阅读说明：本技术 一种多功能复合多孔支架及其制备方法与应用 (Multifunctional composite porous scaffold and preparation method and application thereof ) 是由 黄鹏 杨晨 罗永祥 林静 于 2021-07-12 设计创作，主要内容包括：本发明公开了一种多功能复合多孔支架及其制备方法与应用,其中,制备方法包括步骤：对生物陶瓷块材进行超声剥离处理,得到生物陶瓷纳米片,所述生物陶瓷纳米片具备近红外光热转换性能；将所述生物陶瓷纳米片与生物高分子材料混合,得到打印用复合膜；将所述打印用复合膜进行3D打印,制备得到多功能复合多孔支架。本发明方法制备工艺简单、易于操作,有利于临床推广和应用；通过本发明方法制得的多功能复合多孔支架具备优异的近红外二区光热转换性能,可用于更深层次的肿瘤光热治疗；同时其能够降解释放活性元素Cu,Si等微量元素,有利于骨缺损修复。(The invention discloses a multifunctional composite porous scaffold and a preparation method and application thereof, wherein the preparation method comprises the following steps: carrying out ultrasonic stripping treatment on the biological ceramic block to obtain a biological ceramic nanosheet, wherein the biological ceramic nanosheet has near-infrared photo-thermal conversion performance; mixing the biological ceramic nanosheets with a biological polymer material to obtain a composite film for printing; and 3D printing is carried out on the composite film for printing to prepare the multifunctional composite porous support. The method has simple preparation process and easy operation, and is favorable for clinical popularization and application; the multifunctional composite porous scaffold prepared by the method has excellent near-infrared two-region photothermal conversion performance, and can be used for deeper tumor photothermal treatment; meanwhile, the composite material can degrade and release trace elements such as active elements Cu and Si, and is beneficial to bone defect repair.)

1. The preparation method of the multifunctional composite porous scaffold is characterized by comprising the following steps:

carrying out ultrasonic stripping treatment on the biological ceramic block to obtain a biological ceramic nanosheet, wherein the biological ceramic nanosheet has near-infrared photo-thermal conversion performance;

mixing the biological ceramic nanosheets with a biological polymer material to obtain a composite film for printing;

and 3D printing is carried out on the composite film for printing to prepare the multifunctional composite porous support.

2. The method for preparing the multifunctional composite porous scaffold according to claim 1, wherein the bioceramic bulk material is SrCuSi₄O₁₀And BaCuSi₄O₁₀One or two of them.

3. The preparation method of the multifunctional composite porous scaffold according to claim 1, wherein the step of subjecting the bioceramic bulk material to ultrasonic exfoliation treatment to obtain a bioceramic nanosheet comprises:

adding the biological ceramic block into a stripping solvent to obtain a biological ceramic block stripping solution, wherein the stripping solvent is one or more of pure water, hydrochloric acid, tannic acid and N-methylpyrrolidone;

and carrying out ultrasonic stripping treatment on the biological ceramic block stripping solution to obtain a biological ceramic nanosheet.

4. The preparation method of the multifunctional composite porous scaffold according to claim 1, wherein the biopolymer material is one or more of polycaprolactone, sodium alginate, chitosan and gelatin.

5. The preparation method of the multifunctional composite porous scaffold according to claim 1, wherein in the step of mixing the biological ceramic nanosheets and the biopolymer material, the mass ratio of the biological ceramic nanosheets to the biopolymer material is 0.1-2: 10.

6. The method for preparing the multifunctional composite porous scaffold as claimed in claim 1, wherein the near-infrared photothermal conversion performance comprises a near-infrared first-region photothermal conversion performance and a near-infrared second-region photothermal conversion performance, the wavelength of the near-infrared first region is 780-2526 nm, and the wavelength of the near-infrared second region is 1100-2526 nm.

7. The method for preparing a multifunctional composite porous scaffold according to claim 1, wherein in the step of 3D printing the composite membrane for printing, the temperature of 3D printing is 20-200 ℃.

