CN111388750B - Biological ink, small-caliber tubular structure support and preparation method and application thereof - Google Patents

Biological ink, small-caliber tubular structure support and preparation method and application thereof Download PDF

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CN111388750B
CN111388750B CN202010370760.7A CN202010370760A CN111388750B CN 111388750 B CN111388750 B CN 111388750B CN 202010370760 A CN202010370760 A CN 202010370760A CN 111388750 B CN111388750 B CN 111388750B
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ink
tubular structure
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caliber
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CN111388750A (en
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阮长顺
梁青飞
吴明明
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Shenzhen Institute of Advanced Technology of CAS
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    • A—HUMAN NECESSITIES
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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    • A—HUMAN NECESSITIES
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    • 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
    • A61L27/02—Inorganic materials
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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
    • A61L27/20—Polysaccharides
    • 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
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    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
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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
    • A61L27/50—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
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    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
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    • 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

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Abstract

The embodiment of the application provides biological ink for 3D printing, which comprises N-acryloyl glycinamide, high molecular polymer and nano clay, wherein the high molecular polymer comprises one or more of modified gelatin, double-bond modified alginate, double-bond modified collagen and double-bond modified hyaluronic acid; the mass ratio of the N-acryloyl glycinamide to the high molecular polymer is (0.1-10): 1. The bio-ink has a simple formula, and a composite material network formed by curing the bio-ink has high crosslinking degree, stable structure, strong mechanical property and high biocompatibility activity. The application also provides a small-caliber tubular structure support formed by 3D printing of the biological ink, and a preparation method and application thereof.

Description

Biological ink, small-caliber tubular structure support and preparation method and application thereof
Technical Field
The application relates to the technical field of biomedical materials, in particular to bio-ink, a small-caliber tubular structure support and a preparation method and application thereof.
Background
The 3D printing technology is widely applied to the fields of buildings, spaceflight, automobile industry and the like. With the development of biotechnology, the role played by 3D printing in the biomedical field is also increasingly important. For example, the three-dimensional tubular structure stent constructed by using the 3D coaxial printing technology can be used for simulating tubular tissues such as a human urinary duct, an intestinal duct, an esophagus, a trachea, a bile duct, blood vessels and the like, and has important significance in the medical field. Bio-ink is the main raw material for 3D printing.
At present, the technology for preparing the large-caliber tubular structure stent (phi is more than 6mm) is relatively mature, and can meet the clinical requirement to a certain extent. However, the small-diameter tubular structure stent has the defect of poor mechanical performance, and especially under the action of long-term liquid fluid shear force, the structural stability of the small-diameter tubular structure stent is greatly reduced, so that the application and development of the small-diameter tubular structure stent in regenerative medicine, drug toxicology research and basic research are greatly limited. The traditional agarose template sacrifice method, electrostatic spinning method, stereolithography method, self-assembly method, microfluidic technology and the like have the defects of complex operation, low precision, high difficulty in quick personalized customization and the like, and the prepared tubular structure bracket has the defects of poor mechanical property, poor structural stability, low biocompatibility activity and the like.
Disclosure of Invention
In view of this, embodiments of the present application provide a bio-ink, a small-caliber tubular structural scaffold, and a preparation method and an application thereof, where the bio-ink has a simple formula, and a composite material network formed by curing the bio-ink has a high degree of cross-linking, a stable structure, strong mechanical properties, and high biocompatibility activity.
In a first aspect, the present application provides a bio-ink for 3D printing, comprising N-acryloyl glycinamide (NAGA), a high molecular polymer and nanoclay (Clay), wherein the high molecular polymer comprises one or more of modified gelatin, double bond modified alginate, double bond modified collagen and double bond modified hyaluronic acid; the mass ratio of the N-acryloyl glycinamide to the high molecular polymer is (0.1-10): 1.
The bio-ink is in a hydrogel form. Optionally, the bio-ink consists of N-acryloyl glycinamide, a high molecular weight polymer, nanoclay, and the balance water.
In an embodiment of the application, the side chain of the N-acryloyl glycinamide carries two amide groups. Wherein, the N-acryloyl glycinamide can be prepared by taking glycinamide hydrochloride and acryloyl chloride as raw materials.
Optionally, the modified gelatin is methacrylic anhydride modified gelatin (GelMA). Wherein the gelatin is derived from natural gelatin, e.g., animal gelatin. In one embodiment, the gelatin is derived from porcine skin gelatin.
Optionally, the double bond grafting yield of the modified gelatin is greater than 70%. Optionally, the double bond grafting ratio of the modified gelatin is 70-85%. Optionally, the double bond grafting ratio of the modified gelatin is 81-85%. For example, the double bond grafting ratio of the modified gelatin is 70%, 75%, 78%, 81%, 82%, 83%, 84% or 85%.
Optionally, the modified gelatin has a molecular weight greater than 12-14 kDa. In one embodiment, the modified gelatin has a molecular weight of 15-60 kDa. The double bond grafting rate range and the molecular weight of the modified gelatin are beneficial to the formed biological ink to have higher network crosslinking degree after being cured, and the structure is more stable.
