WO2023109329A1 - 一种医用组织胶及其制备方法和用途 - Google Patents

一种医用组织胶及其制备方法和用途 Download PDF

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WO2023109329A1
WO2023109329A1 PCT/CN2022/127941 CN2022127941W WO2023109329A1 WO 2023109329 A1 WO2023109329 A1 WO 2023109329A1 CN 2022127941 W CN2022127941 W CN 2022127941W WO 2023109329 A1 WO2023109329 A1 WO 2023109329A1
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polyethylene glycol
glycol derivative
solution
medical
trilysine
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PCT/CN2022/127941
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English (en)
French (fr)
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赵博
魏鹏飞
黄一谦
景伟
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北京博辉瑞进生物科技有限公司
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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
    • 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
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/26—Mixtures of macromolecular compounds
    • 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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—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
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/075—Macromolecular gels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
    • C08L71/02—Polyalkylene oxides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the disclosure belongs to the field of biomedical materials, and in particular relates to a medical tissue glue, a preparation method and application thereof, a composition and a kit for preparing the medical tissue glue.
  • Medical tissue glue is a polymer material that produces a certain adhesive strength on the skin or in the body. It is mainly used to bond the interface of damaged or fractured tissues to stop bleeding and prevent liquid and gas leakage. Medical tissue glue adheres to biological tissues, and has been increasingly used to replace or assist sutures or staples to achieve the purpose of closing wounds.
  • Medical tissue glues mainly include natural and synthetic types, among which natural tissue glues include fibrin glue, polysaccharide tissue glue, etc., and synthetic tissue glues include aldehyde-based complexes, cyanoacrylates, and polyethylene glycol modified products, etc. .
  • natural tissue glue has played a significant role in many surgical operations, its sources are limited, the preparation process is complicated, and there are certain immunogenicity and anticoagulant problems.
  • Synthetic tissue glue has advantages in hemostasis in anticoagulated patients, and also has the advantages of low cost, good reproducibility, easy manufacture and customization, and has developed rapidly in the field of tissue glue.
  • Polyethylene glycol is an important hydrophilic polymer material with key properties such as good biocompatibility, non-immunogenicity and resistance to protein adsorption, and has a wide range of applications in the biomedical field .
  • PEG Polyethylene glycol
  • the technical chain of related products has been developed at home and abroad, and a breakthrough has been made.
  • Baxter developed Coseal tissue glue with four-armed polyethylene glycol, which was approved by the FDA in 2001.
  • Shandong Saikesaisi Biotechnology Co., Ltd. launched a four-armed polyethylene glycol derivative absorbable dura mater sealant in 2018. It is currently the main polyethylene glycol modified product circulating in the domestic medical clinical market. Tissue glue products.
  • polyethylene glycol tissue glue The gel and tissue bonding mechanism of polyethylene glycol tissue glue can be summarized as follows: the succinimide ester group in the molecular structure of modified polyethylene glycol has high chemical activity and can chemically react with other substances to form Cross-linking the network to gel; in addition, it can also chemically interact with amino groups in biological tissues to form a tissue bonding effect, but it has no adhesion to non-biological tissues such as metals, glass, ceramics and other materials.
  • polyethylene glycol tissue glue has achieved good biocompatibility and tissue adhesion, there are still some deficiencies that limit its wide application.
  • polyethylene glycol is a hydrophilic polymer, and the formed gel usually swells to a greater extent when soaked in aqueous solution or tissue fluid for a long time. This tendency may compress peripheral blood vessels and nerves, bringing potential safety Hidden danger.
  • polyethylene glycol is a more flexible macromolecule than the conjugated structure existing in natural macromolecules such as chitosan and gelatin, so the elastic modulus of the gel formed is higher than that of gels such as chitosan and gelatin. The mechanical strength is low, and when it is used in the clinical scene of emergency coronary artery bleeding, it is easily washed away by the high liquid burst pressure, so it can only be used for auxiliary hemostasis and sealing after surgical suturing.
  • polyethylene glycol tissue glue has problems such as high swelling rate, low mechanical strength, poor adhesion to tissues, and inability to effectively seal wounds.
  • the present disclosure provides a medical tissue glue, which needs to develop a medical tissue glue with high mechanical strength, good tissue bonding effect, and low swelling performance.
  • the present disclosure provides a medical tissue glue, which has a gel skeleton formed by bonding polyethylene glycol derivative I with polyethylene glycol derivative II and trilysine respectively.
  • the disclosed traditional Chinese medical tissue glue has good biocompatibility, improved mechanical properties and reduced swelling rate, and is biodegradable; the medical tissue glue maintains viscosity under wet conditions, can effectively adhere to different types of tissues, and meets wound sealing requirements. It has important clinical significance and broad application prospects.
  • the present disclosure provides a medical tissue glue
  • the medical tissue glue has a gel skeleton
  • the gel skeleton is composed of polyethylene glycol derivative I, polyethylene glycol derivative II and trilysine respectively. acid bond formation;
  • the values of m and n are natural numbers; the molecular weight of polyethylene glycol derivative I is 2000-20000, preferably 5000-15000, more preferably 8000-12000; the molecular weight of polyethylene glycol derivative II is 2000-20000, preferably 5000-15000, more preferably 8000-12000.
  • the mass ratio of the polyethylene glycol derivative I and the polyethylene glycol derivative II is 1:(0.8-1.2), preferably 1:(0.9 -1.1), more preferably 1:(0.95-1.05).
  • the mass ratio of polyethylene glycol derivative I and trilysine is 1:(0.003-0.1), preferably 1:(0.005-0.05 ); more preferably 1:(0.01-0.02).
  • the present disclosure provides a method for preparing the medical tissue glue described in the first aspect, the preparation method comprising the following steps:
  • the step of preparing solution B comprising polyethylene glycol derivative II and trilysine comprises:
  • the polyethylene glycol derivative II and trilysine are mixed and added to the solvent to obtain the solution B.
  • the mass concentration percentage of polyethylene glycol derivative II in the solution B is 10%-30% (m/v), preferably 18%-22% (m/v).
  • the mass concentration percentage of trilysine in the solution B is 0.06%-2% (m/v), preferably 0.1%-1% (m/v v), more preferably 0.2%-0.4% (m/v).
  • the mass concentration percentage of polyethylene glycol derivative I in the solution A is 10%-30% (m/v), preferably 18%-22% (m/v).
  • the present disclosure provides a medical tissue glue according to the first aspect, or a medical tissue glue obtained according to the preparation method described in the second aspect, used as or in the preparation of biomedical materials; optionally , the biomedical material is selected from at least one of the following (a)-(d):
  • the present disclosure provides a composition for preparing medical tissue glue, the composition comprising:
  • Component E which comprises the polyethylene glycol derivative I of the structure shown in formula (I):
  • Component F which comprises the polyethylene glycol derivative II of the structure shown in formula (II):
  • Component G which comprises trilysine
  • the values of m and n are natural numbers;
  • the molecular weight of polyethylene glycol derivative I is 2000-20000, preferably 5000-15000, more preferably 8000-12000;
  • the molecular weight of polyethylene glycol derivative II is 2000-20000, preferably 5000-15000, more preferably 8000-12000;
  • any one of component E, component F and component G is a powder component or a liquid component.
  • the present disclosure provides a kit for tissue sealing, characterized in that the kit includes the composition according to the fourth aspect.
  • the medical tissue glue provided by the present disclosure is formed by bonding polyethylene glycol derivative I to polyethylene glycol derivative II and trilysine respectively, and has a three-dimensional network gel skeleton structure .
  • the cross-linking network density and intermolecular interaction energy of the gel skeleton are improved, and the tissue bonding strength and Mechanical strength; and, medical tissue glue has a reduced swelling rate, high biocompatibility and biodegradability, can effectively adhere to tissues, seal wounds, and reduce the pressure on nerves and other tissues to achieve wound sealing, Tissue repair, as well as the closure of postoperative blood, interstitial fluid and other fluids, have important clinical significance and broad application prospects.
  • the medical tissue glue provided by the present disclosure can further improve the interaction of the gel skeleton by adjusting the mass ratio of polyethylene glycol derivative I, polyethylene glycol derivative II, and trilysine. Joint density, to achieve high bond strength, mechanical properties, and a good match with the mechanical properties of the tissue.
  • the medical tissue glue in the present disclosure has good adhesion properties to different tissues such as stomach, small intestine, skin, heart, lung, liver, etc., maintains viscosity and elasticity in a liquid environment, and can meet wound sealing, liquid sealing, postoperative Different biomedical needs such as hemostasis.
  • the preparation method provided by the present disclosure has simple steps, easy operation, low cost and abundant sources of raw materials, and is suitable for large-scale industrial mass production.
  • the composition for preparing medical tissue glue provided by the present disclosure can achieve gel in a short time by mixing different material components, and volatilize the tissue bonding effect, which has the advantages of easy implementation and use .
  • Fig. 1 shows the formation process of medical tissue glue and the schematic diagram of tissue bonding, hemostasis mechanism
  • Figure 2 shows the biocompatibility test results of the medical tissue glue on L929 cells, the scale bar is 10 ⁇ m.
  • Figure 3 shows the purity and chemical structure detection results of trilysine
  • Figure 4 shows the effect of the concentration of polyethylene glycol derivatives on the stress-strain curve, elastic modulus and bond strength of the medical tissue glue.
  • Fig. 5 shows the test results of the bonding strength, shear strength and interface toughness of different tissues by medical tissue glue
  • Figure 6 shows the impact of the concentration of polyethylene glycol derivatives on the shear force and shear strength of medical tissue glue
  • Fig. 7 shows the impact result of the concentration of polyethylene glycol derivatives on the peeling force and interface toughness of medical tissue glue
  • Fig. 8 shows the animal experiment of hemostasis on the surface of the liver using the Chinese medical tissue glue of the present disclosure
  • FIG. 9 shows the in vitro degradation characteristics of the medical tissue glue of the present disclosure.
  • % (m/v) means mass concentration percentage.
  • the mass concentration percentage refers to the mass of a certain component in a unit volume of solvent.
  • the "molecular weight" of polyethylene glycol derivatives means the weight average molecular weight of polyethylene glycol derivatives.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments” and the like refer to specific elements described in relation to the embodiments (for example, A feature, structure, property, and/or characteristic) is included in at least one embodiment described herein, and may or may not be present in other embodiments.
  • references to “some specific/preferred embodiments”, “other specific/preferred embodiments”, “embodiments” and the like refer to specific elements described in relation to the embodiments (for example, A feature, structure, property, and/or characteristic) is included in at least one embodiment described herein, and may or may not be present in other embodiments.
  • the described elements may be combined in any suitable manner in the various embodiments.
  • numerical range represented by "numerical value A - numerical value B" means the range which includes numerical value A and B of an end point.
  • the "water” includes any feasible water that can be used such as deionized water, distilled water, ion exchanged water, double distilled water, high-purity water, and purified water.
  • the temperature when “normal temperature” and “room temperature” are used, the temperature may be 10-40°C.
