CN108742750B - Tissue plugging material, preparation method thereof and plugging product - Google Patents
Tissue plugging material, preparation method thereof and plugging product Download PDFInfo
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- CN108742750B CN108742750B CN201810643045.9A CN201810643045A CN108742750B CN 108742750 B CN108742750 B CN 108742750B CN 201810643045 A CN201810643045 A CN 201810643045A CN 108742750 B CN108742750 B CN 108742750B
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/12—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12027—Type of occlusion
- A61B17/1204—Type of occlusion temporary occlusion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/12—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord
- A61B17/12022—Occluding by internal devices, e.g. balloons or releasable wires
- A61B17/12131—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device
- A61B17/12181—Occluding by internal devices, e.g. balloons or releasable wires characterised by the type of occluding device formed by fluidized, gelatinous or cellular remodelable materials, e.g. embolic liquids, foams or extracellular matrices
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods
- A61B17/12—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord
- A61B2017/12004—Surgical instruments, devices or methods for ligaturing or otherwise compressing tubular parts of the body, e.g. blood vessels or umbilical cord for haemostasis, for prevention of bleeding
Landscapes
- Health & Medical Sciences (AREA)
- Surgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Vascular Medicine (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Reproductive Health (AREA)
- Medical Informatics (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention provides a tissue plugging material, a preparation method thereof and a plugging product. The tissue occluding material comprises: a matrix formed by interweaving fiber filaments with the diameter of 10nm-100 mu m, and at least partially having a porous structure; and a wet adhesion layer present on at least one surface of the substrate, the wet adhesion layer being obtained by contacting at least one surface of the substrate with an adhesion solution containing an amino compound and a buffer solution in which the amino compound is dissolved. The tissue plugging material has excellent adhesion performance, bursting strength and proper elongation at break, and can be effectively adhered to the surface of a living body or the surface of a parenchyma organ. The tissue plugging material also has a porous network microstructure formed by the fiber yarns, and can promote wound healing and tissue regeneration.
Description
Technical Field
The invention relates to a tissue plugging material, a preparation method thereof and a plugging product, belonging to the field of medical implant materials.
Background
Tissue occlusion, for example: hemostasis plugging, tissue fluid leakage plugging and the like are important links in operations of various departments of a hospital, and play a great role in success of the operations and safety of patients. Effective hemostasis is the key to alleviating the pain of patients and reducing the death rate, and rapid and effective hemostasis becomes the key point for solving the problem. Various accidents and disasters can lead to damage of body tissues inevitably in daily life.
At present, common hemostatic materials include microporous inorganic materials (zeolite), microporous starch, fibrin glue, gelatin sponge, carboxymethyl cellulose soluble hemostatic gauze, alpha-cyanoacrylate tissue glue and the like, and although the materials have good hemostatic effects, the materials have certain limitations. The gelatin has poor adhesion and is easy to fall off from the wound; the porous zeolite and the microporous starch release heat after absorbing moisture in blood, so that the temperature around the wound is increased to burn the wound, the wound is difficult to heal, and the functions of the tissue plugging materials are relatively single.
The chitosan has low allergenicity and natural antibacterial property, can quickly stop bleeding, and is particularly suitable for emergency treatment; in addition, the chitosan has biocompatibility, can be degraded and absorbed in vivo, promotes wound healing, reduces scar generation, has an anti-inflammatory effect and the like, and therefore has great advantages in the application of hemostatic tissue plugging materials, bacteriostatic tissue plugging materials and wound repair tissue plugging materials. However, the hemostasis speed and the hemostasis amount of the existing chitosan hemostasis products still cannot meet the requirement of emergency treatment during massive rapid bleeding.
In addition, hydrogel as a biocompatible material is a three-dimensional network structure polymer with hydrophilic groups, and due to the physical crosslinking and chemical crosslinking between polymer chains, hydrogel can be swelled by water but not dissolved in water and keeps a certain shape. In medicine, the hydrogel can be used for wound dressing, postoperative adhesion prevention, intraoperative hemostasis, tissue filling or prevention of tissue fluid leakage and the like. But the bursting strength is often lower, and the better adhesion plugging effect cannot be achieved.
Therefore, the development of a tissue plugging material with excellent adhesion performance and burst strength is a technical problem to be solved.
Disclosure of Invention
Problems to be solved by the invention
Based on the above technical problems in the prior art, for example: the adhesive property is poor, and the wound dressing is easy to fall off from the wound; the temperature around the wound is increased to cause a burning wound which is difficult to heal; the hemostasis speed and the hemostasis amount still cannot meet the requirement of emergency treatment during massive rapid bleeding; liquid leakage cannot be stopped quickly; lower bursting strength, etc. The invention firstly provides a tissue plugging material. The tissue plugging material has excellent adhesion performance, bursting strength and proper elongation at break, and can be effectively adhered to the surface of a living body or the surface of a parenchyma organ. Meanwhile, the porous network microstructure formed by the fiber yarns can promote wound healing and tissue regeneration.
Furthermore, the invention also provides a preparation method of the tissue plugging material, which has the advantages of easily obtained raw materials and simple preparation method.
Means for solving the problems
The present invention provides a tissue occluding material comprising:
a matrix formed by interweaving fiber filaments with the diameter of 10nm-100 mu m, and at least partially having a porous structure; and
a wet adhesion layer present on at least one surface of the substrate, the wet adhesion layer being obtained by contacting at least one surface of the substrate with an adhesion solution,
the adhesion solution contains an amino compound and a buffer solution, wherein the amino compound is dissolved in the buffer solution.
