阅读说明：本技术 一种生物可降解PDT/Fe3O4复合材料的制备方法 (Biodegradable PDT/Fe3O4Method for preparing composite material ) 是由 刘昌胜 李玉林 罗炜 刘天舒 于 2020-04-08 设计创作，主要内容包括：本发明涉及医用复合材料领域,公开了一种具有生物相容性和生物可降解性的聚(外消旋丙交酯-三亚甲基碳酸脂)/纳米四氧化三铁(PDT/Fe-(3)O-(4))复合材料,所述方法为：将合成的PDT与一定量的磁性纳米Fe-(3)O-(4)在有机溶剂中借助机械搅拌复合、沉淀、真空干燥,并使用平板硫化机热压获得薄片。本发明合成的PDT-Fe-(3)O-(4)复合材料属于柔性材料,针对传统金属标记夹存在的显影灵敏度差、生物惰性、排异反应等突出问题,具有良好的成像功能、生物可吸收性和生物降解性。(The invention relates to the field of medical composite materials, and discloses poly (racemic lactide-trimethylene carbonate)/nano ferroferric oxide (PDT/Fe) with biocompatibility and biodegradability 3 O 4 ) A composite material, the method comprising: the synthesized PDT and a certain amount of magnetic nano Fe 3 O 4 Compounding by mechanical stirring in an organic solvent, precipitating, vacuum drying, and hot pressing with a flat vulcanizing machine to obtain a thin sheet. PDT-Fe synthesized by the invention 3 O 4 The composite material belongs to a flexible material, and has good imaging function, biological absorbability and biodegradability aiming at the outstanding problems of poor developing sensitivity, biological inertia, rejection reaction and the like of the traditional metal marking clip.)

1. A composite material for development, said composite material being in a solid state and comprising: (a) biodegradable and biocompatible polymers; and (b) ferroferric oxide nanoparticles for development, wherein the average particle diameter of the ferroferric oxide nanoparticles is 50-500nm, and the ferroferric oxide nanoparticles are uniformly dispersed in the biodegradable and biocompatible polymer.

2. The composite material of claim 1, wherein (a) the biodegradable and biocompatible polymer is selected from the group consisting of: PDT, PGA, PLA, PCL, chitosan, hyaluronic acid, etc.

3. The composite material of claim 1, wherein said (a) biodegradable and biocompatible polymer is a PDT polymer.

4. The composite material of claim 1, wherein the average particle size of the ferroferric oxide nanoparticles for developing (b) is 50-500 nm.

5. The composite material of claim 1, wherein the ferroferric oxide nanoparticles used for developing (b) are present in an amount of 0.1 to 8 wt%, based on the total weight of the composite material.

6. The composite material of claim 1 further having the following properties:

(i) developing property: the CT value is obviously different from that of soft tissues;

(ii) biodegradability: can be degraded into micromolecular aliphatic hydroxy acid in biological environment;

(iii) biocompatibility: cytotoxicity is less than grade 1;

(iv) mechanical properties: the tensile modulus is 10-200MPa, the tensile strength is 5-20MPa, and the elongation at break is 400-900%.

7. A method of making the composite material of claim 1, comprising the steps of:

(S1) mixing the ferroferric oxide nanoparticles, the biodegradable and biocompatible polymer and the first solvent to form a first mixture, wherein the biodegradable and biocompatible polymer is soluble in the first solvent;

(S2) adding a second solvent to the first mixture, thereby forming a precipitate from the composite of the ferroferric oxide nanoparticles and the biodegradable and biocompatible polymer; and

(S3) separating the precipitate and drying to obtain the composite material of claim 1.

8. An article comprising or made from the composite material of claim 1.

9. The article of claim 8, made by the method of claim 7.

10. Use of the article according to claims 8 and 9 for the manufacture of marker clips for post-operative localization of breast cancer or also for the tracing of the degradation of polymers in vivo, as a drug carrier and for magneto-caloric therapy is provided.

Technical Field

The invention relates to the field of nano medical composite materials, in particular to a medical composite material with good imaging function, biological absorbability and biodegradability and a preparation method thereof.

