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WO2023103404A1 - 一种管状材料、其制备方法及其应用 - Google Patents

一种管状材料、其制备方法及其应用 Download PDF

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Publication number
WO2023103404A1
WO2023103404A1 PCT/CN2022/108211 CN2022108211W WO2023103404A1 WO 2023103404 A1 WO2023103404 A1 WO 2023103404A1 CN 2022108211 W CN2022108211 W CN 2022108211W WO 2023103404 A1 WO2023103404 A1 WO 2023103404A1
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WO
WIPO (PCT)
Prior art keywords
polymer
pipe
poor solvent
preparation
film
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Application number
PCT/CN2022/108211
Other languages
English (en)
French (fr)
Inventor
杨小牛
李硕
吕红英
杨磊
涂江山
吴海洋
Original Assignee
中国科学院长春应用化学研究所
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Priority to US18/271,446 priority Critical patent/US20240082458A1/en
Publication of WO2023103404A1 publication Critical patent/WO2023103404A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • 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
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/041—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/04—Macromolecular materials
    • A61L29/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
    • B29C41/02—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor for making articles of definite length, i.e. discrete articles
    • B29C41/12—Spreading-out the material on a substrate, e.g. on the surface of a liquid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
    • B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
    • B29C41/02—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor for making articles of definite length, i.e. discrete articles
    • B29C41/22—Making multilayered or multicoloured articles
    • 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
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/22—Materials or treatment for tissue regeneration for reconstruction of hollow organs, e.g. bladder, esophagus, urether, uterus
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2025/00—Use of polymers of vinyl-aromatic compounds or derivatives thereof as moulding material
    • B29K2025/04—Polymers of styrene
    • B29K2025/06—PS, i.e. polystyrene
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00—Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/003—PET, i.e. poylethylene terephthalate
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2067/00—Use of polyesters or derivatives thereof, as moulding material
    • B29K2067/04—Polyesters derived from hydroxycarboxylic acids
    • B29K2067/046—PLA, i.e. polylactic acid or polylactide
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29K—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES B29B, B29C OR B29D, RELATING TO MOULDING MATERIALS OR TO MATERIALS FOR MOULDS, REINFORCEMENTS, FILLERS OR PREFORMED PARTS, e.g. INSERTS
    • B29K2075/00—Use of PU, i.e. polyureas or polyurethanes or derivatives thereof, as moulding material
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2023/00—Tubular articles
    • B29L2023/001—Tubular films, sleeves
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
    • B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
    • B29L2031/00—Other particular articles
    • B29L2031/753—Medical equipment; Accessories therefor
    • B29L2031/7532—Artificial members, protheses

Definitions

  • the invention belongs to the technical field of materials, and in particular relates to a tubular material, its preparation method and its application.
  • vascular transplantation has attracted more and more attention.
  • the best choice for vascular transplantation is the use of autologous blood vessels, but its sources are limited and cannot meet people's needs for vascular transplantation. Therefore, it is particularly important and urgent to prepare small-caliber artificial blood vessels that can replace autologous blood vessels for transplantation.
  • the prior art discloses a variety of methods for preparing artificial blood vessels, mainly including: electrospinning method, solution casting method, leaching and coagulation method, film curling method and the like.
  • the electrospinning method is to atomize the polymer into a tiny jet through the electrostatic atomization of the polymer solution.
  • the conical tip is extended to obtain fiber filaments, and the fiber filaments are connected by a template to obtain a tubular material.
  • This method is prone to problems of nozzle clogging and spinning discontinuity.
  • the solution casting method is to inject a solution between the hollow cylinder and the inner core, and the tubular material can be obtained after removing the solvent.
  • the leaching and coagulation method is to dip the mold into the polymer solution, lift the mold from the solvent, and then form it by volatilizing the solvent or immersing it in a coagulation bath.
  • the tubular material prepared by this method will have obvious ups and downs due to gravity. rough phenomenon.
  • the film curling method is to roll up the prepared film from one side, and use an adhesive to bond the interface or the whole to obtain a tubular material. This method is prone to stress unevenness and pipe collapse.
  • the purpose of this application is to provide a tubular material, its preparation method and its application.
  • the method provided by this application does not require complicated equipment and heating, and can quickly prepare tubular materials with uniform and controllable wall thickness, which can be used as artificial Tubular tissues, especially artificial blood vessels, have good mechanical properties.
  • the invention provides a method for preparing a pipe, comprising the following steps:
  • step c) also includes before:
  • Step a) and step b) are repeated to obtain a rod comprising a multilayer polymer film.
  • said layers of polymer films are the same or different.
  • the curling position when repeating step b) n times, n/2 times or (n+1)/2 times or (n-1)/2 times, the curling position is in the first direction relative to the last curling position Move the first distance, and for the remaining repetitions, the crimped position moves in the second direction relative to the previous crimped position for the first distance, the first direction is opposite to the second direction, and the first distance is 1 cm to 5 cm.
  • step a) and step b) further includes: performing surface treatment on the polymer film.
  • the surface treatment comprises: laser etching the polymer film.
  • the mold surface has a microstructure.
  • the polymer comprises one or more of polyurethane, polycaprolactone, polylactic acid, poly(styrene-ethylene-butylene-styrene) or polyethylene terephthalate kind;
  • the solvent in the polymer solution includes one or more of N,N-dimethylformamide, tetrahydrofuran, hexafluoroisopropanol, dioxane or dimethyl sulfoxide;
  • the poor solvent is water.
  • the polymer solution also contains active substances
  • the present invention also provides a tubular material prepared by the method described in the above technical solution, and the tubular material does not contain a binder.
  • the present invention also provides an application of the tubular material prepared by the method described in the above technical solution in the preparation of artificial tubular tissue.
  • the artificial tubular tissue includes artificial blood vessels, artificial nerve guides or artificial heart stents.
  • the present invention also provides a method for preparing artificial tubular tissue, comprising the following steps:
  • the tubing is modified to obtain an artificial tubular tissue.
  • the present invention dissolves the polymer in a good solvent, and then adds the obtained polymer solution into the poor solvent of the polymer.
  • the good solvent and the poor solvent perform solvent exchange at the interface, and the poor solvent quickly disperses the good solvent , the polymer is diffused on the surface of the poor solvent to form a film.
  • a small amount of solvent remains on the side of the polymer film that is not in contact with the poor solvent, so that the obtained polymer film is viscous.
  • the mold is directly used The polymer film is crimped on the surface of the poor solvent, and the film is tightly bonded by the surface tension of the poor solvent and the shear force of winding around the shaft. After the mold is removed, the pipe can be obtained.
  • This process avoids The introduction of the binder is avoided, thereby avoiding the uneven stress and easy collapse of the obtained pipe, and at the same time, the uniform and controllable wall thickness can be realized, and the uniform and stable mechanical properties can be achieved.
  • the method provided by the present invention does not require complicated equipment and heating, and the whole process can be completed at room temperature without thermal influence or thermal inactivation on the active substances in the tubular material.
  • Fig. 1 is the schematic flow chart of the preparation method of the pipe provided by the present application.