8. A multifunctional composite porous scaffold, characterized by being prepared by the method for preparing the multifunctional composite porous scaffold according to any one of claims 1 to 7.

9. Use of the multifunctional composite porous scaffold according to claim 8 for the preparation of a medicament for the treatment of tumors.

10. Use of the multifunctional composite porous scaffold according to claim 8 for a medicament for bone defect repair.

Technical Field

The invention relates to the technical field of medical biomaterials, in particular to a multifunctional composite porous scaffold and a preparation method and application thereof.

Background

Bone defects are one of the most common diseases in clinic, and the causes of bone defects are various, including congenital bone diseases, trauma, bone tumor removal and the like. Taking the repair of bone defects after tumor resection as an example, although surgery combined with adjuvant chemotherapy can greatly improve the survival rate of patients, the risk of cancer recurrence or metastasis still exists. In addition, bone defects associated with surgical treatment are almost inevitable, which often requires the implantation of bone scaffolds to guide new bone ingrowth. Therefore, it is important to develop a novel skeleton repair material which can promote osteogenesis and remove residual tumor cells.

In recent years, the use of bifunctional scaffolds for bone tissue engineering for the treatment of tumor-related defects has become a major research topic. These scaffolds for bone tissue engineering are generally composed of a bone repair material and a coating of photothermal conversion agent. The photothermal conversion preparation coating can convert near infrared light into heat for tumor treatment, and the bone repair material can promote regeneration of bone defect parts. Although these composite scaffolds have good bone repair and anti-tumor capabilities, the current photothermal agents generally have no bioactivity, and the laser is mainly concentrated in the near infrared region, so that the tissue penetration depth is limited, and the clinical requirements are difficult to meet. Compared with the near-infrared first-region light, the near-infrared second-region light penetrates deeper into tissues, and the maximum allowable energy is higher. Therefore, the near-infrared two-region photothermal preparation with biological activity is developed, and the porous scaffold prepared by the preparation method is more clinically significant for defect repair after bone tumor resection.

Accordingly, the prior art is yet to be improved and developed.

Disclosure of Invention

In view of the defects of the prior art, the invention aims to provide a multifunctional composite porous scaffold and a preparation method and application thereof, and aims to solve the problem that the existing composite scaffold only has infrared one-zone photothermal conversion performance and cannot realize deeper tumor treatment and tissue repair.

The technical scheme of the invention is as follows:

a preparation method of a multifunctional composite porous scaffold comprises the following steps:

carrying out ultrasonic stripping treatment on the biological ceramic block to obtain a biological ceramic nanosheet, wherein the biological ceramic nanosheet has near-infrared photo-thermal conversion performance;

mixing the biological ceramic nanosheets with a biological polymer material to obtain a composite film for printing;

and 3D printing is carried out on the composite film for printing to prepare the multifunctional composite porous support.

The preparation method of the multifunctional composite porous scaffold comprises the step of preparing the biological ceramic block material from SrCuSi₄O₁₀And BaCuSi₄O₁₀One or two of them.

The preparation method of the multifunctional composite porous support comprises the following steps of carrying out ultrasonic stripping treatment on a biological ceramic block to obtain a biological ceramic nanosheet:

adding the biological ceramic block into a stripping solvent to obtain a biological ceramic block stripping solution, wherein the stripping solvent is one or more of pure water, hydrochloric acid, tannic acid and N-methylpyrrolidone;

and carrying out ultrasonic stripping treatment on the biological ceramic block stripping solution to obtain a biological ceramic nanosheet.

The preparation method of the multifunctional composite porous scaffold comprises the step of preparing a biological polymer material, wherein the biological polymer material is one or more of polycaprolactone, sodium alginate, chitosan and gelatin.

The preparation method of the multifunctional composite porous scaffold comprises the step of mixing the biological ceramic nanosheet with a biological polymer material, wherein the mass ratio of the biological ceramic nanosheet to the biological polymer material is 0.1-2: 10.