Background

In recent years, the incidence rate of breast cancer is high, and the incidence rate of breast cancer in women is the first place of malignant tumor worldwide. Among the various neoplastic diseases, breast cancer is the first leading killer faced by women. Breast cancer-preserving breast therapy recommends postoperative radiation therapy to reduce the risk of local recurrence, wherein Whole Breast Irradiation (WBI) is the leading mode of postoperative radiation therapy, but recent research data show that, for early-stage breast cancer patients, Partial Breast Irradiation (PBI) is the same as WBI, which can reduce the local recurrence rate, and meanwhile, the adverse reaction of radiation therapy and the cosmetic effect are similar, and PBI can replace WBI to a certain extent, while the key point of realizing PBI lies in the accurate positioning of a tumor target area.

The breast cancer postoperative locating clip that currently is clinically commonly used is titanium clip or silver clip mostly, and postoperative radiotherapy indicating action effect is better, but is inert metal, settles and exists for a long time after internal, can't be corroded or degrade, causes great psychological burden for the patient easily, and some case can form local induration simultaneously, influences the differentiation of postoperative follow-up to local relapse, and most patients hold passive accepting state to the metal frame, all brings certain puzzlement for doctor and patient. Therefore, the preparation of a composite material with good developability, excellent degradability and biocompatibility for a marking clip is urgently needed in the field, and the outstanding problems of poor image sensitivity, biological inertness, biological rejection and the like of the traditional metal clip are solved.

Disclosure of Invention

The invention aims to provide a composite material with good developability, excellent degradability and biocompatibility for a marking clip, and solves the outstanding problems of poor image sensitivity, biological inertia, biological rejection and the like of the traditional metal clip.

In a first aspect of the present invention, there is provided a composite material for development, the composite material being in a solid state and comprising: (a) biodegradable and biocompatible polymers; and (b) ferroferric oxide nanoparticles for development, wherein the average particle diameter of the ferroferric oxide nanoparticles is 50-500nm, and the ferroferric oxide nanoparticles are uniformly dispersed in the biodegradable and biocompatible polymer.

In another preferred embodiment, said (a) biodegradable and biocompatible polymer is selected from the group consisting of: PDT, PGA, PLA, PCL, chitosan, hyaluronic acid, etc.

In another preferred embodiment, said (a) biodegradable and biocompatible polymer is PDT polymer.

In another preferred embodiment, said PDT polymer has a molecular weight of 100 × 10³～300×10³Mass-average relative molecular weight of 200X 10³～500×10³What is, what isThe Polymer Dispersion Index (PDI) is 1-2.5, and has the following characteristics: the molecular weight distribution is narrow, and the molding is easy.

In another preferred example, the average particle size of the ferroferric oxide nanoparticles for developing (b) is 50-500 nm.

In another preferred embodiment, the content of the ferroferric oxide nanoparticles for developing (b) is 0.1-8 wt% based on the total weight of the composite material.

In another preferred embodiment, the weight ratio of the ferroferric oxide nanoparticles to the biodegradable and biocompatible polymer is 0.25-10: 100, preferably 0.5-5: 100.

in another preferred example, the ferroferric oxide nanoparticles have superparamagnetism.

In another preferred example, the ferroferric oxide nanoparticles also have the following characteristics: the polydispersity index of the nanoparticles is 0.01-0.4.

In another preferred embodiment, the nano Fe₃O₄The mass concentration of the/PDT is 0.5-5%, preferably 0.5%, 1%, 2% or 4%.

In another preferred embodiment, the composite material also has the following characteristics:

(i) developing property: the CT value is obviously different from that of soft tissues;

(ii) biodegradability: can be degraded into micromolecular aliphatic hydroxy acid in biological environment;

(iii) biocompatibility: cytotoxicity is less than grade 1;

(iv) mechanical properties: the tensile modulus is 10-200MPa, the tensile strength is 5-20MPa, and the elongation at break is 400-900%.

In a second aspect of the present invention, there is provided a method for preparing the composite material of the first aspect of the present invention, comprising the steps of:

(S1) mixing the ferroferric oxide nanoparticles, the biodegradable and biocompatible polymer and the first solvent to form a first mixture, wherein the biodegradable and biocompatible polymer is soluble in the first solvent;

(S2) adding a second solvent to the first mixture, thereby forming a precipitate from the composite of the ferroferric oxide nanoparticles and the biodegradable and biocompatible polymer; and

(S3) separating the precipitate and drying to obtain the composite material of claim 1.