Optionally, the mass ratio of the N-acryloyl glycinamide to the modified gelatin is (1-10): 1. For example, the mass ratio of N-acryloyl glycinamide to modified gelatin is 1:9, 3:7, 1:1, 5:5, 7:3, 9:1 or 10: 1.
In the embodiment of the application, the nano clay is in a nano flake shape, and the transverse size of the nano clay is 20-40 nm; the thickness is 0.5-5 nm. Optionally, the nano clay has a lateral dimension of 25-45 nm; the thickness is 0.5-3 nm.
Optionally, the content of the N-acryloyl glycinamide in the bio-ink by mass is 10% to 30%. In one embodiment, the N-acryloyl glycinamide is present in the bio-ink in an amount of 12% to 26% by weight. In another embodiment, the N-acryloyl glycinamide is present in the bio-ink in an amount of 20% to 26% by weight. For example, the N-acryloyl glycinamide may be present in the bio-ink at 10%, 12%, 15%, 18%, 20%, 25%, 28%, 29% or 30% by weight.
Optionally, the mass percentage of the high molecular polymer in the bio-ink is 1% to 16%. In one embodiment, the content of the high molecular polymer in the bio-ink is 2% to 15% by mass. In another embodiment, the high molecular polymer is 5% to 15% by mass of the bio-ink. In a third embodiment, the high molecular polymer is present in the bio-ink in an amount of 10% to 15% by mass. For example, the high molecular polymer is present in the bio-ink at 1%, 2%, 5%, 8%, 10%, 12%, 13%, 15%, or 16% by mass. In the present application, when the bio-ink is cured and crosslinked, the high molecular polymer can participate in crosslinking; wherein the modified gelatin, double bond modified alginate, double bond modified collagen or double bond modified hyaluronic acid are cross-linked through double bonds in molecules.
Optionally, the mass percentage of the nano clay in the bio-ink is 3-10%. Optionally, the mass percentage of the nano clay in the bio-ink is 4-10%. Or the mass percentage of the nano clay in the biological ink is 5-8%. In a specific embodiment of the present application, the nano clay is 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by mass. This application nanometer clay in the biological ink can promote network cross linking degree and mechanical properties after the biological ink solidification.
Optionally, the bio-ink further comprises a photoinitiator, and the photoinitiator is contained in the bio-ink by 0.1-0.5% by mass. For example, the bio-ink is composed of N-acryloyl glycinamide, a high molecular polymer, nanoclay, a photoinitiator, and the balance of water. Optionally, the photoinitiator is contained in an amount of 0.2 to 0.4% by mass. In a specific embodiment of the present application, the photoinitiator is present in an amount of 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% by mass. The photoinitiator can accelerate crosslinking and curing of the biological ink under the irradiation of light, wherein the photoinitiator in the content range can promote the biological ink to crosslink and cure at a proper speed under the irradiation of light so as to form a composite material with good mechanical properties, and the reduction of the mechanical properties of the composite material and the poor fatigue resistance caused by the excessively high crosslinking and curing speed are avoided. For example, the photoinitiator is photoinitiator 1173 (2-Hydroxy-2-methylprophenone).
The biological ink can be used for 3D printing, and is simple in formula and preparation and suitable for industrial production. The composite material network formed by curing the biological ink has high degree of crosslinking, stable structure, strong mechanical property and high biocompatibility activity.
In a second aspect, the present application provides a small-caliber tubular structural scaffold prepared by 3D printing the bio-ink of the first aspect of the present application. Based on different 3D printing processes, this application the specific shape of small-bore tubular structure support can be adjusted.
Optionally, the small-bore tubular structure stent comprises at least one hollow tubular structure, and the tube wall of the hollow tubular structure comprises a single layer or multiple layers of composite material layers formed by curing the bio-ink. In one embodiment, the small-bore tubular structural stent is a hollow tubular structure.
In the embodiment of the present application, the wall of the small-caliber tubular structural scaffold may include, but is not limited to, a single layer, a double layer, a triple layer, or more than three layers of composite material. The composite layers may be the same or different for each layer. The different composite material layers are formed by crosslinking and curing biological ink with different content ratios. In one embodiment, the tube wall of the hollow tubular structure comprises an inner layer, an intermediate layer and an outer layer of composite material which are sequentially stacked from inside to outside.
In the embodiment of the application, the inner diameter of the small-caliber tubular structure support is 0.1-2.8mm, and the outer diameter of the small-caliber tubular structure support is 0.5-6.0 mm.
Optionally, the inner diameter of the small-caliber tubular structure support is 0.1-2.0mm, and the outer diameter of the small-caliber tubular structure support is 0.5-3.0 mm. The small-caliber tubular structure support has small inner diameter and outer diameter and good mechanical property.
