Preparation method of biodegradable PDT / Fe3O4 composite material

Abstract

The present invention relates to the field of medical composite materials and discloses a biocompatible and biodegradable poly(racemic lactide-trimethylene carbonate) / nanoferric oxide (PDT / Fe3O4) composite material. The method comprises combining the synthesized PDT with a certain amount of magnetic nano-Fe3O4 in an organic solvent with mechanical stirring, precipitating, vacuum drying, and hot-pressing using a flat-plate vulcanizer to obtain a thin sheet. The synthesized PDT-Fe3O4 composite material is a flexible material that addresses the prominent issues of traditional metal marker clips, such as poor imaging sensitivity, biological inertness, and rejection reactions, while exhibiting excellent imaging performance, bioabsorbability, and biodegradability.

Description

Technical Field

[0001] The present invention relates to the field of nano medical composite materials, and in particular to a medical composite material with good imaging function, bioabsorbability and biodegradability and a preparation method thereof. Background Art

[0002] In recent years, the incidence of breast cancer has remained high, ranking first among malignant tumors in women worldwide. Among various tumor diseases, breast cancer is the leading cause of death in women. Breast-conserving treatment for breast cancer recommends postoperative radiotherapy to reduce the risk of local recurrence. Whole breast irradiation (WBI) is the dominant mode of postoperative radiotherapy. However, recent research data shows that for patients with early-stage breast cancer, partial breast irradiation (PBI), like WBI, can reduce local recurrence rates, while also providing similar adverse reactions and cosmetic effects. PBI can, to a certain extent, replace WBI. The key to achieving PBI lies in precise localization of the tumor target.

[0003] Currently, most commonly used breast cancer postoperative localization clips are titanium or silver clips. While they are effective as postoperative radiotherapy indicators, they are inert metals and remain in the body for a long time, resistant to corrosion or degradation. This can easily cause significant psychological burden on patients. Furthermore, in some cases, localized nodules may form, hindering the identification of local recurrences during follow-up. Most patients passively accept the metal clips, creating significant challenges for both physicians and patients. Therefore, there is an urgent need to develop composite materials with excellent imaging properties, superior degradability, and biocompatibility for use as marker clips to address the prominent issues of traditional metal clips, such as poor imaging sensitivity, biological inertness, and biological rejection. Summary of the Invention

[0004] The purpose of the present invention is to provide a composite material with good developability, excellent degradability and biocompatibility for use in marking clips, so as to solve the outstanding problems of traditional metal clips such as poor image sensitivity, biological inertness and biological rejection reaction.

[0005] In a first aspect of the present invention, a composite material for development is provided. The composite material is solid and contains: (a) a biodegradable and biocompatible polymer; and (b) ferrosoferric oxide nanoparticles for development, wherein the ferrosoferric oxide nanoparticles have an average particle size of 50-500 nm and are uniformly dispersed in the biodegradable and biocompatible polymer.

[0006] In another preferred embodiment, the (a) biodegradable and biocompatible polymer is selected from the group consisting of PDT, PGA, PLA, PCL, chitosan, hyaluronic acid, and the like.

[0007] In another preferred embodiment, the (a) biodegradable and biocompatible polymer is a PDT polymer.

[0008] In another preferred embodiment, the molecular weight of the PDT polymer is 100×10 3 ~300×10 3 The mass average molecular weight is 200×10 3 ~500×10 3 The obtained polymer dispersity index (PDI) is 1 to 2.5, and has the following characteristics: narrow molecular weight distribution and easy molding.

[0009] In another preferred embodiment, the average particle size of the ferrosoferric oxide nanoparticles used for developing the method (b) is 50-500 nm.

[0010] In another preferred embodiment, the content of the (b) ferrosoferric oxide nanoparticles for developing is 0.1-8 wt %, based on the total weight of the composite material.

[0011] In another preferred embodiment, the weight ratio of the ferrosoferric oxide nanoparticles to the biodegradable and biocompatible polymer is 0.25-10:100, preferably 0.5-5:100.

[0012] In another preferred embodiment, the ferrosoferric oxide nanoparticles have superparamagnetism.

[0013] In another preferred embodiment, the ferrosoferric oxide nanoparticles further have the following characteristics: the polydispersity index of the nanoparticles is 0.01-0.4.

[0014] In another preferred embodiment, the mass concentration of the nano-Fe3O4 / PDT is 0.5%-5%, preferably 0.5%, 1%, 2% or 4%.