In another preferred embodiment, the biodegradable and biocompatible polymer is a PDT polymer.

In another preferred embodiment, the first solvent is selected from the group consisting of: dichloromethane, trichloromethane and acetone. In another preferred embodiment, the second solvent is selected from the group consisting of: absolute ethyl alcohol, deionized water and absolute ethyl ether.

In another preferred example, the step (S1) includes the steps of: dissolving the biodegradable and biocompatible polymer in a first solvent to form a first solution; and then adding the ferroferric oxide nano particles into the first solution to form a first mixture.

In another preferred embodiment, the first solution is a PDT solution comprising a biodegradable and biocompatible polymer dissolved in methylene chloride solvent at a concentration of 0.5-0.2g/mL (preferably 0.08-0.12g/mL, more preferably about 0.1 g/mL).

In another preferred example, the step (S3) includes: separating the precipitate, and carrying out vacuum drying and hot pressing to obtain a molded product.

In another preferred embodiment, the vacuum drying is carried out at 60. + -. 10 ℃ overnight.

In another preferred example, the hot pressing is hot pressing by a flat vulcanizing machine.

In another preferred embodiment, the molded product is a sheet having a thickness of about 0.2. + -. 0.05 mm.

In another preferred embodiment, said biodegradable and biocompatible polymer is a PDT polymer, and, before step (S1), further comprising a step for preparing PDT:

(S01) under the protection of inert gas, in stannous octoate Sn (Oct)₂Racemizing the monomer in the presence of a catalystReacting lactide (DLLA) with trimethylene carbonate (TMC) to form a reaction product;

(S02) dissolving the reaction product in a first solvent to form a solution;

(S03) adding a second solvent to the solution in the previous step, thereby forming a precipitate;

(S04) separating the precipitate, dissolving in a first solvent to form a solution, and repeating the step (S03), wherein the step (S04) can be repeated 0-2 times; and

(S05) separating the precipitate in the previous step and drying, thereby obtaining a PDT material.

In another preferred example, in the step (S01), the reaction is carried out under the protection of argon and heating condition for a period of time T_S01Thereby obtaining a reaction product.

In another preferred example, in the step (S01), the molar ratio of the monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) is 60-75: 20 to 50, preferably 70: 20 to 50.

In another preferred embodiment, the catalyst is stannous octoate Sn (Oct)₂And the mass ratio of the monomer to the monomer (racemic lactide (DLLA) + trimethylene carbonate (TMC)) is 1.0-1.5: 1000.

in another preferred example, in the step (S01), the heating condition is 100 to 150 ℃; and T_S01Is 1 to 24 hours, preferably 2 to 10 hours.

In another preferred example, in the step (S05), the drying is vacuum drying.

In another preferred example, the reaction product obtained in the step (S01) is subjected to purification and vacuum drying, heat-sealed with aluminum foil, and then stored at low temperature (e.g., about-20 ℃).

In another preferred example, before the step (S1), a step for preparing the ferroferric oxide nanoparticles is further included:

(F1) FeCl is added₃And FeSO₄Dissolving in water to obtain Fe³⁺/Fe²⁺The molar ratio is 2:1, yellow-green ferric salt solution;

(F2) dropwise adding the ferric salt solution into (F1) NaOH solution (with the concentration of 0.5-2mol/L), and violently stirring for 5-15 min under ultrasonic to form black suspension;

(F3) introducing argon gas into the black suspension, stirring, and reacting at 50-100 ℃ for 20-60 (such as about 30min) to form ferroferric oxide nanoparticles;

(F4) magnetically separating the ferroferric oxide nano particles, alternately washing with deoxygenated distilled water and absolute ethyl alcohol, and dispersing with deoxygenated distilled water;

(F5) and (3) freeze-drying the product, and then carrying out vacuum drying at 20-100 ℃ to obtain the ferroferric oxide nanoparticles.

In a third aspect of the invention there is provided an article comprising or made from a composite material according to the first aspect of the invention.

In another preferred embodiment, the product is a marking clip and has the following characteristics: the clamp body is indefinite in shape, and the tail end of the clamp body is provided with a needle hole, so that the clamp body can be fixed at a required position by a suture.

