Shape memory material with chelating system and method for its production

Abstract

The application belongs to the technical field of bone tissue repair materials, and provides a shape memory material with a chelating system.The shape memory material with the chelating system comprises polyurethane and a metal complex with a mass ratio of 100:1-10, wherein the polyurethane is formed by reaction of components comprising the following mass fractions: diphenylmethane diisocyanate 9.0%-10.0%; chain extender 0%-2.0%; chelating agent 0%-3.0%; polycaprolactone glycol 87.0%-88.0%. The application provides a novel shape memory polyurethane-manganese dioxide (SMPU-MnO2) chelating material, the mechanical strength, shape memory performance and Mn 2+ The shape recovery is remotely controlled under near-infrared light by utilizing the photo-thermal effect of manganese dioxide, the self-fixing filling in the irregular bone defect site is realized, and the manganese ions are released to realize the biological function of bone repair.

Description

Technical Field

[0001] This invention belongs to the field of bone tissue repair materials technology, specifically relating to a shape memory material with a chelation system and its preparation method. Background Technology

[0002] Repairing large-scale bone defects caused by fractures, trauma, and other injuries has long been a top concern in public health. To address the limitations of autologous bone grafting, bone tissue engineering materials have seen continuous development in recent years. Shape memory polymers (SMPs), as a type of stimulus-responsive smart material, have been used in bone defect repair research. Besides enabling minimally invasive surgery and possessing biocompatibility, they can also achieve self-fixation by tightly filling irregular defects after implantation, enhancing the interaction between the material and the tissue interface. Furthermore, to meet the bio-environment requirements of bone repair, SMPs are often composited with inorganic nanoparticles to improve the material's mechanical strength and bioactivity. Shape memory polyurethane (SMPU) is a typical SMP. It can be given a specific temporary shape and fixed under certain external conditions; subsequently, when exposed to external stimuli such as heat, light, electricity, or water, SMPU responds, returning from the temporary shape to its initial shape, completing a shape memory cycle, and even achieving the memory of multiple states and reversible deformation. SMPU also features lightweight, good recovery performance, mild recovery conditions, good biocompatibility, and low cost, leading to its rapid development in recent years. Shape memory polymers (SMPUs) generally consist of two parts: a molecular chain network structure and a switch. The former, usually composed of cross-linked polymer molecular chains, determines the recovery properties and initial shape of the SMPU; while the latter, formed by the crystal-melt transition of the semi-crystalline structure, the glass transition of amorphous regions, or the reversible switching of chemical bonds, determines the fixation of the temporary shape of the SMPU. Different functions or stimulus-response mechanisms can be easily designed by selecting specific components to meet different application needs. Researchers both domestically and internationally have reported the application of shape memory materials in multiple fields, including aerospace, textiles and apparel, artificial intelligence, and biomedicine. Currently reported intelligent medical materials / devices include biodegradable self-contracting surgical sutures, artificial muscles, self-deploying memory cardiac scaffolds, and vascular scaffolds. In the field of bone repair, scaffolds based on shape memory materials can be compressed to a smaller size before implantation, and after implantation, they recover their shape at the defect site and closely fit the irregular defect, achieving self-fixation. This effectively enhances the interaction between the material and tissue interface, such as the concentration of active ingredients and photothermal effects, thereby better inhibiting in situ tumor recurrence or metastasis and promoting bone tissue regeneration at the defect site.