  • the first aspect of the present disclosure provides a medical tissue glue, which has a gel skeleton formed by bonding polyethylene glycol derivative I with polyethylene glycol derivative II and trilysine respectively ;
  • the values of m and n are natural numbers; the molecular weight of polyethylene glycol derivative I is 2000-20000, preferably 5000-15000, more preferably 8000-12000; the molecular weight of polyethylene glycol derivative II is 2000-20000, preferably 5000-15000, more preferably 8000-12000.
  • the medical hydrogel in the present disclosure is composed of polyethylene glycol derivative I (four-arm polyethylene glycol succinimide glutarate, PEG-SG) shown in formula (I) and formula (II) respectively
  • the shown polyethylene glycol derivative II (four-armed polyethylene glycol amine, PEG-NH 2 ) is formed by bonding with trilysine (SL).
  • a in Figure 1 shows the respective molecular structures of polyethylene glycol derivative I, polyethylene glycol derivative II, and trilysine, as shown in a in Figure 1, polyethylene glycol derivative
  • the diol derivative I has an active succinimide ester group, which reacts chemically with the amino group of the polyethylene glycol derivative II, and forms a covalent bond between the two to form a network crosslinked structure.
  • the polyethylene glycol derivative I and trilysine are covalently combined through amide bonds to strengthen the cross-linking density of the hydrogel skeleton, and the gel formed by the covalent cross-linking of the three substances in a in Figure 1 is obtained.
  • Glue skeleton structure is obtained by the covalent cross-linking of the three substances in a in Figure 1 is obtained.
  • the functional groups in medical tissue glue can be covalently combined with biological tissues to achieve the effect of tissue bonding. It is found in the present disclosure that the medical tissue glue formed by polyethylene glycol derivative I, polyethylene glycol derivative II and trilysine not only has good biocompatibility and degradability, but also has good bonding strength with tissue It can reduce the pressure on nerves and other tissues, effectively adhere to various tissues, and play different biomedical functions such as wound sealing, tissue repair, liquid sealing, and postoperative hemostasis. It has broad clinical application prospects. .
  • the polyethylene glycol derivative I with the structure shown in formula (I), its molecular weight is 2000-20000, preferably 5000-15000, more preferably 8000-12000.
  • the molecular weight of the polyethylene glycol derivative I is 2,000, 5,000, 8,000, 10,000, 15,000 or 20,000, and any numerical range therebetween.
  • the value of n is not specifically limited, and it may be any natural number. Specifically, as long as the value of n can make the molecular weight of the polyethylene glycol derivative I fall within the range of 2000-20000, for example, the value of n is 5-107.
  • the molecular weight of polyethylene glycol derivative I in the present disclosure is 2000-20000, which means that the weight average molecular weight of polyethylene glycol derivative I is 2000-20000, and the value of n in the structure shown in formula (I) As long as the weight average molecular weight of the polyethylene glycol derivative I can fall within the range of 2000-20000.
  • the polyethylene glycol derivative II with the structure represented by formula (II) its molecular weight is 2000-20000, preferably 5000-15000, more preferably 8000-12000.
  • the molecular weight of the polyethylene glycol derivative II is 2,000, 5,000, 8,000, 10,000, 15,000 or 20,000, and any numerical range therebetween.
  • the value of m is not specifically limited, and it may be any natural number. Specifically, as long as the value of m can make the molecular weight of the polyethylene glycol derivative II fall within the range of 2000-20000, for example, the value of m is 10-111.
  • the molecular weight of polyethylene glycol derivative II in this disclosure is 2000-20000, which means that the weight average molecular weight of polyethylene glycol derivative II is 2000-20000, and the value of m in the structure shown in formula (I) As long as the weight average molecular weight of the polyethylene glycol derivative II can fall within the range of 2000-20000.
  • the weight average molecular weight described in the present disclosure can be measured by methods commonly used in the art, for example, MALDI-TOF measurement method.
  • the mass ratio of the polyethylene glycol derivative I and the polyethylene glycol derivative II is 1:( 0.8-1.2), preferably 1:(0.9-1.1), more preferably 1:(0.95-1.05).
  • the mass ratio of polyethylene glycol derivative I and polyethylene glycol derivative II is 1:0.8, 1:0.9, 1:1, 1:1.1 or 1:1.2, and any of them range of values, etc.
  • the mass ratio of polyethylene glycol derivative I to trilysine is 1:(0.003-0.1), preferably 1:(0.005-0.05), more preferably 1:(0.01-0.02).
  • the mass ratio of exemplary polyethylene glycol derivative I and trilysine is 1:0.005, 1:0.01, 1:0.02, 1:0.04 or 1:0.05, and any numerical range between them, etc. .
  • tissue glue can be effectively formed after being fully mixed.
  • the degree of swelling is too high, which may cause pressure on the tissue after implantation; when it is higher than the above range, the crosslinking of the hydrogel network is too high, which will affect the degradation of the hydrogel after implantation .
  • the medical tissue glues of the present disclosure are compared to existing absorbable dural sealants.
  • the absorbable dura mater sealant is formed by cross-linking four-arm polyethylene glycol hydroxysuccinimide glutarate, polyethyleneimine and trilysine.
  • the disclosed Chinese medical tissue glue has improved tissue bonding strength, and significantly improved shear strength and interfacial toughness, indicating that polyethylene glycol derivatives I, polyethylene glycol derivatives II and The three lysines are bonded to each other, enabling synergistically enhanced tissue adhesion and mechanical properties.
  • the gel time of the absorbable dura mater sealing glue is 8-12 seconds, the swelling rate is not higher than 185%, and the degradation time is 4-8 weeks.
  • the medical tissue glue in the present disclosure has shorter gel time, longer degradation time and lower swelling, its gel time is not more than 5 seconds, and the swelling rate is not higher than 145%; the degradation time is not lower in 40 days.
  • the medical tissue glues of the present disclosure are compared to existing tissue sealants.
  • the tissue sealing agent is mainly composed of four-arm polyethylene glycol succinimide ester and four-arm polyethylene glycol ether thiol, and has good tissue bonding effect.
  • the swelling rate of the medical tissue glue in the present disclosure is significantly reduced, indicating that the polyethylene glycol derivative I in the present disclosure is bonded with the polyethylene glycol derivative II and trilysine, which can improve the tissue glue.
  • it can also exert the effect of swelling and convergence, thereby reducing the pressure on tissues such as nerves, and can be applied to tissue wounds with limited space.
  • the medical tissue glue is formed at the tissue wound.
  • the polyethylene glycol derivative I When the polyethylene glycol derivative I is mixed with the polyethylene glycol derivative II and trilysine, it can gel in a short time to produce tissue bonding effect.
  • Medical tissue glue can adhere to tissues in a humid environment, has high bonding strength, mechanical properties and reduced swelling rate, realizes wound sealing, and seals liquids such as blood and tissue fluid, and plays the role of tissue repair and hemostasis .
  • the medical tissue glue in the present disclosure is degraded and absorbed in the body as the material is finally metabolized and excreted by the body, which has good biocompatibility; and avoids the self-limitation of the biological factor source glue, such as the potential immunogenicity of fibrin glue and Insufficient coagulation cascade activity limited in some patients, good bioidentity and biodegradability.
  • a second aspect of the present disclosure provides a method for preparing medical tissue glue, comprising the steps of:
  • solution A and solution B are mixed directly at the tissue wound site.
  • solution A and solution B are extruded synchronously, and solution A and solution B are mixed during extrusion, wherein polyethylene glycol derivative I and polyethylene glycol Derivative II and trilysine were cross-linked, and the transient gel produced adhesive tissue glue.
  • the medical tissue glue adheres to the defective blood vessel after it is formed.
  • the amino group of the vascular tissue and the medical tissue glue have electrostatic and chemical interactions to form a cohesive force, which realizes the sealing of the wound, and in the form of physical closure. Play the role of hemostasis.
  • Medical tissue glue has good biocompatibility, no potential immunogenicity and anti-coagulation problems. With the recovery of the wound, the medical tissue glue is gradually degraded and finally excreted by the body's metabolism.
  • solution A can be obtained by dissolving polyethylene glycol derivative I in a solvent suitable for in vivo or body surface administration.
  • the solvent for dissolving the polyethylene glycol derivative I is phosphate buffer, water or other types of solvents in the art.
  • solution A is formed by dissolving polyethylene glycol derivative I in phosphate buffer.
  • the phosphate buffer is neutral, for example, the pH is 7.0-7.4.
  • solution B can choose any of the following preparation methods:
  • a solution containing polyethylene glycol derivative II and a solution containing trilysine are prepared separately, and the two solutions are mixed to obtain the solution B.
  • a solution containing polyethylene glycol derivative II is prepared, and trilysine is added to the solution containing polyethylene glycol derivative II to obtain the solution B.
  • a solution containing trilysine is prepared, and polyethylene glycol derivative II is added to the solution containing trilysine to obtain the solution B.
  • the polyethylene glycol derivative II and trilysine are mixed and added to a solvent to obtain the solution B.
  • the solvent for dissolving polyethylene glycol derivative II and/or trilysine may be phosphate buffer, water or other types of solvents in the art.
  • solution B comprising polyethylene glycol derivative II and trilysine is a phosphate buffer comprising polyethylene glycol derivative II and trilysine.
  • the phosphate buffer is neutral, for example, the pH is 7.0-7.4.
  • the mass concentration percentage of polyethylene glycol derivative I in solution A is 10-30% (m/v), preferably 18-22% (m/v).
  • the mass concentration percentage of polyethylene glycol derivative I in solution A is 12% (m/v), 14% (m/v), 16% (m/v), 18% (m/v) , 20% (m/v), 22% (m/v), 24% (m/v), 26% (m/v) or 28% (m/v), and any value between them range etc.
  • the mass concentration percentage of polyethylene glycol derivative II in solution B is 10-30% (m/v), preferably 18-22% (m/v).
  • the mass concentration percentage of polyethylene glycol derivative I in solution A is 12% (m/v), 14% (m/v), 16% (m/v), 18% (m/v) , 20% (m/v), 22% (m/v), 24% (m/v), 26% (m/v) or 28% (m/v), and any value between them range etc.
  • Improving the mass concentration of polyethylene glycol derivative I and/or polyethylene glycol derivative II within a certain range can improve the mechanical strength and tissue bonding strength of medical tissue glue.
  • considering the relationship between medical tissue glue and native tissue The matching of mechanical properties, when the mass concentration of polyethylene glycol derivative I and polyethylene glycol derivative II is within the above range, it can be prepared to have both high mechanical properties and bonding strength, and match the original tissue. medical tissue glue.
  • the mass concentration percentage of trilysine in solution B is 0.06%-2% (m/v), preferably 0.1%-1% (m/v), more preferably 0.2%-0.4% (m/v).
  • the mass concentration percentage of trilysine in solution B is 0.08% (m/v), 0.1% (m/v), 0.15% (m/v), 0.2% (m/v), 0.25% (m/v), 0.3% (m/v), 0.35% (m/v), 0.4% (m/v), 0.5% (m/v), 0.7% (m/v), 0.9% (m /v), 1.1% (m/v), 1.5% (m/v), 1.8% (m/v), and any range of values between them, etc.
  • the mass concentration of trilysine in solution B is within the above-mentioned range, while improving the mechanical strength of the medical tissue glue, the swelling rate of the medical tissue glue can be reduced, and a liquid suitable for bonding tissue and blocking can be obtained, and a liquid with good biological properties can be obtained.