The tissue plugging material provided by the invention has the advantages that the bursting strength of the tissue plugging material is 0.01Kpa-60Kpa, and the elongation at break is 0.1% -500%; the porosity of the matrix is 30% -90%.
The tissue plugging material according to the present invention, wherein the material of the fiber filament is derived from one or a combination of two or more of a high molecular polymer or a derivative thereof; preferably, the filaments are cross-linked.
The tissue plugging material according to the present invention, wherein the concentration of the amino compound in the adhesion solution is 0.01g/mL to 0.05 g/mL.
The tissue sealing material according to the present invention, wherein the amino compound comprises a synthetic polymer compound containing an amino group and/or a natural polymer compound containing an amino group.
The tissue plugging material of the invention, wherein the buffer solution has a pH value of 5.5-6.7; preferably, the buffer solution is one of MES buffer solution, Bis-Tris buffer solution, PIPES buffer solution, disodium hydrogen phosphate-citric acid buffer solution, citric acid-sodium hydroxide-hydrochloric acid buffer solution, citric acid-sodium citrate buffer solution, acetic acid-sodium acetate buffer solution, phosphate buffer solution, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution and potassium dihydrogen phosphate-sodium hydroxide buffer solution.
The tissue plugging material of the present invention has an adhesive strength of 1J/m to a tissue surface2-1500J/m2Preferably 200J/m2-1500J/m2。
The tissue plugging material according to the present invention, wherein the adhesion solution further comprises an activating factor; preferably, the concentration of the activating factor in the adhesion solution is 0.1mg/mL-1000 mg/mL; more preferably, the activator includes one or a combination of two or more of carbodiimide, N-hydroxysuccinimide, genipin, or aldehyde compounds.
The tissue plugging material according to the present invention, wherein the tissue plugging material further comprises a drug; preferably, the medicament comprises one or a combination of two of a coagulation factor, a growth factor.
The invention also provides a preparation method of the tissue plugging material, which comprises the step of compounding and molding the matrix and the wet adhesion layer, wherein,
the matrix is formed by interweaving fiber yarns with the diameter of 10nm-100 mu m, and at least part of the matrix has a porous structure;
the wet adhesion layer is obtained by contacting at least one surface of the substrate with an adhesion solution;
the adhesion solution contains an amino compound and a buffer solution, wherein the amino compound is dissolved in the buffer solution.
According to the preparation method of the tissue plugging material, the matrix solution is spun by a spinning process and then subjected to crosslinking treatment.
The preparation method of the tissue plugging material comprises the following steps of carrying out electrostatic spinning, centrifugal spinning, hot-melt spinning and melt electrospinning, wherein the spinning process comprises one or more than two of the electrostatic spinning, the centrifugal spinning, the hot-melt spinning and the melt electrospinning.
The preparation method of the tissue plugging material is characterized in that the crosslinking treatment is chemical crosslinking treatment or physical crosslinking treatment.
The preparation method of the tissue plugging material according to the invention, wherein after the cross-linking treatment, further comprises: the elution treatment was performed by a concentration gradient method to remove the unreacted crosslinking agent.
The preparation method of the tissue plugging material is characterized in that the composite molding comprises the following steps: one or a combination of more than two of tiling, coating, casting and spraying.
The invention also provides an occlusion article comprising a tissue occluding material according to the invention or a tissue occluding material obtained according to the method of preparation of a tissue occluding material according to the invention, wherein optionally a backing layer is provided on the side of the substrate not provided with a wet adhesive layer, and a peelable layer is provided on the wet adhesive layer.
ADVANTAGEOUS EFFECTS OF INVENTION
The tissue plugging material has excellent adhesion performance, bursting strength and proper elongation at break, and can be effectively adhered to the surface of a living body or the surface of a parenchyma organ. Also has good biocompatibility and can be degraded and absorbed by organisms quickly.
Furthermore, the matrix of the tissue plugging material has high porosity and is suitable for regeneration and repair of new tissues.
Furthermore, the preparation method of the tissue plugging material has higher safety, lower cost and easy molding, and is suitable for industrial large-scale production.
Drawings
Fig. 1 is a three-dimensional structure diagram of a tissue plugging material prepared according to an embodiment of the present invention.
Description of reference numerals:
1: a substrate; 2: a wet adhesion layer.
Detailed Description
Various exemplary embodiments, features and aspects of the invention will be described in detail below. The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.
Furthermore, in the following detailed description, numerous specific details are set forth in order to provide a better understanding of the present invention. It will be understood by those skilled in the art that the present invention may be practiced without some of these specific details. In other instances, methods, means, devices and steps which are well known to those skilled in the art have not been described in detail so as not to obscure the invention.
First embodiment
In a first embodiment of the present invention, as shown in fig. 1, there is provided a tissue occluding material comprising: a matrix 1 which is formed by interweaving fiber filaments with the diameter of 10nm-100 mu m and at least partially has a porous structure; and a wet adhesion layer present on at least one surface of the substrate, the wet adhesion layer being obtained by contacting at least one surface of the substrate with an adhesion solution.
The burst strength of the tissue occluding material of the invention is between 0.01Kpa and 60Kpa, for example: can be 0.1Kpa to 60Kpa, also can be 1Kpa to 50Kpa, also can be 10Kpa to 40Kpa, also can be 20Kpa to 30 Kpa; the tissue plugging material of the invention has an elongation at break of 0.1-500%, or 1-500%, or 10-400%, or 50-300%, or 100-200%.