In the embodiment of the application, the tensile breaking strength of the small-caliber tubular structure support is 10-30 MPa; the stretching ratio of the small-caliber tubular structure support is 40-500%. Optionally, the tensile break strength of the small-caliber tubular structural scaffold is 15-25 MPa. For example, the small-caliber tubular structural scaffold has a tensile break strength of 10MPa, 15MPa, 18MPa, 20MPa, 25MPa, or 30 MPa. Optionally, the stretch ratio of the small-caliber tubular structure stent is 100-500%. Or the stretching ratio of the small-caliber tubular structure bracket is 200-500%. For example, the small-caliber tubular structural scaffold has a stretch of 40%, 80%, 100%, 200%, 250%, 300%, or 400%, or 500%. The small-caliber tubular structure support has the advantages of outstanding mechanical property, good tensile rate and tensile breaking strength and strong tensile resistance.
In an embodiment of the present application, the suture holding strength of the small-caliber tubular-structure stent is 80-300 grams-force (GF). Optionally, the suture retaining strength of the small-caliber tubular structure stent is 100-300 gram force. The suture line of the small-caliber tubular structure support is high in holding strength, strong in mechanical property and applicable to suture lines.
In the embodiment of the application, the fatigue resistance of the small-caliber tubular structure support is outstanding. The small-caliber tubular structure support can bear more than 500 times of cyclic stress tests. The small-caliber tubular structure support has good anti-explosion performance.
The small-caliber tubular structural stent of the second aspect of the application has good mechanical strength and high suture line holding strength under the condition of maintaining the small-diameter (inner and outer diameter) dimension, has outstanding tensile property and outstanding fatigue resistance. The small-caliber tubular structure scaffold also has good biocompatibility activity, so the small-caliber tubular structure scaffold can be widely applied to the field of tissue engineering including artificial blood vessels and the like.
In a third aspect, the present application further provides a method for preparing a small-caliber tubular structural scaffold, comprising the following steps:
preparing a high molecular polymer aqueous solution, adding N-acryloyl glycinamide and nano clay, and uniformly mixing to obtain a mixture, wherein the high molecular polymer comprises one or more of modified gelatin, double-bond modified alginate, double-bond modified collagen and double-bond modified hyaluronic acid, and the mass ratio of the N-acryloyl glycinamide to the high molecular polymer is (0.1-10): 1;
adding a photoinitiator into the mixture, stirring uniformly in a dark place to obtain biological ink, filling the biological ink into a printing material cylinder, printing according to a preset size by adopting a 3D coaxial printing process, and then irradiating, crosslinking and curing to obtain the small-caliber tubular structure support.
The 3D coaxial printing process is that one or more materials flow out of different pipelines simultaneously to form a tubular spray head with a coaxial structure for solidification so as to form a tubular structure support. In this application, in an embodiment, carry out 3D through 3D coaxial printer and print, establish small-bore tubular structure support.
Optionally, the content of the N-acryloyl glycinamide in the bio-ink is 10% to 30% by mass. In one embodiment, the N-acryloyl glycinamide is present in the bio-ink in an amount of 12% to 26% by weight. In another embodiment, the N-acryloyl glycinamide is present in the bio-ink in an amount of 20% to 26% by weight. For example, the N-acryloyl glycinamide may be present in the bio-ink at 10%, 12%, 15%, 18%, 20%, 25%, 28%, 29% or 30% by weight.
Optionally, the mass percentage of the high molecular polymer in the bio-ink is 1% to 16%. In one embodiment, the content of the high molecular polymer in the bio-ink is 2% to 15% by mass. In another embodiment, the high molecular polymer is 5% to 15% by mass of the bio-ink. In a third embodiment, the high molecular polymer is present in the bio-ink in an amount of 10% to 15% by mass. For example, the high molecular polymer is present in the bio-ink in an amount of 1%, 2%, 5%, 8%, 10%, 12%, 13%, 15%, or 16% by mass.
In an embodiment of the present application, the modified gelatin is methacrylic anhydride modified gelatin. Optionally, the double bond grafting yield of the modified gelatin is greater than 70%. Optionally, the double bond grafting ratio of the modified gelatin is 70-85%. Optionally, the double bond grafting ratio of the modified gelatin is 81-85%. The application uses the modified gelatin with high double bond grafting rate, and can greatly improve the mechanical property of the prepared small-caliber tubular structure support.
Optionally, the mass percentage of the nano clay in the bio-ink is 3-10%. Optionally, the content of the nano clay in the bio-ink by mass percentage is 4-10%. Or the mass percentage of the nano clay in the biological ink is 5-8%. In a specific embodiment of the present application, the nano clay is 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% by mass. According to the nano clay, in the crosslinking process of N-acryloyl glycinamide and high molecular polymer, positive and negative charges are distributed on the surface of the nano clay, and the N-acryloyl glycinamide and the high molecular polymer are crosslinked in a physical mode and a chemical mode, so that the mechanical performance of the final small-caliber tubular structure support is greatly improved, the structure is more stable, and the service life of the small-caliber tubular structure support is prolonged.
