WO2022120902A1

WO2022120902A1 - Bone repair scaffold and preparation method therefor

Info

Publication number: WO2022120902A1
Application number: PCT/CN2020/136555
Authority: WO
Inventors: 赖毓霄; 张原驰; 张卫
Original assignee: 深圳先进技术研究院
Priority date: 2020-12-11
Filing date: 2020-12-15
Publication date: 2022-06-16
Also published as: CN114618014A

Abstract

A bone repair scaffold. The materials of the bone repair scaffold include shape memory polyurethane and magnesium metal, wherein the mass ratio of the shape memory polyurethane to the magnesium metal is 100:(1-10). A preparation method for the bone repair scaffold comprises: dissolving shape memory polyurethane into an organic solvent, adding magnesium metal, stirring and mixing same to obtain a printing precursor liquid; obtaining a scaffold blank from the printing precursor liquid by means of a 3D printing process; and carrying out cooling drying on the scaffold blank to obtain the bone repair scaffold. By adding the magnesium metal, the mechanical strength of the bone repair scaffold is improved, and the bone repair scaffold has a good osteanagenesis promotion performance; and the preparation method for the bone repair scaffold has the advantages of a simple process flow and easy industrial implementation, and has wide applicability.

Description

Bone repair scaffold and preparation method thereof

technical field

The invention belongs to the technical field of biomedicine, and particularly relates to a bone repair support and a preparation method thereof.

Background technique

The repair of large-scale bone defects caused by fractures, trauma, etc. has always been one of the most concerned issues in the field of public health. To address the limitations of autologous bone transplantation, bone tissue engineering has been continuously developed in recent years. Bone repair scaffolds, as an important means of internal fixation of bone defects caused by fractures and osteoporosis, have always received a lot of attention. When bone defects occur, the reduction of bone quality directly affects the stability and holding power of the fixture. Traditional scaffold materials are three-dimensional scaffolds with certain stability, such as rectangles, cubes, cylinders, etc., so as to form a relatively stable growth space for new tissue after implantation, but many clinical bone defects are irregular defects. , it is difficult for a material with a fixed shape to completely repair the defective space. In addition, there are currently many clinical surgical plans that pursue minimally invasive treatment, and traditional stent materials are difficult to implement.

In recent years, with the rapid development of medical technology and material technology, more polymer materials have been used in bone repair and bone repair scaffolds, and have achieved good fixation and repair effects. Compared with metal internal fixation, its most clinical appeal is that the polymer material has excellent biocompatibility and will not cause secondary infection. However, for the bone defect internal fixator made of general polymer materials, the weak mechanical properties limit its wide application. According to the article published by Rezwan, Kurosh et al. in 2006 (Biomaterials 27.18 (2006): 3413-3431), in vivo degradable polymer bone scaffold products, there is a problem of insufficient mechanical properties.

As a smart medical material with both biocompatibility and shape memory function, shape memory polymer can deform and compress the material to a smaller size as required, and can restore its original shape in a specific environment when implanted in the human body. This special function provides a more convenient and stable direction for the realization of minimally invasive surgery and the fixation and support of bone defects, especially the shape memory material regulated by near-infrared light, which can realize the remote regulation of implanted materials in vivo. How to improve the mechanical properties of shape memory polymer bone repair scaffolds is a problem that needs to be solved in the industry.

SUMMARY OF THE INVENTION

In view of the deficiencies in the prior art, the present invention provides a bone repair scaffold and a preparation method thereof, so as to solve the problem of poor mechanical properties of the existing shape memory polymer bone repair scaffold.

In order to achieve the above object of the invention, one aspect of the present invention is to provide a bone repair scaffold, the material of the bone repair scaffold includes shape memory polyurethane and metal magnesium, and the mass ratio of the shape memory polyurethane to the metal magnesium is 100. : (1 to 10).

Wherein, the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(3-5).

Wherein, the particle size of the metallic magnesium is 40 μm˜100 μm.

Wherein, the particle size of the metallic magnesium is 50 μm˜80 μm.

Wherein, based on the mass of the shape memory polyurethane as 100%, the shape memory polyurethane is formed by the reaction of the following raw material components: 23.0%-25.0% diphenylmethane diisocyanate, 7.0%-8.0% chain extension agent and 67.0% to 70.0% of polycaprolactone diol.