  • Compatible, degradable medical tissue glue is
  • solution A and solution B may be mixed directly on the same tissue area, or applied to two separate tissue areas, and then mixed during the bonding process of the two tissue areas.
  • tissue region in the present disclosure may be located in tissue at any position.
  • first tissue area first tissue area
  • second tissue area second tissue area
  • Solution A and Solution B are mixed directly on the same tissue area.
  • the solution A containing the polyethylene glycol derivative I and the solution B containing the polyethylene glycol derivative II and trilysine are respectively prepared in two separate pipelines of the double syringe.
  • a double syringe is used to apply solution A and solution B to the first tissue area simultaneously, and solution A and solution B are mixed during extrusion, polyethylene glycol derivative I and polyethylene glycol derivative II, three Lysines interact to form hydrogels with tissue-adhesive properties.
  • the side of the first tissue area coated with medical tissue glue is attached to the second tissue area not coated with tissue glue, and the medical tissue glue with adhesive properties can realize the bonding between the first tissue area and the second tissue area. High strength bond.
  • Solution A and Solution B are applied separately to the two tissue areas to be bonded.
  • solution A is applied to the first tissue area
  • solution B is applied to the second tissue area
  • the sides coated with the solution of the first tissue area and the second tissue area are brought into contact with each other.
  • the solution A and the solution B are mixed to form a medical tissue glue with adhesive properties, and realize the mutual bonding of the first tissue region and the second tissue region.
  • the third aspect of the present disclosure provides a composition for preparing the medical tissue glue described in the first aspect, comprising:
  • Component E which comprises the polyethylene glycol derivative I of the structure shown in formula (I):
  • Component G which comprises trilysine
  • the values of m and n are natural numbers; the molecular weight of polyethylene glycol derivative I is 2000-20000, preferably 5000-15000, more preferably 8000-12000; the molecular weight of polyethylene glycol derivative II is 2000-20000, preferably 5000-15000, more preferably 8000-12000.
  • the preparation kit in the present disclosure uses the three components of components E, F, and G to realize gelation within 5 seconds, and the composition can exert a tissue bonding effect after being applied to the surface of the tissue, and obtain a gel with high mechanical properties. It is a medical tissue glue with strong bonding strength with tissue, good biocompatibility and low swelling rate.
  • the medical hydrogel prepared by mixing components E, F, and G on the tissue wound can instantly form adhesive properties to meet different biomedical needs such as wound sealing, tissue adhesion, liquid sealing, and postoperative hemostasis.
  • component E is a solid reagent, for example, component E is a dry powder of polyethylene glycol derivative I.
  • component E is a liquid reagent, for example, component E is obtained by dissolving polyethylene glycol derivative I in a solvent.
  • the solvent for dissolving the polyethylene glycol derivative I it can be PBS buffer, or the types of solvents available in the art.
  • component F is a solid reagent, for example, component F is a dry powder of polyethylene glycol derivative II.
  • component F is a liquid reagent, for example, component F is obtained by dissolving polyethylene glycol derivative II in a solvent.
  • the solvent for dissolving the polyethylene glycol derivative II it can be PBS buffer, or the types of solvents available in the art.
  • component G is a solid reagent, for example, component G is a dry powder of trilysine.
  • component G is a liquid reagent, for example, component G is obtained by dissolving trilysine in a solvent.
  • the solvent for dissolving trilysine it may be PBS buffer, or the types of solvents available in the art.
  • component F and component G may also exist in the form of mixed reagents, for example, mixed dry powder of polyethylene glycol derivative II and trilysine. Alternatively, it is a mixed solution in which polyethylene glycol derivative II and trilysine are simultaneously dissolved.
  • component E is the solid reagent or liquid reagent (for example, component E It is an independently packaged dry powder, solution and other reagent types)
  • component F is an independently existing solid reagent or liquid reagent (for example, component F is an independently packaged dry powder, solution and other reagent types)
  • component G is an independent solid reagent Reagents or liquid reagents (for example, component G is a reagent type such as dry powder or solution in an independent package).
  • component E is an independently existing solid reagent or liquid reagent (for example, component E is reagents such as dry powder, solution, etc. type), solid or liquid reagents in which components F and G are mixed (for example, dry powder, solution and other reagent types that are individually packaged after mixing components E and G).
  • component E is an independently existing solid reagent or liquid reagent (for example, component E is reagents such as dry powder, solution, etc. type), solid or liquid reagents in which components F and G are mixed (for example, dry powder, solution and other reagent types that are individually packaged after mixing components E and G).
  • a fourth aspect of the present disclosure provides a kit for tissue sealing, which includes the composition for preparing medical tissue glue described in the third aspect.
  • the kit in the present disclosure can quickly prepare medical tissue glue with high biocompatibility, degradability, high mechanical strength, and low swelling rate on the surface or inside of the tissue.
  • Different tissues such as the lung and liver have high adhesive properties, which can effectively play the role of wound sealing, fluid sealing, and tissue repair.
  • the kit also includes instructions for use, which provide the following:
  • the mass ratio of the polyethylene glycol derivative I and the polyethylene glycol derivative II of the medical hydrogel prepared by the kit is 1:(0.8-1.2), preferably 1:(0.9-1.1), more preferably 1: (0.95-1.05).
  • the mass ratio of polyethylene glycol derivative I and trilysine prepared by using the kit to prepare the medical hydrogel is 1:(0.003-0.1), preferably 1:(0.005-0.05), more preferably 1:( 0.01-0.02).
  • the instructions for use include the following:
  • the instructions for use include the following:
  • a dual syringe is also included in the kit.
  • the solution A and solution B are mixed evenly during the process of extruding the two, so that the gel can be realized in a short time and the tissue bonding effect can be exerted.
  • the fourth aspect of the present disclosure provides the use of medical tissue glue.
  • the medical tissue glue is used as or prepared for endoscopic sealing medical glue; in some embodiments, the medical tissue glue is used as or prepared for blood vessel sealing. Glue; in some embodiments, the medical tissue glue is used as or prepared for surgical sealing; in some embodiments, the medical tissue glue is used as or prepared for cerebrospinal fluid sealing.
  • the medical tissue glue in the present disclosure can achieve effective adhesion to tissues, quickly stop bleeding, effectively seal wounds, and promote wound tissue healing, and has potential huge application scenarios in the fields of gastrointestinal surgery, hand and foot surgery, neurosurgery, etc. .
  • SL three lysine
  • PEG-SG four-arm polyethylene glycol succinimide glutarate
  • PEG-NH 2 four-arm polyethylene glycol amine
  • three lysine, four-arm polyethylene glycol succinimide glutarate and four-arm polyethylene glycol amine are used as raw materials to prepare medical tissue glue, wherein the four-arm polyethylene glycol succinimide
  • the structure of diacid ester is as shown in formula (I), and molecular weight is 5000
  • the structure of four-arm polyethylene glycol amine is as shown in formula (II), and molecular weight is 5000;
  • three lysine, four-arm polyethylene glycol succinimide glutarate and four-arm polyethylene glycol amine are used as raw materials to prepare medical tissue glue, wherein the four-arm polyethylene glycol succinimide
  • the structure of diacid ester is as shown in formula (I), and molecular weight is 20000
  • the structure of four-arm polyethylene glycol amine is as shown in formula (II), and molecular weight is 20000;
  • three lysine, four-arm polyethylene glycol succinimide glutarate and four-arm polyethylene glycol amine are used as raw materials to prepare medical tissue glue, wherein the four-arm polyethylene glycol succinimide
  • the structure of diacid ester is as shown in formula (I), molecular weight is 20000;
  • the structure of four-arm polyethylene glycol amine is as shown in formula (II), and molecular weight is 15000;
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • three lysine, four-arm polyethylene glycol succinimide glutarate and four-arm polyethylene glycol amine are used as raw materials to prepare medical tissue glue, wherein the four-arm polyethylene glycol succinimide
  • the structure of diacid ester is as shown in formula (I), and molecular weight is 10000
  • the structure of four-arm polyethylene glycol amine is as shown in formula (II), and molecular weight is 10000;
  • Adopt double injector to contain PEG-SG solution and contain PEG-NH 2 and the solution of trilysine and inject simultaneously in the mold of polytetrafluoroethylene (cylindrical mold, diameter 1cm, depth 1cm), according to 0.1g/ The ratio of mL, that is, 0.1 g of hydrocolloid and 1 mL of medium ( ⁇ -MEM medium containing 10% fetal bovine serum and 100 IU/mL of penicillin and streptomycin) was soaked in a cell culture incubator at 37° C. for 24 hours. After 24 hours, the supernatant was extracted.
  • the ordinary medium of L929 cells that had been inoculated on the tissue culture plate for 24 hours was discarded, and replaced with the conditioned medium soaked in tissue glue to continue culturing for 24 hours.
  • FIG. 2 shows the biocompatibility test results of the medical tissue glue on L929 cells, the scale bar is 10 ⁇ m.
  • the medical tissue glue is prepared with 20% (m/v) PEG-SG, 20% (m/v) PEG-NH2 and 0.2% (m/v) SL. It can be seen from FIG. 2 that the medical tissue glue prepared in the present disclosure has good cell compatibility, and the cell activity is above 80%.
  • HPLC and NMR were used to verify the purity and chemical structure of the trilysine used to prepare the medical tissue glue.
  • Figure 3 shows the detection results of the purity and chemical structure of the trilysine. As shown in Figure 3, the purity of trilysine used to prepare medical tissue glue is 99.25%, and the actual chemical structure matches the theoretical structure of trilysine.
  • the bond strength test refers to ASTM F2258, and an electronic universal testing machine is required for the experimental operation. After the freshly purchased back pigskin is washed briefly and soaked with lipase three times to remove the surface fat (the ratio of 100g pigskin to 500mL lipase, the concentration of lipase is 2wt.%, once for 30 minutes, repeated three times, 240W power ultrasonic treatment) , Cut into 2cm ⁇ 2cm square size. Use Qiangni 502 to firmly stick the smoother side of the two pieces of pigskin to the two molds for the bond strength test, compact and fix it for 1 minute, then spray 100 ⁇ L of tissue glue evenly on the surface of the pigskin, and quickly stick to it.
  • bonding strength (Pa) Fmax(N)/stressed area (m 2 ).
  • the shear strength test refers to ASTM F2255. Degrease the fresh back pigskin and cut it into a size of 5cm ⁇ 2.5cm, then apply 100 ⁇ L tissue glue evenly on one end of the pigskin, the coating size is 2.5cm ⁇ 1cm, and quickly bond the pigskin in the opposite direction
  • the peel strength test refers to ATSM F2256. Degrease the fresh back pigskin and cut it into a size of 5cm ⁇ 2.5cm, then apply 100 ⁇ L of tissue glue evenly on one end of the pigskin, the coating size is 2.5cm ⁇ 1cm, and quickly bond the pigskin in the same direction
  • Figure 4 shows the effect of the concentration of polyethylene glycol derivative I and polyethylene glycol derivative II on the stress-strain curve, elastic modulus and bond strength of medical tissue glue. It can be seen from Figure 4 that increasing the concentration within a certain range can significantly improve the mechanical strength and bonding strength of the medical tissue glue. Considering that the mechanical strength of the medical tissue glue needs to match the original tissue, the percentage of the selected mass concentration is 10%-30% ( m/v) I, polyethylene glycol derivative II, and trilysine with a mass concentration percentage of 0.06%-2% (m/v) are used to prepare medical tissue glue.