In the embodiment of the application, the diameter (outer diameter and inner diameter) of the small-caliber tubular structure support can be flexibly regulated and controlled in the preparation process. For example. The expected size is obtained by regulating the printing extrusion pressure and the moving speed of the printed lines. Wherein the biological ink has different solid contents or different viscosities, which have an influence on the biological ink; when the viscosity of the biological ink is higher, the pressure required by printing is higher; when the viscosity is small, the printing pressure is also reduced. The moving speed of the printed lines is inversely proportional to the size of the diameter (outer diameter and inner diameter), for example, the larger the moving speed is, the thinner the lines are; and vice versa.
Optionally, the inner diameter of the semi-finished product of the small-caliber tubular structure support is 0.1-2.8mm, and the outer diameter of the small-caliber tubular structure support is 0.5-6 mm.
Optionally, in the 3D coaxial printing process, the small-bore tubular structure support is extruded from the 3D printing apparatus using an extrusion pressure of 80-200 kPa. In one embodiment, the small-bore tubular structure stent is extruded from the 3D printing device using an extrusion pressure of 80-150 kPa.
Optionally, in the light irradiation crosslinking process, ultraviolet light irradiation is used, the central wavelength of the ultraviolet light is 360-370nm, and the crosslinking time is 0.25-60 min. For example, ultraviolet crosslinking using a UV crosslinker device. The crosslinking time can also be 1-20 min. The crosslinking time was adjusted based on different intensities of uv light.
In the embodiment of the application, the obtained small-caliber tubular structure support is placed in a buffer solution for soaking, and after the small-caliber tubular structure support is swelled and balanced, the small-caliber tubular structure support is subjected to performance test. Alternatively, the buffer may be, but is not limited to, PBS buffer. In this application, the small-bore tubular structure support after the swelling is balanced can make the capability test data more reliable.
The preparation method of the third aspect of the present application can prepare the high-strength small-caliber tubular structure stent having size controllability and mechanical adjustability in one step; the preparation method is simple, low in cost and suitable for industrial production.
In a fourth aspect, the present application also provides a small-caliber tubular structural scaffold according to the second aspect of the present application or prepared by the preparation method of the third aspect of the present application for use in artificial tissues, drug screening and pathology models.
The small-caliber tubular structure has controllable size, has outstanding mechanical performance and good biocompatibility, can be used for simulating tubular tissues such as a human urinary catheter, an intestinal canal, an esophagus, a trachea, a bile duct, a blood vessel and the like, and has wide application prospect in artificial tissue, drug screening and pathological model research.
Since the small-caliber tubular structure can be made smaller in size while still maintaining outstanding mechanical properties, the small-caliber tubular structure has outstanding mechanical properties, and is widely used in the biomedical field or tissue engineering field. For example, the small-caliber tubular structure can be used for solving the problems of lack of source and immunological rejection of human tissue organ transplantation donors.
Advantages of the present application will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the embodiments of the present application.
Drawings
In order to more clearly explain the content of the present application, the following detailed description is given in conjunction with the accompanying drawings and specific embodiments.
FIG. 1 is a hydrogen spectrum of a NAGA monomer provided in an embodiment of the present application;
FIG. 2 shows a hydrogen spectrum of gelatin and GelMA provided in an embodiment of the present application;
fig. 3 is an infrared spectrum of CNG bio-ink provided in an embodiment of the present application;
fig. 4 is a schematic view of 3D printing preparation of a small-caliber tubular structure stent provided in an embodiment of the present application;
FIG. 5 is a drawing of a practical sample of small-caliber tubular structural supports of different diameters provided in accordance with an embodiment of the present application;
FIG. 6 is a scanning electron microscope image of a small-caliber tubular structural support provided in accordance with an embodiment of the present application;
FIG. 7 is a graph illustrating tensile properties of a small-caliber tubular structural scaffold provided in accordance with an embodiment of the present application;
FIG. 8 is a graph of burst pressure and fracture stitch tests for a small diameter tubular structural stent provided in accordance with an embodiment of the present application;
fig. 9 is a fatigue resistance test chart of the small-caliber tubular structure stent provided in an embodiment of the present application.
Detailed Description
While the following is a preferred embodiment of the embodiments of the present application, it should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the embodiments of the present application, and such improvements and modifications are also considered to be within the scope of the embodiments of the present application.
The terms "comprising" and "having," and any variations thereof, as appearing in the specification, claims and drawings of this application, are intended to cover non-exclusive inclusions. For example, a process, method, system, article, or apparatus that comprises a list of steps or elements is not limited to only those steps or elements but may alternatively include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
Unless otherwise specified, the raw materials and other chemicals used in the examples of the present application are commercially available.
An embodiment of the application provides a method for preparing a small-caliber tubular structure support.