Wherein, the ratio of the isocyanate groups contained in the diphenylmethane diisocyanate to the hydroxyl groups of all the raw materials participating in the reaction is (1.0-1.2):1.

Wherein, the chain extender is selected from any one of 1,4-butanediol, 1,6-hexanediol and ethylene glycol.

Wherein, the number average molecular weight of the polycaprolactone diol is 3000-8000.

Another aspect of the present invention is to provide a preparation method of the above-mentioned bone repair scaffold, comprising:

Dissolving the shape memory polyurethane in an organic solvent, adding metal magnesium, stirring and mixing to obtain a printing precursor liquid;

obtaining the scaffold embryo by using the printing precursor solution through a 3D printing process;

The scaffold embryo body is freeze-dried to obtain the bone repair scaffold.

Wherein, in the 3D printing process, the printing speed is 0.1mm/s～1.5mm/s, the temperature of the printing nozzle is 10℃～20℃; the temperature of the freeze drying is -80℃～-70℃, and the time is 48h ~72h.

The material of the bone repair scaffold provided by the embodiment of the present invention includes shape memory polyurethane (SMPU) and metal magnesium (Mg). By adding metal magnesium, it has the following beneficial effects: (1), the mechanical strength of the bone repair scaffold is improved. (2) Magnesium ions can stimulate the sensory nerve terminals in the natural periosteum to release more neurotransmitters, further promote the osteogenic differentiation of stem cells in the periosteum, so that the bone repair scaffold has good bone regeneration performance; (3) ), magnesium has a photothermal effect, under the irradiation of near-infrared light, the magnesium in the composite material converts light energy into heat energy, activates the thermal response mechanism of SMPU, realizes shape recovery in vivo, and provides long-range stimulation-response for bone repair scaffolds Feasibility of regulation.

In the preparation method of the bone repair scaffold provided by the embodiment of the present invention, a bone repair scaffold is rapidly formed under low temperature conditions through a 3D printing process, and its morphology and structure can be controlled in a variety of ways, and a porous scaffold with controllable and uniform pore size can be prepared. , which has the advantages of simple process flow, easy industrialization implementation, and wide applicability.

Description of drawings

Fig. 1 is the test curve diagram of the photothermal effect of the bone repair scaffold in the embodiment of the present invention;

Fig. 2 is the test curve diagram of the stress-strain of the bone repair scaffold in the embodiment of the present invention;

Fig. 3 is the test curve diagram of the shape memory performance of the bone repair scaffold in the embodiment of the present invention;

FIG. 4 is a cell live and dead staining diagram of the bone repair scaffold in the embodiment of the present invention.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings. Examples of these preferred embodiments are illustrated in the accompanying drawings. The embodiments of the invention shown in the drawings and described with reference to the drawings are merely exemplary and the invention is not limited to these embodiments.

Here, it should also be noted that, in order to avoid obscuring the present invention due to unnecessary details, only the structures and/or processing steps closely related to the solution according to the present invention are shown in the drawings, and the related structures and/or processing steps are omitted. Other details not relevant to the invention.

The embodiment of the present invention first provides a bone repair scaffold, the material of the bone repair scaffold includes shape memory polyurethane (SMPU) and metal magnesium (Mg), and the mass ratio of the shape memory polyurethane to the metal magnesium is 100: (1 to 10).

By adding metal magnesium to shape memory polyurethane to form a bone repair scaffold, firstly, the mechanical strength of the bone repair scaffold is improved; secondly, magnesium ions can stimulate the sensory nerve endings in the natural periosteum to release more neurotransmitters. It further promotes the osteogenic differentiation of stem cells in the periosteum, so that the bone repair scaffold has a good performance of promoting bone regeneration; thirdly, magnesium has a photothermal effect. Under the irradiation of near-infrared light, the magnesium in the composite material converts light energy into heat energy, Activating the thermal response mechanism of SMPU to achieve shape recovery in vivo provides the feasibility of remote stimulus-response regulation for bone repair scaffolds.

In a preferred solution, the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(3-5). More preferably, the mass ratio of the two is selected to be 100:4.

In a preferred solution, the particle size of the metal magnesium is 40 μm˜100 μm. In a more preferred solution, the particle size of the metal magnesium is 50 μm to 80 μm, the metal magnesium with a larger particle size range is easier to disperse in the shape memory polyurethane, and the formed bone repair scaffold has higher mechanical strength.