  • Figure 5 shows the test results of the adhesion of medical tissue glue to different tissues. It can be seen from Figure 5 that medical tissue glue has adhesion to animal tissues, and these tissues include stomach, small intestine, heart, lung, liver and other tissues. Due to the different mechanical strengths of different soft tissues, the bonding strength of medical tissue adhesives is also different, but generally has good bonding strength, shear strength and interface toughness, so it can be applied to wounds of different tissues Hemostasis and air leakage and so on.
  • Figure 6 shows the effects of different preparation methods on the gel time and shear bond strength of medical tissue glue.
  • method 1 apply solution A and solution B on both sides of the pigskin respectively, and then bond each other;
  • method 2 directly coat one side of the pigskin in the form of double syringe injection , and then quickly bond another piece of pigskin, and use the ASTM F2255 standard to test the shear strength of the two glue-making methods, which proves that the difference in the preparation method has little effect on the medical tissue glue.
  • Fig. 6 shows the impact result of the concentration of polyethylene glycol derivatives on the shear bond strength of medical tissue glue, a among Fig. 6 is after electron irradiation, the shear force of the medical tissue glue of different concentrations; Fig. b in 6 is the shear strength of different concentrations of medical tissue glue after electron irradiation.
  • Figure 7 shows the effect of the concentration of polyethylene glycol derivatives on the peeling and interface toughness of medical tissue glue.
  • a in Figure 7 is the peeling force of different concentrations of medical tissue glue after electron radiation;
  • b in Figure 7 is the interface toughness of different concentrations of medical tissue glue after electron radiation.
  • concentration of PEG-SG is 10% (m/v), 20% (m/v) and 30% (m /v);
  • concentration of the polyethylene glycol derivative I and the concentration of the polyethylene glycol derivative II are selected as an example to make these schematic diagrams, which are not limited to the concentration of the polyethylene glycol derivative.
  • Fig. 8 shows the animal experiment of hemostasis on the liver surface using the Chinese medical tissue glue of the present disclosure.
  • the experimental animals were healthy Bama pigs.
  • the test pig was anesthetized, and the liver tissue was exposed.
  • b in Fig. 8 shows the manufacture of a liver defect model. A circular knife with a diameter of 8 mm is used to form a liver tissue defect with a depth of 2 mm. At this time, blood flows out of the defect.
  • c in Fig. 8 shows that the medical tissue glue is applied, and the pre-prepared gelling liquid is injected and coated on the defect, and the gel is rapidly formed and the wound is blocked and the bleeding is stopped (d in Fig. 8 ). It can be seen that the medical tissue glue can effectively bond with animal tissues, and can seal the wound to achieve the effect of hemostasis and isolation of the wound.
  • FIG. 9 shows the in vitro degradation characteristics of the medical tissue glue of the present disclosure.
  • the tissue glue formed by the polyethylene glycol derivative I, polyethylene glycol derivative II, and trilysine after implantation in the body can reduce the quality of the tissue glue by not less than 30% when implanted for 35 days. %, less than 10% residual after 42 days of implantation. It shows that the tissue glue can effectively protect the wound healing and degrade completely after the tissue repair is completed.
  • the swelling rate of the hydrogel includes a calculation method using volume or weight, usually the volume and/or weight when gelling is selected and the volume and/or weight after a certain period of time.
  • the method for calculating the swelling rate of the hydrogel used in the present disclosure is: the ratio of the weight of the hydrogel after swelling equilibrium to the weight of the hydrogel when gelling is used, and the interval time is selected as 24 hours.

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Abstract

本公开属于生物医用材料领域，具体涉及一种医用组织胶及其制备方法、用途和制备医用组织胶的组合物、试剂盒。本公开提供的医用组织胶，通过聚乙二醇衍生物I与聚乙二醇衍生物II、三赖氨酸的相互交联，形成三维网状的凝胶骨架结构；并且凝胶骨架的交联网络密度和分子间相互作用能提高，具有提高的组织粘结强度和力学强度；同时，医用组织胶具有降低的溶胀率、高的生物相容性和可生物降解性能，能够有效粘附组织、封合创口，并且减少对神经等组织的压迫，实现创口封合、组织修复，以及对术后血液、组织液等液体的封堵，具有重要的临床意义和广阔应用前景。

Description

一种医用组织胶及其制备方法和用途
优先权和相关申请
本公开要求2021年12月13日提交的名称为“一种医用组织胶及其制备方法和用途”的中国专利申请202111520296.6的优先权，该申请包括附录在内的全部内容作为参考并入本公开。
技术领域
本公开属于生物医用材料领域，具体涉及一种医用组织胶及其制备方法、用途和制备医用组织胶的组合物、试剂盒。
背景技术
医用组织胶是一种在皮肤上或体内产生一定粘合强度的聚合材料，主要用于粘结受损、断裂组织的界面以达到止血和防止液体、气体渗漏等情况。医用组织胶对生物组织产生粘附，已经越来越多地用于替代或辅助缝合线或缝合钉以达到闭合伤口的目的。