(1) Preparation of N-acryloyl glycinamide (NAGA)
Prepared from glycinamide hydrochloride and acryloyl chloride by nuclear magnetic resonance 1 H NMR (NMR, 500MHz, Varian INOVA) demonstrated its successful synthesis, see FIG. 1, where a, b and c in the structural formula are each hydrogen on a carbon atom, with the following characteristic peaks: 1 H NMR(D 2 O)：δ＝4.1(H c ，-NH-CH 2 -)，5.6(H a ，CH 2 CH-), 6.0 and 6.1 (H-) b ，CH 2 ＝CH-)ppm。
(2) Preparation of modified gelatin (GelMA)
Gelatin and methacrylic anhydride from pig skin are used as raw materials.
First, pigskin gelatin was mixed into PBS buffer at a ratio of 10% (w/v), and stirred in a water bath at 50 ℃ until its components were completely dissolved. Subsequently, 8mL (v/v) of methacrylic anhydride was added dropwise to the gelatin solution and reacted at 50 ℃ for 3 hours to form a GelMA solution. Then diluting the solution and dialyzing with distilled water at 40 deg.C for one week in a dialysis bag with molecular weight of 12-14kDa to remove small molecular weight products and reactants; the modified gelatin solution obtained after dialysis was lyophilized for 4 days to give a white porous foamed product, which was then stored at-80 ℃ until use.
Referring to fig. 2, fig. 2 shows nmr hydrogen spectra of gelatin and modified gelatin (GelMA). The two spectrograms are compared to find that the spectrogram of GelMA is&(ii) 5.65 and&two distinct peaks are found at the position of 5.33, namely the proton peak of the double bond of methacrylamide on lysine group and hydroxyl lysine group, which indicates that the double bond has been successfully connected to the gelatin molecular chain, i.e. GelMA is successfully synthesized. In addition, by 1 H NMR (NMR, 500MHz, Varian INOVA) determined the GelMA double bond grafting. Gelatin and modified gelatin were dissolved in D at a concentration of 10mg/mL 2 In O, the result showed that the double bond graft ratio in the modified gelatin was about 81%.
(3) Synthesis of bio-ink
Firstly, dissolving GelMA in deionized water at a certain concentration, fully dissolving in a water bath at 50-60 ℃, then fully and uniformly mixing NAGA monomers and Clay particles with GelMA solution at a certain concentration according to a certain proportion to form a NAGA/Clay/GelMA hydrogel system (CNG for short), then adding a proper amount of photoinitiator into the CNG, and stirring in the dark until the initiator is fully dissolved to obtain the CNG biological ink. Wherein, the mass ratio of NAGA to GelMA can be 1:9, 3:7, 5:5, 7:3, 9: 1. The mass contents of the NAGA, the GelMA, the Clay and the photoinitiator in the CNG biological ink can be respectively 10% -30%, 1% -16%, 3% -10% and 0.1% -0.5%.
Injecting part of prepared CNG bio-ink into a sealed mold clamping plate, placing the mold clamping plate into an ultraviolet crosslinking instrument, and crosslinking for a specific time (0-60min) under a specific ultraviolet intensity (central wavelength of 365 nm). And after full crosslinking, taking out the gel, soaking the gel in PBS overnight to reach swelling balance, thus obtaining the CNG high-strength hydrogel, and then carrying out infrared detection. Referring to fig. 3, fig. 3 is an infrared spectrum of CNG bio-ink. In the figure, NAGA hydrogels also showed 3365, 3194 and 3084cm -1 NH stretching vibration peak at 4546cm -1 NH deformation vibration peak and 1662cm -1 C ═ O stretching vibration peak (a) at (b). Meanwhile, the characteristic peak of GelMA shows the characteristic peak (B) of the gelatin main chain. At 3165cm -1 And 3073cm -1 The strong absorption peak at (A) is due to stretching vibration (amide A) of NH band at 1662cm -1 The characteristic peak at (a) is attributed to the stretching vibration of C ═ O (amide I). At 1540cm -1 The characteristic band of (A) is due to tensile vibration of NH band (amide II) at 1250cm -1 The characteristic peak at (a) is due to CN stretching vibration of the amino acid side chain (amide III). Meanwhile, in the spectrum of the Clay/NAGA/GelMA hydrogel, there are also characteristic peaks of nanoclay (Clay) in addition to the characteristic peaks of NAGA and GelMA. Wherein the peak of Si-O stretching vibration and bending vibration appears at 1006cm -1 And 660cm -1 To (3). This result indicates that the NAGA/GelMA/Clay hybrid hydrogel was successfully crosslinked.
(4) Preparation of small-caliber tubular structure support
Referring to fig. 4, the prepared CNG bio-ink is filled in a material cylinder, a semi-finished product of the small-caliber tubular structure support with controllable size is extruded under the pressure of 80-200kpa through a 3D printing device (such as a 3D coaxial printer), and finally the small-caliber tubular structure support is placed in an ultraviolet cross-linking instrument and cross-linked for a specific time (0.25-60min) under a specific ultraviolet intensity (with a central wavelength of 365nm) and fully cross-linked to obtain the small-caliber tubular structure support. The nano clay particles can play physical interpenetration and thickening effects, and the mechanical stability and the biological activity of the small-caliber tubular structure support are improved through a physical interpenetration mode and a chemical crosslinking mode.