The tissue plugging material has excellent tissue adhesion performance, good water absorption performance and excellent elongation at break. The adhesive can be well adhered to the surfaces of organism tissues or parenchymal organs, and the matrix 1 has good tensile strength and can form an effective physical plugging effect on the surface of a wound. Specifically, the method comprises the following steps:
< substrate >
The matrix of the invention is formed by interweaving fiber yarns with the diameter of 10nm-100 mu m. The fiber yarn can be obtained by spinning through a spinning process by using one or more than two of high molecular polymers or derivatives thereof and then performing crosslinking treatment.
The matrix 1 of the invention has a burst strength of between 0.01Kpa and 60Kpa, for example: can be 0.1Kpa to 60Kpa, also can be 1Kpa to 50Kpa, also can be 10Kpa to 40Kpa, also can be 20Kpa to 30 Kpa; the elongation at break of the substrate 1 of the invention is between 0.1% and 500%, and may be between 1% and 500%, and may also be between 10% and 400%, and may also be between 50% and 300%, and may also be between 100% and 200%. The porosity of the matrix 1 according to the invention is 30% to 90%, may be 40% to 80%, and may be 50% to 70%.
Since the matrix 1 is excellent in burst strength and suitable in elongation at break and porosity, the tissue plugging material of the present invention further has excellent burst strength and suitable elongation at break.
In the present invention, the length of the substrate 1 (for example, the thickness of the substrate 1) in the direction perpendicular to the substrate 1 (the z direction of the substrate 1) is 0.01mm to 5mm, for example, 0.1mm to 4mm, or 1mm to 3 mm.
The high molecular polymer or its derivative of the present invention may be any of various high molecular polymers or its derivatives having biocompatibility and hydrophilicity, which are commonly used in the art. For example, it may be selected from one or both of synthetic high molecular polymers and natural high molecular polymers.
For example, the common high molecular polymer or its derivative can be collagen, hydrophilic polyurethane, cellulose, chondroitin sulfate, chitosan, modified chitosan, fibrin, silk protein, elastin mimetic peptide polymer, heparin, agar, dextran, alginic acid, modified cellulose, alginic acid, starch, polyols, block polyethers, gelatin, polyvinylpyrrolidone, etc.
< adhesion layer in Wet State >
The wet adhesive layer 2 according to the invention is connected to the adhesive solution via at least one surface of the substrate 1Obtained by contacting. When one side of the wet adhesive layer 2 is attached to the tissue surface, the adhesive strength of the tissue plugging material and the tissue surface is 1J/m2～1500J/m2Preferably 200J/m2～1500J/m2In the meantime. For example, it may be 200J/m2～1400J/m2May be 300J/m2～1200J/m2And may be 400J/m2-1000J/m2And may be 500J/m2-800J/m2And may be 500J/m2-600J/m2And the like.
The adhesion solution of the present invention contains an amino compound and a buffer solution, and the amino compound is dissolved in the buffer solution. Generally, the concentration of the amino compound is from 0.01g/mL to 0.05 g/mL.
In the present invention, the amino compound may be a synthetic polymer compound containing an amino group and/or a natural polymer compound containing an amino group.
The synthetic polymer compound of the present invention may be selected from synthetic polymer compounds that are artificially synthesized and have good biocompatibility. Such as acrylamide, polyacrylamide, polyethyleneimine or hyperbranched polyethyleneimine. The synthetic polymer compound of the present invention may be a synthetic polymer compound containing an amino group obtained by grafting an amino group to a polymer compound containing no amino group by chemical graft modification or the like.
The natural polymer compound of the present invention may be selected from one or a combination of two or more of chitosan, hyaluronic acid, gelatin, collagen, and an aminated and modified polysaccharide polymer. In the present invention, the aminated modified polysaccharide polymer may be amino-grafted cellulose, amino-grafted sodium alginate, or the like. In addition, chitosan and hyaluronic acid may be grafted with amino groups in the same manner.
Free amino groups in the amino compound can rapidly react with carboxyl groups on the surface of the tissue to form covalent bonds, so that the tissue plugging material is firmly adhered to the surface of the tissue.
In the present invention, the pH of the buffer is 5.5 to 6.7. Within this pH range, the tissue sealing material can further be firmly adhered to the tissue surface. Preferably, the buffer is one of MES buffer (2- (N-morpholine) ethanesulfonic acid), Bis-Tris buffer, PIPES buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer, phosphate buffer, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer and potassium dihydrogen phosphate-sodium hydroxide buffer.
Further, the adhesion solution of the present invention may further contain an activating factor. The activating factor can activate the carboxyl group on the surface of the biological tissue, so that the tissue surface can more easily and rapidly react with the amino group provided by the wet adhesion layer 2, and the tissue surface can be more firmly adhered, thereby further improving the adhesion performance of the product and the tissue surface.
Preferably, the concentration of the activating factor in the adhesion solution is 0.1mg/mL-1000mg/mL, preferably 1mg/mL-100 mg/mL. For example: may be 1mg/mL-1000mg/mL, may be 10mg/mL-800mg/mL, may be 50mg/mL-600mg/mL, and may further be 100mg/mL-400 mg/mL. More preferably, the activator includes one or a combination of two or more of carbodiimide, N-hydroxysuccinimide, genipin, or aldehyde compounds.
