WO2018090190A1 - 用于三维打印的粘土基水凝胶基质及其制备方法和应用 - Google Patents

用于三维打印的粘土基水凝胶基质及其制备方法和应用 Download PDF

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WO2018090190A1
WO2018090190A1 PCT/CN2016/105922 CN2016105922W WO2018090190A1 WO 2018090190 A1 WO2018090190 A1 WO 2018090190A1 CN 2016105922 W CN2016105922 W CN 2016105922W WO 2018090190 A1 WO2018090190 A1 WO 2018090190A1
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clay
hydrogel matrix
based hydrogel
crosslinking agent
dimensional gel
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French (fr)
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阮长顺
翟欣昀
马宇飞
潘浩波
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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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
    • A61L27/52—Hydrogels or hydrocolloids

Definitions

  • the invention relates to the technical field of biological materials, in particular to a clay-based hydrogel matrix for three-dimensional printing, a preparation method and application thereof.
  • a hydrogel is a polymer having a three-dimensional network structure which is crosslinked by covalent bonds, hydrogen bonds or van der Waals forces, which can swell in water and retain a large amount of water without being dissolved. Due to natural or synthetic Polymer hydrogels are similar in structure and performance to biological tissues. Therefore, hydrogels have been the field of biomedical engineering for the past 20 years, especially in the field of tissue engineering for the diagnosis, treatment, repair or replacement of human tissues and organs. A research hotspot for function and growth factors, drugs and gene vectors.
  • Thermal polymerization and ultraviolet polymerization are the most common polymerization methods in hydrogel preparation.
  • the thermal polymerization after the thermal initiator is added to the gel system, the polymerization time is uncontrollable, and the pressure required for printing needs to be adjusted at any time, or the polymerization may be too fast, which may cause problems in the later stage of printing.
  • the curing of the three-dimensional scaffold by ultraviolet light does not have the above problem, and it can be cured while printing the gel slurry, but the method has higher requirements on the gel slurry and needs to be in a shorter time. UV cross-linking occurs inside the gel, otherwise the structure of the printed gel scaffold cannot be well maintained, thus greatly reducing the material selectivity.
  • the present invention provides a clay-based hydrogel that can be used for ultraviolet curing in three-dimensional printing.
  • a gum base comprising a specific proportion of inorganic clay, a biocompatible macromolecule with a carbon-carbon double bond, an ultraviolet photoinitiator and water, the formulation being simple and the composition being safe, the clay-based water
  • the gel matrix has a certain pre-shape before being cross-linked by ultraviolet light, and can be printed first, then solidified into a glue, and the three-dimensional gel support is printed in batches, which greatly improves the three-dimensional printing efficiency.
  • the present invention provides a clay-based hydrogel matrix for three-dimensional printing comprising a mass percent of a raw material component as follows:
  • Crosslinking agent 10-50%
  • Inorganic clay 3-20%;
  • Ultraviolet light initiator 0.05-0.1%
  • the total mass percentage of each of the above raw material components is 100%; wherein the crosslinking agent is a biocompatible macromolecule with a carbon-carbon double bond, and the biocompatible macromolecule is polyethylene glycol, polyethylene One or more of alcohol, chitosan, gelatin, hyaluronic acid.
  • the clay-based hydrogel matrix obtained by the present invention has a suitable printing viscosity and strength by synergistic action of various raw materials of the above specific mass ratio, and has a certain pre-shape before ultraviolet light crosslinking.
  • the clay-based hydrogel matrix can be printed as a stable three-dimensional gel scaffold precursor with good mechanical strength and tensile properties at room temperature, which facilitates uniform UV curing of the stent precursor in the later stage, and obtains a three-dimensional gel scaffold. .
  • the clay-based hydrogel matrix is suitable for batch printing to obtain a three-dimensional printing gel scaffold, which greatly improves the three-dimensional printing efficiency, and is very suitable for industrial production.
  • the cross-linking of the carbon-carbon double bonds of the cross-linking agent forms a long-chain polymer intercalated in an ordered piece of inorganic clay.
  • a hydrogel of a three-dimensional network structure is formed, so that the shape of the gel is maintained, and the inorganic clay acts as a substance.
  • the role of cross-linking, its hydrogen bonding with biocompatible macromolecules with carbon-carbon double bonds, van der Waals force, etc. also further enhance the strength of the printed three-dimensional gel scaffold, and fully exert physical cross-linking Synergistic effect with chemical crosslinking. Improve the stability of the gel scaffold.
  • the inorganic clay may be selected from the group consisting of kaolin, bentonite, montmorillonite, laponite (lithosite), hectorite, beidellite, saponite, stevensite, magnesium aluminum silicate, Other aluminum silicates and various other natural and/or synthetic clays, and combinations thereof.
  • the inorganic clay has a particle size of not more than 500 nm. More preferably, it is 50-200 nm.
  • the inorganic clay is a laponite clay.
  • the laponite clay can be quickly peeled off and dispersed into a single layer in water to form a colorless transparent colloidal dispersion with good stability.
  • the clay can be purchased from Rockwood's Laponite XLG.
  • Laponite XLG is a synthetic layered clay similar to natural montmorillonite.
  • the addition of inorganic clay can effectively increase the strength of the hydrogel stent, and the inorganic clay acts as a physical crosslinking agent.
  • controlling the content of the inorganic clay can control the viscosity of the clay-based hydrogel matrix, so that the clay-based hydrogel matrix has a certain pre-shape, and can be post-printed and post-cured.
  • the clay-based hydrogel matrix has a viscosity of from 30 to 350 Pa.s.
  • the clay-based hydrogel matrix to be printed should have a certain viscosity, the viscosity is too high, the fluidity is poor, the pressure required for printing is too large, and the material is not easily mixed; the solution viscosity is too low, and the fluidity is too high. It is difficult to shape when printing, and the bracket will collapse and cannot maintain the pre-shape.