In another preferred embodiment, the article is made by the method of the second aspect of the present invention.

In a fourth aspect of the invention there is provided the use of an article according to the third aspect of the invention for the manufacture of a marker clip for post-operative localization of breast cancer or also for tracing of degradation of polymers in vivo, as a drug carrier and in magneto-caloric therapy.

In another preferred example, the marking clamp has developing performance, so that the tracking and identification of cancer cells after operation can be obviously improved;

in another preferred example, the marker clamp has biodegradability, and can degrade automatically after cancer cell identification and tracking is completed, so that the physiological and psychological burden of a patient is reduced;

in another preferred embodiment, the marker clip is biocompatible and can reduce rejection after implantation in a human body.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows values of elastic modulus and tensile strength for PDT prepared with monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) at different mixing ratios, where "PDT _ X-Y" represents PDT prepared with X moles of DLLA and Y moles of TMC.

FIG. 2 shows elongation at break and energy at break of PDT prepared from monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) at different mixing ratios.

Fig. 3 shows elongation at break and tensile modulus of PDT prepared using ethanol or diethyl ether as the second solvent.

FIG. 4 shows a sample obtained by 3D printing using PDT material prepared in one embodiment of the invention.

Figure 5 shows the apparent morphology of the complex sample. Not mixed with Fe₃O₄The PDT is colorless, transparent and white and is compounded with 4 percent of Fe by mass₃O₄The composite PDT color was significantly darker.

FIG. 6 shows PDT/Fe at different mass concentrations₃O₄Complexes and complex sizes.

FIG. 7 shows PDT/Fe₃O₄The resilience test results for the composite (1%), wherein (a) is before stretching; (b) after deformation of 400%; (c) standing at 37 deg.C for 15s after deformation; (d) the sample was allowed to stand at 37 ℃ for 30 seconds after deformation.

Fig. 8 shows PDT degradation results. Wherein (a) is before degradation; (b) degradation is carried out for 4 weeks; the material before degradation was colorless and transparent, and after 4 weeks of degradation, it became milky white.

FIG. 9 shows scanning electron microscope morphologies of surface and cross-section of PDT before and after degradation. Before degradation, PDT has uniform and non-pattern surface and smooth section; after degradation, uniformly and densely small holes appear on the PDT surface, and irregular holes appear on the cross section.

FIG. 10 shows PDT/Fe₃O₄X-ray imaging function of the complex.

FIG. 11 shows PDT/Fe₃O₄Complex performance at CT. With magnetismSexual nano Fe₃O₄The mass fraction is increased, and the number of high-density points is obviously increased.

Detailed Description

The inventor of the present invention has made extensive and intensive studies and has unexpectedly found for the first time that a composite magnetic nano-Fe₃O₄Particles and absorbable Polymers (PDT) are used to prepare a composite material with good developability, degradability and biocompatibility.

Specifically, the method solves the outstanding problems of poor developing sensitivity, biological inertness, rejection reaction and the like of the traditional inert metal radiotherapy labeling clip, and can control the number average molecular mass and the dispersity index (PDI) of the obtained polymer and enhance the forming capability of PDT by controlling the ratio of the amounts of the racemic lactide (DLLA) and trimethylene carbonate (TMC) monomer substances.

Term(s) for

As used herein, the terms "composite of the present invention", "material of the present invention", "composite for development of the present invention", "composite of the present invention" and the like are used interchangeably to refer to the composite for development described in the first aspect of the present invention.

Composite material for development

The present invention provides a composite material suitable for development, said composite material being in the solid state and comprising: (a) biodegradable and biocompatible polymers; and (b) ferroferric oxide nanoparticles for development, wherein the average particle diameter of the ferroferric oxide nanoparticles is 50-500nm, and the ferroferric oxide nanoparticles are uniformly dispersed in the biodegradable and biocompatible polymer.

The composite material has the characteristics of excellent biocompatibility, high biodegradability, good imaging function and the like, and can be prepared into a proper shape or form for clinical development.

Preferably, the invention provides PDT/nano Fe with the thickness of 0.2mm₃O₄A composite sheet.

Preferably, said biodegradable and biocompatible polymers (also referred to as "organic medical composites") include, but are not limited to: PDT, PGA, PLA, PCL, chitosan, hyaluronic acid, or a combination thereof.