  • Fig. 2 is the threaded surface structure schematic diagram of the mold that the embodiment of the present invention uses;
  • Fig. 3 is the schematic diagram of the quincunx cross-sectional structure of the mold used in the embodiment of the present invention.
  • Fig. 4 is a schematic diagram of the axial array surface structure of the mold used in the embodiment of the present invention.
  • Fig. 5 is a schematic diagram of the crimping method of the crimping film formation provided by Example 1 of the present invention.
  • Fig. 6 is the optical magnification photograph of the pipe material of the different wall thickness that the application embodiment 1 prepares;
  • Fig. 7 is the tensile performance curve of the pipe prepared in Example 1 of the present invention.
  • Fig. 8 is a schematic diagram of the crimping method of the crimping film formation provided by Example 2 of the present invention.
  • Fig. 9 is the SEM photo of the pipe material prepared in Example 2 of the present application.
  • Fig. 10 is the stress-strain curve of the pipe prepared in Example 2 of the present application.
  • Fig. 11 is the SEM photo of the pipe provided by the embodiment 3 of the present application.
  • Fig. 12 is the stress-strain curve of the pipe provided by Example 3 of the present invention.
  • Fig. 13 is a schematic diagram of the curling method of curling film formation provided by Example 5 of the present invention.
  • Fig. 14 is the photograph of the pipe material that the application embodiment 5 adopts
  • Figure 15 is an SEM photo of the inner surface of the pipe prepared in Example 5 of the present application, wherein Figure 15 (A) is a 100-fold enlarged SEM photo;
  • Figure 16 is the stress-strain curve of the pipe prepared by the method provided in Example 5 of the present application and the range of mechanical properties of the coronary human artery;
  • Figure 17 shows the compliance of the tubing prepared by the method provided in Example 5 of the present application and the human coronary artery;
  • Figure 18 is the result of the radial tensile cycle test of the pipe prepared by the method provided in Example 5 of the present application;
  • Fig. 19 is the radial compression cycle test result of the pipe prepared by the method provided in Example 5 of the present application.
  • Figure 20 is a comparison of the burst pressure of the tubing prepared by the method provided in Example 5 of the present application and the internal thoracic artery (IMA);
  • Figure 21 is a comparison of the suture strength of the tubing prepared by the method provided in Example 5 of the present application and the internal thoracic artery (IMA);
  • Figure 22 is a fluorescent picture of the tube cultured cells provided in Example 5 of the present application.
  • Figure 23 is the time-density curve of the tube cultured cells provided in Example 5 of the present application.
  • Figure 24 is the time cell-coverage curve of the tube cultured cells provided in Example 5 of the present application.
  • Figure 25 is an optically enlarged photo of the pipe prepared in Example 6 of the present application.
  • Figure 26 is the stress-strain curve of the pipe prepared in Example 6 of the present application.
  • Fig. 27 is an optical enlarged photo of the pipe prepared in Example 7 of the present application.
  • the invention provides a method for preparing a pipe, comprising the following steps:
  • Fig. 1 is the schematic flow chart of the preparation method of the pipe provided by the application, the first step is to dissolve the polymer in a good solvent and then add it to a poor solvent, the polymer diffuses on the surface of the poor solvent to form a film, and then adopts a mold The polymer film is crimped and the mold is removed to obtain a pipe, or the above steps are repeated to obtain a pipe comprising multiple layers of polymer film.
  • the polymer is dissolved in its good solvent to obtain a polymer solution.
  • the polymer is a film-forming polymer, preferably a polymer with better biocompatibility, including but not limited to polyurethane (PU), polycaprolactone (PCL), polylactic acid ( PLA), poly(styrene-ethylene-butylene-styrene) (SEBS), polyethylene terephthalate (PET), etc., may be one or more of them.
  • PU polyurethane
  • PCL polycaprolactone
  • PLA polylactic acid
  • SEBS poly(styrene-ethylene-butylene-styrene)
  • PET polyethylene terephthalate
  • the good solvent includes but is not limited to N,N-dimethylformamide, tetrahydrofuran, hexafluoroisopropanol, dioxane, dimethyl sulfoxide, etc., which can be one of or more.
  • the concentration of the polymer solution is 10-200 mg/mL, preferably 30-180 mg/mL, more preferably 50-150 mg/mL.
  • the polymer solution further includes active substances, such as anti-inflammatory active factors, anti-inflammatory drugs, growth factors or other physiologically active drugs, proteins, etc., which are not particularly limited in the present invention.
  • the polymer solution is added into its poor solvent, and the polymer is diffused on the liquid surface of the poor solvent to form a film to obtain a polymer film.
  • the present invention adopts the principle of diffusion film formation.
  • the polymer solution is added to the poor solvent, it is necessary to control the amount and speed of polymer solution addition so as to realize the diffusion and film formation on the liquid surface.
  • the polymer can be formed into a film on the surface of the poor solvent by means of dropping or spraying.
  • the good solvent is dissolved in the poor solvent, so that when the polymer solution is dripped or sprayed, solvent exchange can be performed on the interface to form a film.
  • the poor solvent is water.
  • the polymer solution is added dropwise to the poor solvent using an autosampler with a flat angle needle.
  • the distance between the injector and the liquid surface of the poor solvent is 1-15 cm, preferably 3-10 cm.
  • the dropping rate is 1-15ml/min, preferably 5-10ml/min.
  • the dropping amount is preferably 1-10 drops, more preferably 1-5 drops.
  • those skilled in the art can select the type of polymer and its molecular weight according to the actual situation, and at the same time determine the concentration of the polymer solution, the dropping speed and the height from the poor solvent liquid surface according to the principle of diffusion film formation. There are no special restrictions on the application.
  • those skilled in the art can determine the good solvent and the poor solvent, as long as the good solvent dissolves in the poor solvent.
  • the polymer film is obtained, there is no need to operate it, and the polymer film is directly curled by using a mold, so that the polymer film is wrapped on the outer surface of the mold to form a rod.
  • the polymer film is crimped within 8 min after film formation, preferably within 5 min.
  • the mold is a rod of material.
  • a rod-shaped material is used on one side of the polymer film, with the rod-shaped material as the axis, and the rod-shaped material is tangent to the liquid surface of the poor solvent. , roll up the film on the liquid surface of the poor solvent, and wrap it on the surface of the rod-shaped material.
  • the rod-shaped material has a surface structure or surface microstructure, so that the inner surface of the obtained pipe has a structure or microstructure, for example, the surface of the rod-shaped material has a thread structure, as shown in Figure 2, which is a diagram of the present invention
  • Figure 4 is a schematic diagram of the axial array surface structure of the mold used in the embodiment of the present invention, the obtained pipe
  • the inner surface is an axial array structure.
  • the diameter of the rod-shaped material is related to the diameter of the required pipe, for example
  • step a) to step b) can be repeated, that is, after the polymer solution is diffused on the surface of the poor solvent to form a film, the mold that has wrapped the polymer film is used to continue curling to form a multilayer polymer film on the mould. , a rod with a multilayer structure is obtained, and a pipe with a multilayer structure is obtained after removing the mold.