In a preferred solution, based on the mass of the shape memory polyurethane as 100%, the shape memory polyurethane is formed by the reaction of the following raw material components: 23.0%-25.0% of diphenylmethane diisocyanate, 7.0%-8.0% % of chain extender and 67.0% to 70.0% of polycaprolactone diol.

Wherein, the ratio of the isocyanate groups contained in the diphenylmethane diisocyanate to the hydroxyl groups of all the raw materials participating in the reaction is (1.0-1.2):1, preferably 1:1.

Wherein, the chain extender is selected from any one of 1,4-butanediol, 1,6-hexanediol and ethylene glycol, and 1,4-butanediol is preferably used.

Wherein, the number average molecular weight of the polycaprolactone diol is 3000-8000, preferably 5000.

The embodiment of the present invention also provides a preparation method of the above-mentioned bone repair scaffold, and the preparation method includes the following steps:

Step 1: Dissolving the shape memory polyurethane in an organic solvent, adding metal magnesium, stirring and mixing to obtain a printing precursor liquid.

In a preferred solution, the shape memory polyurethane is prepared by the following process:

(1) Place diphenylmethane diisocyanate, chain extender and polycaprolactone diol respectively in a vacuum drying oven for a certain period of time to completely remove moisture. The specific drying process conditions are, for example, drying in a vacuum environment at a temperature of 105° C. for more than 2 hours.

(2), mixing and stirring the dried diphenylmethane diisocyanate, the chain extender and the polycaprolactone diol in a predetermined proportion, heating up to the reaction temperature and continuing to stir. The specific drying process conditions are, for example, the temperature is raised to 85° C. and the reaction temperature is kept at 85° C., the stirring speed is set to 150 rmp/min, and the stirring time is 5 min.

(3), pour the reaction mixture into a polytetrafluoroethylene mold quickly after stirring, put it into an oven to solidify, and obtain the SMPU solid. Specifically, the temperature of the oven can be set to 85°C, and the curing time can be 16h.

In a more preferred solution, the ratio of the isocyanate group contained in diphenylmethane diisocyanate (MDI) to the hydroxyl group of all the raw materials participating in the reaction is 1:1, and the chain extender (BDO) is selected as 1,4 -Butanediol, polycaprolactone diol (PCL-diol) has a number average molecular weight of 5000. Among them, PCL-diol constitutes the soft segment of the SMPU, and BDO and MDI constitute the hard segment of the SMPU. The reaction formula is as follows:

in

Specifically

In a preferred scheme, the organic solvent is preferably a mixed solvent of 1,4-dioxane and dimethyl sulfoxide, and the volume ratio of 1,4-dioxane and dimethyl sulfoxide is preferably 5: 1. After the shape memory polyurethane is completely dissolved in the mixed solvent, the metal magnesium is added, and the quality of the added metal magnesium is controlled so that the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(1～10), preferably 100:(3～ 5), most preferably 100:4.

Step 2, using the printing precursor solution to obtain a scaffold embryo body through a 3D printing process.

Specifically, the printing device is preferably a low temperature rapid prototyping (LT-RP) printer, the printing speed can be set to 0.1mm/s～1.5mm/s, and the temperature of the printing nozzle can be set to 10℃～20℃. In a preferred solution, the printing speed is 0.2 mm/s, and the temperature of the printing nozzle is 12°C.

Step 3, freeze-drying the scaffold embryo to obtain the bone repair scaffold.

Wherein, the temperature of the freeze-drying is -80°C～-70°C, and the time is 48h～72h.

The preparation method of the bone repair scaffold provided in the above embodiment can be rapidly formed into a bone repair scaffold through a 3D printing process under low temperature conditions. It has the advantages of simple process flow and easy industrialization implementation, and has wide applicability.

The bone repair scaffold provided by the embodiment of the present invention is subjected to deformation and compression treatment at a temperature of 55°C to 65°C, and is cooled and shaped at room temperature. Under the irradiation (wavelength is 808nm, power density range is P=0.5w/cm ² ~ 2w/cm ² , power density is preferably 1w/cm ² ), the bone repair scaffold gradually returns to its natural state, and the bone defect is further fixed and supported site and promote the growth and healing of bone tissue.