In addition, the tissue plugging material of the invention can also contain medicines; preferably, the medicament comprises one or a combination of two of a coagulation factor and a growth factor, and promotes coagulation and/or tissue growth while the tissue is blocked.
In the present invention, a three-layer structure may be included, that is, wet adhesion layers 2 are provided on both surfaces of a substrate 1, and similarly, the wet adhesion layers 2 are obtained by contacting both surfaces of the substrate 1 with an adhesion solution containing an amino compound and a buffer solution in which the amino compound is dissolved.
In addition, in the present invention, the tissue plugging material may further include other layer structures, and the other layer structures included in the present invention are not particularly limited, and may achieve the functions of the present invention.
Second embodiment
In a second embodiment of the present invention, a method for preparing a tissue plugging material is provided, which comprises a step of composite molding a substrate and a wet adhesion layer, wherein,
the matrix is formed by interweaving fiber yarns with the diameter of 10nm-100 mu m, and at least part of the matrix has a porous structure;
the wet adhesion layer is obtained by contacting at least one surface of the substrate with an adhesion solution;
the adhesion solution contains an amino compound and a buffer solution, wherein the amino compound is dissolved in the buffer solution.
In the invention, the substrate can be prepared in situ, or the substrate finished product prepared in advance can be directly compounded and molded with the wet adhesion layer.
In the present invention, the preparation method of the matrix comprises: and spinning the matrix solution by using a spinning process, and then performing crosslinking treatment. The solute of the matrix solution contains one or a combination of two or more of high molecular polymers or derivatives thereof. The high molecular polymer or the derivative thereof may be the high molecular polymer or the derivative thereof in the first embodiment. The solvent of the base solution may be at least one fluorine-based solvent, and may be, for example: trifluoroethanol, hexafluoroisopropanol, trifluoroacetic acid, and the like.
In the invention, the spinning process comprises one or more of electrostatic spinning technology, centrifugal force spinning technology, hot melt spinning technology and melt electrospinning technology, preferably electrostatic spinning technology.
The principle of electrospinning is that a high voltage is applied to a polymer liquid during electrospinning to induce charge into the liquid. When charges in the liquid are accumulated to a certain amount, the liquid can form a Taylor cone at the spray head, liquid jet flow is formed by overcoming surface tension under the action of an external electric field force, and then polymer jet flow moves along an irregular spiral track under the combined action of electrostatic repulsion, Coulomb force (Coulomb) and surface tension. The jet is drawn and stretched in a very short time, and as the solvent evaporates or heat is dissipated, the polymer jet solidifies to form the micro/nano fibers. In the electrostatic spinning process, a plurality of parameters can influence the final electrostatic spinning fiber, and the micron/nano fiber with different sizes, forms and structures can be prepared and obtained by controlling the process parameters.
In the electrostatic spinning process, the technological parameters can influence the nanofiber material obtained by electrostatic spinning, and matrixes with different sizes, forms and structures can be prepared and obtained by controlling the technological parameters. The present invention is not particularly limited to the electrospinning method, and may be any electrospinning method commonly used in the art.
In the case of electrospinning, a fiber raw material may be prepared in advance, and the fiber raw material may be dissolved in an appropriate solvent to prepare a spinning dope of the fiber raw material at a certain concentration. The fiber material may be one or a combination of two or more of the high molecular weight polymers or derivatives thereof in the first embodiment. The specific concentration of the solvent species forming the solution is not particularly limited as long as the requirements of the subsequent electrospinning process can be met.
In the present invention, the crosslinking treatment is a chemical crosslinking treatment or a physical crosslinking treatment. The term "crosslinking" as used herein has the same or similar meaning as "crosslinking modification" and may have some feature of "modification" attached thereto, and in the present invention, "crosslinking treatment" or "crosslinking" may be used instead of "crosslinking modification" for the sake of convenience. In the present invention, the purpose of the cross-linking modification is to make the tissue plugging material absorb a large amount of liquid and maintain the fiber shape well, so that the tissue plugging material is not dissolved or dispersed by the absorbed body fluid quickly.
When chemical crosslinking treatment is adopted, the selected crosslinking agent comprises one or more of glutaraldehyde, formaldehyde, genipin, acetic anhydride, diglycidyl ether, methyl suberanilate and the like. The physical crosslinking treatment of the present invention is, for example: the matrix with the adaptive performance can be prepared by selecting a proper crosslinking treatment mode, such as high-temperature heating crosslinking treatment, ultraviolet crosslinking treatment, gamma-ray irradiation crosslinking treatment and the like.
Further, when the chemical crosslinking treatment is employed, the crosslinking modification can be controlled by adjusting the reaction conditions of the crosslinking treatment and the amount of the crosslinking agent. For example, the crosslinking temperature, the crosslinking time, the mass ratio of the crosslinking agent to the high-molecular polymer or the derivative thereof, and the like. In addition, the requirements of different traumas or clinical operations on the degradation period can be met by regulating and controlling the crosslinking degree.
When physical crosslinking treatment is adopted, the condition of crosslinking modification can be controlled by adjusting physical parameters. For example: crosslinking temperature, crosslinking time, and the like.
In the present invention, the matrix solution may be crosslinked first and then treated by the spinning process, and preferably, the matrix solution may be treated by the spinning process first and then crosslinked.
In the present invention, after the crosslinking treatment, the method further comprises: the elution treatment was performed by a concentration gradient method to remove the unreacted crosslinking agent.