  • the content of the inorganic clay is controlled to be between 3% and 20%, and the viscosity of the clay-based hydrogel matrix can be controlled to be 30 to 350 Pa ⁇ s.
  • the inorganic clay has a mass percentage of 5-15%. More preferably, it is 8-15%.
  • the mass percentage of the inorganic clay is increased to 8% or more, the clay-based hydrogel matrix reaches With higher viscosity, the gel stent after printing is cured, the stretch rate of the cured gel stent can reach about 5000%, and the mechanical strength is obviously improved.
  • the clay-based hydrogel matrix comprises a mass percent of the raw material component as follows:
  • Crosslinking agent 10-50%
  • Inorganic clay 5-15%
  • Ultraviolet light initiator 0.05-0.1%
  • the total mass percentage of each of the above raw material components was 100%.
  • the clay-based hydrogel matrix has a viscosity of 50 to 250 Pa ⁇ s. More preferably, it is 100-200 Pa.s.
  • the biocompatible macromolecule with a carbon-carbon double bond has a good gel-forming effect, and in the dispersion formed of the inorganic clay and water, no additional chemical crosslinking agent is required, and ultraviolet polymerization is performed. A higher strength gel structure can be obtained.
  • the formed three-dimensional gel scaffold has low toxicity and good cell compatibility. While providing a three-dimensional environment required for the growth of cells such as osteoblasts and bone marrow mesenchymal stem cells, the cells are promoted to promote adhesion, growth and proliferation.
  • the crosslinking agent may be methacrylic acid, acrylic acid, polyethylene glycol diacrylate (PEGDA) modified gelatin, hyaluronic acid, polyvinyl alcohol, polyvinyl alcohol or the like.
  • PEGDA polyethylene glycol diacrylate
  • hyaluronic acid polyvinyl alcohol
  • polyvinyl alcohol polyvinyl alcohol or the like.
  • it may be methacrylic acid modified gelatin, acrylic acid modified hyaluronic acid, acrylic acid modified polyvinyl alcohol, low molecular weight (molecular weight less than 1000 Dalton) PEGDA modified chitosan, and the like.
  • At least one end of the molecular chain of the crosslinking agent has a carbon-carbon double bond, and the molecular chain of the crosslinking agent is a main chain structure of polyethylene glycol.
  • the crosslinking agent is polyethylene glycol diacrylate.
  • the cross-linking agent can also control the adhesion, growth, proliferation and even differentiation of the cells on the prepared scaffold by controlling the molecular weight and solid content thereof. For example, when the molecular weight of polyethylene glycol is 4000 and the solid content is 20%, the cells can adhere and stretch well on the stent; but when the molecular weight of polyethylene glycol is 10000 or more, the cells are spherical on the stent, which cannot be very Well developed, cell proliferation behavior is relatively weak.
  • the main chain structure of the polyethylene glycol has a molecular weight of from 1,000 to 10,000.
  • it may be 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000 or 9000. More preferably, it is 2000-8000.
  • the crosslinking agent has a mass percentage of 10-50%.
  • it may be 15%, 20%, 25%, 30%, 35%, 40% or 45%. More preferably, it is 20-40%.
  • the clay-based hydrogel matrix comprises a mass percent of the raw material component as follows:
  • Crosslinking agent 20-40%
  • Inorganic clay 3-20%;
  • Ultraviolet light initiator 0.05-0.1%
  • the total mass percentage of each of the above raw material components was 100%.
  • the clay-based hydrogel matrix comprises a mass percent of the raw material component as follows:
  • Crosslinking agent 20-40%
  • Inorganic clay 5-15%
  • Ultraviolet light initiator 0.05-0.1%
  • the total mass percentage of each of the above raw material components was 100%.
  • the ultraviolet photoinitiator selected in the present application is a biocompatible initiator which is used in a very small amount and hardly affects the cell experiments of the later three-dimensional gel scaffold.
  • the ultraviolet photoinitiator is 2-hydroxy-2-methyl-1-phenyl-1-propanone, 2-hydroxy-4'-(2-hydroxyethoxy)-2 -methylpropiophenone, 1-[4-(2-hydroxyethoxy)-phenylene]-2-hydroxy-2',2'-dimethylethyl ketone (Irgacure 2959), 1-hydroxycyclohexylbenzene One of ketone, ⁇ , ⁇ '-dimethoxy- ⁇ -phenylacetophenone and 2-methyl-1-(4-methylthiophenyl)-2-morpholine-1-propanone Or a variety. It is not limited to the ones listed in this application.
  • the water has a mass percentage of 35-84%. Further preferably, it is 40-76%. More preferably, it is 45-74%.
  • the present invention provides a method of preparing the above clay-based hydrogel matrix, comprising the steps of:
  • the crosslinking agent, the inorganic clay, the ultraviolet light initiator are weighed, and the water is uniformly mixed to obtain the clay-based hydrogel matrix, and the above raw materials are mixed according to the following mass percentages:
  • Crosslinking agent 10-50%
  • Inorganic clay 3-20%;
  • Ultraviolet light initiator 0.05-0.1%
  • the total mass percentage of each of the above raw material components is 100%; wherein the crosslinking agent is a biocompatible macromolecule with a carbon-carbon double bond, and the biocompatible macromolecule is polyethylene glycol, polyethylene One or more of alcohol, chitosan, gelatin, hyaluronic acid.
  • the preparation method provided by the second aspect of the present invention has a simple process, and the prepared clay-based hydrogel matrix has a suitable viscosity and a certain pre-shape, and can be printed first, then cured into a glue, and is suitable for batch printing.
  • the three-dimensional gel holder greatly improves the efficiency of 3D printing.