Example 1

(1) Dry PCL-diol, MDI and BDO in a vacuum drying oven at a vacuum environment of 105°C for more than 2 hours to completely remove moisture.

(2) After drying, PCL-diol, MDI and BDO were mixed and stirred in proportion, the reaction temperature was kept at 85° C., the stirring speed was 150 rmp/min, and the stirring time was 5 minutes.

(3) After the stirring is completed, the mixture is quickly poured into a polytetrafluoroethylene mold, placed in an oven for curing for 16 hours, and the temperature is maintained at 85 ° C to obtain SMPU solid.

(4), stir and dissolve the prepared SMPU with a mixed solution of 1,4-dioxane and dimethyl sulfoxide (volume ratio is 5:1), add metal Mg after the SMPU is completely dissolved, and mix uniformly to prepare into printing fluid. The metal Mg added in this embodiment makes the mass percentage of Mg relative to SMPU to be 2%, that is, the mass ratio of SMPU to Mg is 100:2.

(5), using the LT-RP printer for 3D printing with the printing liquid of the above step (4), the filling speed of the nozzle is 0.2 mm/s, and the temperature of the nozzle is 12°C.

(6) After printing, freeze-dry at -80°C for 2 days to obtain the SMPU composite bone repair scaffold sample S-1 with shape memory function.

Example 2

The difference between this example and Example 1 is that the metal Mg added in step (4) of Example 1 makes the mass percentage of Mg relative to SMPU to be 4%, that is, the mass ratio of SMPU to Mg is 100:4, The rest of the process is the same as that of Example 1. In this example, the bone repair scaffold sample S-2 was prepared and obtained.

Example 3

The difference between this example and Example 1 is that the metal Mg added in step (4) of Example 1 makes the mass percentage of Mg relative to SMPU to be 6%, that is, the mass ratio of SMPU to Mg is 100:6, The rest of the process is the same as that of Example 1. In this example, the bone repair scaffold sample S-3 was prepared and obtained.

Example 4

The difference between this example and Example 1 is that the metal Mg added in step (4) of Example 1 makes the mass percentage of Mg relative to SMPU to be 8%, that is, the mass ratio of SMPU to Mg is 100:8, The rest of the process is the same as that of Example 1. In this example, the bone repair scaffold sample S-4 was prepared.

Comparative ratio

The difference between the comparative example and the examples 1-4 is that Mg is not added in step (4), that is, the Mg content is 0%, and the rest of the process is the same as that of the examples 1-4. Comparative Example Preparation of bone repair scaffold sample S-0.

The raw materials used in Comparative Examples and Examples 1-4 and their consumptions are shown in the following table:

The photothermal effect test of the bone repair scaffolds obtained in Examples 1-4 and Comparative Examples is shown in FIG. 1 . The wavelength of the irradiated near-infrared light was 808 nm, and the power density was 1 w/cm ² . The sample of the comparative example has basically no temperature rise. The temperature of the samples of Examples 1-4 increases with the increase of the irradiation time. The temperature of the sample of Example 4 rises relatively fastest, and the rise is also the largest, and the photothermal effect is the best. .

The stress-strain tests of the bone repair scaffolds obtained in Examples 1-4 and Comparative Examples are shown in FIG. 2 . Among them, the compressive strength of the sample of Example 4 is the highest, and the compressive strength of the sample of Example 2 and Example 3 is not much different.

The shape memory properties of the bone repair scaffolds obtained in Examples 1-4 and Comparative Example under the irradiation of near-infrared light (wavelength of 808 nm, power density of 1 w/cm ² ) are shown in FIG. 3 . The comparative example had a higher fixation rate, but almost no response. In the samples of Examples 1-4, as the Mg content increases, the shape fixation rate of the samples increases, but the recovery rate decreases.

The cytocompatibility comparison of the bone repair scaffolds obtained in Examples 1-4 and the comparative example is shown in FIG. 4 . Compared with the cells of the blank group (no sample) and the live and dead staining of the comparative example, the cells in Examples 1-4 have a more obvious number of live cells, and the higher the number of live cells, the better the compatibility of the sample cells, and The number of dead cells (middle column of images) in Comparative Examples and Examples was also very low, indicating that the samples of Examples 1-4 had better cytocompatibility.