The following examples are intended to illustrate the invention in more detail.
Example 1: a preparation method of a small-caliber tubular structure support comprises the following steps:
dissolving 40mg of GelMA in 1mL of deionized water, and fully dissolving in a water bath at 50-60 ℃;
then fully and uniformly mixing 100mg of clay, 360mg of NAGA monomer and GelMA mixed solution; adding about 3-6 μ L of ultraviolet initiator 1713, stirring in dark until the initiator is completely dissolved; obtaining Clay/NAGA/GelMA mixed hydrogel bio-ink, which is called CNG-01 for short (wherein, the mass of Clay is 100mg, and the mass ratio of NAGA to GelMA is 9: 1).
Filling CNG-01 mixed hydrogel bio-ink into a printing material cylinder, extruding a hollow tubular structure with controllable size (the outer diameter OD is 0.5mm-3mm, the inner diameter ID is 0.1-2.8mm) by a 3D coaxial printer under the pressure of 80-100kPa, finally putting the hollow tubular structure into an ultraviolet cross-linking instrument, and cross-linking for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Example 2: a preparation method of a small-caliber tubular structure support comprises the following steps:
dissolving 120mg of GelMA in 1mL of deionized water, and fully dissolving in a water bath at 50-60 ℃;
then fully and uniformly mixing 100mg of clay, 280mg of NAGA monomer and GelMA solution; adding about 3-6 μ L of ultraviolet initiator 1713, stirring in dark until the initiator is completely dissolved; obtaining Clay/NAGA/GelMA mixed hydrogel bio-ink, which is called CNG-02 for short (wherein, the mass of Clay is 100mg, and the mass ratio of NAGA to GelMA is 7: 3).
Filling the CNG-02 mixed hydrogel bio-ink into a printing material cylinder, extruding a size-controllable hollow tubular structure (the outer diameter OD is 0.5mm-3mm, and the inner diameter ID is 0.1-2.8mm) by a 3D coaxial printer under the pressure of 100-120kPa, and finally placing the hollow tubular structure into an ultraviolet crosslinking instrument to crosslink for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Example 3: a preparation method of a small-caliber tubular structure support comprises the following steps:
dissolving 200mg of GelMA in 1mL of deionized water, and fully dissolving in a water bath at 50-60 ℃;
then fully and uniformly mixing 100mg of clay, 200mg of NAGA monomer and GelMA solution; adding about 3-6 μ L of ultraviolet initiator 1713, stirring in dark until the initiator is completely dissolved; obtaining Clay/NAGA/GelMA mixed hydrogel biological ink, which is called CNG-03 for short (wherein, the mass of Clay is 100mg, and the mass ratio of NAGA to GelMA is 5: 5).
Filling the CNG-03 mixed hydrogel bio-ink into a printing material cylinder, extruding a size-controllable hollow tubular structure (with the outer diameter OD of 0.5-3 mm and the inner diameter ID of 0.1-2.8mm) by a 3D coaxial printer under the pressure of 100-130kPa, and finally putting the hollow tubular structure into an ultraviolet crosslinking instrument to crosslink for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Example 4: a preparation method of a small-caliber tubular structure support comprises the following steps:
200mg of double bond-modified hyaluronic acid (Hyaluronan, abbreviated as HA) was dissolved in 1mL of deionized water sufficiently;
then fully and uniformly mixing 100mg of clay and 200mg of NAGA monomer with the double-bond modified hyaluronic acid solution; adding about 3-6 μ L of ultraviolet initiator 1713, stirring in dark until the initiator is completely dissolved; obtaining the mixed hydrogel bio-ink of Clay/NAGA/double bond modified HA, which is called CNH-01 for short (wherein, the mass of Clay is 100mg, and the mass ratio of NAGA to double bond modified HA is 5: 5).
And (2) filling the CNH-01 mixed hydrogel bio-ink into a printing material cylinder, extruding a hollow tubular structure with a controllable size (the outer diameter OD is 0.5-6mm, and the inner diameter ID is 0.1-2.8mm) by using a 3D coaxial printer, and finally placing the hollow tubular structure into an ultraviolet crosslinking instrument to crosslink for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Example 5: a preparation method of a small-caliber tubular structure support comprises the following steps:
dissolving 200mg of double-bond modified collagen in 1mL of deionized water for full dissolution;
then fully and uniformly mixing 100mg of clay and 200mg of NAGA monomer with the double-bond modified collagen solution; adding about 3-6 μ L of ultraviolet initiator 1713, stirring in dark until the initiator is completely dissolved; obtaining the mixed hydrogel bio-ink of Clay/NAGA/double bond modified collagen, wherein the mass of Clay is 100mg, and the mass ratio of NAGA to double bond modified collagen is 5: 5).