  • a third aspect of the invention provides a method for preparing a three-dimensional gel scaffold comprising the following steps:
  • the three-dimensional gel scaffold precursor is subjected to cross-linking curing under ultraviolet light to obtain a three-dimensional gel scaffold.
  • the three-dimensional gel scaffold is formed by ultraviolet light polymerization of inorganic clay, biocompatible macromolecules with carbon-carbon double bonds, and ultraviolet photoinitiators.
  • the crosslinking cures for a time of from 1200 s to 3000 s, ie from 30 to 50 min.
  • the ultraviolet light used has an energy density of from 0.1 to 999, 990 ⁇ J/cm 2 .
  • it is 100-500 mJ/cm ⁇ 2> . More preferably, it is 120 mJ/cm ⁇ 2> .
  • the ultraviolet light used has a wavelength of from 230 to 400 nm. More preferably, it is 250-350 nm. More preferably, it is 254 nm.
  • the three-dimensional printing technology can flexibly control the aperture, pores, and connectivity of the stent. It is necessary to adjust parameters such as air pressure, spacing, and height to obtain the desired stent.
  • parameters such as air pressure, spacing, and height.
  • the viscosity of the clay-based hydrogel matrix is large, the gas pressure required for printing is large, and when the viscosity is small, the gas pressure required for printing is small.
  • the larger the line spacing of the stent during printing the larger the porosity of the resulting three-dimensional gel stent and the smaller the compressive strength of the stent.
  • the three-dimensional gel scaffold precursor and the three-dimensional gel scaffold are regular geometric bodies (such as a cuboid, a cube, a cylinder, etc., but are not limited thereto) and other irregular three-dimensional porous structures. It is preferably a regular geometry. More preferably, it is a rectangular parallelepiped.
  • the three-dimensional gel scaffold has a bottom side length of 10-30 mm, a height of 3-8 mm, and a line spacing of 200-500 ⁇ m, but is not limited thereto, and can be determined by a person skilled in the art according to specific cell culture conditions.
  • a suitable correspondingly sized three-dimensional gel scaffold is selected and prepared.
  • the three-dimensional gel scaffold has a porosity of 70-95%.
  • a plurality of holes are formed in the three-dimensional gel scaffold, and the holes have a pore diameter of 200 to 600 ⁇ m.
  • the clay-based hydrogel matrix (clay base) composed of the above specific ratio of inorganic clay, crosslinking agent, ultraviolet light initiator and water is used.
  • the three-dimensional printing paste of the gel scaffold has a suitable viscosity and a certain pre-shape, which is suitable for continuous and batch printing, and obtains a three-dimensional gel scaffold after curing, thereby greatly improving the three-dimensional printing efficiency.
  • the preparation method of the three-dimensional gel scaffold has the advantages of simple process, strong controllability, low energy consumption, no need to change the pressure in the printing process, low manufacturing cost and strong practicability.
  • the present invention also provides a three-dimensional gel scaffold obtained by the method for preparing a three-dimensional gel scaffold according to the third aspect of the present invention.
  • the invention provides a clay-based hydrogel matrix according to the first aspect of the invention or a three-dimensional gel scaffold according to the fourth aspect of the invention for use in the preparation of a tissue repair material. It is preferably used in bone tissue repair materials.
  • 1 is a nuclear magnetic spectrum of polyethylene glycol (B, D) having a molecular weight of 4000 and 10,000, respectively, and polyethylene glycol (A, C) having a molecular weight of 4000 and 10,000 after double bond modification;
  • Figure 2 shows the infrared spectrum of Laponite XLG clay (a) produced by Rockwood Company, polyethylene glycol (b, c) with molecular weight of 4000 and 10000 modified by double bond, and crosslinked with the above clay to form a gel scaffold. (d,e);
  • Figure 3 is a scanning electron micrograph of osteoblasts spread on a clay-based three-dimensional gel scaffold prepared in Examples 1-3 of the present invention.
  • the polyvinyl alcohol used in the following examples is commercially available (Model 1788, degree of alcoholysis 87-89%, Aladdin); the hydroxyapatite is purchased from Nanjing Eppui Nano Materials Co., Ltd., medical grade .
  • a method for preparing a clay-based three-dimensional gel scaffold comprises the following steps:
  • acryloyl chloride 1.2 ml of acryloyl chloride was dissolved in 10 ml of dichloromethane to prepare an acryloyl chloride solution.
  • UV photoinitiator 0.05%
  • the printing parameters are set, and the clay-based hydrogel matrix is three-dimensionally printed at normal temperature to obtain a three-dimensional gel stent precursor.
  • the three-dimensional printing parameter of the three-dimensional gel stent precursor is that the bottom side length is 15mm, height 5mm, bracket spacing is 300 ⁇ m;
  • the printed three-dimensional gel scaffold precursor was placed in an ultraviolet cross-linker and photocured at 254 nm for 25 min to obtain a clay-based three-dimensional gel scaffold.
  • the clay-based three-dimensional gel scaffold was tested to have a porosity of 75% and a stent compressive strength of 1 MPa.
  • a method for preparing a clay-based three-dimensional gel scaffold comprises the following steps:
  • Inorganic clay 8%;
  • Ultraviolet light initiator 0.05%
  • a method for preparing a clay-based three-dimensional gel scaffold comprises the following steps:
  • Inorganic clay 7%;
  • Ultraviolet light initiator 0.05%
  • Figure 1 shows polyethylene glycol (B, D) having a molecular weight of 4000 and 10,000, respectively, and polyethylene glycol (A, C) having a molecular weight of 4000 and 10,000 modified by a double bond (i.e., polyethylene glycol diacrylate).
  • Nuclear magnetic spectrum That is, (A) is PEGDA4000, (B) is PEG 4000, (C) is PEGDA 10000, and (D) PEG 10000.