The preparation method of the multifunctional composite porous scaffold comprises the steps that the near-infrared photo-thermal conversion performance comprises near-infrared first-zone photo-thermal conversion performance and near-infrared second-zone photo-thermal conversion performance, the wavelength of the near-infrared first zone is 780-2526 nm, and the wavelength of the near-infrared second zone is 1100-2526 nm.

The preparation method of the multifunctional composite porous scaffold comprises the step of carrying out 3D printing on the composite film for printing, wherein the temperature of the 3D printing is 20-200 ℃.

The invention relates to a multifunctional composite porous scaffold, which is prepared by the preparation method of the multifunctional composite porous scaffold.

The invention discloses application of a multifunctional composite porous scaffold, wherein the multifunctional composite porous scaffold is used for preparing a medicament for treating tumors.

The invention discloses application of a multifunctional composite porous scaffold, wherein the multifunctional composite porous scaffold is used for preparing a medicament for repairing bone defects.

Has the advantages that: the invention provides a preparation method of a multifunctional composite porous scaffold, which is prepared by utilizing excellent printing performance and biocompatibility of a biopolymer material. The multifunctional composite porous scaffold prepared by the invention has excellent near-infrared two-region photothermal conversion performance and can be used for deeper tumor photothermal treatment; meanwhile, the composite material can degrade and release trace elements such as active elements Cu and Si, and is beneficial to bone defect repair.

Drawings

FIG. 1 is a flow chart of a method for preparing a multifunctional composite porous scaffold provided by the invention.

FIG. 2 is a photograph of a scanning and transmission electron microscope of a sample according to example 1 of the present invention.

Fig. 3 is a photomicrograph and a scanning electron microscope photograph of a sample provided in example 2 of the present invention.

Fig. 4 is an ion release curve of the composite porous scaffold prepared in example 2 of the present invention.

Fig. 5 is a photothermal conversion curve of the composite porous scaffold prepared in example 2 of the present invention.

FIG. 6 is a graph showing the inhibition of tumor growth by the composite porous scaffold of example 3 of the present invention.

FIG. 7 is a photograph showing staining (H & E) of a tissue section in example 4 of the present invention.

Detailed Description

The invention provides a multifunctional composite porous scaffold and a preparation method and application thereof, and the invention is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and more clear and definite. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Researches show that the photothermal conversion preparation can be used for endowing materials with photothermal tumor treatment effects by modifying the surface of the bone repair materials, but the currently used photothermal conversion preparation is generally concentrated in a near infrared region and lacks of biological activity, so that the photothermal conversion preparation is not an ideal bone repair material.

Based on this, the present invention provides a method for preparing a multifunctional composite porous scaffold, as shown in fig. 1, comprising the steps of:

s10, carrying out ultrasonic stripping treatment on the biological ceramic block to obtain a biological ceramic nanosheet, wherein the biological ceramic nanosheet has near-infrared photo-thermal conversion performance;

s20, mixing the biological ceramic nanosheets with a biological polymer material to obtain a composite film for printing;

s30, performing 3D printing on the composite film for printing to prepare the multifunctional composite porous support.

In the embodiment, the biological ceramic nanosheets in the multifunctional composite porous scaffold have excellent near-infrared first-zone (780-1100nm) photothermal conversion performance and near-infrared second-zone (1100-2526nm) photothermal conversion performance, so that the multifunctional composite porous scaffold can be used for deeper tumor treatment; meanwhile, the active elements Cu, Si and the like released by the degradation of the biological ceramic nanosheets are beneficial to angiogenesis and new bone ingrowth, and the defect repair of the filling part can be promoted. The biological polymer material in the multifunctional composite porous scaffold is a biological polymer material with excellent biocompatibility, has a lower melting point and proper rheological property, is very suitable for an extrusion type 3D printing technology, and can be compounded with biological ceramic nanosheets to obtain the final required multifunctional composite porous scaffold through a printing procedure.

