中，a是GT-N组织粘合剂粘附在鸡心和肝脏上的照片，b是GT-N组织粘合剂的体外粘合性能，c是采用凝胶贴片贴住漏液的离体猪胃组织止漏图片。
实施例5：
使用CCK-8试剂测定L929细胞与水凝胶的细胞相容性：在细胞试验前，水凝胶紫外灭菌1小时，随后置于细胞培养基中浸提24小时并收集浸提液。将L929细胞接种在96孔细胞培养皿中(每孔4000个细胞)，贴壁培养24h后去除96孔培养皿中的培养基，用PBS冲洗细胞。随后在孔中加入24h的水凝胶提取液，与提取液(每组n＝5)再孵育24h。实验组细胞活力采用CCK-8检测，以活细胞相对于对照组细胞的百分比表示。
如图6所示，图6是依照本公开实施例5对替代可吸收缝合线的脂肪组织粘合剂进行细胞活性测试的示意图，其中，a是L929细胞在GT-N组织粘合剂提取物中培养1天、3天和5天后，活体和死体染色的荧光图像；b是CCK8细胞活性测试结果。
实施例6：
将革兰阳性金黄色葡萄球菌和革兰阴性大肠杆菌在150rpm，37℃的摇床中孵育过夜，孵育后收集细菌培养物用于研究水凝胶的抗菌活性。离心收集细菌并用磷酸盐缓冲盐水(PBS，PH 7.4)稀释成终浓度为108CFU/mL(OD600＝0.5)的菌液待用。然后测试所用水凝胶在干净的实验 台上紫外杀菌30分钟，随后在PBS缓冲液(PH＝7.4)中清洗1小时。取出水凝胶，加入4mL菌液(PBS，OD600＝0.5)中，37℃共孵育24小时。将与水凝胶孵育后的菌液稀释105次倍，涂于LB琼脂平板上，37℃培养24小时后采用CFU计数法测定细菌存活率。上述抗菌实验均独立进行3次以确保数据的准确性。
将水凝胶置于5mL PBS中并在37℃下孵育。在每个时间间隔内测量水凝胶的湿重。通过将剩余样品的重量除以原始水凝胶的重量来计算降解百分比；体内生物相容性：雄性大鼠(约250g)被用于体内生物相容性研究。在大鼠中轴表皮上切开一个1厘米的切口并在侧面制备一个皮下囊袋。在无菌条件下，将不同组别水凝胶植入背侧皮下囊袋中。在指定的时间间隔(第1周、第2周以及1个月)，处死大鼠并对样本进行处理以进行组织学分析。
如图7所示，图7是依照本公开实施例6对替代可吸收缝合线的脂肪组织粘合剂进行抗菌活性及体内降解试验的示意图，其中，a是GT-N组织粘合剂的抗菌活性，b是通过大鼠皮下植入模型进行体内降解试验：GT和GT-N组织粘合剂在小鼠皮下植入1周和1个月后的组织切片的截面面积。
以上所述的具体实施例，对本公开的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本公开的具体实施例而已，并不用于限制本公开，凡在本公开的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本公开的保护范围之内。

Claims (11)

  1. 一种替代可吸收缝合线的脂肪组织粘合剂，该脂肪组织粘合剂包括天然高分子、交联剂与拓扑小分子，采用天然高分子为主网络，利用物理交联形成脂肪组织粘合剂。
  2. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，该脂肪组织粘合剂在粘附界面形成聚集的斑驳电荷，这些电荷使得该脂肪组织粘合剂在粘附界面处产生长距离的非DLVO长程力，突破了油脂表面的疏水作用，实现脂肪组织的瞬时黏附。
  3. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，该脂肪组织粘合剂依赖于所述拓扑小分子的先驱作用，随着时间变化在粘附界面处形成拓扑缠结，粘附界面的氢键分布由散点状向环状逆转变，增强界面力传导，界面粘附强度增加，实现与皮下脂肪组织的强粘附。
  4. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，该脂肪组织粘合剂的脂肪组织粘接最大强度为100kPa。
  5. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％。
  6. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，所述交联剂为多酚类物质，所述交联剂与所述天然高分子的质量比为1∶1～3∶1。
  7. 根据权利要求1所述的替代可吸收缝合线的脂肪组织粘合剂，其中，所述拓扑小分子提供静电作用与拓扑粘接驱动力，所述拓扑小分子与所述天然高分子的质量比为1∶2～1∶8。
  8. 一种权利要求1至7中任一项所述的替代可吸收缝合线的脂肪组织粘合剂的制备方法，包括：
    将交联剂与天然高分子按照质量比1∶1～3∶1充分反应，强物理交联后得到具有环状氢键分布的组织粘合剂前驱体；
    按照拓扑小分子与天然高分子质量比为1∶2～1∶8向组织粘合剂前驱体中加入拓扑小分子，持续搅拌充分反应，实现氢键分布由环状向散点状转变，即可得到对脂肪组织强粘附的脂肪组织粘合剂。
  9. 根据权利要求8所述的替代可吸收缝合线的脂肪组织粘合剂的制备方法，其中，
    所述交联剂为多酚类物质；
    所述天然高分子为猪源明胶，所述天然高分子被配置为溶液，所述天然高分子溶液的质量分数为10wt％；
    所述拓扑小分子提供静电作用与拓扑粘接驱动力。
  10. 一种权利要求1至7中任一项所述的替代可吸收缝合线的脂肪组织粘合剂在外科手术缝合、3D打印、生物医学或环境工程领域的应用。
  11. 根据权利要求10所述的应用，所述脂肪组织粘合剂作为注入式生物粘合剂，对表皮及皮下脂肪组织具有最大强度为100kPa的强粘附性能，并具有生物相容性，表现出生物活性、抗菌活性、抗炎活性及抗氧化活性，能够在体内或体外降解。
PCT/CN2023/074392 2022-09-23 2023-02-03 替代可吸收缝合线的脂肪组织粘合剂、制备方法及其应用 WO2024060481A1 (zh)

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