  • the structural formula of polyethylene glycol diacrylate is as shown in the following formula (I):
  • c, d, and e are characteristic peaks of hydrogen on the double bond modified on polyethylene glycol diacrylate, indicating that the double bond was successfully modified onto polyethylene glycol.
  • Figure 2 shows the infrared spectrum of Laponite XLG clay (a) produced by Rockwood Company, polyethylene glycol (b, c) with molecular weight of 4000 and 10000 modified by double bond, and crosslinked with the above clay to form a gel scaffold.
  • a Laponite XLG clay
  • polyethylene glycol b, c
  • D, E are infrared images of a clay-based three-dimensional gel scaffold formed by the clay-based hydrogel matrix of Examples 2 and 3, respectively.
  • PEGDA ethylene glycol diacrylate
  • Figure 3 is a scanning electron micrograph of osteoblasts spread on a clay-based three-dimensional gel scaffold prepared in Examples 1-3 of the present invention. As can be seen from Figure 3, osteoblasts (cells at the box in the figure) successfully adhered to the pore walls of the pores on the three-dimensional gel scaffold.
  • a method for preparing a clay-based three-dimensional gel scaffold comprises the following steps:
  • Inorganic clay 10%;
  • Ultraviolet light initiator 0.1%
  • the three-dimensional printing parameters of the three-dimensional gel scaffold precursor are 15 mm on the bottom side and 5 mm in height.
  • the pitch is 500 ⁇ m;
  • the printed three-dimensional gel scaffold precursor was placed in an ultraviolet cross-linking instrument, and light-cured at an energy density of 254 nm and 120 mJ/cm 2 for 20 min to obtain a clay-based three-dimensional gel scaffold.
  • An ultraviolet curable clay-based hydrogel matrix for three-dimensional printing comprising a mass percent of a raw material component as follows:
  • Crosslinking agent 40%;
  • Inorganic clay 15%;
  • Ultraviolet light initiator 0.05%
  • the crosslinking agent is methacrylic acid modified gelatin;
  • the inorganic clay is kaolin,
  • the ultraviolet photoinitiator is 2-methyl-1-(4-methylthiophenyl)-2-morpholine-1-propanone.
  • An ultraviolet curable clay-based hydrogel matrix for three-dimensional printing comprising a mass percent of a raw material component as follows:
  • Crosslinking agent 50%;
  • Inorganic clay 12%;
  • crosslinking agent is acrylic acid modified hyaluronic acid and polyethylene glycol diacrylate (prepared in Example 1);
  • the inorganic clay is kaolin, and the ultraviolet photoinitiator is 1-hydroxycyclohexyl Phenyl ketone.

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Abstract