In the present invention, preferred PDT has the following characteristics: number average relative molecular weight 100X 10³～300×10³Mass-average relative molecular weight of 200X 10³～500×10³The Polymer Dispersion Index (PDI) is 1-2.5.

Preferably, PDT of the present invention is performed using a copolymer of racemic lactide (DLLA) and trimethylene carbonate (TMC), wherein the mixing ratio (by moles) of racemic lactide (DLLA) and trimethylene carbonate (TMC) is 78: 22 to 60: 40, preferably 75: 25 to 65: 35, more preferably about 70: 30.

note: the ratio is based on FIGS. 1 and 2 and the following table

Preparation method

The invention also provides a method for preparing the composite material.

Preferably, the invention provides a method for preparing PDT-nano Fe with good biological development function, biocompatibility and biodegradability₃O₄A preparation method of medical composite material. The method solves the outstanding problems of poor developing sensitivity, biological inertness, rejection reaction and the like of the traditional inert metal radiotherapy marking clip, and can control the number average molecular mass and the dispersion index (PDI) of the obtained polymer and enhance the forming capability of PDT by controlling the ratio of the amount of the racemic lactide (DLLA) and trimethylene carbonate (TMC) monomer substances.

Typically, the preparation method of the present invention comprises the steps of:

(S1) mixing the ferroferric oxide nanoparticles, the biodegradable and biocompatible polymer and the first solvent to form a first mixture, wherein the biodegradable and biocompatible polymer is soluble in the first solvent;

(S2) adding a second solvent to the first mixture, thereby forming a precipitate from the composite of the ferroferric oxide nanoparticles and the biodegradable and biocompatible polymer; and

(S3) separating the precipitate and drying to obtain the composite material of claim 1.

Preferably, the composite material of the invention is PDT/Fe₃O₄A composite material.

In a preferred embodiment, the invention provides a method of preparing PDT/Fe₃O₄The method for preparing the composite material specifically comprises the following steps:

(1) synthesis of PDT

S1.1, the ratio of the amounts of monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) material was 70: 10 to 50;

s1.2, selecting a catalyst stannous octoate Sn (Oct)₂The mass ratio of the monomer to the monomer is 1.0 to 1.5: 1000, parts by weight;

s1.3, vacuumizing for 4 hours, heating to 100-150 ℃ in an argon atmosphere, and reacting for 2-10 hours;

s1.4, dissolving and precipitating the product for 2-3 times by using dichloromethane and absolute ethyl alcohol, purifying, and drying in vacuum at 20-100 ℃ to obtain a PDT sample.

S1.5, heat-sealing the product by using an aluminum foil, and storing the product in a refrigerator at the temperature of-20 ℃.

Typically, in the synthesis of PDT, the ratio of the amounts of racemic lactide (DLLA) and trimethylene carbonate (TMC) species is 70: 10 to 50; catalyst stannous octoate Sn (Oct)₂The mass ratio of the monomer to the monomer is 1.0 to 1.5: 1000.

preferably, in the step S1.3, the temperature is raised to 100-150 ℃ in an argon atmosphere, and the reaction time is 2-10 h.

(2) Nano Fe₃O₄Synthesis of (2)

S2.1, dissolving 4g of NaOH solution in 100mL of deoxidized distilled water, and stirring to completely dissolve the NaOH solution to obtain 1mol/L of NaOH solution;

s2.2, respectively taking 5.40g FeCl₃.6H₂O and2.78gFeSO₄.7H₂dissolving O in 20mL of deoxidized distilled water to obtain a yellow-green iron salt solution;

s2.3, dropwise adding the solution obtained in the step S2 into the solution S1 at room temperature, and carrying out ultrasonic vigorous stirring for 5-15 min;

s2.4, mechanically stirring the black suspension obtained in the step S3, introducing argon, and reacting for 30min at 50-100 ℃;

s2.5, magnetically separating a product obtained in the step S4, alternately washing the product for 2 times by using deoxygenated distilled water and absolute ethyl alcohol, and dispersing the product by using the deoxygenated distilled water and the absolute ethyl alcohol;

s2.6, freeze-drying the product, then carrying out vacuum drying at 20-100 ℃ overnight, and putting the product into a dryer for vacuum storage.