医用组织胶主要有天然类和合成类，其中天然组织胶包括纤维蛋白胶、多糖类组织胶等，合成组织胶包括醛基复合物、氰基丙烯酸酯和聚乙二醇改性的产品等。天然组织胶虽然在许多外科手术中已发挥明显效果，但其来源有限、制备过程复杂并且存在一定的免疫原性和抗凝血问题。合成类组织胶对抗凝患者的止血具有优势作用，并且还具有成本低、重现性好、易于制造和可定制等优点，在组织胶领域的发展较快。
聚乙二醇(PEG)具有良好的生物相容性、非免疫原性和对蛋白质吸附的耐受性等关键性能，是一种重要的亲水高分子材料，在生物医学领域有着广泛的应用。根据聚乙二醇的结构设计性，国内外已开发相关产品的技术链条，取得了突破性进展。例如，百特公司以四臂聚乙二醇开发了Coseal组织胶，已在2001年获FDA批准上市。山东赛克赛斯生物科技有限公司于2018年推出一款四臂聚乙二醇衍生物的可吸收硬脑膜封合胶，是目前在国内医学临床市场流通的主要一款聚乙二醇改性组织胶产品。聚乙二醇类组织胶的凝胶及组织粘结机理，可概述如下：改性聚乙二醇分子结构中琥珀酰亚胺酯基团化学活性较高，可与别的物质发生化学作用形成交联网络，从而凝胶；此外，还可与生物组织中氨基发生化学相互作用，形成组织粘结效果，但对非生物组织如金属、玻璃、陶瓷等材料无粘结性。
尽管聚乙二醇的组织胶实现了良好的生物相容性和组织粘结性，但仍然一定不足，限制其广泛应用。例如，聚乙二醇属于亲水性高分子，形成的凝胶当长时间浸泡水溶液或组织液通常会发生较大程度的溶胀，这种趋势可能会压迫周围血管和神经，带来潜在的安全性隐患。又如，较壳聚糖、明胶等天然高分子中存在的共轭结构，聚乙二醇属于更有柔性的高分子，因此形成的凝胶弹性模量较壳聚糖、明胶等凝胶的力学强度较低，当用于紧急的冠状动脉出血的临床场景时，易被较高的液体爆破压力冲走，因此目前仅可用于手术线缝合后的辅助止血和密封。
因此，目前亟需开发基于聚乙二醇改性的组织胶规避甚至消除以上缺点，为了手术的顺利开展以及病人的生命健康、安全，提供可行性方法策略。
发明内容
发明要解决的问题
鉴于现有技术中存在的问题，例如，聚乙二醇组织胶存在溶胀率高、力学强度低，对组织的黏附效果差、无法有效封合创口等问题。为此，本公开提供了一种医用组织胶，其由需要开发机械强度高、组织粘结效果好，且溶胀性能低的医用组织胶。为此，本公开提供了一种医用组织胶，其具有由聚乙二醇衍生物I分别与聚乙二醇衍生物II和三赖氨酸键合形成的凝胶骨架。本公开中医用组织胶具有良好的生物相容性，提高的力学性能以及降低的溶胀率，可生物降解；医用组织胶在湿润条件下保持粘性，可有效粘附不同类型的组织，满足创口封合、组织修复、液体封堵等不同的生物医用需求， 具有重要的临床意义和广阔的应用前景。
用于解决问题的方案
第一方面，本公开提供了一种医用组织胶，所述医用组织胶具有凝胶骨架，所述凝胶骨架由聚乙二醇衍生物I分别与聚乙二醇衍生物II和三赖氨酸键合形成；
所述聚乙二醇衍生物I的结构如式(I)所示：
Figure PCTCN2022127941-appb-000001
所述聚乙二醇衍生物II的结构如式(II)所示：
Figure PCTCN2022127941-appb-000002
其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000。
在一些实施方式中，根据本公开所述的医用组织胶，所述聚乙二醇衍生物I和聚乙二醇衍生物II的质量比为1:(0.8-1.2)，优选1:(0.9-1.1)，更优选1:(0.95-1.05)。
在一些实施方式中，根据本公开所述的医用水凝胶，所述聚乙二醇衍生物I和三赖氨酸的质量比为1:(0.003-0.1)，优选1:(0.005-0.05)；更优选1:(0.01-0.02)。
第二方面，本公开提供了一种第一方面所述的医用组织胶的制备方法，所述制备方法包括如下步骤：
制备包含聚乙二醇衍生物I的溶液A；
制备包含聚乙二醇衍生物II和三赖氨酸的溶液B；
将溶液A和溶液B混合，得到医用组织胶。
在一些实施方式中，根据本公开所述的制备方法，所述制备包含聚乙二醇衍生物II和三赖氨酸的溶液B的步骤包括：
分别制备包含聚乙二醇衍生物II的溶液和包含三赖氨酸的溶液，将两种溶液混合，得到所述溶液B；或者，
制备包含聚乙二醇衍生物II的溶液，将三赖氨酸加入所述包含聚乙二醇衍生物II的溶液中，得到所述溶液B；或者，
制备包含三赖氨酸的溶液，将聚乙二醇衍生物II加入所述包含三赖氨酸的溶液中，得到所述溶液B；或者，
将聚乙二醇衍生物II和三赖氨酸混合，加入溶剂中，得到所述溶液B。
在一些实施方式中，根据本公开所述的制备方法，所述溶液B中聚乙二醇衍生物II的质量浓度百分数为10％-30％(m/v)，优选为18％-22％(m/v)。
在一些实施方式中，根据本公开所述的制备方法，所述溶液B中三赖氨酸的质量浓度百分数为0.06％-2％(m/v)，优选为0.1％-1％(m/v)，更优选为0.2％-0.4％(m/v)。
在一些实施方式中，根据本公开所述的制备方法，所述溶液A中聚乙二醇衍生物I的质量浓度百分数为10％-30％(m/v)，优选为18％-22％(m/v)。
第三方面，本公开提供了一种根据第一方面所述的医用组织胶，或根据第二方面所述的制备方法得到的医用组织胶，在作为或制备生物医用材料中用途；可选地，所述生物医用材料选自如下(a)-(d)中的至少一种：
(a)内镜下封合医用胶；
(b)血管封合医用胶；
(c)外科封合医用胶；
(d)脑脊液封合医用胶。
第四方面，本公开提供了一种制备医用组织胶的组合物，所述组合物包括：
组分E，其包含如式(I)所示结构的聚乙二醇衍生物I：
Figure PCTCN2022127941-appb-000003
组分F，其包含如式(II)所示结构的聚乙二醇衍生物II：
Figure PCTCN2022127941-appb-000004
组分G，其包含三赖氨酸；
其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000；
可选地，所述组分E、组分F和组分G中的任意一种为粉体组分或液体组分。
第五方面，本公开提供了一种用于组织封合的试剂盒，其特征在于，所述试剂盒包括根据第四方面所述的组合物。
发明的效果
在一些实施方式中，本公开提供的医用组织胶，由聚乙二醇衍生物I分别与聚乙二醇衍生物II和三赖氨酸键合形成，具有呈三维网状的凝胶骨架结构。通过聚乙二醇衍生物I与聚乙二醇衍生物II、三赖氨酸的相互交联，凝胶骨架的交联网络密度和分子间相互作用能提高，具有提高的组织粘结强度和力学强度；并且，医用组织胶具有降低的溶胀率、高的生物相容性和可生物降解性能，能够有效粘附组织、封合创口，并且减少对神经等组织的压迫，实现创口封合、组织修复，以及对术后血液、组织液等液体的封堵，具有重要的临床意义和广阔应用前景。
在一些实施方式中，本公开提供的医用组织胶，通过对聚乙二醇衍生物I、聚乙二醇衍生物II、三赖氨酸的质量比例进行调整，可以进一步提高凝胶骨架的交联密度，实现高的粘结强度、力学性能，并且与组织力学性能良好匹配。本公开中的医用组织胶对胃、小肠、皮肤、心脏、肺、肝脏等不同组织均具有良好的黏附性能，在液体环境下保持粘性和弹性，可满足创口封合、液体封堵、术后止血等不同的生物医用需求。
在一些实施方式中，本公开提供的制备方法，步骤简单、易于操作，制备原料的成本低、来源丰富，适合大规模的工业化量产。
在一些实施方式中，本公开提供的制备医用组织胶的组合物，通过混合不同的物质组分，即可在短时间内实现凝胶，并挥发组织粘结效果，具有易于实施、使用的优势。
附图说明
图1示出了医用组织胶的形成过程及组织粘结、止血机理的示意图；
图2示出了医用组织胶对L929细胞的生物相容性检测结果，标尺10μm。
图3示出了三赖氨酸的纯度及化学结构检测结果；
图4示出了聚乙二醇衍生物的浓度对医用组织胶的应力应变曲线、弹性模量及粘结强度的影响结果。
图5示出了医用组织胶对不同组织的粘结强度、剪切强度及界面韧性的检测结果；
图6示出了聚乙二醇衍生物的浓度对医用组织胶的剪切力和剪切强度的影响；
图7示出了聚乙二醇衍生物的浓度对医用组织胶的剥离力及界面韧性的影响结果；
图8示出了采用本公开中医用组织胶进行肝脏表面止血的动物试验；
图9示出了本公开中医用组织胶的体外降解特性。
具体实施方式
以下将详细说明本发明的各种示例性实施例、特征和方面。在这里专用的词“示例性”意为“用作例子、实施例或说明性”。这里作为“示例性”所说明的任何实施例不必解释为优于或好于其它实施例。
另外，为了更好地说明本发明，在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解，没有某些具体细节，本发明同样可以实施。在另外一些实例中，对于本领域技术人员熟知的方法、手段、器材和步骤未作详细描述，以便于凸显本发明的主旨。
如无特殊声明，本说明书中所使用的单位均为国际标准单位，并且本发明中出现的数值，数值范围，均应当理解为包含了工业生产中所不可避免的系统性误差。
本说明书中，如没有特别说明，则“％(m/v)”均表示质量浓度百分数。该质量浓度百分数是指单位体积的溶剂中某组分的质量。本说明书中的质量浓度百分数是以mL为体积单位，以g为质量单位计算得到。示例性的，将0.002g的物质组分加入1mL的溶剂中，则该物质组分的质量浓度百分数为(0.002g/1mL)*100％＝0.2％(m/v)。
本说明书中，如没有特别说明，则聚乙二醇衍生物的“分子量”均表示聚乙二醇衍生物的重均分子量。
本说明书中，使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。
本说明书中，所提及的“一些具体/优选的实施方案”、“另一些具体/优选的实施方案”、“实施方案”等是指所描述的与该实施方案有关的特定要素(例如，特征、结构、性质和/或特性)包括在此处所述的至少一种实施方案中，并且可存在于其它实施方案中或者可不存在于其它实施方案中。另外，应理解，所述要素可以任何合适的方式组合在各种实施方案中。
本说明书中，使用“数值A～数值B”表示的数值范围是指包含端点数值A、B的范围。
另外，本说明书中，所述“水”包含去离子水、蒸馏水、离子交换水、双蒸水、高纯水、纯净水等能够使用的任何可行的水。
本说明书中，使用“常温”、“室温”时，其温度可以是10-40℃。
医用组织胶
本公开的第一方面提供了一种医用组织胶，其具有凝胶骨架，所述凝胶骨架由聚乙二醇衍生物I分别与聚乙二醇衍生物II和三赖氨酸键合形成；
所述聚乙二醇衍生物I的结构如式(I)所示：
Figure PCTCN2022127941-appb-000005
所述聚乙二醇衍生物II的结构如式(II)所示：
Figure PCTCN2022127941-appb-000006
其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000。
本公开中的医用水凝胶，由式(I)所示的聚乙二醇衍生物I(四臂聚乙二醇琥珀酰亚胺戊二酸酯，PEG-SG)分别与式(II)所示的聚乙二醇衍生物II(四臂聚乙二醇胺，PEG-NH 2)和三赖氨酸(SL)键合形成。如图1所示，图1中a示出了聚乙二醇衍生物I、聚乙二醇衍生物II、三赖氨酸各自的分子结构，如图1中的a中所示，聚乙二醇衍生物I具有活性的琥珀酰亚胺酯基团，其与聚乙二醇衍生物II的氨基基团发生化学反应，两者之间形成共价键，形成网络交联结构。同时，聚乙二醇衍生物I与三赖氨酸通过酰胺键共价结合，加强水凝胶骨架的交联密度，得到了图1中的a中由三种物质共价交联形成的凝胶骨架结构。