提供了一种用于三维打印的粘土基水凝胶基质，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：交联剂：10-50％；无机粘土：3-20％；紫外光引发剂：0.05-0.1％；水：30-86％；上述各原料组分的总质量百分含量为100％；其中，所述交联剂为带碳碳双键的生物相容大分子，所述生物相容大分子为聚乙二醇、聚乙烯醇、壳聚糖、明胶和透明质酸中的一种或多种。所述粘土基水凝胶基质的配方简单、成分安全，其粘度合适、具有一定的预形状，适合连续挤出的三维支架打印，可实现先打印，后固化成胶，批量打印三维凝胶支架，大大提高了三维支架的打印效率。还提供了基于该粘土基水凝胶基质的制备方法及应用。

Description

用于三维打印的粘土基水凝胶基质及其制备方法和应用 技术领域
本发明涉及生物材料技术领域，具体涉及一种用于三维打印的粘土基水凝胶基质及其制备方法和应用。
背景技术
水凝胶是一种通过共价键、氢键或范德华力等作用相互交联构成的具有三维网状结构、能在水中溶胀并保持大量水分而又不溶解的聚合物.由于天然或合成的聚合物水凝胶在结构及性能上与生物体组织相似，因此近20年来，水凝胶一直是生物医用工程领域，特别是组织工程方面的诊断、治疗、修复或替换人体组织器官或增进其功能与生长因子、药物和基因载体等的一个研究热点。
热聚合、紫外聚合是水凝胶制备中较常用的聚合方法。其中热聚合在凝胶体系中加入热引发剂后，聚合时间不可控，需要随时调整打印时所需压力，或可能由于聚合过快，造成后期无法打印的问题。而采用紫外光对三维支架进行固化，则不存在上述问题，它可以在打印凝胶浆料的同时对其进行固化，但该方法对凝胶浆料的要求较高，需要其在较短时间内发生紫外交联成胶，否则打印出的凝胶支架的结构无法良好地保持，因此大大缩小了材料的可选择性。
发明内容
有鉴于此，本发明提供了一种可用于三维打印中紫外光固化的粘土基水凝 胶基质，所述粘土基水凝胶基质包括特定配比的无机黏土、带碳碳双键的生物相容大分子、紫外光引发剂和水，其配方简单、成分安全，所述粘土基水凝胶基质在经紫外光交联前具有一定的预形状，可实现先打印，后固化成胶，批量打印三维凝胶支架，大大提高了三维打印效率。
第一方面，本发明提供了一种用于三维打印的粘土基水凝胶基质，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：10-50％；
无机粘土：3-20％；
紫外光引发剂：0.05-0.1％；
水：30-86％；
上述各原料组分的总质量百分含量为100％；其中，所述交联剂为带碳碳双键的生物相容大分子，所述生物相容大分子为聚乙二醇、聚乙烯醇、壳聚糖、明胶、透明质酸中的一种或多种。
本发明通过上述特定质量配比的各种原料的协同作用，获得的所述粘土基水凝胶基质具有适宜的打印粘度和强度，在紫外光交联前具有一定的预形状。在常温下可以将所述粘土基水凝胶基质打印成力学强度、拉伸性能较好的稳定三维凝胶支架前驱体，便于后期对支架前驱体进行统一的紫外光固化，得到三维凝胶支架。所述粘土基水凝胶基质适用于批量打印制得三维打印凝胶支架，大大提高了三维打印效率，非常适合工业化生产。
在紫外光的作用下，本申请的所述粘土基水凝胶基质中，所述交联剂的碳碳双键之间发生交联，形成的聚合物长链穿插在无机黏土的有序片层结构中，形成三维网络结构的水凝胶，使得凝胶形状得以保持，同时无机粘土也充当物 理交联的作用，其与带碳碳双键的生物相容大分子之间形成的氢键作用、范德华力等，也使得打印出的三维凝胶支架的强度进一步提高，充分发挥物理交联与化学交联的协同效应。提高凝胶支架的稳定性。
所述无机粘土可以选自高岭土、膨润土、蒙脱土、锂皂石(laponite，锂藻土)、锂蒙脱石(hectorite)、贝得石、皂石、硅镁石、硅酸镁铝、其它硅酸铝和各种其它天然和/或合成的粘土，以及它们的组合。
优选地，所述无机粘土的粒径不超过500nm。进一步优选为50-200nm。
在本发明的一优选实施方式中，所述无机粘土为锂皂石粘土。该锂皂石粘土可以在水中快速剥离分散成单片层，形成无色透明的胶体分散液，稳定性好。该黏土可以为购买自Rockwood公司的Laponite XLG。Laponite XLG是合成的层状粘土(layeredclay)，与天然蒙脱石类似。
本申请中，无机黏土的加入，可有效提高水凝胶支架的强度，无机黏土相当于充当了物理交联剂的作用。此外，控制所述无机黏土的含量可以调控所述粘土基水凝胶基质的粘度，使所述粘土基水凝胶基质具有一定的预形状，可以实现先打印后固化。
优选地，所述粘土基水凝胶基质的粘度为30-350Pa·s。待打印的所述粘土基水凝胶基质应该具有一定的粘度，粘度过高，流动性较差，打印时需要的压力过大，且材料不容易混匀；溶液黏度过低，流动性太高，打印时塑形困难，支架会发生塌陷，无法保持预形状。本申请中，将无机粘土的含量控制在3％-20％之间，可以使所述粘土基水凝胶基质的粘度控制在30-350Pa·s。
进一步优选地，所述无机黏土的质量百分含量为5-15％。更优选为8-15％。当所述无机黏土的质量百分含量提高至8％以上，所述粘土基水凝胶基质达到 较高的黏度，其打印成的凝胶支架前驱体经固化后，固化的凝胶支架的拉伸率可以达到5000％左右，力学强度有了明显提高。
优选地，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：10-50％；
无机粘土：5-15％；
紫外光引发剂：0.05-0.1％；
水：35-84％；
上述各原料组分的总质量百分含量为100％。
进一步优选地，所述粘土基水凝胶基质的粘度为50-250Pa·s。更优选为100-200Pa·s。
本申请中，带碳碳双键的生物相容大分子的成胶效果较好，在所述无机粘土与水形成的分散液中，不需要额外添加化学交联剂，经紫外光聚合，即可得到强度较高的凝胶结构。形成的三维凝胶支架的毒性低，细胞相容性好。在提供细胞(例如成骨细胞以及骨髓间充质干细胞)生长所需的三维环境的同时，对细胞起到促进其黏附、生长与增殖的作用。
在本发明一实施方式中，所述交联剂的分子链的至少一端带有碳碳双键。所述交联剂可以为甲基丙烯酸、丙烯酸、聚乙二醇二丙烯酸酯(PEGDA)修饰的明胶、透明质酸、聚乙烯醇、聚乙烯醇等。例如可以是甲基丙烯酸修饰的明胶，丙烯酸修饰的透明质酸、丙烯酸修饰的聚乙烯醇、低分子量(分子量小于1000道尔顿)的PEGDA修饰的壳聚糖等。