[0015] In another preferred embodiment, the composite material further has the following characteristics:

[0016] (i) Development: CT values ​​are significantly different from those of soft tissue;

[0017] (ii) Biodegradability: can be degraded into small molecular weight aliphatic hydroxy acids in the biological environment;

[0018] (iii) Biocompatibility: Cytotoxicity is less than grade 1;

[0019] (iv) Mechanical properties: tensile modulus 10-200 MPa, tensile strength 5-20 MPa, elongation at break 400-900%.

[0020] In a second aspect of the present invention, a method for preparing the composite material according to the first aspect of the present invention is provided, comprising the steps of:

[0021] (S1) mixing ferrosoferric oxide nanoparticles, a biodegradable and biocompatible polymer, and a first solvent to form a first mixture, wherein the biodegradable and biocompatible polymer is soluble in the first solvent;

[0022] (S2) adding a second solvent to the first mixture, thereby forming a precipitate of the complex of the ferrosoferric oxide nanoparticles and the biodegradable and biocompatible polymer; and

[0023] (S3) separating the precipitate and drying it to obtain the composite material according to claim 1.

[0024] In another preferred embodiment, the biodegradable and biocompatible polymer is a PDT polymer.

[0025] In another preferred embodiment, the first solvent is selected from the group consisting of dichloromethane, chloroform, and acetone. In another preferred embodiment, the second solvent is selected from the group consisting of anhydrous ethanol, deionized water, and anhydrous ether.

[0026] In another preferred embodiment, step (S1) includes the steps of: first dissolving the biodegradable and biocompatible polymer in a first solvent to form a first solution; and then adding the ferrosoferric oxide nanoparticles to the first solution to form a first mixture.

[0027] In another preferred embodiment, the first solution is a PDT solution with a concentration of 0.5-0.2 g / mL (preferably 0.08-0.12 g / mL, more preferably about 0.1 g / mL) formed by dissolving a biodegradable and biocompatible polymer in a dichloromethane solvent.

[0028] In another preferred embodiment, step (S3) includes: separating the precipitate, and performing vacuum drying and hot pressing to obtain a formed product.

[0029] In another preferred embodiment, the vacuum drying is carried out at 60±10°C overnight.

[0030] In another preferred embodiment, the hot pressing refers to hot pressing using a flat vulcanizing machine.

[0031] In another preferred embodiment, the molded product is a thin sheet with a thickness of about 0.2±0.05 mm.

[0032] In another preferred embodiment, the biodegradable and biocompatible polymer is a PDT polymer, and before step (S1), the method further comprises the following steps for preparing the PDT:

[0033] (S01) reacting monomeric racemic lactide (DLLA) with trimethylene carbonate (TMC) in the presence of a stannous octoate (Sn(Oct)2) catalyst under inert gas protection to form a reaction product;

[0034] (S02) dissolving the reaction product in a first solvent to form a solution;

[0035] (S03) adding a second solvent to the solution in the previous step to form a precipitate;

[0036] (S04) separating the precipitate, dissolving it in a first solvent to form a solution, and repeating step (S03), wherein step (S04) may be repeated 0-2 times; and

[0037] (S05) The precipitate in the previous step is separated and dried to obtain a PDT material.

[0038] In another preferred embodiment, in step (S01), under argon protection, the reaction is carried out under heating conditions for a period of time T S01 , thereby obtaining the reaction product.

[0039] In another preferred embodiment, in step (S01), the molar ratio of the monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) is 60-75:20-50, preferably 70:20-50.

[0040] In another preferred embodiment, the mass ratio of the catalyst stannous octoate Sn(Oct)2 to the monomers (racemic lactide (DLLA) + trimethylene carbonate (TMC)) is 1.0-1.5:1000.

[0041] In another preferred embodiment, in step (S01), the heating condition is 100-150°C; and T S01 1-24 hours, preferably 2-10 hours.

[0042] In another preferred embodiment, in step (S05), the drying is vacuum drying.

[0043] In another preferred embodiment, the reaction product obtained in step (S01) is purified and vacuum-dried, then heat-sealed with aluminum foil and stored at a low temperature (eg, about -20°C).

[0044] In another preferred embodiment, before step (S1), the method further comprises the following steps for preparing ferrosoferric oxide nanoparticles:

[0045] (F1) Dissolve FeCl3 and FeSO4 in water to obtain Fe 3+ / Fe 2+ A yellow-green iron salt solution with a molar ratio of 2:1;

[0046] (F2) adding the iron salt solution dropwise to the NaOH solution (F1) (concentration of 0.5-2 mol / L), stirring vigorously under ultrasound for 5-15 minutes to form a black suspension;

[0047] (F3) introducing argon gas into the black suspension while stirring, reacting at 50-100° C. for 20-60 minutes (e.g., about 30 minutes) to form ferrosoferric oxide nanoparticles;

[0048] (F4) magnetically separating the ferrosoferric oxide nanoparticles, washing them alternately with deoxygenated distilled water and anhydrous ethanol, and dispersing them with deoxygenated distilled water;

[0049] (F5) The product is freeze-dried and then dried in a vacuum at 20-100° C. to obtain ferrosoferric oxide nanoparticles.