  • the present invention has no special limitation on the number of repetitions, it can be adjusted according to the thickness of the required pipe and the concentration of the polymer solution.
  • the polymers used in each layer of polymer film can be the same or different, and can be selected according to the use scene of the pipe, which is not particularly limited in the present invention.
  • the curling position moves the first distance in the first direction relative to the previous curling position, and the remaining During the first repetition, the crimped position moves a first distance in a second direction relative to the previous crimped position, the first direction and the second direction are the same or opposite, and the first distance is 1 cm to 5 cm.
  • curl can be done as follows:
  • the position of the second crimp is moved to the right by the first distance relative to the edge of the first pipe, the position of the third crimp is moved to the right by the first distance relative to the edge of the second pipe, and the position of the fourth crimp is moved to the left by the first distance relative to the edge of the third crimp , that is, the same position as the second curl, the fifth curl is moved to the left by the first distance relative to the fourth curl edge, and the sixth curl is moved to the right by the first distance relative to the fifth curl edge, which is the same as the second curl
  • the position is the same, the first distance is moved to the right relative to the edge of the sixth curl during the seventh curl, and the first distance is moved to the left relative to the edge of the seventh curl during the eighth curl, which is the same position as the second curl, and according to this rule to repeat.
  • curl can be done as follows:
  • Each crimp moves to the right by the first distance relative to the last pipe edge, returns to the first crimp position at the n/2th crimp, and continues to move right by the first distance relative to the last pipe edge.
  • curl can be done as follows:
  • Each crimp moves the first distance to the right relative to the previous pipe edge, moves to the left the first distance for the n/2th crimp, and continues to move the first distance to the left relative to the previous pipe edge.
  • the polymer film obtained by spreading on the surface of the poor solvent can also be subjected to surface treatment, such as laser etching, to obtain the desired surface microstructure.
  • surface treatment such as laser etching
  • the present invention has no special restrictions on the surface treatment, and can only carry out surface treatment on the first layer of polymer film, and can also carry out surface treatment on all layers of polymer films, and can also carry out surface treatment on one or some layers of polymer films. For surface preparation.
  • the rod can be post-treated to remove the residual solvent to further bond the multi-layer polymer film tightly, and the pipe can be obtained after removing the rod.
  • the post-treatment can be static treatment, such as standing at room temperature for 20 to 60 minutes; in one embodiment, the post-treatment can be liquid nitrogen freezing; in one embodiment, the The post-treatment may be applying a circumferential force to the rod; in one embodiment, the post-treatment may be vacuum drying.
  • the rod may not be post-treated, and after the mold is directly removed, the obtained pipe is soaked in the solution as an artificial tubular tissue for use, for example, it is soaked in deionized water, TBST solution ( Tris-Hcl buffer), PBS solution (phosphate buffer saline), any one of physiological saline for use.
  • TBST solution Tris-Hcl buffer
  • PBS solution phosphate buffer saline
  • the pipe prepared by the method provided by the present invention utilizes the residual solvent in the film-forming process to realize the self-adhesion of the film, and does not need to introduce an adhesive for bonding, which avoids the uneven stress and easy collapse of the obtained pipe, and at the same time can Achieve uniform and controllable wall thickness and uniform and stable mechanical properties.
  • the method provided by the present invention does not require complicated equipment and heating, and the whole process can be completed at room temperature without thermal influence or thermal inactivation on the active substances in the tubular material.
  • the tubular material provided by the invention can be used as artificial tubular tissue, such as artificial blood vessels, artificial nerve guides and artificial heart stents, etc., and has good biocompatibility and mechanical properties.
  • the present invention also provides a method for preparing artificial tubular tissue.
  • the artificial tubular tissue can be obtained by further modifying the pipe.
  • the prepared pipes are trimmed and surface modified to obtain artificial blood vessels; the prepared pipes are modified by pore making, filling or drug loading to obtain artificial nerve guides; the prepared pipes are subjected to pore making and surface modification etc., get artificial heart stents, etc.
  • the stretching cycle is pulled to 30% (50%) strain at a speed of 5mm/min and then restored to 0% at a speed of 2.5mm/min, and the cycle is 30 times;
  • the compression cycle is compressed to 50% strain at a speed of 5mm/min and then restored to 0% at a speed of 2.5mm/min, and the cycle is 30 times;
  • Polyurethane with a molecular weight of 80,000 was purchased from Shandong Youso Chemical Technology Co., Ltd., and N,N-dimethylformamide was used to prepare a solution at a concentration of 50 mg/ml. 5 drops at a rate of 10mL/min to the water surface at a distance of 5cm from the water surface, the solution will spread on the water surface to form a film, and then within 2min, use a polytetrafluoroethylene rod with a diameter of 5mm to directly wrap around the film from one side of the film. Shaft crimping, this process can be repeated, see Figure 5, Figure 5 is a schematic diagram of the crimping method provided by Example 1 of the present invention.
  • the sixth, eighth, and tenth times... are all the same as the second curl and pass the measurement Until the wall thickness meets the requirements, such as 100 ⁇ m, 200 ⁇ m, 300 ⁇ m, 400 ⁇ m, 500 ⁇ m and 600 ⁇ m, place it at room temperature for 0.5 hours, then pull out the mold, and trim it to get a pipe with uniform wall thickness.
  • Figure 6 is an optical magnification photo of pipes with different wall thicknesses prepared in Example 1 of the present application
  • Figure 6(A) is an optical magnification of a pipe with a wall thickness of 100 ⁇ m Photo
  • Figure 6 (B) is an optically enlarged photo of a pipe with a wall thickness of 200 ⁇ m
  • Figure 6 (C) is an optically enlarged photo of a pipe with a wall thickness of 300 ⁇ m
  • Figure 6 (D) is an optically enlarged photo of a pipe with a wall thickness of 400 ⁇ m
  • Figure 6(E) is an optically enlarged photo of a pipe with a wall thickness of 500 ⁇ m
  • Figure 6(F) is an optically enlarged photo of a pipe with a wall thickness of 600 ⁇ m. It can be seen from Fig. 6 that the wall thickness of the pipe prepared by the method provided in the present application is relatively uniform.
  • Figure 7 is the tensile performance curve of the pipe prepared in Example 1 of the present invention.
  • Figure 7(A) is the tensile curve of a pipe with a wall thickness of 100 ⁇ m
  • Figure 7(B) is the tensile curve of a pipe with a wall thickness of 300 ⁇ m
  • Figure 7(C) is the tensile curve of a pipe with a wall thickness of 500 ⁇ m
  • Figure 7(D) shows the tensile curves of pipes with wall thicknesses of 100 ⁇ m, 300 ⁇ m and 500 ⁇ m, where curves 11, 12 and 13 are the tensile curves of pipes with 100 ⁇ m, 300 ⁇ m and 500 ⁇ m, respectively. It can be seen from FIG. 7 that the pipe prepared by the method provided
  • Example 2 of the present invention Provide a schematic diagram of the crimping method of crimping into a film. Return to the first crimping position at the sixth crimping, and follow this rule, and measure until the wall thickness meets the requirements, then freeze it with liquid nitrogen, pull it out, and trim it to get the pipe.