And (2) filling the mixed hydrogel biological ink into a printing material barrel, extruding a hollow tubular structure with controllable size (the outer diameter OD is 0.5mm-6mm, and the inner diameter ID is 0.1-2.8mm) by a 3D coaxial printer, finally putting the hollow tubular structure into an ultraviolet crosslinking instrument, and crosslinking for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Example 6: a preparation method of a small-caliber tubular structure support comprises the following steps:
dissolving 200mg of double-bond modified sodium alginate in 1mL of deionized water for full dissolution;
then fully and uniformly mixing 100mg of clay and 200mg of NAGA monomer with the double-bond modified sodium alginate solution; adding about 3-6 mu L of ultraviolet initiator 1713, and stirring in dark until the initiator is completely dissolved; obtaining the Clay/NAGA/double-bond modified sodium alginate mixed hydrogel bio-ink, wherein the mass of the Clay is 100mg, and the mass ratio of the NAGA to the double-bond modified sodium alginate is 5: 5).
And (2) filling the mixed hydrogel biological ink into a printing material barrel, extruding a hollow tubular structure with controllable size (the outer diameter OD is 0.5mm-6mm, and the inner diameter ID is 0.1-2.8mm) by a 3D coaxial printer, finally putting the hollow tubular structure into an ultraviolet crosslinking instrument, and crosslinking for 40min under the specific ultraviolet intensity with the central wavelength of 365nm to obtain a small-caliber tubular structure support sample.
Effect embodiment:
(1) preparation of small-caliber tubular structure supports with different diameters
Based on the preparation method described in the embodiment of the present application, samples of small-caliber tubular structural stents with different diameters are prepared, and referring to fig. 5 a to 5F, the outer diameters D of the small-caliber tubular structural stents in a to F are respectively: 3mm, 2.8mm, 2.0mm, 1.5mm, 1.2mm and 0.8 mm. A small-caliber tubular structure stent sample is randomly extracted to carry out scanning electron microscope test, and the result is shown in fig. 6.
From the data of the samples of the small-caliber tubular-structure stent with different diameters presented in the figure, the preparation method can be used for preparing the small-caliber tubular-structure stent with different diameters (the outer diameter OD is 0.5mm-3mm, and the inner diameter ID is 0.1-2.8mm), and the prepared small-caliber tubular-structure stent is stable in structure.
(2) Performance measurement of small-caliber tubular structure support
The small-caliber tubular structure support prepared in the above embodiments 1 to 3 was used to test the mechanical properties of the small-caliber tubular structure support of each embodiment by the following method:
(a) tensile property: the stretching was carried out on an electronic universal tester with a sample diameter of 3mm (outer/inner diameter of about 3mm/2.4mm) and a stretching rate of 50mm/min, as shown in FIG. 7, for CNG-01 (group a), CNG-02 (group b), CNG-03 (group c), biological esophageal duct (group d) and aortic duct (group e), respectively.
The results show that the small-caliber tubular structure support CNG-01 prepared in example 1 has tensile breaking strength (22 MPa) and tensile rate (500%) at an outer diameter/inner diameter of about 3mm/2.4 mm; the small-caliber tubular structure support CNG-02 prepared in the embodiment 2 has tensile breaking strength (10 MPa) and tensile rate (60%); the small-caliber tubular structural scaffold CNG-03 prepared in example 3 has tensile break strength (8 MPa) and tensile elongation (43%). As can be seen from the data of the performance test results, the small-caliber tubular structure scaffold prepared in the examples of the application has a tensile rate of 43-500% and excellent mechanical properties. The Young's modulus of each example is tested at the same time, and the results also show that the Young's modulus of examples 1-3 can reach 35MPa, 24MP and 21MPa respectively.
(b) Burst pressure and fracture stitch testing: burst pressure tests were carried out according to the national standard AS ISO 7198-2003. The tubular structure support anti-explosion performance is detected through a self-made anti-explosion pressure device platform. A test specimen having a total length of 4cm and a diameter of 3mm (outer diameter/inner diameter of about 3mm/2.4mm) was produced using 6-0 filamentsThe hollow tube was secured to the device with a wire at 50mmHg s -1 Until the microtubes rupture. The burst pressure (mmHg) at which the tubular scaffold burst was recorded. The fracture suture test was performed according to ASISO 7198-. The total length of the small-caliber tubular structure support sample is about 3 cm. Fixing one end of a tubular structure support on a bench clamp of a uniaxial tensile testing machine, penetrating a pipe wall of a pipe at a position 3mm away from the edge by using a 6-0 polypropylene suture needle, and pulling a suture line at a constant speed of 50mm/min until a sample is completely torn; the maximum force was recorded as suture retention strength. The small-bore tubular scaffolds of each outer/inner diameter prepared in example 1 and example 2 were tested and the set of samples were soaked overnight in PBS at 37 ℃ before testing, the results are shown in figure 8.