[0050] In a third aspect of the present invention, a product is provided. The product contains the composite material described in the first aspect of the present invention or is made of the composite material described in the first aspect of the present invention.

[0051] In another preferred embodiment, the product is a marking clip, and has the following characteristics: the shape of the clip body is irregular, and the end has a needle hole, which is convenient for suture to fix it in the desired position.

[0052] In another preferred embodiment, the product is made by the method described in the second aspect of the present invention.

[0053] In the fourth aspect of the present invention, the use of the product as described in the third aspect of the present invention is provided, which is used to manufacture a marker clip for positioning after breast cancer surgery or can also be used for tracing the degradation of polymers in vivo, as a drug carrier and for magnetic thermal treatment.

[0054] In another preferred embodiment, the marker clip has a developing property that can significantly improve the tracking and identification of cancer cells after surgery;

[0055] In another preferred embodiment, the marker clip is biodegradable and can be degraded by itself after completing the identification and tracking of cancer cells, thereby reducing the physiological and psychological burden on patients.

[0056] In another preferred embodiment, the marking clip is biocompatible and can reduce rejection reactions after implantation into the human body.

[0057] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Figure 1 Figure 2 shows the elastic modulus and tensile strength of PDTs prepared at different mixing ratios of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC). "PDT_X-Y" indicates the PDT prepared with X moles of DLLA and Y moles of TMC.

[0059] Figure 2 The elongation at break and energy at break of PDT prepared by monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) at different mixing ratios are shown.

[0060] Figure 3 Shown are the elongation at break and tensile modulus of PDTs prepared using ethanol or diethyl ether as the second solvent.

[0061] Figure 4 A sample obtained by 3D printing using the PDT material prepared in one embodiment of the present invention is shown.

[0062] Figure 5 The morphology of the composite samples is shown. The PDT without Fe3O4 composite is colorless, transparent and white, while the color of the PDT composite with 4% Fe3O4 is significantly darker.

[0063] Figure 6 Shown are the PDT / Fe3O4 composites with different mass concentrations and the composite sizes.

[0064] Figure 7 The rebound resilience test results of the PDT / Fe3O4 composite (1%) are shown, where (a) is before stretching; (b) is after 400% deformation; (c) is after being placed at 37°C for 15s after deformation; and (d) is after being placed at 37°C for 30s after deformation.

[0065] Figure 8 The PDT degradation results are shown. (a) shows the material before degradation; (b) shows the material after 4 weeks of degradation. Before degradation, the material was colorless and transparent, but after 4 weeks of degradation, it turned milky white.

[0066] Figure 9 The scanning electron microscopy images of the surface and cross-section of PDT before and after degradation are shown. Before degradation, the PDT surface is uniform and patternless, and the cross-section is smooth. After degradation, the PDT surface has uniform and dense pores, and the cross-section has irregular holes.

[0067] Figure 10 The X-ray imaging function of the PDT / Fe3O4 composite was demonstrated.

[0068] Figure 11 The CT performance of the PDT / Fe3O4 composite is shown. As the mass fraction of magnetic nano-Fe3O4 increases, the number of high-density points increases significantly. DETAILED DESCRIPTION

[0069] After extensive and in-depth research, the inventors unexpectedly discovered for the first time a method for preparing a composite material with good developability, degradability and biocompatibility by composite magnetic nano-Fe3O4 particles and absorbable polymer (PDT).

[0070] Specifically, this method solves the prominent problems of traditional inert metal radiotherapy marker clips, such as poor development sensitivity, biological inertness, and rejection reactions. It can also enhance the PDT molding ability by controlling the ratio of the amount of racemic lactide (DLLA) and trimethylene carbonate (TMC) monomers, controlling the number average molecular weight and dispersion index (PDI) of the resulting polymer.

[0071] the term

[0072] As used herein, the terms "composite material of the present invention", "material of the present invention", "composite material for development of the present invention", "composite of the present invention" and the like are used interchangeably to refer to the composite material for development described in the first aspect of the present invention.

[0073] Composite materials for development

[0074] The present invention provides a composite material suitable for development. The composite material is solid and contains: (a) a biodegradable and biocompatible polymer; and (b) ferrosoferric oxide nanoparticles for development, wherein the ferrosoferric oxide nanoparticles have an average particle size of 50-500 nm and are uniformly dispersed in the biodegradable and biocompatible polymer.