Preferably, Fe is obtained after the iron salt in the step S2.2 is dissolved³⁺/Fe²⁺A yellow-green iron salt solution in a molar ratio of about 2: 1.

(3)PDT/Fe₃O₄Preparation of the Complex

S3.1, adding the PDT obtained in the step (1) into a dichloromethane solvent, and dissolving to obtain 0.1g/mL of PDT solution;

s3.2, adding a certain amount of magnetic nano Fe₃O₄Continuing to stir for a period of time;

s3.3, precipitating the product in the last step by using absolute ethyl alcohol, drying the product in vacuum at 60 ℃ overnight, and hot-pressing the dried product into a thin sheet with the thickness of about 0.2mm by using a flat vulcanizing machine.

Preferably, the mass ratio in step S3.2 is nano Fe₃O₄The mass concentration of PDT is 0.5%, 1%, 2% and 4%, respectively, wherein the mass of PDT is 100%.

Articles and uses

The invention also provides the application of the composite material and a corresponding product.

In the present invention, the article comprises or is made from a composite material comprising or made from the composite material of the present invention.

One preferred article is a 3D printed article. The inventors have surprisingly found that the PDT of the present invention, being not only a biodegradable and biocompatible polymer, but also being liquefiable at relatively low temperatures (e.g. 130-.

Typically, the composite material or article of the present invention is applicable in the medical field, for example as a marker clip, or as a magnetic imaging material. The composite material of the present invention can be used for both medical and research purposes.

The main advantages of the invention include:

1) provides a degradable flexible biomaterial with good imaging function.

2) Provides a brand-new PDT biodegradable material/nano Fe₃O₄A composite material synthesis method of the material;

3) the material is innovatively applied to preparation of the postoperative bio-absorbable marker clamp for breast cancer, and the outstanding problems of poor image sensitivity, discomfort and the like caused by the traditional metal marker clamp are solved.

4) The PDT material is suitable for being made into various products by means of 3D printing and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.

General procedure

And (3) CT measurement: respectively taking magnetic nano Fe₃O₄PDT/Fe at 0%, 0.5%, 1%, 2% and 4% mass concentration₃O₄Cutting sheet with length of 20mm, width of 4mm and thickness of 0.2mm from the composite, cutting 4 corners to form obtuse angles, and cutting different magnetic nano Fe₃O₄The mass concentration of the compound was placed in a CT machine and the imaging performance was observed.

And (3) measuring the mechanical property: according to the national standard GB/T1040-2006, selecting a national standard II type dumbbell-shaped sample knife, cutting sample strips for each sample by using a CP-25 type manual punching machine, and testing the sample strips by using an electronic universal tester (CMT-2503, Meitess Industrial System (China) Co., Ltd.). The gauge length was 25mm, the rate of stretching was 10mm/min, the test was carried out at 25 ℃ and a relative humidity of 50%, and the number of samples tested per group was 5. After the test is finished, obtaining values of the tensile modulus, the tensile strength and the elongation at break of the sample strip from the stress-strain image, and integrating the stress-strain image to obtain the energy at break W_e。

The 3D printing method comprises the following steps: 3D printing was performed using a MAM dual-jet three-dimensional micro-jet free-form machine (Shanghai Fuqifan electromechanical technologies, Inc.). PDT printing conditions comprise 165 ℃ of a stock bin, 170 ℃ of a spray head, 1mm/s of XY axis movement speed and 0.1mm/s of T1 axis extrusion speed. A21-gauge needle was used, and the layer thickness was set to 0.3 mm.

Example 1 PDT preparation at different ratios

1.1. Method of producing a composite material

In this example, polymers having different mixing ratios of racemic lactide (DLLA) and trimethylene carbonate (TMC) were prepared and the performances were compared. The method comprises the following steps:

(a) taking a certain amount of monomer racemic lactide (DLLA) and trimethylene carbonate (TMC), wherein the mass ratio of the two is 100: 0,98: 2,95: 5,90: 10, 85: 15, 80: 20, 70:30 and 0: 100, respectively;

(b) selecting catalyst stannous octoate Sn (Oct)₂The ratio to the total mass of the monomers was 1.25: 1000, parts by weight;

(c) vacuumizing for 4h, heating to 120 ℃ in an argon atmosphere, and reacting for 6 h;

(d) and dissolving, precipitating and purifying the product for 2-3 times by using dichloromethane and anhydrous ether, and drying in vacuum at 50 ℃ to obtain a PDT sample.