[0003] To meet the requirements of the bone repair environment, SMPU needs further modification to improve its mechanical properties and biological functions. A common solution is to prepare shape memory composites (SMCs) by adding inorganic particulate fillers, thereby endowing them with bioactivity and improving mechanical strength. Manganese dioxide (MnO2) has great research value and clinical application potential. For example, MnO2 can release manganese ions (MnO2) in the bone tumor tissue microenvironment due to acidic conditions and the action of glutathione. 2+ ), while Mn 2+ MnO2 exhibits excellent performance in activating the immune system to inhibit tumors; in addition, it has been used to prepare composite materials to promote bone regeneration. However, even with the addition of inorganic fillers, SMCs may still exhibit some limitations that restrict their clinical application, including the difficulty in precisely controlling the release of active ions. The release of bioactive ions plays an important role in realizing the effectiveness of SMCs' biological functions, but current research both domestically and internationally on the release behavior of active ions in SMCs within the bone repair environment and their biological effects remains insufficient. Furthermore, in a 2007 article, Guarino, Vincenzo, et al. mentioned that shape memory bone repair materials can have their mechanical properties increased by adding inorganic nanoparticles, but their shape memory properties decrease (Expert review of medical devices, 4.3 (2007): 405-418). In 2018, Ruiqi Xie et al. improved upon previous methods, using water as a foaming agent to prepare shape memory polyurethane (SMPU) / hydroxyapatite (HA) composite scaffolds (Biochimica et Biophysica Acta (BBA) - General Subjects 1862.4 (2018): 936-945). However, their synthetic route was complex, and the pore size uniformity of the prepared porous scaffolds was poor. Patent application CN102921038A discloses a method for preparing porous scaffolds with shape memory function, using benzoyl peroxide as a crosslinking initiator, allyl alcohol as a plasticizer, and polycaprolactone diol as a matrix material. However, polycaprolactone diol has certain drawbacks: its melting point is approximately 60°C, and its heat resistance and machinability are poor, with a shape memory performance of only 20%. Furthermore, while SMCs improve mechanical strength, the response temperature required for deformation may exceed body temperature, preventing them from self-restoring their shape in vivo. Therefore, shape memory composite materials (SMCs) currently used for bone repair face the challenges of precisely controlling the release of active ions and achieving synergistic effects in mechanical strength, shape memory properties, and response temperature. Summary of the Invention

[0004] To address the challenges of precisely controlling the release of active ions and achieving synergistic effects of mechanical strength, shape memory properties, and response temperature in existing shape memory composite materials (SMCs) used for bone repair, this invention provides a shape memory material with a chelation system.

[0005] The shape memory material with a chelating system comprises polyurethane and a metal complex in a mass ratio of 100:1-10, wherein the polyurethane is reacted from components comprising the following parts by mass:

[0006]

[0007] Further, the mass ratio of the diphenylmethane diisocyanate, the chain extender, the chelating agent, and the polycaprolactone diol is 11.1:1:15.4:100.

[0008] Furthermore, the ratio of the number of hydroxyl groups in the chain extender, the chelating agent, and the polycaprolactone diol to the number of isocyanate groups in the diphenylmethane diisocyanate is 1.0-1.2:1.

[0009] Furthermore, the metal complex is manganese dioxide with a particle size of 20-100 nanometers, and the mass ratio of manganese dioxide to polyurethane is 2-10:100, preferably 10:100.

[0010] Furthermore, the chelating agent is selected from one of pyridinediethanol, N,N-bis(2-hydroxyethyl)isonicotinamide and 2,2-dihydroxymethylpropionic acid.

[0011] Furthermore, the chain extender is selected from one of 1,4-butanediol, 1,6-hexanediol, and ethylene glycol.

[0012] Furthermore, the number-average molecular weight of the polycaprolactone diol is 3000-8000.

[0013] One object of the present invention is to provide a method for preparing shape memory materials with a chelation system.

[0014] The preparation method of the shape memory material with a chelation system includes the following steps:

[0015] S1: Mix dried polycaprolactone diol and diphenylmethane diisocyanate and react them at a reaction temperature of 85°C, a stirring speed of 150 rpm / min, and a stirring time of 2-3 hours.

[0016] S2: Chain extender and chelating agent are dispersed in solvent and added dropwise to the prepolymer formed in S1. The reaction continues and the prepolymer is cured to obtain polyurethane.