The elution is carried out in order to remove unreacted cross-linking agent. Specifically, the elution step may comprise: and eluting the crosslinked fiber raw material by using an eluent at a low temperature of 0-20 ℃ through a concentration gradient method to remove the unreacted crosslinking agent. The eluent comprises a mixed solution of alcohol and water, preferably a mixed solution of ethanol and water, and more preferably the mass fraction of ethanol in the mixed solution of ethanol and water is more than 70%.
Further, the present invention can use alcohol-water solution with different concentration to perform multiple elution by concentration gradient method. Preferably, the elution conditions are: the elution temperature is 1-20 ℃, and the preferred temperature is 4-10 ℃; the elution time is 0.1-5 h, preferably 0.5-2 h, and the elution is repeated for 3-5 times.
In the present invention, after the elution step, a drying step may be further included, and the drying may be freeze-drying or normal-temperature vacuum drying. The drying is performed in order to remove excess solvent and eluent in the crosslinking process, and may also help maintain the three-dimensional porous structure of the tissue plugging material.
In the present invention, the composite molding includes: one or a combination of more than two of tiling, coating, casting and spraying. The wet adhesive layer is compounded on one side of the substrate through composite molding, so that the tissue plugging material is obtained. Specifically, a homogeneous adhesion solution can be prepared at a concentration, wherein the concentration of the amino compound in the adhesion solution is from 0.01g/mL to 0.05 g/mL. Preferably, the activating factor is added to the adhesion solution. The activating factor is the activating factor in the first embodiment.
In addition, the tissue plugging material obtained after shearing can be sealed and packaged, and can be subjected to Co-60 gamma ray irradiation sterilization treatment. Specifically, the sealed package can be rapidly packaged in a dry environment with the ambient humidity below 30%; the Co-60 gamma ray irradiation dose is 15-30 kGY.
The tissue plugging material prepared by the invention does not need to be prepared in advance when in use, can be used for wound surfaces only by taking the tissue plugging material out of a package, can save precious rescue time, is convenient and simplifies the operation, and is simpler and more convenient to carry and store.
Third embodiment
In a third embodiment of the present invention, there is provided an occlusion article comprising a tissue occluding material according to the first embodiment, or a tissue occluding material obtained by the method of preparation of a tissue occluding material according to the second embodiment.
In the plugging article of the present invention, optionally, a backing layer is provided on the side of the substrate not provided with a wet adhesive layer, on which a peelable layer is provided. In the present invention, the peelable layer may be provided for the purpose of keeping the wet adhesive layer having a certain humidity and free from other substances. The materials of the backing layer and the releasable layer are not particularly limited in the present invention, and do not affect the functioning of the occluding article of the present application.
The plugging product can be used for stopping bleeding during tissue bleeding, capillary bleeding, arteriole bleeding and lacuna bleeding, and/or for stopping bleeding of burns, wounds, surgical wounds and the like, and has wide application prospect. The plugging product can also be used for cerebrospinal fluid leakage or parenchymal organ fluid leakage and the like.
In addition, the backing layer of the present invention may be peelable or non-peelable, for example: when the backing layer is used for internal hemostasis of a human body or cerebrospinal fluid leakage or parenchymal organ liquid leakage during tissue bleeding, capillary bleeding, arteriole bleeding and lacuna bleeding, the backing layer can be arranged to be strippable; the backing layer may be provided non-peelable when used for hemostasis of external skin such as burns, wounds and the like.
Examples
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Example 1
(1) Dissolving Silk Fibroin (Silk fibriin) in a trifluoroethanol solvent, wherein the mass concentration of the Silk Fibroin is 15% (g/mL), and stirring and dissolving to obtain a uniform polymer solution, namely a spinning solution (namely a matrix solution). And (3) placing the polymer solution into an electrostatic spinning injector, adjusting the speed of a micro injection pump to be 6mL/h, adjusting the voltage of a high-voltage generator to be 25kV, adjusting the receiving distance of a receiving device to be 10cm, setting the relative humidity of a spinning environment to be 40%, and setting the ambient temperature to be 30 ℃ to carry out electrostatic spinning. The nanofiber material which is formed by interweaving fiber yarns and has a porous structure is prepared by a high-voltage electrostatic spinning technology.
(2) Adding 95% ethanol-water solution into a 1000mL reactor, then weighing 1mL glutaraldehyde (25%) solution, dissolving in the 95% ethanol-water solution at normal temperature, putting 20g nanofiber material into the reactor, performing crosslinking modification at 25 ℃, and treating for 3h to obtain the crosslinked nanofiber material.
(3) Preparing an ethanol-water solution with the ethanol mass fraction of 70%, precooling for 1h at the low temperature of-20 ℃, and then transferring the crosslinked nanofiber material to the ethanol-water solution with the ethanol mass fraction of 70% for elution; after eluting for 1h, transferring the mixture to an ethanol-water solution with the ethanol mass fraction of 95 percent and the temperature of-20 ℃; after the elution is carried out for 1h, the mixture is transferred to an ethanol-water solution with the ethanol mass fraction of 70 percent and the temperature of 20 ℃ below zero for elution, and the elution is carried out for 1 h. Elution was performed using a concentration gradient method to remove unreacted glutaraldehyde species, and was repeated 3 times.
(4) And (3) putting the eluted nanofiber material into a clean container, precooling for 3h at-80 ℃, transferring the container into a freeze dryer for freeze drying, drying for 3h at 10 ℃, drying for 24h at 20 ℃ and setting the vacuum degree to 30pa to obtain the matrix I.