(e) The product was heat-sealed with aluminum foil and stored in a refrigerator at-20 ℃.

The results are shown in FIGS. 1-2, and show that the tensile strength and tensile modulus of the copolymer sharply decrease at a TMC ratio of more than 20%, while the elongation at break increases with an increase in the TMC ratio, and the energy at break peaks at a ratio of 70:30, so that a ratio of 70:30 is preferred as the proportion of the copolymer required to have good flexibility.

Comparative example 1

Example 1 was repeated, with the difference that the ratio of the amounts of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC), was 70:30 and in step (d) the anhydrous ether is replaced with anhydrous ethanol.

The results of elongation at break and tensile modulus are shown in fig. 3, and show that the copolymer prepared using absolute ethanol as the second solvent performed better than absolute ethyl ether, which resulted in a decrease in elongation at break from about 820% to 470% and a significant decrease in tensile modulus (from 160MPa to 35 MPa).

Example 2 PDT Material 3D printing

Example 1 was repeated, except that the ratio of the amounts of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) was 70:30 and in step (d) the anhydrous ether is replaced with anhydrous ethanol. The article shown in fig. 4 was made after 3D printing. As can be seen from fig. 4, the PDT material has a ratio of the amounts of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) of 70:30 has the property of easy printing and forming.

EXAMPLE 3 PDT preparation and characterization

Example 1 was repeated, except that the ratio of the amounts of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) was 70:30 and in step (d) the anhydrous ether is replaced with anhydrous ethanol.

Results

FIG. 5 is a graph on the left side of the graph, which is a PDT sample obtained by synthesizing PDT by a lactide ring-opening polymerization method, copolymerizing monomer racemic lactide and trimethylene carbonate by using a catalyst stannous octoate under a certain condition, and performing multiple dissolution, precipitation and purification; FIG. 5 right side shows PDT sample and prepared magnetic nano Fe₃O₄Mixing, stirring and precipitating the particles in a dichloromethane solvent to obtain PDT/Fe₃O₄And (c) a complex. Drawing (A)6A is sequentially different magnetic nano Fe from left to right₃O₄PDT/Fe at Mass concentration₃O₄A composite form. FIG. 6B is PDT/Fe₃O₄And (4) measuring the size of the composite material.

Comparing the left and right images of FIG. 5, it is found that nano-Fe is added₃O₄PDT/Fe of₃O₄The color of the composite material is obviously deepened; comparing different magnetic nano-Fe in FIG. 6A from left to right in sequence₃O₄PDT/Fe at Mass concentration₃O₄The composite material picture shows that the composite material has better uniformity and is accompanied with magnetic nano Fe₃O₄The color of the composite material is deepened when the mass concentration is increased; as shown in FIG. 6B, the length of the composite was around 2 cm.

Example 4 PDT/Fe₃O₄Mechanical behavior of the composite

4.1 method

Mixing 5 kinds of magnetic nano Fe₃O₄PDT/Fe of particle mass fraction₃O₄The composite material (the mass fractions are respectively 0%, 0.5%, 1%, 2% and 4%) (prepared in example 1), was subjected to tensile property test according to the national standard GB/T1040-.

Table 1: PDT/Fe₃O₄Elastic parameter of composite material

4.2 results

As can be seen from Table 1, PDT copolymer is added with magnetic nano Fe₃O₄After the particles, the elastic modulus is obviously improved, but with the magnetic nano Fe₃O₄The increase in the mass percentage of the particles gradually decreases the value of the modulus of elasticity and tends to be stable. For PDT/Fe₃O₄The composite material (1%) was subjected to a fixed-length tensile test, and the springback condition was observed, as shown in fig. 7, and the deformation was completely recovered at 37 ℃ for 30 s.

Example 5 in vitro degradation of PDT

5.1 methods

The PDT sample film (thickness 0.2mm) prepared by the thermocompression method was cut into a square sample of 1cm × 1cm, immersed in Phosphate Buffered Saline (PBS), and placed in a 37 ℃ incubator. And taking out the bag after the bag is soaked for a set time, and observing the PDT degradation condition. And then cleaning with deionized water, drying in vacuum, and shooting the surface and section morphology.