[0017] S3: Weigh the polyurethane and metal complex at a mass ratio of 100:10, dissolve the weighed polyurethane in an organic solvent, add the metal complex to react, and cure to obtain the shape memory material with chelation system.

[0018] This invention provides a novel shape memory polyurethane-manganese dioxide (SMPU-MnO2) chelate material, which achieves its mechanical strength, shape memory properties, and MnO2 content through a chelation system. 2+ The synergistic release of manganese dioxide utilizes the photothermal effect of manganese dioxide to achieve shape recovery under remote control of near-infrared light, enabling self-fixation and filling of irregular bone defects. The responsive release of manganese ions realizes the biological function of bone repair. Attached Figure Description

[0019] Figure 1 Surface morphology and elemental distribution diagrams;

[0020] Figure 2 Infrared spectrum;

[0021] Figure 3 XPS N1s spectrum;

[0022] Figure 4 This refers to the concentration of manganese ions released.

[0023] Figure 5 To investigate the effects of different manganese ion concentrations on promoting bone differentiation;

[0024] Figure 6 The mechanical strength comparison diagrams are as follows: (a) Comparison of modulus in the thin film state; (b) Comparison of maximum compressive force after fabrication of bone repair devices (porous scaffolds);

[0025] Figure 7 It combines photothermal effect and shape memory effect. Detailed Implementation

[0026] To make the above-mentioned objects, features and advantages of the present invention more apparent and understandable, the specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but this should not be construed as limiting the scope of the present invention.

[0027] To address the challenges of precisely controlling the release of active ions and synergistic effects of mechanical strength, shape memory properties, and response temperature in current shape memory composite materials (SMCs) used for bone repair, this invention aims to provide a shape memory material with a chelation system that can responsively release active ions and synergistically enhance multiple material properties, improving processability, mechanical properties, bone-promoting properties, and shape memory properties. Furthermore, the manufacturing method of this material is relatively simple, easy to implement in industrial applications, and has broad applicability.

[0028] In this patent application, the description of the molecular weight of polycaprolactone diol raw material refers to the average molecular weight of the raw material product, not the molecular weight of each polymer molecule.

[0029] In the raw materials used in the preparation method of SMPU / MnO2 chelate materials provided in the comparative examples and embodiments of the present invention, the polycaprolactone diol (PCL-diol) has a molecular weight of 5000; the chain extender used is 1,4-butanediol (BDO); ​​and the chelating agent used is pyridinediethanol (PDM). Optionally, pyridinediethanol can be replaced with small molecule compounds such as N,N-bis(2-hydroxyethyl)isonicotinamide and 2,2-dimethylolpropionic acid, which simultaneously have bis / trihydroxy and pyridine nitrogen / carboxyl groups. PCL-diol constitutes the soft segment of SMPU, while BDO, PDM, and diphenylmethane diisocyanate (MDI) constitute the hard segment of SMPU. In the SMPU / MnO2 chelate material, the mass fraction of MnO2 (relative to SMPU) is 10% in the examples. Optionally, manganese dioxide can be replaced with other metals and their oxides that can form active metal coordination bonds. The raw materials and their amounts used in comparative examples 1-4 and embodiments 1-2 of the present invention are shown in the table below:

[0030]

[0031] The preparation method of polyurethane (SMPU) in the comparative examples and embodiments includes the following steps:

[0032] 1. Dry PCL-diol, MDI and BDO in a vacuum drying oven at 105°C for more than 2 hours to completely remove moisture;

[0033] 2. After drying, mix PCL-diol and MDI in proportion and stir. Maintain the reaction temperature at 85°C, the stirring speed at 150 rpm, and the stirring time at 2-3 hours.

[0034] 3. BDO and PDM are first stirred and dispersed in 10ml of tetrahydrofuran at a certain ratio for 1 hour, then ultrasonically dispersed for 1 hour. After that, the mixed solution is added dropwise to the prepolymer solution and the reaction is continued with stirring for 5-10 minutes.