[0075] The composite material of the present invention has the characteristics of excellent biocompatibility, high biodegradability, good imaging function, etc., and can be made into a suitable shape or form for clinical imaging use.

[0076] Preferably, the present invention provides a PDT / nano-Fe3O4 composite sheet with a thickness of 0.2 mm.

[0077] Preferably, the biodegradable and biocompatible polymer (also referred to as "organic medical composite material") includes but is not limited to: PDT, PGA, PLA, PCL, chitosan, hyaluronic acid, or a combination thereof.

[0078] In the present invention, the preferred PDT has the following characteristics: the number average relative molecular weight is 100×10 3 ~300×10 3 The mass average molecular weight is 200×10 3 ~500×10 3 The obtained polymer dispersity index (PDI) is 1 to 2.5.

[0079] Preferably, the PDT of the present invention uses a copolymer of racemic lactide (DLLA) and trimethylene carbonate (TMC), wherein the mixing ratio (by mole) of racemic lactide (DLLA) to trimethylene carbonate (TMC) is 78:22 to 60:40, preferably 75:25 to 65:35, and more preferably about 70:30.

[0080] Note: This ratio is based on Figure 1 and 2 And the following table

[0081]

[0082] Preparation method

[0083] The present invention also provides a method for preparing the composite material of the present invention.

[0084] The present invention provides a method for preparing a PDT-nano-Fe₃O₄ medical composite material with excellent bio-imaging properties, biocompatibility, and biodegradability. This method addresses the prominent issues of traditional inert metal radiotherapy markers, such as poor imaging sensitivity, biological inertness, and rejection. Furthermore, by controlling the molar ratio of racemic lactide (DLLA) and trimethylene carbonate (TMC) monomers, the number average molecular weight and polydispersity index (PDI) of the resulting polymer can be manipulated, enhancing PDT molding capabilities.

[0085] Typically, the preparation method of the present invention comprises the steps of:

[0086] (S1) mixing ferrosoferric oxide nanoparticles, a biodegradable and biocompatible polymer, and a first solvent to form a first mixture, wherein the biodegradable and biocompatible polymer is soluble in the first solvent;

[0087] (S2) adding a second solvent to the first mixture, thereby forming a precipitate of the complex of the ferrosoferric oxide nanoparticles and the biodegradable and biocompatible polymer; and

[0088] (S3) separating the precipitate and drying it to obtain the composite material according to claim 1.

[0089] Preferably, the composite material of the present invention is a PDT / Fe3O4 composite material.

[0090] In a preferred embodiment, the present invention provides a method for preparing a PDT / Fe3O4 composite material, which specifically comprises the following steps:

[0091] (1) Synthesis of PDT

[0092] S1.1, the molar ratio of monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) is 70:10-50;

[0093] S1.2, select the catalyst Sn(Oct)2, the mass ratio of which to the monomer is 1.0-1.5:1000;

[0094] S1.3, after evacuating for 4 h, heat to 100-150°C in an argon atmosphere and react for 2-10 h;

[0095] S1.4, the above product is purified by dissolving and precipitating in dichloromethane and anhydrous ethanol 2-3 times, and vacuum drying at 20-100°C to obtain a PDT sample.

[0096] S1.5. Heat-seal the above product with aluminum foil and store it in a refrigerator at -20°C.

[0097] Typically, in the synthesis of PDT, the molar ratio of racemic lactide (DLLA) and trimethylene carbonate (TMC) is 70:10-50; the mass ratio of the catalyst stannous octoate Sn(Oct)2 to the monomer is 1.0-1.5:1000.

[0098] Preferably, in step S1.3, the temperature is raised to 100-150° C. in an argon atmosphere, and the reaction time is 2-10 h.

[0099] (2) Synthesis of nano-Fe3O4

[0100] S2.1. Dissolve 4 g of NaOH solution in 100 mL of deoxygenated distilled water and stir until completely dissolved to obtain a 1 mol / L NaOH solution.

[0101] S2.2, dissolve 5.40 g of FeCl3.6H2O and 2.78 g of FeSO4.7H2O in 20 mL of deoxygenated distilled water to obtain a yellow-green iron salt solution;

[0102] S2.3. Add the solution obtained in S2 dropwise to the solution in S1 at room temperature and stir vigorously with ultrasonication for 5-15 minutes.

[0103] S2.4. The black suspension obtained in S3 was stirred mechanically and purged with argon for 30 min at 50-100°C.