在本发明另一实施方式中，所述交联剂的分子链的至少一端带有碳碳双键，所述交联剂的分子链中间为聚乙二醇的主链结构。
进一步优选地，所述交联剂为聚乙二醇二丙烯酸酯。
所述交联剂除了可促进凝胶形成、提高凝胶力学强度外，还可以通过控制其分子量和固含量，以达到控制细胞在制得的支架上黏附、生长、增殖甚至分化等目的。例如，聚乙二醇分子量为4000，固含量为20％时，细胞能够在支架上黏附及伸展情况良好；但当聚乙二醇的分子量为10000以上时，细胞在支架上成球形，不能很好地展开，细胞增殖行为相对较弱。
优选地，所述交联剂中，聚乙二醇的主链结构的分子量为1000-10000。例如可以为2000、2500、3000、3500、4000、4500、5000、5500、6000、6500、7000、7500、8000或9000。进一步优选为2000-8000。
本申请中，所述交联剂的质量百分含量为10-50％。例如可以为15％、20％、25％、30％、35％、40％或45％。进一步优选为20-40％。
优选地，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：20-40％；
无机粘土：3-20％；
紫外光引发剂：0.05-0.1％；
水：40-76％；
上述各原料组分的总质量百分含量为100％。
进一步优选地，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：20-40％；
无机粘土：5-15％；
紫外光引发剂：0.05-0.1％；
水：45-74％；
上述各原料组分的总质量百分含量为100％。
本申请中所选用的紫外光引发剂为生物相容性良好的引发剂，其用量极少，且几乎不会对后期三维凝胶支架的细胞实验产生影响。
在本发明一实施方式中，所述紫外光引发剂为2-羟基-2-甲基-1-苯基-1-丙酮、2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮、1-[4-(2-羟乙氧基)-亚苯基]-2-羟基-2’，2’-二甲基乙酮(Irgacure2959)、1-羟基环己基苯基酮、α,α’-二甲氧基-α-苯基苯乙酮和2-甲基-1-(4-甲硫基苯基)-2-吗啉-1-丙酮中的一种或多种。并不限于本申请所列举的这几种。
优选地，所述水的质量百分含量为35-84％。进一优选为40-76％。更优选为45-74％。
第二方面，本发明提供了一种上述粘土基水凝胶基质的制备方法，包括以下步骤：
按上述配方量，称取交联剂、无机黏土、紫外光引发剂，加入水混合均匀，得到所述粘土基水凝胶基质，上述各原料按如下质量百分含量混合：
交联剂：10-50％；
无机粘土：3-20％；
紫外光引发剂：0.05-0.1％；
水：30-86％；
上述各原料组分的总质量百分含量为100％；其中，所述交联剂为带碳碳双键的生物相容大分子，所述生物相容大分子为聚乙二醇、聚乙烯醇、壳聚糖、明胶、透明质酸中的一种或多种。
本发明实施例第二方面提供的制备方法，工艺简单，制备得到的所述粘土基水凝胶基质的粘度合适，具有一定的预形状，可实现先打印，后固化成胶，适用于批量打印三维凝胶支架，大大提高了三维打印效率。
本发明第三方面提供了一种三维凝胶支架的制备方法，包括以下步骤：
(1)取本发明第一方面的所述粘土基水凝胶基质，将其在常温下进行三维打印，得到三维凝胶支架前驱体；
(2)将所述三维凝胶支架前驱体置于紫外光下进行交联固化，得到三维凝胶支架。所述三维凝胶支架由无机黏土、带碳碳双键的生物相容大分子、紫外光引发剂通过紫外光聚合而成。
优选地，所述交联固化的时间为1200s-3000s，即30-50min。
优选地，所用紫外光的能量密度为0.1-999,990μJ/cm2。
进一步优选为100-500mJ/cm2。更优选为120mJ/cm2。
优选地，所用紫外光的波长为230-400nm。进一步优选为250-350nm。更优选为254nm。
三维打印技术可以对支架的孔径、孔隙、连通率等进行灵活调控。需要调控气压、间距、层高等参数来获得所期望的支架。一般而言，所述粘土基水凝胶基质的粘度较大时，打印所需的气压较大，粘度较小时，打印所需要的气压较小。打印时支架的行间距越大，最终得到的三维凝胶支架的孔隙率越大，支架的压缩强度越小。
本发明实施例中，所述三维凝胶支架前驱体、三维凝胶支架为规则的几何体(如长方体、正方体、圆柱体等，但不限于此)以及其他不规则的三维多孔结构体。优选为规则几何体。进一步优选为长方体。
本发明一实施例中，所述三维凝胶支架的底面边长为10-30mm，高度为3-8mm，行间距为200-500μm，但不限于此，本领域技术人员可根据具体细胞培养条件选择并制备合适的相应大小的三维凝胶支架。
本发明一实施例中，所述三维凝胶支架的孔隙率为70-95％。
所述三维凝胶支架上形成有多个孔洞，所述孔洞的孔径为200-600μm。
本发明第三方面提供的所述三维凝胶架的制备方法中，采用上述特定配比的无机粘土、交联剂、紫外光引发剂、水构成的所述粘土基水凝胶基质(黏土基凝胶支架的三维打印浆料)，所述粘土基水凝胶基质的粘度合适，具有一定的预形状，适合连续、批量打印，固化后得到三维凝胶支架，大大提高了三维打印效率。所述三维凝胶支架的制备方法，工艺简单，可控性强，能耗较低，无需改变打印过程中的压力，制造成本低廉，实用性较强。
第四方面，本发明还提供了如本发明第三方面所述的三维凝胶支架的制备方法得到的三维凝胶支架。
第五方面，本发明还提供了一种如本发明第一方面所述的粘土基水凝胶基质或如本发明第四方面所述的三维凝胶支架在制备组织修复材料中的应用。优选为在骨组织修复材料的应用。
本发明实施例的优点将会在下面的说明书中部分阐明，一部分根据说明书是显而易见的，或者可以通过本发明实施例的实施而获知。
附图说明
图1是分子量分别为4000和10000的聚乙二醇(B，D)以及双键修饰后的分子量为4000和10000的聚乙二醇(A，C)的核磁图谱；
图2为Rockwood公司生产的Laponite XLG黏土(a)、双键修饰后的分子量为4000和10000的聚乙二醇(b，c)以及其分别与上述粘土交联形成凝胶支架后的红外图谱(d，e)；