  • Figure 9 is a SEM photo of the pipe prepared in Example 2 of the present application. It can be seen from Figure 9 that the wall thickness of the pipe prepared by the method provided in the present application is relatively uniform .
  • Example 1 use the polyurethane in Example 1 and Example 2 to build a double-layer structure, that is, first use the polyurethane in Example 2 to curl into a tube to form an inner layer structure, and then use the polyurethane in Example 1 to form an inner layer structure.
  • the polyurethane-formed tube in Example 2 was used to curl the polyurethane-formed film in Example 1 to form an outer layer to obtain a pipe with a double-layer structure.
  • Fig. 11 is the SEM photo of the pipe provided in Example 3 of the present application, as can be seen from Fig. 11, the pipe wall thickness obtained by the method provided in the present application is comparatively uniform .
  • SEBS with a molecular weight of 90,000 was purchased from Kraton, and it was prepared into a solution with tetrahydrofuran at a concentration of 75 mg/ml. After it was completely dissolved, 10 drops were added to the water surface at a speed of 5 ml/min at a distance of 10 cm from the water surface. After forming a film on the water surface, within 10 seconds Use a polytetrafluoroethylene rod with a diameter of 3 mm to curl from one side of the film, apply a circumferential force to it after curling to promote interlayer adhesion, and pull out and trim directly to obtain a tube.
  • Example 1 The polyurethane in Example 1 and Example 2 was formulated into a solution with dioxane at a concentration of 100mg/ml according to the mass ratio of 2:1, and 3 drops were added dropwise at a speed of 10ml/min at a distance of 5cm from the water surface.
  • Figure 13 is a schematic diagram of the curling method of curling film formation provided by Example 5 of the present invention, the sixth curl Move left 1.5cm relative to the edge of the fifth crimp and continue crimping four times by moving 3cm left relative to the previous edge, then the crimping position is the same as the first time, and repeat the operation according to this rule until the pipe wall thickness is 0.5mm, effective If the length is longer than 5cm, it is simply trimmed after being frozen in liquid nitrogen and soaked in PBS solution for later use. It can be used as an artificial blood vessel.
  • Fig. 14 is the photo of the pipe material that the application embodiment 5 adopts;
  • the inner surface of the described sample section is carried out SEM characterization, the result is referring to Fig. 15, and Fig. 15 is that the application implements The SEM photo of the inner surface of the pipe prepared in Example 5, wherein, Fig. 15 (A) is a 100-fold SEM photo, and Fig. 15 (B) is a 1000-fold SEM photo of the method.
  • the method provided by the application prepares The resulting tubing has a porous inner surface.
  • Figure 16 is the application The stress-strain curve of the pipe prepared by the method provided in Example 5 and the range of mechanical properties of the coronary human artery.
  • Figure 17 shows the compliance of the pipe prepared by the method provided in Example 5 of the present application and the human coronary artery.
  • the ratio of the diameter D under pressure to the original diameter D0 indicates that Figure 18 is the radial tensile cycle test result of the pipe prepared by the method provided in Example 5 of the present application, and Figure 19 is the pipe prepared by the method provided in Example 5 of the present application.
  • Figure 20 is the comparison of the burst pressure of the tubing prepared by the method provided in Example 5 of the present application and the internal thoracic artery (IMA)
  • Figure 21 is the comparison of the tubing and the thoracic artery prepared by the method provided in Example 5 of the present application
  • the suture strength comparison of the internal artery (IMA), from Figure 16, Figure 17, Figure 18, Figure 19, Figure 20 and Figure 21, the mechanical properties of the pipe prepared by the method provided by the application are stable and similar to the human coronary artery, and can be used as Artificial blood vessels are used.
  • the tubing prepared by the method provided by the application has a burst pressure similar to that of the internal thoracic artery and higher suture strength
  • Fig. 22 is the fluorescence picture of the tube cultured cells provided in Example 5 of the present application, wherein the left column of pictures is the control group, that is, HUVECs are cultured on glass slides, and the right column is the experimental group, that is, HUVECs are cultured on the inner surface of the tube;
  • FIG. 23 For the time-density curve of the tube cultured cells provided in Example 5 of the present application, FIG.
  • Example 24 is the time cell-coverage curve of the tube cultured cells provided in Example 5 of the present application. It can be seen from Figures 22, 23 and 24 that the tube prepared in Example 5 of the present invention has a certain effect of promoting endothelialization as an artificial blood vessel compared with glass, and there is a significant difference.
  • Polycaprolactone (molecular weight 80,000 purchased from Yuanye Biology) was dissolved in acetone at a concentration of 50 mg/ml, and mixed with the polyurethane solution used in Example 1 at a volume ratio of 1:2, and mixed thoroughly with 10 ml/ Add 3 drops at a speed of min.
  • Teflon bolt with a diameter of M3 and a pitch of 0.5mm to crimp within 1 minute.
  • Each crimp moves 3.5cm to the right relative to the edge of the previous pipe, and the fourth crimp is relative to the third.
  • the edge of the second curl is moved to the left by 3.5cm, which is the same position as the second curl, and according to this rule, the sixth, eighth, tenth... are all in the same position as the second curl, after vacuum drying Rotate and take off to obtain a pipe with a threaded interior.
  • Figure 26 is the stress-strain curve of the pipe prepared in Example 6 of the present application , wherein curves 41, 42 and 43 are the stress-strain curves of the left, middle and right sections respectively; it can be seen from Figure 26 that the pipe prepared by the preparation method provided by the present invention has good tensile properties and relatively uniform mechanical properties.
  • Example 1 and Example 5 Prepare the polyurethane solution and polycaprolactone solution in Example 1 and Example 5 respectively, first operate according to Example 1 until the wall thickness of the pipe is 60 ⁇ m, and then use the same method to use the PCL solution within 10s after each film formation. The wall thickness is increased to 100 ⁇ m, and finally the pipe wall thickness reaches 140 ⁇ m according to the operation in Example 1, and the pipe is obtained by directly pulling out the mold and cutting.
  • Figure 27 is an optically enlarged photo of the pipe prepared in Example 7 of the present application. It can be seen from Figure 27 that the wall thickness of the pipe prepared by the method provided in the present application is relatively uniform .