[0104] S2.5, magnetically separating the product obtained in S4, washing it twice with deoxygenated distilled water and anhydrous ethanol alternately, and dispersing it with deoxygenated distilled water;

[0105] S2.6. Freeze-dry the above product, then vacuum-dry it at 20-100°C overnight, and store it in a desiccator under vacuum.

[0106] Preferably, the iron salt described in step S2.2 is dissolved to obtain Fe 3+ / Fe 2+ A yellow-green iron salt solution with a molar ratio of approximately 2:1.

[0107] (3) Preparation of PDT / Fe3O4 composite

[0108] S3.1, adding the PDT obtained in (1) into dichloromethane solvent and dissolving it to obtain a 0.1 g / mL PDT solution;

[0109] S3.2, add a certain amount of magnetic nano-Fe3O4 and continue stirring for a while;

[0110] S3.3, the product of the previous step was precipitated with anhydrous ethanol, and the product was vacuum dried at 60°C overnight. After drying, it was hot-pressed into a thin sheet with a thickness of about 0.2 mm using a flat plate vulcanizer.

[0111] Preferably, the mass ratios of nano-Fe3O4 / PDT in step S3.2 are 0.5%, 1%, 2% and 4% by mass, respectively, wherein the mass of PDT is 100%.

[0112] Products and Applications

[0113] The present invention also provides applications of the composite material and corresponding products.

[0114] In the present invention, the article comprises or is made of the composite material of the present invention.

[0115] A preferred article is a 3D-printed article. The inventors unexpectedly discovered that because the PDT of the present invention is not only a biodegradable and biocompatible polymer, but also can be liquefied at relatively low temperatures (e.g., 130-150°C) and has excellent mechanical properties (e.g., elongation at break exceeding 400% and shape memory function at 37°C), it is particularly suitable for use as a substrate or raw material for 3D printing, thereby producing a variety of different 3D-printed articles.

[0116] Typically, the composite material or product of the present invention can be used 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 purposes and research purposes.

[0117] The main advantages of the present invention include:

[0118] 1) Provided is a degradable flexible biomaterial with good imaging function.

[0119] 2) Provides a novel method for synthesizing a composite material of PDT biodegradable material / nano-Fe3O4 material;

[0120] 3) This material was innovatively applied to the preparation of bioabsorbable marker clips after breast cancer surgery, solving prominent problems such as poor image sensitivity and discomfort caused by traditional metal marker clips.

[0121] 4) The PDT material of the present invention is suitable for making various products through 3D printing and other methods.

[0122] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0123] General Methods

[0124] CT measurement: PDT / Fe3O4 complexes with magnetic nano-Fe3O4 mass concentrations of 0%, 0.5%, 1%, 2% and 4% were cut into thin slices with a length of 20 mm, a width of 4 mm and a thickness of 0.2 mm. The four corners were cut into obtuse angles. The complexes with different magnetic nano-Fe3O4 mass concentrations were placed in a CT machine to observe the imaging manifestations.

[0125] Mechanical property determination: The tensile property test was carried out in accordance with the national standard GB / T 1040-2006. For the prepared composite film, the national standard type II dumbbell-shaped sample knife was selected, and the CP-25 manual punching machine was used to cut the sample strips for each sample. The sample strips were tested using an electronic universal testing machine (CMT-2503, Meters Industrial Systems (China) Co., Ltd.). The gauge length was 25 mm, the stretching rate was 10 mm / min, the test was carried out at 25 ° C and a relative humidity of 50%, and the number of samples tested in each group was 5. After the test, the tensile modulus, tensile strength and elongation at break of the sample strip were obtained from the stress-strain image. The stress-strain image was integrated to obtain the fracture energy W. e .

[0126] 3D Printing Method: 3D printing was performed using a MAM dual-nozzle 3D microjet free-former (Shanghai Fuqifan Electromechanical Technology Co., Ltd.). PDT printing conditions were: a hopper temperature of 165°C, a nozzle temperature of 170°C, an XY axis speed of 1 mm / s, and a T1 axis extrusion speed of 0.1 mm / s. A 21-gauge needle was used, and the layer thickness was set to 0.3 mm.

[0127] Example 1. Preparation of PDT with different ratios

[0128] 1.1. Methods

[0129] In this example, polymers containing different mixing ratios of racemic lactide (DLLA) and trimethylene carbonate (TMC) were prepared and their properties were compared. The method is as follows:

[0130] (a) taking a certain amount of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) at a molar ratio of 100:0, 98:2, 95:5, 90:10, 85:15, 80:20, 70:30 and 0:100;

[0131] (b) Selecting the catalyst Sn(Oct)2, the ratio of the total mass of the catalyst to the total mass of the monomer is 1.25:1000;

[0132] (c) After evacuating for 4 h, the temperature was raised to 120°C in an argon atmosphere and the reaction was continued for 6 h;

[0133] (d) The above product was purified by dissolving and precipitating in dichloromethane and anhydrous ether 2-3 times, and then dried in vacuum at 50°C to obtain a PDT sample.