(5) 0.5g of chitosan powder having a deacetylation degree of 90% was weighed and dissolved in 20ml mes buffer (pH 6), and sufficiently stirred and dissolved to obtain a binding solution I.
(6) And (3) uniformly coating 10mL of adhesive solution on one side of the matrix I to obtain the tissue plugging material I.
(7) And hermetically packaging the obtained tissue plugging material, and performing Co-60 gamma ray irradiation sterilization treatment of 25kGY to obtain a tissue plugging product I.
Example 2
(1) Dissolving poly (glycolide-co-lactide) (PGLA) in hexafluoroisopropanol solvent, wherein the mass concentration of the poly (glycolide-co-lactide) is 5% (g/mL), and stirring to dissolve to obtain a uniform polymer solution, namely the spinning solution (namely the matrix solution). And (3) placing the polymer solution into an electrostatic spinning injector, adjusting the speed of a micro injection pump to be 10mL/h, adjusting the voltage of a high-voltage generator to be 10kV, adjusting the receiving distance of a receiving device to be 15cm, setting the relative humidity of a spinning environment to be 30 percent, and setting the ambient temperature to be 30 ℃ to carry out electrostatic spinning. The nanofiber material which is formed by interweaving fiber yarns and has a porous structure is prepared by a high-voltage electrostatic spinning technology.
(2) Adding 100mL of absolute ethyl alcohol solution into a 500mL reactor, adding 100mL of aqueous solution and 1mL of formaldehyde solution, uniformly stirring, adding 5g of nanofiber material into the reactor, performing crosslinking modification at 40 ℃, and treating for 2h to obtain the crosslinked nanofiber material.
(3) Preparing an ethanol-water solution with the ethanol mass fraction of 70%, precooling for a period of time of 3h at the low temperature of 4 ℃, and then transferring the crosslinked nanofiber material to the ethanol-water solution with the ethanol mass fraction of 70% for elution; after eluting for 1h, transferring the mixture to an ethanol-water solution with the ethanol mass fraction of 95 percent and the temperature of 4 ℃; after elution for 1h, the mixture is transferred to an ethanol-water solution with the ethanol mass fraction of 70 percent and the temperature of 4 ℃ for elution for 1 h. Elution was performed using a concentration gradient method to remove unreacted formaldehyde, and was repeated 3 times.
(4) And (3) putting the eluted nano-fiber material into a clean container, and drying in a vacuum drying oven at the drying temperature of 30 ℃ for 24 hours to obtain a matrix II.
(5) Gelatin powder (1 g) was weighed and dissolved in 20ml mes buffer (pH 6), and the solution was sufficiently stirred and dissolved to obtain a gelatin solution. Then, 0.2g of activated factor (carbodiimide) powder was weighed and added to 20mL of the gelatin solution, and sufficiently stirred and dissolved to obtain an adhesive solution II.
(6) And (3) taking 15mL of adhesive solution to cast one side of the substrate II to obtain the tissue plugging material II.
(7) And hermetically packaging the obtained tissue plugging material, and performing Co-60 gamma ray irradiation sterilization treatment of 25kGY to obtain a tissue plugging product II.
Example 3
(1) Dissolving hydroxypropyl methyl cellulose (HPMC) material in a mixed solution of hexafluoroisopropanol and water, wherein the mass concentration of the hydroxypropyl methyl cellulose is 5% (g/mL), and stirring to dissolve to obtain a uniform polymer solution, namely the spinning solution (namely the matrix solution). At the same time, 20 mass% of fibrinogen (blood coagulation factor) was added to the above polymer solution to dissolve it. Placing the polymer solution dissolved with the fibrinogen into an electrostatic spinning injector, adjusting the speed of a micro injection pump to be 5mL/h, adjusting the voltage of a high-voltage generator to be 38kV, adjusting the receiving distance of a receiving device to be 10cm, setting the relative humidity of a spinning environment to be 30 percent, and setting the ambient temperature to be 40 ℃, and carrying out electrostatic spinning. The nanofiber material which is formed by interweaving fiber yarns and has a porous structure and is used for compounding the blood coagulation factors is prepared by a high-voltage electrostatic spinning technology.
(2) And adding 160mL of absolute ethyl alcohol solution into a 500mL reactor, adding 40mL of aqueous solution and 8mL of glutaraldehyde solution, adjusting the pH value to acidity (pH is less than 4), uniformly stirring, adding 3g of nanofiber material into the reactor, performing crosslinking modification at 40 ℃, and treating for 36h to obtain the crosslinked nanofiber material.
(3) Preparing an ethanol-water solution with the ethanol mass fraction of 70%, precooling for a period of time of 3h at the low temperature of 4 ℃, and then transferring the crosslinked nanofiber material to the ethanol-water solution with the ethanol mass fraction of 70% for elution; after eluting for 1h, transferring the mixture to an ethanol-water solution with the ethanol mass fraction of 95 percent and the temperature of 4 ℃; after elution for 1h, the mixture is transferred to an ethanol-water solution with the ethanol mass fraction of 70 percent and the temperature of 4 ℃ for elution for 1 h. Elution was performed using a concentration gradient method to remove unreacted glutaraldehyde, and was repeated 3 times.
(4) And (3) placing the eluted nanofiber material into a clean container, pre-cooling for 3h at-80 ℃, transferring the container into a freeze dryer for freeze drying, drying for 3h at the freeze drying temperature of 30 ℃, drying for 24h at the temperature of 20 ℃, and setting the vacuum degree to 40pa to obtain the matrix III.