And degrading the poly-PDT degradable material. Wherein (a) is before degradation; (b) after 4 weeks for degradation. FIG. 8 is a graph of the morphology of the material before and after degradation under electron microscope scanning, shown in FIG. 8 from both the surface and the cross section.

5.2 results

As shown in fig. 8, the appearance of the material changed relatively greatly with increasing degradation time. The material was colorless and transparent before degradation (fig. a) and turned milky white after 4 weeks of degradation (fig. b).

As can be seen from FIG. 9, the surface topography of the material changed significantly, and when the material degraded to 8 months, the surface of the material became very rough and the surface appeared granular. It can be seen from the section scanning electron microscope photo that the section of the material before degradation is relatively flat, and a plurality of relatively uniform small holes appear on the section of the material after 8 months of degradation, which indicates that the inside of the material is also relatively quickly degraded while the surface of the material is degraded.

Example 6 PDT/Fe₃O₄Qualitative performance under complex X-ray

6.1 methods

Respectively taking magnetic nano Fe₃O₄PDT/Fe at 0%, 0.5%, 1%, 2% and 4% mass concentration₃O₄Cutting sheet with length of 20mm, width of 4mm and thickness of 0.2mm from the composite, and cutting 4 corners to form obtuse angles by comparing different magnetic nano Fe₃O₄Imaging performance of mass concentration, screening magnetic nano Fe₃O₄The optimum mass concentration.

The result is shown in FIG. 10, which is magnetic nano Fe from left to right₃O₄PDT/Fe with the mass fraction of 0%, 0.5%, 1%, 2% and 4%₃O₄And (4) carrying out X-ray development on the compound sample. PDT/Fe₃O₄The visualization effect of the compound on CT scan is shown in fig. 11. Magnetic nano Fe₃O₄The increase in mass fraction gradually increases the composite density. Magnetic nano Fe₃O₄The composite with the mass fraction of 0 percent has uniform and consistent density and contains magnetic nano Fe₃O₄The composite is uniformly distributed with uniform high-density points along with magnetic nano Fe₃O₄The mass fraction is increased, and the number of high-density points is obviously increased.

6.2 results

As shown in FIG. 10, under X-ray irradiation, the complex follows the magnetic nano Fe from left to right₃O₄The quality fraction is increased, and the X-ray developing effect of the compound is more obvious. Illustrating PDT/Nano Fe₃O₄The composite material has good developability.

Example 7 PDT/Fe₃O₄Quantitative Performance of the Compound under CT (CT value)

7.1 methods

For PDT/Fe₃O₄CT test is carried out on the compound, and different nanometer Fe are recorded₃O₄PDT/Fe in mass fraction₃O₄The CT value of the complex. TABLE 2 PDT/Fe measured₃O₄CT values of the composite samples.

TABLE 2 PDT/Fe₃O₄CT value of the Complex

Mass fraction (%)	Mean value (Hu)	Standard deviation of	Minimum value (Hu)	Maximum value (Hu)
					0	-378.3	113.9	-571.3	-87.8
0.5	-305.7	57.1	-519.5	-171.6
					1	-177.8	75.6	-320	71.6
2	36.2	116.5	-267.7	467.6
					4	177.2	308.3	-197.3	1762.2

7.2 results

As can be seen from Table 2, with Fe₃O₄The mass fraction increased and the CT value of the complex gradually increased. Due to the common human tissue andCT value of medium: air is-1000 Hu, fat is-90 to-70 Hu, water is 0Hu, soft tissue is 20 to 50Hu, hematoma is 6 to 80Hu, and bone is +1000 Hu. It can be known from the combination of Table 1 that in the compound with the mass fraction of 0% -1%, the nano Fe is associated with the magnetism₃O₄Mass increase, CT value of the complex gradually increases, but is lower than CT value of adipose tissue; in the compound with the mass fraction of 2-4%, the magnetic nano Fe is carried out₃O₄The mass is increased, and the CT value of the compound is gradually increased and is higher than that of fat tissue and water; but the CT value of the compound with the mass fraction of 2 percent is similar to that of soft tissue; the mass fraction of the compound of 4 percent is obviously higher than the hematoma of the tissue.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.