In the embodiment, the activity of the multifunctional composite porous scaffold can be used as a filler of a postoperative defect part to play a role in guiding bone ingrowth on the one hand, and can be used for generating heat through near-infrared two-zone laser irradiation to remove residual tumors around the defect on the other hand. Therefore, the multifunctional composite porous scaffold prepared by the embodiment can be used for preparing a medicament for treating tumors or a medicament for repairing bone defects, and has a good clinical application prospect.

In some embodiments, the bioceramic bulk is added to a stripping solvent to obtain a bioceramic bulk stripping solution, the stripping solvent being one or more of pure water, hydrochloric acid, tannic acid, and N-methylpyrrolidone; and carrying out ultrasonic stripping treatment on the biological ceramic block stripping solution to obtain a biological ceramic nanosheet. In this embodiment, the bioceramic block is SrCuSi₄O₁₀And BaCuSi₄O₁₀One or two of them, but not limited thereto. By way of example, when the bioceramic bulk is SrCuSi₄O₁₀In the process, the biological ceramic nano-sheet obtained by ultrasonic stripping treatment has good photo-thermal conversion performance in a near-infrared region, and endows the material with potential of photo-thermal treatment of tumorsAnd the biological ceramic nanosheet is composed of trace elements necessary for a human body, and can degrade and release bioactive ions such as Sr, Cu, Si and the like in a living body to promote bone tissue regeneration.

In some embodiments, the biopolymer material is one or more of polycaprolactone, sodium alginate, chitosan, and gelatin. In this embodiment, the biopolymer materials have a lower melting point, a better biocompatibility and a proper rheological property, and are very suitable for an extrusion 3D printing technology, and after being compounded with the bioceramic nanosheets, the final required multifunctional composite porous scaffold can be obtained through a printing procedure.

In some embodiments, the composite film for printing is prepared by physically mixing the bio-ceramic nanosheets and the biopolymer material, and in this embodiment, the physical mixing includes heating or room temperature mixing.

In other embodiments, the biological ceramic nanosheet and the biopolymer material are added into a chloroform solution and stirred uniformly, and the printing composite film is obtained after the chloroform is volatilized.

In some embodiments, in the step of mixing the biological ceramic nanosheet with a biopolymer material to prepare the composite film for printing, the mass ratio of the biological ceramic nanosheet to the biopolymer material is 0.1-2: 10. In this embodiment, if the content ratio of the bio-ceramic nanosheets is too low, the prepared multifunctional composite porous scaffold cannot be guaranteed to have sufficient photothermal conversion performance; if the content of the biological ceramic nanosheets is too high, certain cytotoxicity can be generated.

In some embodiments, the composite film for printing is printed into a multifunctional composite porous scaffold by a set printing procedure. In this embodiment, the temperature of 3D printing is 20 to 120 ℃, but is not limited thereto.

In some specific embodiments, the 3D printing is extrusion 3D printing, the needle used for 3D printing is 23-32G, and the printing parameters include: the single layer thickness is 0.05-0.5mm, the printing speed is 1-20mm/s, the air pressure is 100-800Kpa, and the printing temperature is 60-120 ℃.

In some embodiments, a multifunctional composite porous scaffold is also provided, which is prepared by the preparation method of the multifunctional composite porous scaffold. The multifunctional composite porous scaffold has good mechanical strength, and can be printed according to the size of a bone defect and filled in the defect part; the multifunctional composite porous scaffold also has good photo-thermal property, and can generate heat under the irradiation of near-infrared two-zone laser to remove residual tumor in operation; meanwhile, the active elements Sr, Cu and Si released by the degradation of the stent can promote the growth of blood vessels and the regeneration of new bones, and the stent is expected to be used for repairing bone defects after tumor resection.

The present invention will be described in detail below with reference to specific examples.