In FIG. 8A, groups 4-6 are small-caliber tubular stent samples with NAGA/GelMA mass ratio of 7:3 in example 2, respectively, and outer/inner diameters are: 2.2mm/0.3mm, 2.8mm/0.1mm, 3mm/0.5 mm. Groups 7-10 are small bore tubular scaffold samples of example 1 with a 9:1 NAGA/GelMA mass ratio, respectively, with outer/inner diameters: 2.2mm/0.3mm, 2.8mm/0.1mm, 3mm/0.3 mm. In FIG. 8, B, groups 2-4 are small-caliber tubular-structure stent samples with NAGA/GelMA mass ratio of 7:3 in example 2, respectively, and outer/inner diameters are: 2.2mm/0.3mm, 2.8mm/0.1mm, 3mm/0.5 mm; groups 5-8 are small bore tubular scaffold samples of example 1 with a 9:1 NAGA/GelMA mass ratio, respectively, with outer/inner diameters: 2.2mm/0.3mm, 2.8mm/0.1mm, 3mm/0.3 mm.
As can be seen from the data of fig. 8, the burst pressure of the small-caliber tubular stent sample of example 1 of the present application can be about 1900mmHg, and the suture thread holding strength can be 280 gf. The burst pressure of the small-caliber tubular stent sample of example 2 may be about 2500mmHg, and the suture holding strength may be 85 gf. The sample of the small-caliber tubular-structure support prepared by the embodiment of the application has excellent anti-explosion performance, the suture line has high holding strength, and the explosion pressure can be comparable to or even superior to the parameters of the existing main artery tube, esophagus tube and trachea; the suture retaining strength can reach 280gf, and the structure stability and the mechanical property are excellent.
(c) Fatigue resistance test referring to fig. 9, a graph of the fatigue resistance test data of the small-caliber tubular structural scaffold of example 1, wherein the outer diameter/inner diameter is about 3mm/2.4mm, the small-caliber tubular structural scaffold can withstand more than 500 cyclic stress tests.
It should be noted that, according to the disclosure and the explanation of the above description, the person skilled in the art to which the present application belongs may make variations and modifications to the above embodiments. Therefore, the present application is not limited to the specific embodiments disclosed and described above, and some equivalent modifications and variations of the present application should be covered by the protection scope of the claims of the present application. In addition, although specific terms are used herein, they are used in a descriptive sense only and not for purposes of limitation.

Claims (9)

1. A biological ink for 3D printing of a small-caliber tubular structure support is characterized by comprising N-acryloyl glycinamide, methacrylic anhydride modified gelatin and nano clay; the transverse size of the nano clay is 20-40 nm; the thickness is 0.5-5 nm; the double bond grafting rate of the methacrylic anhydride modified gelatin is more than 70 percent; the mass ratio of the N-acryloyl glycinamide to the methacrylic anhydride modified gelatin is (0.1-10): 1.
2. The bio-ink of claim 1, wherein the N-acryloyl glycinamide is present in the bio-ink in an amount of 10% to 30% by weight.
3. The bio-ink as claimed in claim 1, wherein the bio-ink further comprises a photoinitiator, and the photoinitiator is present in the bio-ink in an amount of 0.1% to 0.5% by weight.
4. The bio-ink according to claim 1, wherein the nano-clay is in a nano-flake shape, and a mass percentage of the nano-clay in the bio-ink is 3% to 10%.
5. A small-caliber tubular structural scaffold, wherein the small-caliber tubular structural scaffold is prepared by 3D printing the bio-ink according to any one of claims 1 to 4; the suture line holding strength of the small-caliber tubular structure support is 80-300 gram force.
6. The small-caliber tubular structural scaffold of claim 5, wherein the small-caliber tubular structural scaffold comprises at least one hollow tubular structure, the wall of the hollow tubular structure comprising a single layer or multiple layers of composite material cured from the bio-ink; the inner diameter of the small-caliber tubular structure support is 0.1-2.8mm, and the outer diameter of the small-caliber tubular structure support is 0.5-6.0 mm.
7. The small-bore tubular structural scaffold of any one of claims 5-6, wherein said small-bore tubular structural scaffold has a tensile break strength of 10-30 MPa; the stretching ratio of the small-caliber tubular structure support is 40-500%.
8. A preparation method of a small-caliber tubular structure support is characterized by comprising the following steps:
preparing a high molecular polymer aqueous solution, adding N-acryloyl glycinamide and nano clay, and uniformly mixing to obtain a mixture, wherein the high molecular polymer comprises methacrylic anhydride modified gelatin; the transverse size of the nano clay is 20-40 nm; the thickness is 0.5-5 nm; the mass ratio of the N-acryloyl glycinamide to the methacrylic anhydride modified gelatin is (0.1-10) to 1;
adding a photoinitiator into the mixture, stirring uniformly in a dark place to obtain biological ink, filling the biological ink into a printing material cylinder, printing according to a preset size by adopting a 3D coaxial printing process, and then irradiating, crosslinking and curing by light to obtain the small-caliber tubular structure support; the suture line holding strength of the small-caliber tubular structure support is 80-300 gram force.
9. Use of the small-caliber tubular-structure scaffold of any one of claims 5 to 7 or the small-caliber tubular-structure scaffold produced by the process of claim 8 for producing a material for artificial tissues, a material for drug screening and a material for pathological models.
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