医用组织胶中的官能团能够与生物组织共价结合，达到组织粘结的效果。本公开发现，以聚乙二醇衍生物I、聚乙二醇衍生物II和三赖氨酸形成的医用组织胶，不仅具有良好的生物相容性、可降解，其与组织的粘结强度提高，而溶胀率降低，能够减少对神经等组织的压迫，有效黏附各类组织，发挥创口封合、组织修复、液体封堵、术后止血等不同的生物医学功能，具有广阔的临床应用前景。
在一些实施方式中，对于式(I)所示结构的聚乙二醇衍生物I，其分子量为2000-20000，优选5000-15000，更优选8000-12000。示例性的，聚乙二醇衍生物I的分子量为2000，5000，8000，10000，15000或20000，以及它们任意两者之间的数值范围等。本公开中对于n的取值不作具体限定，其可以取任意的自然数。具体而言，只要n的取值能够使聚乙二醇衍生物I的分子量落入2000-20000的范围内即可，例如，n的取值为5-107。更具体地，本公开中聚乙二醇衍生物I分子量为2000-20000，是指聚乙二醇衍生物I的重均分子量为2000-20000，式(I)所示结构中n的取值只要使聚乙二醇衍生物I的重均分子量能够落入2000-20000的范围内即可。
在一些实施方式中，对于式(II)所示结构的聚乙二醇衍生物II，其分子量为2000-20000，优选5000-15000，更优选8000-12000。示例性的，聚乙二醇衍生物II的分子量为2000，5000，8000，10000，15000或20000，以及它们任意两者之间的数值范围等。本公开中对于m的取值不作具体限定，其可以取任意的自然数。具体而言，只要m的取值能够使聚乙二醇衍生物II的分子量落入2000-20000的范围内即可，例如，m的取值为10-111。更具体地，本公开中聚乙二醇衍生物II分子量为2000-20000，是指聚乙二醇衍生物II的重均分子量为2000-20000，式(I)所示结构中m的取值只要使聚乙二醇衍生物II的重均分子量能够落入2000-20000的范围内即可。
本公开中所述的重均分子量可以通过本领域常用的方法测定得到，例如，MALDI-TOF的测定方法。
在一些实施方式中，为提高凝胶骨架的交联度、增强医用水凝胶对组织的粘结强度，聚乙二醇衍生物I和聚乙二醇衍生物II的质量比为1:(0.8-1.2)，优选1:(0.9-1.1)，更优选1:(0.95-1.05)。示例 性的，聚乙二醇衍生物I和聚乙二醇衍生物II的质量比为1:0.8，1:0.9，1:1，1:1.1或1:1.2，以及它们任意两者之间的数值范围等。
在一些实施方式中，聚乙二醇衍生物I和三赖氨酸的质量比为1:(0.003-0.1)，优选1:(0.005-0.05)更优选1:(0.01-0.02)。示例性的聚乙二醇衍生物I和三赖氨酸的质量比为1:0.005，1:0.01，1:0.02，1:0.04或1:0.05，以及它们任意两者之间的数值范围等。当聚乙二醇衍生物I和三赖氨酸的质量比在上述范围内时，在充分混合后，能够有效形成组织胶。若低于上述范围，则溶胀程度过高，在植入体内后可能对组织产生压迫；当高于上述范围时，水凝胶网络交联度过高，影响水凝胶在植入后的降解。
在一些实施方式中，本公开中的医用组织胶与现有可吸收硬脑膜封合胶进行对比。该可吸收硬脑膜封合胶由四臂聚乙二醇羟基丁二酰亚胺戊二酸酯、聚乙烯亚胺和三赖氨酸交联形成。与之相比，本公开中医用组织胶具有提高的组织粘结强度，以及显著提高的剪切强度和界面韧性，说明本公开中聚乙二醇衍生物I、聚乙二醇衍生物II与三赖氨酸相互键合，能够实现协同增强的组织粘结性能和力学性能。该可吸收硬脑膜封合胶凝胶时间为8-12秒，溶胀率不高于185％，降解时间4-8周。而本公开中的医用组织胶具有更短的凝胶时间更长的降解时间和更低的溶胀，其凝胶时间为不大于5秒，溶胀率为不高于145％；降解时间为不低于40天。
在一些实施方式中，本公开中的医用组织胶与现有组织封合剂进行对比。该组织封合剂以四臂聚乙二醇琥珀酰亚胺酯和四臂聚乙二醇醚硫醇为主要组分，具有较好的组织粘结效果。与之相比，本公开中医用组织胶的溶胀率显著降低，说明本公开中聚乙二醇衍生物I与聚乙二醇衍生物II和三赖氨酸键合连接，在提高组织胶的力学性能及组织粘结强度的同时，还可以发挥溶胀收敛的效果，从而减轻对神经等组织的压迫，能够应用于空间有限的组织创口处。
在一些实施方式中，医用组织胶形成于组织创口处，当聚乙二醇衍生物I与聚乙二醇衍生物II和三赖氨酸混合后，在短时间内即可凝胶，产生组织粘结的效果。医用组织胶可以在湿润环境下黏附组织，具有高的粘结强度、力学性能和降低的溶胀率，实现对创口封合，以及对血液、组织液等液体的封堵，发挥组织修复、止血的作用。
本公开中的医用组织胶随着材料在体内降解吸收，最终被机体代谢排出，具有良好的生物相容性；并且规避了生物因子源胶水的自身局限，如纤维蛋白胶水的潜在免疫原性及部分患者的凝血级联反应活性有限的不足，兼具良好的生物相同性和生物可降解性。
医用组织胶的制备方法
本公开的第二方面提供了医用组织胶的制备方法，包括如下步骤：
制备包含聚乙二醇衍生物I的溶液A；
制备包含聚乙二醇衍生物II和三赖氨酸的溶液B；
将溶液A和溶液B混合，得到医用组织胶。
在一些实施方式中，溶液A和溶液B直接混合于组织创口处。示例性的，如图1中b所示，将溶液A和溶液B同步挤出，溶液A和溶液B在挤出的过程中相混合，其中的聚乙二醇衍生物I与聚乙二醇衍生物II和三赖氨酸发生交联，瞬时凝胶产生具有黏附性的组织胶。医用组织胶在在形成后即黏附与缺损的血管上，血管组织的氨基基团与医用组织胶发生静电、化学相互作用形成粘结力，实现对创口的封合，并且以物理封堵的形式发挥止血的作用。医用组织胶良好的生物相容性、无潜在的免疫原性和抗凝血问题，随着创面的恢复，医用组织胶逐渐降解，最终被机体代谢排出。
在本公开中，溶液A可以是将聚乙二醇衍生物I溶解于适合向体内或体表施用的溶剂中得到。示例性的，溶解聚乙二醇衍生物I的溶剂为磷酸盐缓冲液、水或本领域中其他类型的溶剂。在一些实施方式中，溶液A由聚乙二醇衍生物I溶解于磷酸盐缓冲液中形成。其中，磷酸盐缓冲液呈中性，例如，pH为7.0-7.4。
在本公开中，溶液B可以选择如下的任一种制备方式：
在一些实施方式中，分别制备包含聚乙二醇衍生物II的溶液和包含三赖氨酸溶液，将两种溶液混合，得到所述溶液B。
在一些实施方式中，制备包含聚乙二醇衍生物II的溶液，将三赖氨酸加入所述包含聚乙二醇衍生物II的溶液中，得到所述溶液B。
在一些实施方式中，制备包含三赖氨酸的溶液，将聚乙二醇衍生物II加入所述包含三赖氨酸的溶液中，得到所述溶液B。
在一些实施方式中，将聚乙二醇衍生物II和三赖氨酸混合，加入溶剂中，得到所述溶液B。
对于溶解聚乙二醇衍生物II和/或三赖氨酸的溶剂，可以是磷酸盐缓冲液、水或本领域中其他类型的溶剂。在一些实施方式中，包含聚乙二醇衍生物II和三赖氨酸的溶液B，为包含聚乙二醇衍生物II和三赖氨酸的磷酸盐缓冲液。其中，磷酸盐缓冲液呈中性，例如，pH为7.0-7.4。
在一些更为具体的实施方式中，将三赖氨酸与聚乙二醇衍生物II混合后溶于磷酸盐缓冲液，得到溶液B。或者，首先将聚乙二醇衍生物II溶于磷酸盐缓冲液，然后向溶液中加入三赖氨酸，得到溶液B；或者，首先将三赖氨酸溶于磷酸盐缓冲液，然后向溶液中加入聚乙二醇衍生物II，得到溶液B。或者，分别将三赖氨酸溶于磷酸盐缓冲液，将聚乙二醇衍生物II溶于磷酸盐缓冲液，然后将两种溶液混合，得到溶液B。
在一些实施方式中，溶液A中聚乙二醇衍生物I的质量浓度百分数为10-30％(m/v)，优选为18-22％(m/v)。示例性的，溶液A中聚乙二醇衍生物I的质量浓度百分数为12％(m/v)、14％(m/v)、16％(m/v)、18％(m/v)、20％(m/v)、22％(m/v)、24％(m/v)、26％(m/v)或者28％(m/v)，以及它们任意两者之间的数值范围等等。
在一些实施方式中，溶液B中聚乙二醇衍生物II的质量浓度百分数为10-30％(m/v)，优选为18-22％(m/v)。示例性的，溶液A中聚乙二醇衍生物I的质量浓度百分数为12％(m/v)、14％(m/v)、16％(m/v)、18％(m/v)、20％(m/v)、22％(m/v)、24％(m/v)、26％(m/v)或者28％(m/v)，以及它们任意两者之间的数值范围等等。
在一定范围内提高聚乙二醇衍生物I和/或聚乙二醇衍生物II的质量浓度，能够提高医用组织胶的力学强度和组织粘结强度，然而，考虑到医用组织胶与原生组织的力学性能的匹配性，当聚乙二醇衍生物I和聚乙二醇衍生物II的质量浓度在上述范围内时，可制备得到兼具高力学性能、粘结强度，且匹配原生组织匹配的医用组织胶。
在一些实施方式中，溶液B中三赖氨酸的质量浓度百分数为0.06％-2％(m/v)，优选为0.1％-1％(m/v)，更优选为0.2％-0.4％(m/v)。示例性的，溶液B中三赖氨酸的质量浓度百分数为0.08％(m/v)、0.1％(m/v)、0.15％(m/v)、0.2％(m/v)、0.25％(m/v)、0.3％(m/v)、0.35％(m/v)、0.4％(m/v)、0.5％(m/v)、0.7％(m/v)、0.9％(m/v)、1.1％(m/v)、1.5％(m/v)、1.8％(m/v)，以及它们任意两者之间的数值范围等等。当溶液B中三赖氨酸的质量浓度在上述范围内时，在提高医用组织胶力学强度的同时，可降低医用组织胶的溶胀率，得到适合粘合组织、封堵液体，得到具有良好生物相容性、可降解的医用组织胶。
在本公开中，溶液A和溶液B进行混合的方式可以是直接混合于同一组织区域，或是分别施加于分开的两处组织区域，然后在两处组织区域相贴合的过程中进行混合。
本公开中的术语“同一组织区域”可以位于任意位置处的组织。为便于描述，以下采用“第一组织区域”和“第二组织区域”分别描述待粘结的两处组织区域。
在一些实施方式中，溶液A和溶液B直接混合于同一组织区域。示例性的，在双联注射器的两个分离的管路中分别配制形成包含聚乙二醇衍生物I的溶液A，和包含聚乙二醇衍生物II与三赖氨酸的溶液B。采用双联注射器向第一组织区域上同时施加溶液A和溶液B，溶液A和溶液B在挤出的过程中即发生混合，聚乙二醇衍生物I与聚乙二醇衍生物II、三赖氨酸相互作用形成具有组织粘附性能的水凝胶。此时，将第一组织区域涂覆医用组织胶的一面与未涂覆组织胶的第二组织区域相贴合，具有粘结特性的医用组织胶可实现第一组织区域和第二组织区域的高强度粘结。
在一些实施方式中，溶液A和溶液B分别施加于需要进行粘结的两处组织区域。示例性的，将溶液A施加于第一组织区域，将溶液B施加于第二组织区域，然后将第一组织区域和第二组织区域涂覆溶液的一面相贴合，在两者接触的过程中，溶液A与溶液B进行混合，形成具有粘结性能的医 用组织胶，并且实现第一组织区域与第二组织区域的相互粘结。
医用组织胶的制备组合物
本公开的第三方面提供一种制备第一方面所述的医用组织胶的组合物，包括：
组分E，其包含如式(I)所示结构的聚乙二醇衍生物I：
Figure PCTCN2022127941-appb-000007
组分F，其包含如式(II)所示结构的聚乙二醇衍生物II：
Figure PCTCN2022127941-appb-000008
组分G，其包含三赖氨酸；