[0035] 4. After stirring, quickly pour the mixture into a polytetrafluoroethylene mold, place it in an oven to cure for 16 hours, and maintain the temperature at 85°C to obtain solid SMPU.

[0036] The preparation methods of MnO2-containing materials in Comparative Example 4 and Examples 1-2 include the following steps:

[0037] 1. Dissolve the prepared SMPU in an organic solvent by stirring;

[0038] 2. After the SMPU has completely dissolved, add MnO2 (mass ratio of SMPU:MnO2 = 100:10) and stir thoroughly to mix well;

[0039] 3. After stirring, quickly pour the mixture into a polytetrafluoroethylene mold, place it in an oven to cure for 16 hours, and maintain the temperature at 85°C to obtain solid SMPU.

[0040] Compared with the prior art, the advantages of the present invention are reflected in the following aspects:

[0041] 1. This invention addresses the characteristics of bone repair, especially the problems of large, irregular, and easily recurring bone defects that are difficult to heal after osteosarcoma surgery. It proposes a shape memory polyurethane-manganese dioxide chelate material to achieve a self-fixation function that tightly fills irregular defect sites and enhances the interaction between the material and the tissue interface.

[0042] 2. The chelating material described in this invention can possess shape memory properties, improve the mechanical strength of the material, and simultaneously release active metal ions in response, effectively promoting regeneration and making it more suitable for real bone repair environments.

[0043] 3. Traditional shape memory devices mostly utilize body temperature response, which limits the mechanical properties of the materials and the response environment. This invention uses near-infrared light to activate the photothermal effect of the material to regulate the in vivo response process, thus avoiding the limitation of body temperature on the shape recovery of traditional thermally responsive polyurethane.

[0044] This invention applies the prepared material to the field of bone tissue repair materials, which can solve the problems of difficulty in precisely controlling the release of active ions and difficulty in coordinating mechanical strength, shape memory performance and response temperature. For example, in bone defects, the material can perform shape recovery to enhance the interaction between the material and the tissue interface; in addition, in bone defects caused by bone tumor surgery, it can release manganese ions in response to the tumor microenvironment, activate the body's own immune system and repair the defect at the same time, thus achieving multiple functions.

[0045] For the surface morphology and elemental distribution of Comparative Examples 1-3 and Example 2, please refer to [link / reference]. Figure 1 The presence of the Mn element can be clearly seen in the examples.

[0046] For a comparison of the infrared spectra of Comparative Examples 1-4 and Examples 1-2, please see [link / reference]. Figure 2 The presence of urethane groups in SMPU can be seen in the infrared spectra of all samples.

[0047] XPS N in Examples 1-2 1s For a comparison of the graphs, please see [link / reference]. Figure 3 Compared to N in Comparative Example 4 1s The binding energy position is at 400 eV. In Examples 1 and 2, due to the presence of chelate bonds, N 1sThe binding energy position has shifted to 399 eV.

[0048] For a comparison of manganese ion release concentrations at different glutathione concentrations in Examples 1-2 and Comparative Example 4, please see [link to example]. Figure 4 No chelating agent was added in Comparative Example 4, therefore the prepared sample did not contain a chelating system. Both Examples 1 and 2 contained chelating agents, therefore the prepared samples contained a chelating system. The manganese content added in Examples 1, 2, and Comparative Example 4 was similar. Under glutathione conditions, the concentration of manganese ions released by the samples prepared in Examples 1 and 2 was higher than that released by the sample prepared in Comparative Example 1. The examples containing the chelating system released a higher concentration of active manganese ions than the comparative examples without the chelating system, indicating that the chelates in the shape memory composite material for bone repair provided by this invention can improve the release capacity of manganese ions and the ability to promote bone regeneration, making it suitable for bone tissue repair.