(5) Weighing 1g of polyethyleneimine, dissolving in 40 mM MES buffer solution (pH 6), and sufficiently stirring to dissolve to obtain a polyethyleneimine solution; then 0.2g of activating factors (carbodiimide and succinimide) were weighed into 40mL of polyethyleneimine solution, where m isCarbonizingA diimine: m isSuccinimidesDissolve with sufficient stirring to give adhering solution III as 4: 1.
(6) And (3) spraying 30mL of the adhesive solution on one side of the substrate III by using a sprayer to obtain the tissue plugging material III.
(7) And hermetically packaging the obtained tissue plugging material, and performing Co-60 gamma ray irradiation sterilization treatment of 25kGY to obtain a tissue plugging product III.
Comparative example 1
(1) Dissolving hydroxypropyl methyl cellulose (HPMC) material in a mixed solution of hexafluoroisopropanol and water, wherein the mass concentration of the hydroxypropyl methyl cellulose is 5% (g/mL), and stirring to dissolve to obtain a uniform polymer solution, namely the spinning solution (namely the matrix solution). At the same time, 20 mass% of fibrinogen (blood coagulation factor) was added to the above polymer solution to dissolve it. Placing the polymer solution dissolved with the fibrinogen into an electrostatic spinning injector, adjusting the speed of a micro injection pump to be 5mL/h, adjusting the voltage of a high-voltage generator to be 38kV, adjusting the receiving distance of a receiving device to be 10cm, setting the relative humidity of a spinning environment to be 30 percent, and setting the ambient temperature to be 40 ℃, and carrying out electrostatic spinning. The nanofiber material which is formed by interweaving fiber yarns and has a porous structure and is used for compounding the blood coagulation factors is prepared by a high-voltage electrostatic spinning technology.
(2) And adding 160mL of absolute ethyl alcohol solution into a 500mL reactor, adding 40mL of aqueous solution and 8mL of glutaraldehyde solution, adjusting the pH value to acidity (pH is less than 4), uniformly stirring, adding 3g of nanofiber material into the reactor, performing crosslinking modification at 40 ℃, and treating for 36h to obtain the crosslinked nanofiber material.
(3) Preparing an ethanol-water solution with the ethanol mass fraction of 70%, precooling for a period of time of 3h at the low temperature of 4 ℃, and then transferring the crosslinked nanofiber material to the ethanol-water solution with the ethanol mass fraction of 70% for elution; after eluting for 1h, transferring the mixture to an ethanol-water solution with the ethanol mass fraction of 95 percent and the temperature of 4 ℃; after elution for 1h, the mixture is transferred to an ethanol-water solution with the ethanol mass fraction of 70 percent and the temperature of 4 ℃ for elution for 1 h. Elution was performed using a concentration gradient method to remove unreacted glutaraldehyde, and was repeated 3 times.
(4) And (3) placing the eluted nanofiber material into a clean container, pre-cooling for 3h at-80 ℃, transferring the container into a freeze dryer for freeze drying, drying for 3h at the freeze drying temperature of 30 ℃, drying for 24h at the temperature of 20 ℃, and setting the vacuum degree to 40pa to obtain the matrix IV.
(5) Weighing 1g of polyethyleneimine, and dissolvingDissolving in 40 mM MES buffer (pH 6) under stirring; then 0.2g of activating factors (carbodiimide and succinimide) were weighed into 40mL of polyethyleneimine solution, where m isCarbodiimides：mSuccinimidesDissolve with sufficient stirring to give a coherent solution IV.
(6) And (3) spraying 30mL of the adhesive solution on one side of the substrate IV by using a sprayer, then freezing the whole material at the low temperature of-80 ℃ for 30min, and then carrying out freeze drying treatment to obtain the tissue plugging material IV of the comparative example I.
(7) And hermetically packaging the obtained tissue plugging material, and performing Co-60 gamma ray irradiation sterilization treatment of 25kGY to obtain a tissue plugging product IV.
Performance testing
Burst strength test
The plugging articles of examples 1-3 were tested according to ASTM F2458-04, with the results shown in Table 1.
TABLE 1
| Sample name | Example 1 | Example 2 | Example 3 |
| Burst Strength/Kpa | 40 | 58 | 30 |
Elongation at break test
According to GB/T3923.1-2013, a sample is cut into a sample strip with the width of 50mm, then the original gauge length of the equipment is set to be 100mm, the constant elongation rate is 20mm/min, and the test is carried out under the normal temperature condition.
The elongation at break was calculated according to the following formula:
＝ΔL/L×100％。
wherein: elongation at break (%);
Δ L is the total deformation length (mm);
l is the length (mm) of the original gauge length.
The test was performed on the plugging articles of examples 1-3 and the test results are shown in table 2.
TABLE 2
| Sample name | Example 1 | Example 2 | Example 3 |
| Elongation at break/% | 310 | 456 | 120 |
Porosity test
The porosity of the matrix was determined as follows: the porosity of the test material was determined by solvent filling. Ethanol was used as a reagent because it readily penetrated into the interior of the test material without causing shrinkage and swelling of the material. The method comprises the following steps: a50 mL small beaker was charged with absolute ethanol, and the test material (mass m) dried to a constant weight was weighed1) Soaking in ethanol, and circulatingVacuumizing the ring till no air bubbles overflow, and weighing the beaker containing the ethanol and the material to obtain the total weight m2Taking out the material containing ethanol, and weighing the rest beaker and ethanol as m3Each sample was run in 3 replicates and the results are shown in table 3 below.