[0134] (e) The above product was heat-sealed with aluminum foil and stored in a refrigerator at -20°C.

[0135] The results are as follows Figure 1-2 As shown in the figure, the results indicate that the tensile strength and tensile modulus of the copolymer decrease sharply when the TMC ratio is greater than 20%, while the elongation at break increases with the increase of the TMC ratio, and the breaking energy reaches a peak at the ratio of 70:30. Therefore, the ratio of 70:30 is preferred as the required copolymer ratio with good flexibility.

[0136] Comparative Example 1

[0137] Example 1 was repeated, except that the molar ratio of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) was 70:30, and anhydrous ethyl ether was replaced by anhydrous ethanol in step (d).

[0138] The results of elongation at break and tensile modulus are as follows Figure 3As shown, the results show that the performance of the copolymer prepared using anhydrous ethanol as the second solvent is better than that using anhydrous ether. When anhydrous ether is used, the elongation at break decreases from about 820% to 470%, and the tensile modulus decreases significantly (from 160 MPa to 35 MPa).

[0139] Example 2. 3D printing of PDT materials

[0140] Example 1 was repeated, except that the molar ratio of monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) was 70:30, and anhydrous ethyl ether was replaced by anhydrous ethanol in step (d). Figure 4 Products shown. Depend on Figure 4 It can be seen that the PDT material has the property of being easy to print and form when the molar ratio of monomeric racemic lactide (DLLA) and trimethylene carbonate (TMC) is 70:30.

[0141] Example 3 PDT preparation and characterization

[0142] Example 1 was repeated, except that the molar ratio of monomeric racemic lactide (DLLA) to trimethylene carbonate (TMC) was 70:30, and anhydrous ethyl ether was replaced by anhydrous ethanol in step (d).

[0143] result

[0144] Figure 5 The image on the left shows the synthesis of PDT using the lactide ring-opening polymerization method. Using the catalyst stannous octoate, the monomeric racemic lactide is copolymerized with trimethylene carbonate under certain conditions. The resulting PDT sample is purified through multiple dissolution and precipitation steps. Figure 5 On the right is the PDT / Fe3O4 composite obtained by mixing, stirring and precipitating the PDT sample with the prepared magnetic nano-Fe3O4 particles in dichloromethane solvent. Figure 6 A From left to right are the morphologies of PDT / Fe3O4 composite materials at different magnetic nano-Fe3O4 mass concentrations. Figure 6 B is the size measurement of PDT / Fe3O4 composites.

[0145] contrast Figure 5 The left and right pictures show that the color of the PDT / Fe3O4 composite material with the addition of nano-Fe3O4 is significantly darker; compared from left to right Figure 6 The images of PDT / Fe3O4 composite materials at different concentrations of magnetic nano-Fe3O4 in A show that the composite materials have good uniformity, and the color of the composite materials deepens with the increase of the concentration of magnetic nano-Fe3O4. Figure 6 B shows that the length of the composite material is about 2 cm.

[0146] Example 4. Mechanical properties of PDT / Fe3O4 composite

[0147] 4.1 Methods

[0148] The PDT / Fe3O4 composite materials with five different mass fractions of magnetic nano-Fe3O4 particles (mass fractions of 0%, 0.5%, 1%, 2%, and 4%) (prepared in Example 1) were subjected to tensile property tests in accordance with the national standard GB / T 1040-2006. The obtained elastic parameters and their trends are shown in Table 1.

[0149] Table 1: Elastic parameters of PDT / Fe3O4 composites

[0150]

[0151] 4.2 Results

[0152] From Table 1, we can see that the elastic modulus of the PDT copolymer increases significantly after adding magnetic nano-Fe3O4 particles. However, as the mass percentage of magnetic nano-Fe3O4 particles increases, the elastic modulus value gradually decreases and tends to be stable. The PDT / Fe3O4 composite material (1%) was subjected to a fixed-length tensile test to observe its rebound performance. Figure 7 At 37 degrees Celsius, the deformation can be fully recovered in 30 seconds.

[0153] Example 5 In vitro degradation of PDT

[0154] 5.1 Methods

[0155] A PDT sample film (0.2 mm thick) prepared by hot pressing was cut into 1 cm × 1 cm squares, immersed in phosphate buffered saline (PBS), and placed in a 37°C constant-temperature shaker. After soaking for a set time, the film was removed and PDT degradation was observed. The film was then rinsed with deionized water, vacuum-dried, and the surface and cross-sectional morphologies were photographed.