图3为成骨细胞在本发明实施例1-3制得的黏土基三维凝胶支架上铺展的扫描电镜图。
具体实施方式
以下所述是本发明实施例的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明实施例原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也视为本发明实施例的保护范围。
下面分多个实施例对本发明实施例进行进一步的说明。其中，本发明实施例不限定于以下的具体实施例。在不变主权利的范围内，可以适当的进行变更实施。
下述实施例中所用的聚乙烯醇为市售商品，(1788型，醇解度87-89％，阿拉丁)；所述羟基磷灰石购买自南京埃普瑞纳米材料有限公司，医用级。
若无特别说明，本发明实施例所采用的试剂皆为市售商品。
实施例1：
一种黏土基三维凝胶支架的制备方法，包括如下步骤：
A.双键修饰的聚乙二醇(Mn＝4000)大分子交联剂的制备
首先将1.2ml的丙烯酰氯溶于10ml二氯甲烷中，配制成丙烯酰氯溶液。随后将10g的聚乙二醇(Mn＝4000)置于50ml的三口烧瓶中，加入20ml的二 氯甲烷溶解，室温下搅拌均匀。在冰水浴条件下，缓慢加入2.1ml的三乙胺溶液。随后，在冰水浴条件下，逐滴加入提前配置好的丙烯酰氯溶液。控制体系温度为零度，直至丙烯酰氯全部滴加完毕，氮气保护状态下，室温反应24h。反应结束后，滤去体系中形成的三乙胺盐酸盐，并用无水乙醚沉淀出合成出的双键修饰的聚乙二醇(Mn＝4000)，得到的粗产物经过真空干燥1d、透析7d、过滤、冻干2d后得到纯度较高的双键修饰的聚乙二醇大分子交联剂，即为聚乙二醇二丙烯酸酯，其分子式为CH2＝CHCO-(OCH2CH2)nOCOCH＝CH2(n为88)。
B.可用于三维打印的紫外光固化纳米粘土基水凝胶基质的制备
将步骤A得到的双键修饰的聚乙二醇大分子交联剂(Mn＝4000)、Laponite XLG锂皂石粘土、紫外光引发剂2-羟基-2-甲基-1-苯基-1-丙酮与水相混合，其中，上述各原料按如下质量百分含量混合：
聚乙二醇二丙烯酸酯(聚乙烯的分子量Mn＝4000)20％
Laponite XLG粘土：5％
紫外光引发剂：0.05％
水：74.95％；
室温下混合均匀后，得到可用于三维打印的紫外光固化粘土基水凝胶基质，所述粘土基水凝胶基质的粘度为160Pa·s。
C、支架制备：
按照所期望的支架结构来设置打印参数，将上述粘土基水凝胶基质在常温下进行三维打印，得到三维凝胶支架前驱体，该三维凝胶支架前驱体的三维打印参数为底面边长为15mm，高度为5mm，支架行间距为300μm；
将打印好的所述三维凝胶支架前驱体置于紫外交联仪中，在254nm下进行光固化25min，得到黏土基三维凝胶支架。检测该黏土基三维凝胶支架的孔隙率为75％，支架压缩强度为1MPa。
实施例2：
一种黏土基三维凝胶支架的制备方法的方法，包括如下步骤：
(1)采用与实施例1相同的方法，对分子量为4000的聚乙二醇进行双键修饰，得到交联剂聚乙二醇二丙烯酸酯，CH2＝CHCO-(OCH2CH2)nOCOCH＝CH2(n为88)；
(2)采用2-羟基-4’-(2-羟乙氧基)-2-甲基苯丙酮作为紫外光引发剂，Laponite XLG作为无机黏土，按下述配方量，称取交联剂、无机黏土、紫外光引发剂，加入水混合均匀，得到粘度为170Pa·s的粘土基水凝胶基质，上述各原料按如下质量百分含量混合：
交联剂：30％；
无机粘土：8％；
紫外光引发剂：0.05％；
水：61.95％；
(3)将上述粘土基水凝胶基质在常温下进行三维打印(打印参数同实施例1)，得到三维凝胶支架前驱体，将打印好的将打印好的所述三维凝胶支架前驱体置于紫外交联仪中，在254nm下进行光固化40min后，得到黏土基三维凝胶支架。
实施例3：
一种黏土基三维凝胶支架的制备方法，包括如下步骤：
(1)采用与实施例1相同的方法，对分子量为10000的聚乙二醇进行双键修饰，得到交联剂聚乙二醇二丙烯酸酯，CH2＝CHCO-(OCH2CH2)nOCOCH＝CH2(n为224)；
(2)采用2-羟基-2-甲基-1-苯基-1-丙酮作为紫外光引发剂，Laponite XLG作为无机黏土，按下述配方量，称取交联剂、无机黏土、紫外光引发剂，加入水混合均匀，得到粘度为150Pa·s的粘土基水凝胶基质，上述各原料按如下质量百分含量混合：
交联剂：20％；
无机粘土：7％；
紫外光引发剂：0.05％；
水：72.95％；
(3)将上述粘土基水凝胶基质在常温下进行三维打印(打印参数同实施例1)，得到三维凝胶支架前驱体，将打印好的将打印好的所述三维凝胶支架前驱体置于紫外交联仪中，在254nm下进行光固化20min后，得到黏土基三维凝胶支架。
图1为分子量分别为4000和10000的聚乙二醇(B，D)以及双键修饰后的分子量为4000和10000的聚乙二醇(A，C)(即聚乙二醇二丙烯酸酯)的核磁图谱。即(A)为PEGDA4000，(B)为PEG 4000，(C)为PEGDA 10000,(D)PEG 10000。其中聚乙二醇二丙烯酸酯的结构式如下式(Ⅰ)所示：
Figure PCTCN2016105922-appb-000001
从图1可以看出，c,d,e为聚乙二醇二丙烯酸酯上修饰的双键上氢元素的特征峰，说明双键被成功地修饰到聚乙二醇上。
图2为Rockwood公司生产的Laponite XLG黏土(a)、双键修饰后的分子量为4000和10000的聚乙二醇(b，c)以及其分别与上述粘土交联形成凝胶支架后的红外图谱(d，e)。图2中D，E分别为实施例2、3中的所述粘土基水凝胶基质形成的黏土基三维凝胶支架的红外图。
从图2可以看出，d，e不仅具有Laponite XLG粘土的红外特征峰，还具有乙二醇二丙烯酸酯(PEGDA)在2887，1725，1110，1467cm-1处的特征峰，以上特征峰分别代表PEGDA上C-H键，C＝O双键，C-O-C的伸缩振动吸收峰，以及-CH2-的摇摆振动吸收峰，说明粘土基复合凝胶成功地被制备出来。
图3为成骨细胞在本发明实施例1-3制得的黏土基三维凝胶支架上铺展的扫描电镜图。从图3可以看出，成骨细胞(图中方框处为细胞)成功粘附在三维凝胶支架上的孔洞的孔壁上。
实施例4：
一种黏土基三维凝胶支架的制备方法，包括如下步骤：