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Abstract

本发明提供了一种管材的制备方法，包括以下步骤：a)将聚合物溶液加入不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；b)采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；c)去除模具，得到管材。本发明还提供了上述管材作为人工管状组织的应用。本发明提供的方法避免了粘结剂的引入，从而避免了得到的管材应力不均、容易崩坏等情况，同时能够实现壁厚的均匀可控，力学性能的均一稳定。另外，本发明提供的方法不需要复杂设备，无需加热，整个过程在室温下即可完成，不会对管状材料中的活性物质产生热影响或热失活。

Description

一种管状材料、其制备方法及其应用
本申请要求于2021年12月06日提交中国专利局、申请号为202111481231.5、发明名称为“一种管状材料、其制备方法及其应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于材料技术领域，具体涉及一种管状材料、其制备方法及其应用。
背景技术
近年来，心血管类疾病严重危害到人类的健康，血管移植越来越受到人们的关注。血管移植的最佳选择是采用自体血管，但是其来源有限，已经不能满足人们对血管移植的需求。因此，制备能够替代自体血管进行移植的小口径人工血管尤为重要且非常急迫。
现有技术公开了多种制备人工血管的方法，主要包括：静电纺丝法、溶液浇筑法、浸沥凝固法、薄膜卷曲法等。其中，静电纺丝法是通过聚合物溶液静电雾化的形式，将聚合物雾化为微小射流，在电场作用下，针头处的液滴由球形变为圆锥形(即泰勒锥)，并从圆锥尖端延展得到纤维细丝，将纤维细丝用模板承接，即可得到管状材料，该方法容易出现喷嘴堵塞和纺丝不连续的问题。溶液浇筑法是通过向中空的圆柱和内芯两层之间注射溶液，去除溶剂后即可得到管状材料，但是，该方法需要去除溶剂，加热法去除溶剂可能会破坏材料含有的对温度敏感的成分，冷冻法去除溶剂需要较长的时间。浸沥凝固法是通过模具向聚合物溶液中浸渍，将模具从溶剂中提拉起来后通过挥发溶剂或浸入凝固浴中成型，该方法制备得到的管状材料由于重力作用会出现明显的上细下粗的现象。薄膜卷曲法是通过将制备好的薄膜由一侧卷起，采用粘结剂进行接口处或整体的粘接，得到管状材料，该方法容易出现应力不均、管材崩坏的情况。
发明内容
有鉴于此，本申请的目的在于提供一种管状材料、其制备方法及其应用，本申请提供的方法无需复杂设备、无需加热，可以快速制备出壁厚均匀可控的管状材料，用作人工管状组织，尤其是人工血管时具有良好的力学性能。
本发明提供了一种管材的制备方法，包括以下步骤：
a)将聚合物溶液加入不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；
b)采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；
c)去除模具，得到管材。
在一个实施例中，步骤c)之前还包括：
重复步骤a)和步骤b)，得到包括多层聚合物膜的棒材。
在一个实施例中，所述包括多层聚合物膜的棒材中，所述多层聚合物膜相同或不同。
在一个实施例中，重复步骤b)n次，n/2次或(n+1)/2次或(n-1)/2次重复时，卷曲位置相对于上一次卷曲位置向第一方向移动第一距离，剩余次重复时，卷曲位置相对于上一次卷曲位置向第二方向移动第一距离，所述第一方向和第二方向相反，所述第一距离为1cm～5cm。
在一个实施例中，所述步骤a)和步骤b)之间还包括：对所述聚合物膜进行表面处理。
在一个实施例中，所述表面处理包括：对所述聚合物膜进行激光刻蚀。
在一个实施例中，所述模具表面具有微结构。
在一个实施例中，所述聚合物包括聚氨酯、聚己内酯、聚乳酸、聚(苯乙烯-乙烯-丁烯-苯乙烯)或聚对苯二甲酸乙二醇酯中的一种或多种；
所述聚合物溶液中的溶剂包括N,N-二甲基甲酰胺、四氢呋喃、六氟异丙醇、二氧六环或二甲基亚砜中的一种或多种；
所述不良溶剂为水。
在一个实施例中，所述聚合物溶液中还包含活性物质
本发明还提供了一种上述技术方案所述的方法制备得到的管状材料，所述管状材料不包含粘结剂。
本发明还提供了一种上述技术方案所述的方法制备得到的管状材料在制备人工管状组织中的应用。
在一个实施例中，所述人工管状组织包括人工血管、人工神经导管或人工心脏支架。
本发明还提供了一种人工管状组织的制备方法，包括以下步骤：
将聚合物溶液加入不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；
采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；
去除模具，得到管材；
将所述管材进行修饰，得到人工管状组织。
本发明将聚合物溶于良溶剂中，然后将得到的聚合物溶液加入聚合物的不良溶剂中，在滴加过程中，良溶剂和不良溶剂在界面进行溶剂交换，不良溶剂将良溶剂迅速分散，使聚合物在所述不良溶剂液面上扩散成膜，此时，聚合物膜未与不良溶剂接触的一面中还残留有少量溶剂，使得到的聚合物膜具有粘性，此时直接采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，通过不良溶剂的表面张力和绕轴卷曲的剪切力使薄膜紧紧粘接，去除模具后，即可得到管材，该过程避免了粘结剂的引入，从而避免了得到的管材应力不均、容易崩坏等情况，同时能够实现壁厚的均匀可控，力学性能的均一稳定。另外，本发明提供的方法不需要复杂设备，无需加热，整个过程在室温下即可完成，不会对管状材料中的活性物质产生热影响或热失活。
附图说明
图1为本申请提供的管材的制备方法的流程示意图；
图2为本发明实施例使用的模具的螺纹表面结构示意图；
图3为本发明实施例使用的模具的梅花形横截面结构示意图；
图4为本发明实施例使用的模具的轴向阵列表面结构示意图；
图5为本发明实施例1提供的卷曲成膜的卷曲方式示意图；
图6为本申请实施例1制备的不同壁厚的管材的光学放大照片；
图7为本发明实施例1制备的管材的拉伸性能曲线；
图8为本发明实施例2提供的卷曲成膜的卷曲方式示意图；
图9为本申请实施例2制备的管材的SEM照片；
图10为本申请实施例2制备的管材的应力应变曲线；
图11为本申请实施例3提供的管材的SEM照片；
图12为本发明实施例3提供的管材的应力应变曲线；
图13为本发明实施例5提供的卷曲成膜的卷曲方式示意图；
图14为本申请实施例5采用的管材的照片；
图15为本申请实施例5制备的管材的内表面SEM照片，其中，图15(A)是放大100倍的SEM照片；
图16为本申请实施例5提供的方法制备的管材的应力应变曲线及冠状人体动脉的力学性能范围；