其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000。本公开中的制备试剂盒，利用组分E、F、G三种组分，可以在5s内实现凝胶，组合物在涂覆于组织 表面即可发挥组织粘结效果，得到具有高力学性能和组织粘结强度，且生物相容性好、溶胀率低的医用组织胶。在在组织创面处混合组分E、F、G制备医用水凝胶，可以瞬间形成粘附性能，满足创口封合、组织粘合、液体封堵、术后止血等不同的生物医用需求。
在一些实施方式中，组分E为固体试剂，例如，组分E为聚乙二醇衍生物I的干粉。在一些实施方式中，组分E为液体试剂，例如，组分E是将聚乙二醇衍生物I溶于溶剂中得到。对于溶解聚乙二醇衍生物I的溶剂，可以是PBS缓冲液，或本领域中可用的溶剂类型。
在一些实施方式中，组分F为固体试剂，例如，组分F为聚乙二醇衍生物II的干粉。在一些实施方式中，组分F为液体试剂，例如，组分F是将聚乙二醇衍生物II溶于溶剂中得到。对于溶解聚乙二醇衍生物II的溶剂，可以是PBS缓冲液，或本领域中可用的溶剂类型。
在一些实施方式中，组分G为固体试剂，例如，组分G为三赖氨酸的干粉。在一些实施方式中，组分G为液体试剂，例如，组分G是将三赖氨酸溶于溶剂中得到。对于溶解三赖氨酸的溶剂，可以是PBS缓冲液，或本领域中可用的溶剂类型。
在一些实施方式中，组分F和组分G还可以是以混合试剂的方式存在，例如，聚乙二醇衍生物II和三赖氨酸的混合干粉。或者，是同时溶解有聚乙二醇衍生物II和三赖氨酸的混合溶液。
示例性的，在用于制备医用组织胶的组合物中，组分E、组分F、组分G以如下方式存在：组分E是独立存在的固体试剂或液体试剂(例如，组分E为独立包装的干粉、溶液等试剂类型)，组分F是独立存在的固体试剂或液体试剂(例如，组分F为独立包装的干粉、溶液等试剂类型)，组分G是独立存在的固体试剂或液体试剂(例如，组分G为独立包装的干粉、溶液等试剂类型)。
或者，在组合物中，组分E、组分F、组分G以如下方式存在：组分E为独立存在的固体试剂或液体试剂(例如，组分E为独立包装的干粉、溶液等试剂类型)，组分F和组分G以混合方式存在的固体试剂或液体试剂(例如，组分E和组分G混合后进行独立包装的干粉、溶液等试剂类型)。
用于组织封合的试剂盒
本公开的第四方面提供一种用于组织封合的试剂盒，其包括第三方面所述的用于制备医用组织胶的组合物。本公开中的试剂盒能够在组织表面或内部快速制备具有高生物相容性、可降解、力学强度高、溶胀率低的医用组织胶，同时，医用组织胶对胃、小肠、皮肤、心脏、肺、肝脏等不同组织均具有高的黏附性能，可有效发挥创口封合、液体封堵、组织修复等作用。
在一些实施方式中，试剂盒中还包括使用说明书中，其提供如下内容：
(1)使用试剂盒制备医用水凝胶的聚乙二醇衍生物I和聚乙二醇衍生物II的质量比为1:(0.8-1.2)，优选1:(0.9-1.1)，更优选1:(0.95-1.05)。
(2)使用试剂盒制备医用水凝胶的聚乙二醇衍生物I和三赖氨酸的质量比为1:(0.003-0.1)，优选1:(0.005-0.05)，更优选1:(0.01-0.02)。
在一些实施方式中，试剂盒中还包括使用说明书，试剂盒中的使用说明书中提供如下内容：
(1)以组分E制备包含聚乙二醇衍生物II的溶液A；
(2)以组分F和组分G制备包含聚乙二醇衍生物II和三赖氨酸的溶液B；
(3)将溶液A和溶液B混合，得到医用水凝胶。
在一些更为具体的实施方式中，使用说明书中包含如下内容：
以聚乙二醇衍生物II和三赖氨酸制备溶液B，并且溶液B中三赖氨酸的质量浓度百分数为0.06％-2％(m/v)，优选为0.1％-1％(m/v)，更优选为0.2％-0.4％(m/v)；溶液B中聚乙二醇衍生物II的质量浓度百分数为10-30％(m/v)，优选为18-22％(m/v)。
在一些更为具体的实施方式中，使用说明书中包含如下内容：
以聚乙二醇衍生物I制备溶液A，并且溶液A中聚乙二醇衍生物I的质量浓度百分数为10-30％(m/v)，优选为18-22％(m/v)。
在一些实施方式中，试剂盒中还包括双联注射器。通过双联注射器定制的混合喷头，在挤出溶液A和溶液B的过程中使两者混合均匀，在短时间内实现凝胶并发挥组织粘结效果。
医用组织胶的用途
本公开的第四方面提供了医用组织胶的用途，在一些实施方式中，医用组织胶作为或制备内镜下封合医用胶；在一些实施方式中，医用组织胶作为或制备血管封合医用胶；在一些实施方式中，医用组织胶作为或制备外科封合医用胶；在一些实施方式中，医用组织胶作为或制备脑脊液封合医用胶。
本公开中的医用组织胶可实现对组织的有效粘附，以快速止血、有效封合伤口，促进伤口组织的愈合，在胃肠外科、手足外科、神经外科等领域都有着潜在的巨大应用场景。
实施例
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例1
本实施例以三赖氨酸(SL)、四臂聚乙二醇琥珀酰亚胺戊二酸酯(PEG-SG)和四臂聚乙二醇胺(PEG-NH 2)为原料制备医用组织胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯的结构如式(I)所示，分子量为10000；四臂聚乙二醇胺的结构如式(II)所示，分子量为10000；
医用组织胶的具体制备步骤如下：
(1)精确称取200mg四臂聚乙二醇琥珀酰亚胺戊二酸酯，溶于1mL中性磷酸盐缓冲液(PBS溶液)，得到溶液A；其中，四臂聚乙二醇琥珀酰亚胺戊二酸酯的质量浓度百分数为20％(m/v)；
(2)精确称取200mg四臂聚乙二醇胺和2mg三赖氨酸，溶于1mL中性磷酸盐缓冲液，得到溶液B；其中，四臂聚乙二醇胺的质量浓度百分数为20％(m/v)，三赖氨酸的质量浓度百分数为0.2％(m/v)；
(3)通过双联注射器同时推注出两种液体，即可形成可吸收医用组织胶。
实施例2
本实施例以三赖氨酸、四臂聚乙二醇琥珀酰亚胺戊二酸酯和四臂聚乙二醇胺为原料制备医用组织胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯的结构如式(I)所示，分子量为5000；四臂聚乙二醇胺的结构如式(II)所示，分子量为5000；
医用组织胶的具体制备步骤如下：
(1)精确称取300mg四臂聚乙二醇琥珀酰亚胺戊二酸酯，溶于1mL中性磷酸盐缓冲液，得到溶液A；其中，四臂聚乙二醇琥珀酰亚胺戊二酸酯的质量浓度百分数为30％(m/v)；
(2)精确称取300mg四臂聚乙二醇胺和1mg三赖氨酸，溶于1mL中性磷酸盐缓冲液，得到溶液B；其中，四臂聚乙二醇胺的质量浓度百分数为30％(m/v)，三赖氨酸的质量浓度百分数为0.1％(m/v)；
(3)通过双联注射器同时推注出两种液体，即可形成可吸收医用组织胶。
实施例3
本实施例以三赖氨酸、四臂聚乙二醇琥珀酰亚胺戊二酸酯和四臂聚乙二醇胺为原料制备医用组织胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯的结构如式(I)所示，分子量为20000；四臂聚乙二醇胺的结构如式(II)所示，分子量为20000；
医用组织胶的具体制备步骤如下：
(1)精确称取100mg四臂聚乙二醇琥珀酰亚胺戊二酸酯，溶于1mL中性磷酸盐缓冲液，得到溶液A；其中，四臂聚乙二醇琥珀酰亚胺戊二酸酯的质量浓度百分数为10％(m/v)；
(2)精确称取100mg四臂聚乙二醇胺和3mg三赖氨酸，溶于1mL中性磷酸盐缓冲液，得到溶液B；其中，四臂聚乙二醇胺的质量浓度百分数为10％(m/v)，三赖氨酸的质量浓度百分数为0.3％(m/v)；
(3)通过双联注射器同时推注出两种液体，即可形成可吸收医用组织胶。
实施例4：
本实施例以三赖氨酸、四臂聚乙二醇琥珀酰亚胺戊二酸酯和四臂聚乙二醇胺为原料制备医用水凝胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯(4arm-PEG-SG)的结构如式(I)所示，分子量为10000；四臂聚乙二醇胺(4arm-PEG-NH 2)的结构如式(II)所示，分子量为15000；。
医用水凝胶的具体制备步骤如下：
(1)取200mg四臂聚乙二醇琥珀酰亚胺戊二酸酯(4arm-PEG-SG)溶解到1mL pH为7.0-7.4的PBS缓冲液中，溶解完全，得到4arm-PEG-SG的质量浓度百分数20％(m/v)的溶液B，备用。
(2)取200mg四臂聚乙二醇胺和2mg三赖氨酸，溶解于1mL pH为7.0-7.4的PBS缓冲液中，待三赖氨酸和四臂聚乙二醇胺溶解完全，得到溶液A，其中，三赖氨酸的质量浓度百分数为0.2％(m/v)，四臂聚乙二醇胺的质量浓度百分数为20％(m/v)，备用。
(3)将上述溶液A和溶液B添加至双联注射器中，同时推注出两种液体，即可形成可吸收医用组织胶。
实施例5：
本实施例以三赖氨酸、四臂聚乙二醇琥珀酰亚胺戊二酸酯和四臂聚乙二醇胺为原料制备医用组织胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯的结构如式(I)所示，分子量为20000；四臂聚乙二醇胺的结构如式(II)所示，分子量为15000；
医用组织胶的具体制备步骤如下：
(1)制备溶液A四臂聚乙二醇琥珀酰亚胺戊二酸酯的中性磷酸盐溶液(1mL，100mg/mL)；
(2)制备溶液B四臂聚乙二醇胺和三赖氨酸的中性磷酸盐溶液(1mL，四臂聚乙二醇胺：100mg/mL，三赖氨酸：2mg/mL)；
(3)将溶液A和B分别吸入2.5mL的注射器内，并装入双联注射器架；
(4)通过同时推注两种溶液，喷出后在组织表面混合，形成可吸收医用组织胶。
实施例6：
本实施例以三赖氨酸、四臂聚乙二醇琥珀酰亚胺戊二酸酯和四臂聚乙二醇胺为原料制备医用组织胶，其中四臂聚乙二醇琥珀酰亚胺戊二酸酯的结构如式(I)所示，分子量为10000；四臂聚乙二醇胺的结构如式(II)所示，分子量为10000；
医用组织胶的具体制备步骤如下：
(1)制备溶液A四臂聚乙二醇琥珀酰亚胺戊二酸酯的中性磷酸盐溶液(1mL，100mg/mL)；
(2)制备溶液B四臂聚乙二醇胺和三赖氨酸的中性磷酸盐溶液(1mL，四臂聚乙二醇胺：100mg/mL，三赖氨酸：2mg/mL)；
(3)将溶液A和B分别涂布于不同组织表面，然后将分别带有溶液A和B的两个组织表面贴合，形成可吸收医用组织胶。
性能测试
1、生物相容性
按照GB/T 16886浸提液标准，检测医用组织胶浸提液对L929细胞的细胞毒性。采用双联注射器分别将含有PEG-SG溶液和含有PEG-NH 2与三赖氨酸的溶液同时注射至聚四氟乙烯的模具中(圆柱形模具，直径1cm，深度1cm)，按照0.1g/mL的比例，即0.1g水胶体和1mL培养基(α-MEM培养基，含10％胎牛血清和100IU/mL的青霉素、链霉素)在细胞培养箱中37℃下浸泡24h。24h后，提取上清液，此时弃置已接种在组织培养板上24h的L929细胞的普通培养基，更换成浸泡过组织胶的条件培养基继续培养24h。24h后，采用10％CCK-8试剂孵育细胞2h，取上清液在酶标仪上读取450nm的光密度值(OD)，经过细胞活性公式计算，细胞活性(％)＝(OD组织胶-OD空白)/(OD培养板-OD空白)，其中OD空白指CCK-8试剂的光密度值，OD培养板指L929细胞在普通培养基下的光密度值。与此同时，L929细胞在calcein-AM/PI荧光染料进行标记20min，在激光共聚焦显微 镜下观察细胞状态(calcein激发：488nm，发射：515nm；PI激发：530nm，发射：580nm)。图2示出了医用组织胶对L929细胞的生物相容性检测结果，标尺10μm。其中，医用组织胶采用以20％(m/v)PEG-SG、20％(m/v)PEG-NH2和0.2％(m/v)SL制备得到。由图2可知，本公开中制备的医用组织胶具有良好的细胞相容性，细胞活性在80％以上。