(1)采用与实施例1相同的方法，对分子量为4000的聚乙二醇进行双键修饰，得到交联剂聚乙二醇二丙烯酸酯，CH2＝CHCO-(OCH2CH2)nOCOCH＝CH2(n为88)；
(2)采用α,α’-二甲氧基-α-苯基苯乙酮作为紫外光引发剂，膨润土作为无机黏土，按下述配方量，称取交联剂、无机黏土、紫外光引发剂，加入水混合均匀，得到粘度为190Pa·s的粘土基水凝胶基质，其中，上述各原料按如下质量百分含量混合：
交联剂：25％；
无机粘土：10％；
紫外光引发剂：0.1％；
水：74.9％；
(3)将上述粘土基水凝胶基质在常温下进行三维打印，得到三维凝胶支架前驱体，该三维凝胶支架前驱体的三维打印参数为底面边长为15mm，高度为5mm，支架行间距为500μm；
将打印好的所述三维凝胶支架前驱体置于紫外交联仪中，于254nm、120mJ/cm2的能量密度下，进行光固化20min后，得到黏土基三维凝胶支架。
实施例5
一种用于三维打印的紫外光固化粘土基水凝胶基质，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：40％；
无机粘土：15％；
紫外光引发剂：0.05％；
水：44.95％；
其中，所述交联剂为甲基丙烯酸修饰的明胶；所述无机黏土为高岭土，所 述紫外光引发剂为2-甲基-1-(4-甲硫基苯基)-2-吗啉-1-丙酮。
实施例6
一种用于三维打印的紫外光固化粘土基水凝胶基质，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
交联剂：50％；
无机粘土：12％；
紫外光引发剂：0.08％；
水：37.92％；
其中，所述交联剂为丙烯酸修饰的透明质酸和聚乙二醇二丙烯酸酯(实施例1中制得)；所述无机黏土为高岭土，所述紫外光引发剂为1-羟基环己基苯基酮。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，本领域普通技术人员可以理解实现上述实施例的全部或部分流程，并依本发明权利要求所作的等同变化，仍属于发明所涵盖的范围。

Claims (16)

  1. 一种用于三维打印的紫外光固化粘土基水凝胶基质，其特征在于，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
    交联剂：10-50％；
    无机粘土：3-20％；
    紫外光引发剂：0.05-0.1％；
    水：30-86％；
    上述各原料组分的总质量百分含量为100％；其中，所述交联剂为带碳碳双键的生物相容大分子，所述生物相容大分子为聚乙二醇、聚乙烯醇、壳聚糖、明胶和透明质酸中的一种或多种。
  2. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述交联剂的分子链的至少一端带有碳碳双键，所述交联剂的分子链中间为聚乙二醇的主链结构；所述聚乙二醇的主链结构的分子量为1000-10000。
  3. 如权利要求2所述的粘土基水凝胶基质，其特征在于，所述交联剂为聚乙二醇二丙烯酸酯。
  4. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述交联剂包括甲基丙烯酸、丙烯酸或聚乙二醇二丙烯酸酯修饰的明胶、透明质酸、科举陶和聚乙烯醇。
  5. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述无机黏土的质量百分含量为5-15％。
  6. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述交联剂的质量百分含量为20-40％。
  7. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述黏土选自高岭土、膨润土、蒙脱土、锂皂石、锂蒙脱石、贝得石、皂石、硅镁石、硅酸镁铝、其它硅酸铝和各种其它天然和/或合成的粘土，以及它们的组合。
  8. 如权利要求1所述的粘土基水凝胶基质，其特征在于，所述粘土基水凝胶基质包括如下质量百分含量的原料组分：
    交联剂：20-40％；
    无机粘土：5-15％；
    紫外光引发剂：0.05-0.1％；
    水：45-74％；
    上述各原料组分的总质量百分含量为100％。
  9. 如权利要求1-8任一项所述的粘土基水凝胶基质，其特征在于，所述粘土基水凝胶基质的粘度为30-350Pa·s。
  10. 一种粘土基水凝胶基质的制备方法，其特征在于，包括以下步骤：
    按下述配方量，称取交联剂、无机黏土、紫外光引发剂，加入水混合均匀，得到所述粘土基水凝胶基质，上述各原料按如下质量百分含量混合：
    交联剂：10-50％；
    无机粘土：3-20％；
    紫外光引发剂：0.05-0.1％；
    水：30-86％；
    上述各原料组分的总质量百分含量为100％；其中，所述交联剂为带碳碳双键的生物相容大分子，所述生物相容大分子为聚乙二醇、聚乙烯醇、壳聚糖、明胶、透明质酸中的一种或多种。
  11. 一种三维凝胶支架的制备方法，其特征在于，包括以下步骤：
    (1)取权利要求1-9任一项所述的粘土基水凝胶基质，将其在常温下进行三维打印，得到三维凝胶支架前驱体；
    (2)将所述三维凝胶支架前驱体置于紫外光下进行交联固化，得到三维凝胶支架。
  12. 如权利要求11所述的制备方法，其特征在于，所述交联固化的时间为30-50min。
  13. 如权利要求11所述的制备方法，其特征在于，所述三维凝胶支架的底面边长为10-30mm，高度为3-8mm，行间距为200-500μm。
  14. 如权利要求13所述的制备方法，其特征在于，所述三维凝胶支架上形成有多个孔洞，所述孔洞的孔径为200-600μm。
  15. 一种如权利要求11-14任一项所述的制备方法得到的三维凝胶支架。
  16. 一种如权利要求1-9任一项所述的粘土基水凝胶基质或如权利要求15所述的三维凝胶支架在制备组织修复材料中的应用。
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