Based on the above test results, the sample in Example 2 has the most balanced photothermal effect, mechanical strength, shape memory performance and biocompatibility. Therefore, in the composite bone repair scaffold provided in the embodiment of the present invention, SMPU and Mg The mass ratio is preferably 100:(3 to 5), and most preferably 100:4.

The bone repair scaffold provided by the present invention improves the mechanical strength of the bone repair scaffold by adding metal magnesium and has a good performance of promoting bone regeneration, and can utilize the photothermal effect of magnesium to provide the bone repair scaffold with remote stimulation-response regulation and control. Feasibility; the preparation method of the bone repair scaffold of the present invention has the advantages of simple process flow, easy industrialization and wide applicability.

The above are only specific embodiments of the present application. It should be pointed out that for those skilled in the art, without departing from the principles of the present application, several improvements and modifications can also be made. It should be regarded as the protection scope of this application.

Claims

A bone repair scaffold, wherein the material of the bone repair scaffold comprises shape memory polyurethane and metal magnesium, and the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(1-10).
The bone repair scaffold according to claim 1, wherein the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(3-5).
The bone repair scaffold according to claim 2, wherein the mass ratio of the shape memory polyurethane to the metal magnesium is 100:4.
The bone repair scaffold according to claim 1, wherein the particle size of the metal magnesium is 40 μm to 100 μm.
The bone repair scaffold according to claim 4, wherein the particle size of the metal magnesium is 50 μm to 80 μm.
The bone repair scaffold according to claim 1, wherein, based on the mass of the shape memory polyurethane as 100%, the shape memory polyurethane is formed by the reaction of the following raw material components: 23.0%-25.0% of diphenylmethane Diisocyanate, 7.0%-8.0% chain extender and 67.0%-70.0% polycaprolactone diol.
The bone repair scaffold according to claim 6, wherein the ratio of the isocyanate group contained in the diphenylmethane diisocyanate to the hydroxyl group of all the raw materials participating in the reaction is (1.0-1.2):1.
The bone repair scaffold according to claim 7, wherein the ratio of the isocyanate group contained in the diphenylmethane diisocyanate to the hydroxyl group of all the raw materials participating in the reaction is 1:1.
The bone repair scaffold according to claim 6, wherein the chain extender is selected from any one of 1,4-butanediol, 1,6-hexanediol and ethylene glycol.
The bone repair scaffold according to claim 6, wherein the polycaprolactone diol has a number average molecular weight of 3000-8000.
A preparation method of a bone repair scaffold, comprising:

Dissolving the shape memory polyurethane in an organic solvent, adding metal magnesium, stirring and mixing to obtain a printing precursor liquid;

using the printing precursor solution to obtain a scaffold embryo body through a 3D printing process;

The scaffold embryo body is freeze-dried to obtain the bone repair scaffold.
The method for preparing a bone repair scaffold according to claim 11, wherein, in the 3D printing process, the printing speed is 0.1mm/s～1.5mm/s, and the temperature of the printing nozzle is 10℃～20℃; the freeze drying The temperature is -80℃～-70℃, and the time is 48h～72h.
The method for preparing a bone repair scaffold according to claim 11, wherein the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(1-10).
The method for preparing a bone repair scaffold according to claim 11, wherein the mass ratio of the shape memory polyurethane to the metal magnesium is 100:(3-5).
The method for preparing a bone repair scaffold according to claim 11, wherein the particle size of the metal magnesium is 40 μm˜100 μm.
The method for preparing a bone repair scaffold according to claim 15, wherein the particle size of the metal magnesium is 50 μm˜80 μm.
The preparation method of the bone repair scaffold according to claim 11, wherein, based on the mass of the shape memory polyurethane as 100%, the shape memory polyurethane is formed by the reaction of the following raw material components: 23.0%-25.0% of the two Phenylmethane diisocyanate, 7.0%-8.0% chain extender, and 67.0%-70.0% polycaprolactone diol.
The preparation method of bone repair scaffold according to claim 17, wherein, the ratio of the isocyanate group contained in the diphenylmethane diisocyanate to the hydroxyl group of all the raw materials participating in the reaction is (1.0～1.2): 1.
The method for preparing a scaffold for bone repair according to claim 17, wherein the chain extender is selected from any one of 1,4-butanediol, 1,6-hexanediol and ethylene glycol.
The method for preparing a bone repair scaffold according to claim 17, wherein the polycaprolactone diol has a number average molecular weight of 3000-8000.