Example 1

20mg of bioceramic (SrCuSi) is taken₄O₁₀) Dispersing the blocks into a water solution, carrying out ultrasonic stripping on the biological ceramic blocks by using a cell disruptor, wherein the ultrasonic power is 1000W, the time is 6h, and the obtained biological ceramic nanosheets are enriched in a segmented centrifugation mode (4000-8000 rmp).

Scanning Electron Microscope (SEM) photographs of the bioceramic bulk material used in this example and Transmission Electron Microscope (TEM) photographs of the prepared bioceramic nanosheets are shown in fig. 2.

FIG. 2b shows that the size of the prepared biological ceramic nanosheet is 200-300 nm, and the thickness is 5-10 nm.

Example 2

Composite porous scaffolds were prepared in varying ratios by extrusion 3D printing techniques. Briefly, a biopolymer (polycaprolactone, PCL) and SrCuSi are mixed₄O₁₀The nanosheets (2, 4, 8 wt%) were mixed uniformly in chloroform and cast onto the inner wall of a beaker to form a thin film. After evaporation of the chloroform, the composite film was transferred to a printing syringe for 3D printing (bioscafmelt 3.1, Gesim, germany) at a printing temperature of 80 ℃. As a control, pure PCL scaffolds were also 3D printed using the same procedure.

The macro photograph and SEM photograph of the composite porous scaffold prepared in this example are shown in fig. 3, the ion release property is shown in fig. 4, and the photothermal property is shown in fig. 5.

The macroscopic photograph (a) of FIG. 3 shows the following SrCuSi₄O₁₀The content of the nanosheets is increased, and the integral transparency of the support is reduced; SEM photograph (b) shows that the scaffolds were similar in size and regular in structure with no significant difference.

FIG. 4 shows that the active elements Sr, Cu, Si can be released from the composite porous scaffold continuously, and the release amount is along with SrCuSi₄O₁₀The content of the nano sheets is increased.

FIG. 5 shows that the composite porous scaffold has very good photothermal conversion performance compared with a pure PCL scaffold, and the photothermal intensity of the scaffold is along with SrCuSi₄O₁₀The content of the nano sheets is increased.

Example 3

SrCuSi obtained in example 2₄O₁₀The composite porous scaffold with the nano-sheet content of 4 percent is implanted near subcutaneous tumors of tumor-bearing mice, and the tumors are killed by generating a photothermal effect by irradiating materials with 1064nm laser. The tumor volume curve of figure 6 shows that the laser irradiation composite porous scaffold group can effectively inhibit tumor growth with low degree, which indicates that the material has good anti-tumor effect.

Example 4

SrCuSi obtained in example 2₄O₁₀The composite porous scaffold with the nano-sheet content of 4 percent is implanted into skull defects of rats, and the pure biological high molecular scaffold is used as a contrast.

The hematoxylin-eosin (H & E) photograph of figure 7 shows that the sample prepared in this example shows that after being applied to the repair of rat skull, obvious new bone growth is observed, indicating that the material has good osteogenesis promoting effect.

As can be seen from the above examples, the present invention is based on SrCuSi₄O₁₀The nano-sheet has good photo-thermal conversion performance and bioactivity, and is compounded with PCL by using a 3D printing technology to prepare SrCuSi₄O₁₀The nano-sheet/PCL composite porous scaffold has high mechanical strength and photo-thermal performance and biological activity of the biological ceramic nano-sheet. The stent is implanted into the bodyOn the other hand, Sr, Cu and Si active elements released by the material degradation are beneficial to the growth of blood vessels and the formation of new bones, and can promote the regeneration of bone defects. The preparation method provided by the invention has the advantages of simple process and low preparation cost, and meets the requirements of industrial production. The multifunctional composite scaffold has the advantages that the construction elements of the multifunctional composite scaffold are all biological macromolecules or bioactive ceramics which are safe to human bodies, and the multifunctional composite scaffold has good biocompatibility, biodegradability and bioactivity and has good application prospects.

It will be understood that modifications and variations can be made by persons skilled in the art in light of the above teachings, and all such modifications and variations are intended to be included within the scope of the invention as defined in the appended claims.