[0156] The polyPDT degradable material was degraded. (a) is before degradation; (b) is after 4 weeks of degradation. Figure 8 Figure 8 The morphology of the material before and after degradation was displayed under electron microscope scanning from both the surface and cross-section directions.

[0157] 5.2 Results

[0158] Depend on Figure 8 The results show that the appearance of the material changes significantly with the increase of degradation time. Before degradation, the material was colorless and transparent (Figure a), and after 4 weeks of degradation, it turned milky white (Figure b).

[0159] from Figure 9 As can be seen from the figure, the surface morphology of the material changes significantly. After 8 months of degradation, the surface of the material becomes very rough and granular. From the cross-sectional scanning electron microscopy photos, it can be seen that the cross-section of the material is relatively flat before degradation. After 8 months of degradation, many relatively uniform small holes appear in the cross-section of the material, indicating that while the surface of the material is degrading, the internal degradation is also rapid.

[0160] Example 6 Qualitative performance of PDT / Fe3O4 composite under X-ray

[0161] 6.1 Methods

[0162] PDT / Fe3O4 complexes with magnetic nano-Fe3O4 mass concentrations of 0%, 0.5%, 1%, 2% and 4% were cut into thin slices with a length of 20 mm, a width of 4 mm and a thickness of 0.2 mm, and the four corners were cut into obtuse angles. By comparing the imaging manifestations of different magnetic nano-Fe3O4 mass concentrations, the optimal mass concentration of magnetic nano-Fe3O4 was screened.

[0163] The results are as follows Figure 10 As shown in the figure, from left to right, the PDT / Fe3O4 composite samples with a mass fraction of 0%, 0.5%, 1%, 2%, and 4% of magnetic nano-Fe3O4 were used for X-ray imaging. The imaging effect of PDT / Fe3O4 composite on CT scan is shown in the figure. Figure 11 As the mass fraction of magnetic nano-Fe3O4 increases, the density of the composite gradually increases. The density of the composite with a 0% mass fraction of magnetic nano-Fe3O4 is uniform, while the composite containing magnetic nano-Fe3O4 has a relatively uniform distribution of high-density points. The number of high-density points increases significantly with the increase of the mass fraction of magnetic nano-Fe3O4.

[0164] 6.2 Results

[0165] like Figure 10 As shown in the figure, under X-ray irradiation, as the mass fraction of magnetic nano-Fe3O4 increases from left to right, the X-ray development effect of the composite becomes more obvious, indicating that the PDT / nano-Fe3O4 composite material has good development properties.

[0166] Example 7 Quantitative performance of PDT / Fe3O4 composite under CT (CT value)

[0167] 7.1 Methods

[0168] The CT values ​​of the PDT / Fe3O4 composite samples were measured under different nano-Fe3O4 mass fractions. Table 2 shows the CT values ​​of the PDT / Fe3O4 composite samples.

[0169] Table 2. CT values ​​of PDT / Fe3O4 composites

[0170] Mass fraction (%) Average value (Hu) Standard Deviation 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

[0171] 7.2 Results

[0172] As can be seen from Table 2, the CT value of the composite gradually increases with increasing Fe₃O₄ mass fraction. The CT values ​​of common human tissues and media are: -1000 Hu for air, -90 to -70 Hu for fat, 0 Hu for water, 20 to 50 Hu for soft tissue, 6 to 80 Hu for hematoma, and +1000 Hu for bone. Combined with Table 1, we can see that in composites with a mass fraction of 0% to 1%, the CT value of the composite gradually increases with increasing Fe₃O₄ mass, but remains lower than that of fat tissue. In composites with a mass fraction of 2% to 4%, the CT value of the composite gradually increases with increasing Fe₃O₄ mass, exceeding that of fat tissue and water. However, the CT value of the composite with a mass fraction of 2% is similar to that of soft tissue, and the CT value of the composite with a mass fraction of 4% is significantly higher than that of hematoma.