[0049] Figure 5 Quantitative analysis data of Alizarin Red staining at different manganese ion concentrations were provided. It can be seen that the highest data was obtained at a manganese ion concentration of 6 μmol / L, indicating the best osteogenic effect. This demonstrates that different manganese ion concentrations have different effects on cellular osteogenic effects; therefore, the chelation system regulating manganese ion release can better promote bone regeneration. According to... Figure 4 The difference in manganese ion concentration released from the samples in Examples 1 and 2, along with the ingredient list, shows that increasing the manganese content by a small amount can significantly increase the concentration of manganese ions released. Figure 4 In Example 1, the manganese ion release concentration of the sample prepared under glutathione environment can reach as high as 0.2 mg / L, or 3.6 μmol / L. Based on this, the release concentration of the sample at the bone defect site can be increased to 6 μmol / L by adjusting the amount of manganese added to the sample, thus obtaining the best effect of promoting bone differentiation.

[0050] For a comparison of the tensile modulus (thin film state) of Comparative Examples 1-3 and Example 2, please see [link / reference]. Figure 6 a. The tensile modulus of the material increased after the addition of the chelating agent. Among them, Comparative Example 3, which had the highest modulus, and Example 2, which contained composite manganese dioxide, were further manufactured into porous scaffolds, and their maximum compressive forces were compared to... Figure 6 As shown in b. From Figure 6 b. It can be seen that the compressive force of the porous scaffold made from the sample with the chelation system of composite manganese ions prepared in Example 2 is higher than that of the porous scaffold made from the sample without the chelation system of composite manganese ions prepared in Comparative Example 3. This indicates that the presence of a chelation system formed by manganese dioxide in the sample further improves the strength of the sample material.

[0051] For Example 1, please see the section on photothermal effect and shape memory effect. Figure 7This demonstrates that the sample prepared in Example 1 can recover its original shape after 120 seconds of near-infrared light irradiation. The wavelength of the near-infrared light is 808 nm, and the power density is 1 W / cm². 2 .

[0052] The above experimental results demonstrate that the shape memory material with a chelation system provided by this invention contains a chelation structure of composite manganese ions. This chelation structure not only regulates the release concentration of manganese ions to promote bone regeneration but also enhances the mechanical strength of the material. Furthermore, the material can achieve shape self-recovery in response to photothermal changes. Therefore, the shape memory material with a chelation system provided by this invention solves the problems of precise control over the release of active ions and the difficulty in synergistically combining mechanical strength, shape memory performance, and response temperature in existing bone repair materials, thus achieving multifunctionality in bone repair materials.

Claims

1. A shape memory material with a chelation system, characterized in that, The mixture comprises a polyurethane and a metal complex in a mass ratio of 100:10, wherein the polyurethane is formed by reacting the following components in parts by mass: Diphenylmethane diisocyanate 9.0%-10.0%; Chain extender 0%-2.0%; Chelating agent 0%-3.0%; Polycaprolactone diol 87.0%-88.0%; The chain extender is selected from one of 1,4-butanediol, 1,6-hexanediol, and ethylene glycol; The chelating agent is pyridinediethanol; The metal complex is manganese dioxide with a particle size of 20-100 nanometers.

2. The shape memory material with a chelating system as described in claim 1, characterized in that, The number-average molecular weight of the polycaprolactone diol is 3000-8000.

3. A method for preparing a shape memory material with a chelating system as described in any one of claims 1 to 2, characterized in that, Includes the following steps: S1: Mix dried polycaprolactone diol and diphenylmethane diisocyanate and react them at a reaction temperature of 85°C, a stirring speed of 150 rpm, and a stirring time of 2-3 hours. S2: Chain extender and chelating agent are dispersed in solvent and added dropwise to the prepolymer formed in S1. The reaction continues and the prepolymer is cured to obtain polyurethane. S3: Weigh the polyurethane and metal complex according to a mass ratio of 100:10, dissolve the weighed polyurethane in an organic solvent, add the metal complex to react, and cure to obtain a shape memory material with a chelating system.

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