图17为本申请实施例5提供的方法制备的管材及人体冠状动脉的顺应性；
图18为本申请实施例5提供的方法制备的管材的径向拉伸循环测试结果；
图19为本申请实施例5提供的方法制备的管材的径向压缩循环测试结果；
图20为本申请实施例5提供的方法制备的管材和胸廓内动脉(IMA)的爆破压对比；
图21为本申请实施例5提供的方法制备的管材和胸廓内动脉(IMA)的缝合强度对比；
图22为本申请实施例5提供的管材培养细胞的荧光图片；
图23为本申请实施例5提供的管材培养细胞的时间-密度曲线；
图24为本申请实施例5提供的管材培养细胞的时间细胞-覆盖率曲线；
图25为本申请实施例6制备的管材的光学放大照片；
图26为本申请实施例6制备的管材的应力应变曲线；
图27为本申请实施例7制备的管材的光学放大照片。
具体实施方式
本发明提供了一种管材的制备方法，包括以下步骤：
a)将聚合物溶液加入不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；
b)采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；
c)去除模具，得到管材。
参见图1，图1为本申请提供的管材的制备方法的流程示意图，第一步将聚合物溶解于良溶剂后加入不良溶剂中，聚合物在不良溶剂液面上扩散成膜， 然后采用模具将所述聚合物膜卷曲，去除模具后得到管材，或者重复上述步骤，得到包含多层聚合物膜的管材。
本发明首先将聚合物溶解于其良溶剂中，得到聚合物溶液。在一个实施例中，所述聚合物为能够成膜的聚合物，优选为生物相容性较好的聚合物，包括但不限于聚氨酯(PU)、聚己内酯(PCL)、聚乳酸(PLA)、聚(苯乙烯-乙烯-丁烯-苯乙烯)(SEBS)、聚对苯二甲酸乙二醇酯(PET)等，可以为其中的一种或多种。在一个实施例中，所述良溶剂包括但不限于N,N-二甲基甲酰胺、四氢呋喃、六氟异丙醇、二氧六环、二甲基亚砜等，可以为其中的一种或多种。在一个实施例中，所述聚合物溶液的浓度为10～200mg/mL，优选为30～180mg/mL，更优选为50～150mg/mL。在一个实施例中，所述聚合物溶液中还包括活性物质，例如抗炎活性因子、抗炎药物、生长因子或者其他具有生理活性的药物、蛋白等，本发明对此并无特殊限制。将所述聚合物溶液加入其不良溶剂中，使聚合物在所述不良溶剂的液面上扩散成膜，得到聚合物膜。可以理解的是，本发明采用扩散成膜原理，将聚合物溶液加入不良溶剂时，需要控制聚合物溶液加入的量和速度，以便能够实现在液面上扩散成膜。在一个实施例中，可以通过滴加或喷涂的方式使聚合物在不良溶剂液面上成膜。在发明中，所述良溶剂溶于所述不良溶剂，使得滴加或喷涂聚合物溶液时，能够在界面上进行溶剂交换，从而成膜。在一个实施例中，所述不良溶剂为水。在一个实施例中，使用带有平角针头的自动进样器将聚合物溶液滴加到不良溶剂中。在一个实施例中，所述进样器距离不良溶剂液面的距离为1～15cm，优选为3～10cm。在一个实施例中，滴加速度1～15ml/min，优选为5～10ml/min。在一个实施例中，所述滴加量优选为1～10滴，更优选为1～5滴。
在其他实施例中，本领域技术人员可以根据实际情况选择聚合物种类及其分子量，同时根据扩散成膜的原理确定聚合物溶液的浓度、滴加速度和距离不良溶剂液面的高度等参数，本申请对此并无特殊限制。
在其他实施例中，根据聚合物种类及其分子量的不同，本领域技术人员可以确定其良溶剂和不良溶剂，满足良溶剂溶于不良溶剂中即可。
得到聚合物膜后，无需对其进行操作，直接采用模具将所述聚合物膜进行卷曲，使聚合物膜包裹在模具外表面，形成棒材。在一个实施例中，成膜后 8min内将所述聚合物膜进行卷曲，优选5min内将所述聚合物膜进行卷曲。在一个实施例中，所述模具为棒状材料。在一个实施例中，聚合物在不良溶剂液面上扩散成膜后，使用棒状材料在所述聚合物膜一侧，以所述棒状材料为轴，且棒状材料与不良溶剂的液面相切，在不良溶剂的液面上将薄膜卷起，包裹在棒状材料表面。在一个实施例中，所述棒状材料具有表面结构或表面微结构，使得到的管材内表面具有结构或微结构，例如，棒状材料表面具有螺纹结构，如图2所示，图2为本发明实施例使用的模具的螺纹表面结构示意图，得到的管材内表面具有螺纹结构；或者棒状材料横截面为异形结构，如图3所示，图3为本发明实施例使用的模具的梅花形横截面结构示意图，得到的管材的横截面为梅花形；或者棒状材料表面为轴向阵列结构，如图4所示，图4为本发明实施例使用的模具的轴向阵列表面结构示意图，得到的管材内表面为轴向阵列结构。在同一个实施例中，所述棒状材料的直径与所需管材的直径相关，例如可以为5mm、3mm，本发明并无特殊限制。
在本发明中，可以重复步骤a)～步骤b)，即将聚合物溶液在不良溶剂液面上扩散成膜后，用已包裹聚合物膜的模具继续卷曲，在模具上形成多层聚合物膜，得到具有多层结构的棒材，去除模具后，得到具有多层结构的管材。本发明对所述重复次数没有特殊限制，根据所需管材的厚度以及聚合物溶液的浓度进行调整即可。
在形成多层聚合物膜的过程中，每层聚合物膜采用的聚合物可以相同也可以不同，可以根据管材的使用场景进行选择，本发明对此并无特殊限制。
在形成多层聚合物膜的过程中，为了获得壁厚均一的管材，优选按照以下方法进行卷曲：
重复步骤b)n次，n/2次或(n+1)/2次或(n-1)/2次重复时，卷曲位置相对于上一次卷曲位置向第一方向移动第一距离，剩余次重复时，卷曲位置相对于上一次卷曲位置向第二方向移动第一距离，所述第一方向和第二方向相同或相反，所述第一距离为1cm～5cm。
具体而言，可以按照以下方法进行卷曲：
第二次卷曲位置相对第一次管材边缘右移第一距离，第三次卷曲位置相对第二次管材边缘右移第一距离，第四次卷曲时相对第三次卷曲边缘左移第一距 离，即与第二次卷曲位置相同，第五次卷曲时相对第四次卷曲边缘左移第一距离，第六次卷曲时相对第五次卷曲边缘右移第一距离，即与第二次卷曲位置相同，第七次卷曲时相对第六次卷曲边缘右移第一距离，第八次卷曲时相对第七次卷曲边缘左移第一距离，即与第二次卷曲位置相同，并按此规律进行重复。
或者，可以按照以下方法进行卷曲：
每次卷曲相对上一次管材边缘右移第一距离，第n/2次卷曲时回到第一次卷曲位置，继续相对上一次管材边缘右移第一距离。
或者，可以按照以下方法进行卷曲：
每次卷曲相对上一次管材边缘右移第一距离，第n/2次卷曲时左移第一距离，继续相对上一次管材边缘左移第一距离。
在一个实施例中，还可以对在不良溶剂液面上扩散得到的聚合物膜进行表面处理，例如对其进行激光刻蚀，得到想要的表面微结构。本发明对所述表面处理无特殊限制，可以只对第一层聚合物膜进行表面处理，也可以对所有层的聚合物膜进行表面处理，还可以对其中某层或某些层聚合物膜进行表面处理。
得到棒材后，可以对所述棒材进行后处理，去除残余溶剂使多层聚合物膜进一步粘接紧密，去除棒材后即可得到管材。在一个实施例中，所述后处理可以为静置处理，例如在常温下静置20～60min；在一个实施例中，所述后处理可以为液氮冷冻；在一个实施例中，所述后处理可以为对所述棒材施加周向力；在一个实施例中，所述后处理可以为真空干燥。