2、三赖氨酸的纯度及化学结构
采用HPLC和NMR对制备医用组织胶的三赖氨酸的纯度和化学结构进行验证，图3示出了三赖氨酸的纯度及化学结构的检测结果。如图3所示，用于制备医用组织胶的三赖氨酸纯度为99.25％，且实际化学结构与理论的三赖氨酸结构匹配。
3、凝胶时间测试：
将四臂聚乙二醇琥珀酰亚胺戊二酸酯、四臂聚乙二醇胺和三赖氨酸分别溶解在中性磷酸盐完全溶解后，依次装在双联注射器上，迅速同时挤出两种液体共2mL至西林瓶，通过倒置西林瓶看瓶中液体是否发生流动判断是否凝胶完全并计时。经测试，凝胶时间不大于5秒。
4、力学性能：
4.1弹性模量测试：
将医用组织胶注入定制的哑铃型聚四氟乙烯模具(有效拉伸长度为2cm，宽度为0.5cm，深度为0.5cm)，使其充分填满且医用胶无明显气泡，待凝胶完成(约10分钟)；小心取出样条，准备弹性模量的检测。固定医用胶两端，保证测试前2cm的有效长度，设置测试样品参数(2cm距离、2cm长度、0.5cm厚度、0.5cm宽度)，测试前清空所有无关数值(包括力、位移、时间等)，在室温下以5mm/min拉伸速度拉伸样条至断裂。记录应力-应变数据，做图分析应力-应变曲线，图中材料弹性变形阶段的斜率即为医用组织胶的弹性模量。
4.2粘结强度测试：
粘结强度测试参考ASTM F2258，实验操作需配备电子万能试验机。新鲜购入的背部猪皮经过简单冲洗和三次脂肪酶浸泡去除表面脂肪后(100g猪皮与500mL脂肪酶的比例，脂肪酶浓度为2wt.％，一次30分钟，重复三次，240W功率超声处理)，裁成2cm×2cm方块大小。将两块猪皮表面较光滑的一面使用强力502分别牢固地粘在两块粘结强度测试的模具上，稍压实固定1分钟，然后将100μL组织胶水均匀喷涂在猪皮表面，并迅速粘结两块猪皮，在室温下固定60分钟，待后续测试。在室温下以1mm/min拉伸速度拉伸样条至两块猪皮发生断裂。记录力-位移数据，做图分析力-位移曲线，记录最大的粘结力(Fmax)。根据公式：粘结强度(Pa)＝Fmax(N)/受力面积(m 2)计算医用组织胶的粘结强度。
4.3剪切及剥离测试：
剪切强度测试参考ASTM F2255。将新鲜背部猪皮经脱脂处理后裁成5cm×2.5cm大小，然后将100μL组织胶均匀地涂在猪皮的一端，涂覆大小为2.5cm×1cm，并且以相反方向迅速粘结猪皮的两端(粘结面积即为涂覆组织胶的面积)，在室温下固定30分钟，在室温下以5mm/min拉伸速度拉伸猪皮至发生断裂。记录力-位移数据，做图分析力-位移曲线，记录最大剪切力(Fmax)。根据公式：剪切强度(Pa)＝Fmax(N)/受力面积(m 2)，计算医用组织胶的剪切强度。
剥离强度测试参考ATSM F2256。将新鲜背部猪皮经脱脂处理后裁成5cm×2.5cm大小，然后将100μL组织胶均匀地涂在猪皮的一端，涂覆大小为2.5cm×1cm，并且以相同方向迅速粘结猪皮的两端(粘结面积即为涂覆组织胶的面积)，在室温下固定30分钟，在室温下以5mm/min拉伸速度拉伸猪皮至发生断裂。记录力-位移数据，做图分析力-位移曲线，记录最大剥离力(Fmax)。根据公式：界面韧性(J m -2)＝2×F max/宽度(m)，计算医用组织胶的界面韧性。
使用15kGy和20kGy对医用组织胶进行辐射灭菌，辐射均已验证达到100％灭菌效果。图4示出了聚乙二醇衍生物I和聚乙二醇衍生物II的浓度对医用组织胶的应力应变曲线、弹性模量及粘结强度的影响结果。由图4可知，一定范围内提高浓度，可显著提高医用组织胶的力学强度和粘结强度，考虑到医用组织胶与原生组织的力学强度需匹配，选择质量浓度百分数为10％-30％(m/v)的I、聚乙二醇衍生物II，与质量浓度百分数为0.06％-2％(m/v)的三赖氨酸用于制备医用组织胶。
图5示出了医用组织胶对不同组织的粘结检测结果，由图5可知，医用组织胶对于动物组织具 有粘结性，这些组织包括胃、小肠、心脏、肺、肝等组织也具有一定的粘结性，出于不同软组织的力学强度不同，医用组织胶的粘结强度也存在差异，但普遍具有较好的粘结强度、剪切强度和界面韧性，因此可应用于不同组织的伤口止血及漏气等情况。
基于取样的便捷性，采用与猪皮作为示例。图6示出了不同的制备方法对医用组织胶的凝胶时间和剪切粘结强度的影响。图6中采用如下两种制备方法：方法1，分别在猪皮两侧涂覆溶液A和溶液B，然后相互粘结；方法2，以双联注射器注射的形式直接涂覆在猪皮一侧，然后迅速粘结另一块猪皮，采用ASTM F2255标准测试这两种制胶方式的剪切强度，证明制备方法的不同对医用组织胶的影响较小。
图6示出了聚乙二醇衍生物的浓度对医用组织胶的剪切粘结强度的影响结果，图6中的a为经电子辐射后，不同浓度的医用组织胶的剪切力；图6中的b为经电子辐射后，不同浓度的医用组织胶的剪切强度。
图7示出了聚乙二醇衍生物的浓度对医用组织胶的剥离及界面韧性的影响结果。图7中的a为经电子辐射后，不同浓度的医用组织胶的剥离力；图7中的b为经电子辐射后，不同浓度的医用组织胶的界面韧性。
对不同浓度医用组织胶的剪切粘结实验和剥离实验，结果如图6和图7所示，可以发现剪切强度在不同浓度的医用组织胶之间变化不大，但是受不同浓度的医用组织胶的弹性模量的影响，界面韧性随着浓度上升先增加后减小的变化趋势。图4、6和7中用SG-10％、SG-20％和SG-30％分别表示PEG-SG的浓度为10％(m/v)、20％(m/v)和30％(m/v)；同时选择聚乙二醇衍生物I浓度与聚乙二醇衍生物II浓度相同为示例制作这些示意图，并非对聚乙二醇衍生物浓度的限定。
图8示出了采用本公开中医用组织胶进行肝脏表面止血的动物试验。其中实验动物为健康巴马猪。图8中的a中，将试验用猪麻醉后，暴露肝组织。图8中的b示出了制造肝脏缺损模型，采用8mm直径环形刀形成2mm深度的肝脏组织缺损，此时缺损处有血液流出。图8中的c示出了涂覆医用组织胶，在缺损处推注涂覆提前制备好的成胶液体，迅速成胶并封堵创面并止血(图8中的d)。可见，该医用组织胶能够与动物组织有效粘结，并能够封堵创面实现止血和隔离创面的效果。
图9示出了本公开中医用组织胶的体外降解特性。基于体外降解曲线换算，在植入体内后该聚乙二醇衍生物I、聚乙二醇衍生物II、三赖氨酸形成的组织胶在植入35天时能够组织胶质量下降不低于30％，在植入42天后残余量低于10％。表明该组织胶能够有效保护创面愈合，组织修复完成后完全降解。
水凝胶成胶后，在溶液中会继续吸收溶液发生溶胀，此时水凝胶的体积和重量都会增加，直至达到溶胀平衡。相应的，水凝胶的溶胀率包括利用体积或重量进行计算的方法，通常为在选择成胶时的体积和/或重量以及经过一定时间的体积和/或重量进行计算。本公开中采用的水凝胶溶胀率计算方法为：采用溶胀平衡后的水凝胶重量与成胶时水凝胶重量相比的比率，间隔时间为选择为24小时。
本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (11)

  1. 一种医用组织胶，其特征在于，所述医用组织胶具有凝胶骨架，所述凝胶骨架由聚乙二醇衍生物I分别与聚乙二醇衍生物II和三赖氨酸键合形成；
    所述聚乙二醇衍生物I的结构如式(I)所示：
    Figure PCTCN2022127941-appb-100001
    所述聚乙二醇衍生物II的结构如式(II)所示：
    Figure PCTCN2022127941-appb-100002
    其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000。
  2. 根据权利要求1所述的医用组织胶，其特征在于，所述聚乙二醇衍生物I和聚乙二醇衍生物 II的质量比为1:(0.8-1.2)，优选1:(0.9-1.1)，更优选1:(0.95-1.05)。
  3. 根据权利要求1或2所述的医用水凝胶，其特征在于，所述聚乙二醇衍生物I和三赖氨酸的质量比为1:(0.003-0.1)，优选1:(0.005-0.05)，更优选1:(0.01-0.02)。
  4. 一种根据权利要求1-3任一项所述的医用组织胶的制备方法，其特征在于，所述制备方法包括如下步骤：
    制备包含聚乙二醇衍生物I的溶液A；
    制备包含聚乙二醇衍生物II和三赖氨酸的溶液B；
    将溶液A和溶液B混合，得到医用组织胶。
  5. 根据权利要求4所述的制备方法，其特征在于，所述制备包含聚乙二醇衍生物II和三赖氨酸的溶液B的步骤包括：
    分别制备包含聚乙二醇衍生物II的溶液和包含三赖氨酸的溶液，将两种溶液混合，得到所述溶液B；或者，
    制备包含聚乙二醇衍生物II的溶液，将三赖氨酸加入所述包含聚乙二醇衍生物II的溶液中，得到所述溶液B；或者，
    制备包含三赖氨酸的溶液，将聚乙二醇衍生物II加入所述包含三赖氨酸的溶液中，得到所述溶液B；或者，
    将聚乙二醇衍生物II和三赖氨酸混合，加入溶剂中，得到所述溶液B。
  6. 根据权利要求4或5所述的制备方法，其特征在于，所述溶液B中聚乙二醇衍生物II的质量浓度百分数为10％-30％(m/v)，优选为18％-22％(m/v)。
  7. 根据权利要求4或5所述的制备方法，其特征在于，所述溶液B中三赖氨酸的质量浓度百分数为0.06％-2％(m/v)，优选为0.1％-1％(m/v)，更优选为0.2％-0.4％(m/v)。
  8. 根据权利要求4或5所述的制备方法，其特征在于，所述溶液A中聚乙二醇衍生物I的质量浓度百分数为10％-30％(m/v)，优选为18％-22％(m/v)。
  9. 一种根据权利要求1-3任一项所述的医用组织胶，或根据权利要求4-8任一项所述的制备方法得到的医用组织胶，在作为或制备生物医用材料中用途；可选地，所述生物医用材料选自如下(a)-(d)中的至少一种：
    (a)内镜下封合医用胶；
    (b)血管封合医用胶；
    (c)外科封合医用胶；
    (d)脑脊液封合医用胶。
  10. 一种制备医用组织胶的组合物，其特征在于，所述组合物包括：
    组分E，其包含如式(I)所示结构的聚乙二醇衍生物I：
    Figure PCTCN2022127941-appb-100003
    组分F，其包含如式(II)所示结构的聚乙二醇衍生物II：
    Figure PCTCN2022127941-appb-100004
    组分G，其包含三赖氨酸；
    其中，m和n取值为自然数；聚乙二醇衍生物I的分子量为2000-20000，优选5000-15000，更优选8000-12000；聚乙二醇衍生物II的分子量为2000-20000，优选5000-15000，更优选8000-12000；
    可选地，所述组分E、组分F和组分G中的任意一种为粉体组分或液体组分。
  11. 一种用于组织封合的试剂盒，其特征在于，所述试剂盒包括根据权利要求10所述的组合物。
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