[0173] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A composite material for development, characterized in that: The composite material is solid and contains: (a) biodegradable and biocompatible polymers, i.e., PDT polymers, Wherein PDT is a copolymer of racemic lactide (DLLA) and trimethylene carbonate (TMC), wherein the mixing ratio of racemic lactide (DLLA) and trimethylene carbonate (TMC) is 70:20-50 by mole; and The molecular weight of the PDT polymer is 100×10 3 ~300×10 3 The mass average molecular weight is 200×10 3 ~500×10 3 , the resulting polymer dispersion index, i.e., PDI, is 1 to 2.5; and (b) ferroferric oxide nanoparticles for development, wherein the ferroferric oxide nanoparticles have an average particle size of 50-500 nm and are uniformly dispersed in the biodegradable and biocompatible polymer; and the ferroferric oxide nanoparticles for development are present in an amount of 0.1-8 wt % based on the total weight of the composite material; The composite material has the following mechanical properties: tensile modulus 10-200 MPa, tensile strength 5-20 MPa, and elongation at break 400-900%.

2. The composite material according to claim 1, wherein The composite material also has the following developability: the CT value is significantly different from that of soft tissue.

3. The composite material according to claim 1, wherein The weight ratio of the ferrosoferric oxide nanoparticles to the biodegradable and biocompatible polymer is 0.5-5:

100.

4. The composite material according to claim 1, wherein The composite material also has the following biodegradability: it can be degraded into small-molecule aliphatic hydroxy acid in a biological environment.

5. The composite material according to claim 1, wherein The composite material also has the following biocompatibility: the cytotoxicity is less than level 1.

6. The composite material according to claim 1, wherein The composite material is prepared by the following method, comprising the steps of: (S1) mixing ferrosoferric oxide nanoparticles, a biodegradable and biocompatible polymer, and a 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 of the complex of the ferrosoferric oxide nanoparticles and the biodegradable and biocompatible polymer; wherein the second solvent is anhydrous ethanol; and (S3) separating the precipitate and drying it to obtain the composite material according to claim 1; Furthermore, before step (S1), the method further comprises the following steps for preparing PDT: (S01) reacting monomeric racemic lactide (DLLA) with trimethylene carbonate (TMC) under inert gas protection in the presence of a stannous octoate (Sn(Oct)2) catalyst to form a reaction product; wherein the molar ratio of the monomeric racemic lactide (DLLA) to the trimethylene carbonate (TMC) is 70:20-50; (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 to form a precipitate; wherein the second solvent is anhydrous ethanol; (S04) separating the precipitate, dissolving it in a first solvent to form a solution, and repeating step (S03), wherein step (S04) may be repeated 0-2 times; and (S05) The precipitate in the previous step is separated and dried to obtain a PDT material.

7. The composite material according to claim 6, wherein The first solvent is selected from the group consisting of dichloromethane, chloroform, and acetone.

8. A method for preparing the composite material according to claim 1, characterized in that: Including steps: (S1) mixing ferrosoferric oxide nanoparticles, a biodegradable and biocompatible polymer, and a 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 of the complex of the ferrosoferric oxide nanoparticles and the biodegradable and biocompatible polymer; and (S3) separating the precipitate and drying it to obtain the composite material according to claim 1; wherein the second solvent is anhydrous ethanol; Furthermore, before step (S1), the method further comprises the following steps for preparing PDT: (S01) reacting monomeric racemic lactide (DLLA) with trimethylene carbonate (TMC) under inert gas protection in the presence of a stannous octoate (Sn(Oct)2) catalyst to form a reaction product; wherein the molar ratio of the monomeric racemic lactide (DLLA) to the trimethylene carbonate (TMC) is 70:20-50; (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 to form a precipitate; (S04) separating the precipitate, dissolving it in a first solvent to form a solution, and repeating step (S03), wherein step (S04) may be repeated 0-2 times; and (S05) The precipitate in the previous step is separated and dried to obtain a PDT material.

9. The preparation method according to claim 8, wherein The first solvent is selected from the group consisting of dichloromethane, chloroform, and acetone.

10. A product, characterized in that The product contains the composite material according to claim 1 or is made of the composite material according to claim 1.

11. The article according to claim 10, wherein The product is a 3D printed product.

12. The article of claim 10, wherein: The product is a marking clip and has the following characteristics: the shape of the clip body is irregular and the end is provided with a needle hole, which is convenient for suture to fix the clip at a desired position.

13. The article of claim 10, wherein: Made by the method of claim 8.

14. Use of the product according to any one of claims 10 to 13, characterized in that It can be used to manufacture marker clips for positioning after breast cancer surgery, or can be used to track the degradation of polymers in vivo, as a drug carrier, and for magnetic thermal treatment.

15. The use according to claim 14, characterized in that The marker clip has a developing property and can significantly improve the tracking and identification of cancer cells after surgery; The marker clip is biodegradable and can degrade on its own after completing the identification and tracking of cancer cells, thus reducing the physiological and psychological burden on patients. and / or The marking clip has biocompatibility and can reduce rejection reaction after being implanted into the human body.

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