得到棒材后，也可以不对所述棒材进行后处理，直接将模具去除后，将得到的管材浸泡在溶液中作为人工管状组织待用，例如，将其浸泡在去离子水、TBST溶液(Tris-Hcl缓冲液)、PBS溶液(磷酸盐缓冲液)、生理盐水的任意一种中待用。
本发明提供的方法制备得到的管材利用成膜过程中的残余溶剂实现薄膜的自粘结，无需引入粘结剂进行粘接，避免了得到的管材应力不均、容易崩坏等情况，同时能够实现壁厚的均匀可控，力学性能的均一稳定。另外，本发明提供的方法不需要复杂设备，无需加热，整个过程在室温下即可完成，不会对管状材料中的活性物质产生热影响或热失活。
本发明提供的管状材料可以用作人工管状组织，例如人工血管、人工神经 导管和人工心脏支架等，具有良好的生物相容性和力学性能。
本发明还提供了一种人工管状组织的制备方法，按照上文所述的方法，制备得到管材后，对管材进行进一步修饰即可得到人工管状组织。例如，将制备得到的管材进行修剪、表面修饰等，得到人工血管；将制备得到的管材进行造孔、填充或载药等修饰，得到人工神经导管；将制备得到的管材进行造孔、表面修饰等，得到人工心脏支架等。
本申请通过实施例进一步说明本发明，然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和以下要求保护的本发明范围之内。
以下各实施例中，力学性能按照以下参数测试：
1、所有拉伸应力应变曲线均以5mm/min的速度进行测试直至材料断裂；
2、拉伸循环以5mm/min的速度拉至30％(50％)应变后以2.5mm/min的速度恢复至0％，循环30次；
3、压缩循环以5mm/min的速度压至50％应变后以2.5mm/min的速度恢复至0％，循环30次；
4、所有拉伸以及压缩力学测试均为径向测试。
实施例1
分子量80000的聚氨酯购自山东优索化工科技有限公司，使用N,N-二甲基甲酰胺以50mg/ml浓度配置成溶液，待完全溶解后，通过自动进样器(带有内径为1.0mm的平角针头)在距水面5cm处以10mL/min的速度向水面滴加5滴，溶液会在水面上铺展成膜，随后在2min内使用直径为5mm的聚四氟乙烯棒从薄膜一侧直接绕轴卷曲，此过程可重复，参见图5，图5为本发明实施例1提供的卷曲成膜的卷曲方式示意图，每次卷曲位置相对上一次管材边缘右移3cm，第四次卷曲时相对第三次卷曲边缘左移3cm，即与第二次卷曲位置相同，并按此规律，第六次、第八次、第十次.......均与第二次位置相同并通过测量直至壁厚达到要求，如100μm、200μm、300μm、400μm、500μm和600μm，常温放置0.5小时后将模具抽出，经修剪即得到壁厚均匀的管材。
对所述管材管壁横截面进行表征，结果参见图6，图6为本申请实施例1制备的不同壁厚的管材的光学放大照片，图6(A)是壁厚为100μm管材的 光学放大照片，图6(B)是壁厚为200μm管材的光学放大照片，图6(C)是壁厚为300μm管材的光学放大照片，图6(D)是壁厚为400μm管材的光学放大照片，图6(E)是壁厚为500μm管材的光学放大照片，图6(F)是壁厚为600μm管材的光学放大照片。由图6可知，本申请提供的方法制备得到的管材壁厚较为均匀。
对上述壁厚为100μm、300μm和500μm的管材进行30次应变30％的拉伸循环以及拉伸断裂测试，结果参见图7，图7为本发明实施例1制备的管材的拉伸性能曲线，其中，图7(A)为壁厚为100μm的管材的拉伸曲线，图7(B)为壁厚为300μm的管材的拉伸曲线，图7(C)为壁厚为500μm的管材的拉伸曲线，图7(D)为壁厚为100μm、300μm和500μm的管材的拉伸曲线，其中，曲线11、12和13分别为100μm、300μm和500μm的管材的拉伸曲线。由图7可知，本申请提供的方法制备得到的管材具有良好的拉伸性能。
实施例2
分子量30000的聚氨酯由实验室合成，使用二甲基亚砜以150mg/ml浓度配置成溶液，待完全溶解后，通过自动进样器(同实施例)在距水面3cm处向水面滴加1滴，溶液在水面上铺展成膜，在5min内使用直径5mm的玻璃棒从薄膜一侧卷曲，每次卷曲相对上一次管材边缘右移5cm，如图8所示，图8为本发明实施例2提供的卷曲成膜的卷曲方式示意图，第六次卷曲时回到第一次卷曲位置，并按此规律，并通过测量直至壁厚达到要求后经液氮冷冻后抽出，修剪后得到管材。
对所述管材管壁横截面进行SEM表征，结果参见图9，图9为本申请实施例2制备的管材的SEM照片，由图9可知，本申请提供的方法制备得到的管材壁厚较为均匀。
将所述管材沿轴向分别截取5段，分别计为左1、左2、中、右2、右1，对所述管材进行力学性能测试，结果参见图10，图10为本申请实施例2制备的管材的应力应变曲线，其中，曲线21、22、23、24和25分别为左1、左2、中、右2、右1段的应力应变曲线；由图10可知，本发明提供的制备方法制备得到的管材具有良好的拉伸性能，且管材力学性能较为均一。
实施例3
按照实施例1公开的方法，使用实施例1和实施例2中的聚氨酯构筑双层结构，即首先采用实施例2中的聚氨酯卷曲成管形成内层结构，然后采用实施例1中的聚氨酯在水面上成膜，采用实施例2中的聚氨酯形成的管将实施例1中的聚氨酯形成膜卷曲形成外层，得到双层结构的管材。
对所述管材的管壁横截面进行SEM表征，结果参见图11，图11为本申请实施例3提供的管材的SEM照片，由图11可知，本申请提供的方法获得的管材壁厚较为均匀。
将所述管材沿轴向分别截取5段，分别计为左1、左2、中、右2、右1，对所述管材进行力学性能测试，结果参见图12，图12为本发明实施例3提供的管材的应力应变曲线，其中，曲线31、32、33、34和35分别为左1、左2、中、右2、右1段的应力应变曲线，由图12可知，本申请提供的方法制备的管材具有良好的力学性能，且管材力学性能较为均一。
实施例4
分子量90000的SEBS购自科腾，使用四氢呋喃以75mg/ml浓度配置成溶液，待完全溶解后，在距水面10cm处以5ml/min速度向水面滴加10滴，在水面上成膜后在10s内使用直径3mm的聚四氟乙烯棒从薄膜一侧卷曲，卷曲后对其施加周向力以促进层间粘合，直接抽出并修剪后得到管材。
实施例5
将实施例1与实施例2中的聚氨酯按照质量比2：1的比例用二氧六环以100mg/ml浓度配置成溶液，在距水面5cm处以10ml/min速度滴加3滴，成膜后使用直径5mm聚四氟乙烯卷起，每次卷曲相对上一次管材边缘右移3cm，如图13所示，图13为本发明实施例5提供的卷曲成膜的卷曲方式示意图，第六次卷曲时相对第五次卷曲边缘左移1.5cm并以相对上一次边缘左移3cm的方式继续卷曲四次，随后卷曲位置与第一次相同，并按此规律重复操作至管材壁厚0.5mm，有效长度大于5cm，经液氮冷冻后进行简单修剪并浸泡在PBS溶液中备用，其可以作为人工血管使用。