Porosity is calculated by the following formula:
P＝(m2-m3-m1)/(m2-m3)×100％
wherein: p is porosity (%);
(m2-m3-m1) To test the mass (g) of ethanol contained in the pores of the material;
(m2-m3) The total mass (g) of the test material containing ethanol.
TABLE 3
| Sample name | Example 1 | Example 2 | Example 3 |
| Porosity of the matrix/%) | 80 | 85 | 70 |
Adhesion test
The test was performed according to ASTM F2458-05, with the plugging articles of examples 1-3 and comparative example 1, and the test results are shown in Table 4.
TABLE 4
| Sample name | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Adhesive Strength (J/m)2) | 750 | 900 | 1100 | 160 |
As can be seen from tables 1-4, the plugging articles of the present invention have relatively high porosity, excellent adhesion and burst strength, and suitable elongation at break.
As can be seen from Table 4, the plugging article IV of comparative example 1 was prepared to have an adhesive strength of only 160J/m when the adhesive solution was sprayed on one side of the substrate and dried, i.e., no wet adhesive layer was present2Much lower than the plugging articles I-III of examples 1-3 of the present application.
The above examples of the present invention are merely examples for clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (19)
1. A tissue occluding material, comprising:
a matrix formed by interweaving fiber filaments with the diameter of 10nm-100 mu m, and at least partially having a porous structure; and
a wet adhesion layer present on at least one surface of the substrate, the wet adhesion layer being obtained by contacting at least one surface of the substrate with an adhesion solution,
the adhesion solution contains an amino compound and a buffer solution, wherein the amino compound is dissolved in the buffer solution, and the pH value of the buffer solution is 5.5-6.7;
the adhesion strength of the tissue plugging material and the tissue surface is 200J/m2-1500J/m2。
2. The tissue sealing material of claim 1, wherein the tissue sealing material has a burst strength of 0.01Kpa to 60Kpa, an elongation at break of 0.1% to 500%; the porosity of the matrix is 30% -90%.
3. The tissue sealing material according to claim 1 or 2, wherein the material of the fiber filaments is derived from one or a combination of two or more of high molecular polymers or derivatives thereof.
4. The tissue sealing material of claim 3, wherein the fiber filaments are cross-linked.
5. The tissue occluding material of claim 1 or 2, wherein the concentration of the amino compound in the adhesion solution is between 0.01g/mL and 0.05 g/mL.
6. The tissue sealing material according to claim 1 or 2, wherein the amino compound comprises a synthetic polymer compound containing an amino group and/or a natural polymer compound containing an amino group.
7. The tissue sealing material according to claim 1 or 2, wherein the buffer is one of MES buffer, Bis-Tris buffer, PIPES buffer, disodium hydrogen phosphate-citric acid buffer, citric acid-sodium hydroxide-hydrochloric acid buffer, citric acid-sodium citrate buffer, acetic acid-sodium acetate buffer, phosphate buffer, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer, potassium dihydrogen phosphate-sodium hydroxide buffer.
8. The tissue sealing material according to claim 1 or 2, wherein the adhesive solution further comprises an activating factor.
9. The tissue occluding material of claim 8, wherein the concentration of the activating factor in the adhesion solution is between 0.1mg/mL and 1000 mg/mL.
10. The tissue occluding material of claim 9, wherein the activating factor comprises one or a combination of two or more of carbodiimide, N-hydroxysuccinimide, genipin, or aldehyde compounds.
11. The tissue sealing material of claim 1 or 2, wherein said tissue sealing material further comprises a drug.
12. The tissue sealing material of claim 11, wherein the drug comprises one or a combination of two of a coagulation factor, a growth factor.
13. A preparation method of a tissue plugging material is characterized by comprising the step of compounding and molding a matrix and a wet adhesion layer, wherein,
the matrix is formed by interweaving fiber yarns with the diameter of 10nm-100 mu m, and at least part of the matrix has a porous structure;
the wet adhesion layer is obtained by contacting at least one surface of the substrate with an adhesion solution;
the adhesion solution contains an amino compound and a buffer solution, wherein the amino compound is dissolved in the buffer solution, and the pH value of the buffer solution is 5.5-6.7;
the adhesion strength of the tissue plugging material and the tissue surface is 200J/m2-1500J/m2。
14. The method for preparing a tissue sealing material according to claim 13, wherein the matrix solution is spun by a spinning process and then cross-linked.
15. The method for preparing the tissue plugging material according to claim 14, wherein the spinning process comprises one or more of electrospinning, centrifugal force spinning, hot melt spinning, and melt electrospinning.
16. The production method according to claim 14 or 15, wherein the crosslinking treatment is a chemical crosslinking treatment or a physical crosslinking treatment.
17. The production method according to claim 14 or 15, characterized by further comprising, after the crosslinking treatment: the elution treatment was performed by a concentration gradient method to remove the unreacted crosslinking agent.
18. The production method according to any one of claims 13 to 15, wherein the composite molding includes: one or a combination of more than two of tiling, coating, casting and spraying.
19. An occlusion article comprising a tissue occluding material according to any of claims 1 to 12 or obtained by a method of preparation of a tissue occluding material according to any of claims 13 to 18, wherein optionally a backing layer is provided on the side of the substrate not provided with the wet adhesive layer and a peelable layer is provided on the wet adhesive layer.
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