取5cm所述管材样段，如图14所示，图14为本申请实施例5采用的管材的照片；对所述样段内表面进行SEM表征，结果参见图15，图15为本申 请实施例5制备的管材的内表面SEM照片，其中，图15(A)是放大100倍的SEM照片，图15(B)是方法1000倍的SEM照片，由图15可知，本申请提供的方法制备得到的管材具有多孔的内表面。
对所述管材进行性能测试，包括拉伸循环、压缩循环、顺应性、爆破压以及缝合强度，结果参见图16、图17、图18、图19、图20和图21，图16为本申请实施例5提供的方法制备的管材的应力应变曲线及冠状人体动脉的力学性能范围，图17为本申请实施例5提供的方法制备的管材及人体冠状动脉的顺应性，其中，顺应性用不同压强下的直径D与原始直径D0的比值表示，图18为本申请实施例5提供的方法制备的管材的径向拉伸循环测试结果，图19为本申请实施例5提供的方法制备的管材的径向压缩循环测试结果，图20为本申请实施例5提供的方法制备的管材和胸廓内动脉(IMA)的爆破压对比，图21为本申请实施例5提供的方法制备的管材和胸廓内动脉(IMA)的缝合强度对比，由图16、图17、图18、图19、图20和图21，本申请提供的方法制备的管材的力学性能稳定且与人体冠状动脉相似，可以作为人工血管使用，同时，本申请提供的方法制备得到的管材具有与胸廓内动脉相似的爆破压和更高的缝合强度
对所述管材进行HUVECs(人脐静脉内皮细胞)的培养，在96孔板中以5000个/孔的密度接种细胞，培养12，24，48小时，参见图22、图23和图24，图22为本申请实施例5提供的管材培养细胞的荧光图片，其中，左侧一列图片为对照组，即HUVECs在玻璃片上培养，右侧一列为实验组，即HUVECs在管材内表面培养；图23为本申请实施例5提供的管材培养细胞的时间-密度曲线，图24为本申请实施例5提供的管材培养细胞的时间细胞-覆盖率曲线。由图22、23和24可知，本发明实施例5制备的管材作为人工血管与玻璃相比具有一定促内皮化作用，且具有显著性差异。
实施例6
聚己内酯(分子量80000购自源叶生物)以50mg/ml浓度使用丙酮溶解，并与实施例1中所用聚氨酯溶液以体积比1：2比例混合，充分混合后在距水面5cm处以10ml/min速度滴加3滴，成膜后在1min内使用直径M3，牙距0.5mm的聚四氟乙烯螺栓卷曲，每次卷曲相对上一次管材边缘右移3.5cm，第四次卷 曲时相对第三次卷曲边缘左移3.5cm，即与第二次卷曲位置相同，并按此规律，第六次、第八次、第十次......均与第二次位置相同，真空干燥后旋转取下，得到内部具有螺纹状的管材。
对所述管材内表面进行表征，结果参见图25，图25为本申请实施例6制备的管材的光学放大照片，由图25可知，本申请提供的方法制备得到的管材具有螺纹状内表面。
将所述管材沿轴向分别截取3段，分别计为左、中、右，对所述管材进行力学性能测试，结果参见图26，图26为本申请实施例6制备的管材的应力应变曲线，其中，曲线41、42和43分别为左、中、右段的应力应变曲线；由图26可知，本发明提供的制备方法制备得到的管材具有良好的拉伸性能，且力学性能较为均一。
实施例7
分别准备实施例1与实施例5中的聚氨酯溶液与聚己内酯溶液，首先按照实施例1中操作至管材壁厚60μm，再使用相同的方法在每次成膜后10s内使用PCL溶液将壁厚增至100μm，最后再按照实施例1中操作使管材壁厚达到140μm，直接抽出模具经过裁剪得到管材。
对所述管材管壁横截面进行表征，结果参见图27，图27为本申请实施例7制备的管材的光学放大照片，由图27可知，本申请提供的方法制备得到的管材壁厚较为均匀。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。

Claims (13)

  1. 一种管材的制备方法，其特征在于，包括以下步骤：
    a)将聚合物溶液加入不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；
    b)采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；
    c)去除模具，得到管材。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤c)之前还包括：
    重复步骤a)和步骤b)，得到包括多层聚合物膜的棒材。
  3. 根据权利要求2所述的制备方法，其特征在于，所述包括多层聚合物膜的棒材中，所述多层聚合物膜相同或不同。
  4. 根据权利要求3所述的制备方法，其特征在于，重复步骤b)n次，n/2次或(n+1)/2次或(n-1)/2次重复时，卷曲位置相对于上一次卷曲位置向第一方向移动第一距离，剩余次重复时，卷曲位置相对于上一次卷曲位置向第二方向移动第一距离，所述第一方向和第二方向相反，所述第一距离为1cm～5cm。
  5. 根据权利要求1～4任意一项所述的制备方法，其特征在于，所述步骤
    a)和步骤b)之间还包括：对所述聚合物膜进行表面处理。
  6. 根据权利要求5所述的制备方法，其特征在于，所述表面处理包括：对所述聚合物膜进行激光刻蚀。
  7. 根据权利要求1～4任意一项所述的制备方法，其特征在于，所述模具表面具有微结构。
  8. 根据权利要求1～4任意一项所述的制备方法，其特征在于，所述聚合物包括聚氨酯、聚己内酯、聚乳酸、聚(苯乙烯-乙烯-丁烯-苯乙烯)或聚对苯二甲酸乙二醇酯中的一种或多种；
    所述聚合物溶液中的溶剂包括N,N-二甲基甲酰胺、四氢呋喃、六氟异丙醇、二氧六环或二甲基亚砜中的一种或多种；
    所述不良溶剂为水。
  9. 根据权利要求1～4任意一项所述的制备方法，其特征在于，所述聚合物溶液中还包含活性物质。
  10. 权利要求1～9任意一项所述的制备方法制备得到的管状材料，所述管状材料不包含粘结剂。
  11. 权利要求1～9任意一项所述的制备方法制备得到的管状材料或权利要求10所述的管状材料在制备人工管状组织中的应用。
  12. 根据权利要求11所述的应用，其特征在于，所述人工管状组织包括人工血管、人工神经导管或人工心脏支架。
  13. 一种人工管状组织的制备方法，包括以下步骤：
    将聚合物溶液加入到不良溶剂中，使聚合物在所述不良溶剂液面上扩散成膜，得到聚合物膜，所述聚合物溶液中的溶剂溶于所述不良溶剂；
    采用模具在所述不良溶剂液面上将所述聚合物膜进行卷曲，得到棒材；
    去除模具，得到管材；
    对所述管材进行修饰，得到人工管状组织。
PCT/CN2022/108211 2021-12-06 2022-07-27 一种管状材料、其制备方法及其应用 WO2023103404A1 (zh)

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