CN114699524B - Cross-scale multifunctional intelligent therapeutic and reparative system and preparation method thereof - Google Patents

Cross-scale multifunctional intelligent therapeutic and reparative system and preparation method thereof Download PDF

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CN114699524B
CN114699524B CN202210288754.6A CN202210288754A CN114699524B CN 114699524 B CN114699524 B CN 114699524B CN 202210288754 A CN202210288754 A CN 202210288754A CN 114699524 B CN114699524 B CN 114699524B
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heterostructure
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CN114699524A (en
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姜澜
马云龙
胡洁
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Yangtze River Delta Research Institute Of Beijing University Of Technology Jiaxing
Beijing Institute of Technology BIT
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Yangtze River Delta Research Institute Of Beijing University Of Technology Jiaxing
Beijing Institute of Technology BIT
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Abstract

The invention discloses a cross-scale multifunctional intelligent therapeutic and reparative system and a preparation method thereof, belonging to the technical field of laser application. The preparation method comprises the following steps: (1) Processing a three-dimensional multi-level micro/nano composite structure with various configurations on the surface of the biomedical material by femtosecond laser direct writing; (2) Modifying the black phosphorus nanosheets on a three-dimensional multi-stage micro/nano composite structure by adopting an electrostatic adsorption method to construct a cross-scale heterostructure; (3) Loading chemotherapy drug adriamycin on the trans-scale heterostructure by a vacuum physical adsorption method; (4) And further wrapping a polydopamine coating on the drug-loaded trans-scale heterostructure to obtain the trans-scale multifunctional intelligent therapeutic and repairing system. The cross-scale multifunctional intelligent therapeutic and reparative system has excellent photo-thermal conversion and intelligent drug release characteristics, can accelerate bone regeneration, and has the functions of tumor cooperation photo-thermal-chemotherapy and antibiosis. The invention is suitable for biomedical materials with various sizes, shapes and types.

Description

Cross-scale multifunctional intelligent therapeutic and reparative system and preparation method thereof
Technical Field
The invention relates to a cross-scale multifunctional intelligent therapeutic and reparative system and a preparation method thereof, which have the functions of bone defect repair, tumor cooperation photo-thermal-chemotherapy and bacterial infection eradication, and belong to the technical field of laser application.
Background
Bone tumors, a common primary bone malignancy, are one of the most fatal tumors and pose a serious threat to human health worldwide. In addition to autologous skeletal system cancer, bone metastasis is a catastrophic complication that occurs in 30-80% of cancer patients. Clinically, destructive surgical resection combined with radiotherapy/chemotherapy is the first choice treatment method for treating bone tumor, and the survival rate of patients is remarkably improved. However, the associated tumor recurrence after surgical resection of bone tumor (recurrence rate of 10% -20%), large-area bone defect and postoperative bacterial infection (infection rate of 20% -50%) are great challenges in clinic, and bring endless pain to patients. Adjuvant chemo/radiotherapy has been widely used to kill the remaining surviving tumor cells after surgery, but it has inevitable drawbacks such as various serious systemic side effects, chemo/radiotherapy resistance, and bone non-healing diseases. To date, there is still an urgent clinical need for a cross-scale multifunctional therapeutic and repair (therapy and repair) system based on biomedical material surface design, manufacture and application after bone tumor surgery, which can kill residual tumor cells and eradicate bacterial infection in a safe and efficient manner, and can meet the requirements of filling and guiding bone defect parts and accelerating bone tissue regeneration. However, at present, biomedical materials of a cross-scale multifunctional therapeutic system which has the performances of treating tumors, eradicating bacterial infection and repairing bone defects are very limited.
Compared with the traditional chemo/radiotherapy, in recent years, photothermal therapy has attracted attention as a novel noninvasive treatment means due to the characteristics of noninvasiveness and no toxic or side effect. The material with photothermal conversion capability is targeted to the vicinity of tumor tissues, and the heat generated by absorbing near infrared laser (NIR) is utilized to kill tumor cells in a targeted area, so that the damage to a non-targeted area is prevented. However, the use of photothermal therapy alone is still limited, and particularly in the treatment of highly malignant tumors, the search for new therapeutic modalities is urgently needed. The synergistic photothermal-chemotherapy method is considered as a promising strategy for improving the treatment effect, and can skillfully integrate the individual advantages, minimize the dosage of the chemotherapeutic drug and realize intelligent control of the drug release behavior. Therefore, the combination of the biomedical material with bone regeneration performance and the synergic photothermal-chemotherapy method is expected to become an effective way for simultaneously having the functions of bone defect repair, tumor synergic photothermal-chemotherapy and bacterial infection eradication. It is important to note that the multifunctional material with excellent photothermal effect, high drug loading and high osteogenesis performance is selected for preparing the cross-scale multifunctional intelligent therapeutic and repairing system.
In the prior art, for example, chinese patent CN 107261211A discloses a composite material containing polyimide sulfone and hydroxyapatite for human bone replacement and a preparation method thereof, but the material has a single function, only focuses on the bone repair function, and does not relate to the functions of tumor treatment and bacterial infection resistance. For another example, chinese patent CN 110302421A discloses a photothermal bone repair material for treating bone tumor, which is prepared by using photothermal effect of metal/metal oxide particles and osteogenic property of polymer, but this method only has a single photothermal therapeutic ability, cannot perform synergistic photothermal-chemotherapy, has certain therapeutic limitations, and the metal/metal oxide particle material cannot be degraded, and has low in vivo biosafety. In summary, the invention provides a cross-scale multifunctional intelligent therapeutic system which is based on biomedical materials, has the advantages of universality, low cost, high biocompatibility, long-term durability, degradability, bone defect repair, tumor-assisted photothermal-chemotherapy and bacterial infection resistance, and is in need of great use.
Disclosure of Invention
The invention aims to solve the serious problems of related tumor recurrence, large-area bone defect and postoperative bacterial infection after surgical resection of bone tumor, and provides a cross-scale multifunctional intelligent therapeutic and reparative system based on biomedical materials, which solves the great challenges after surgical resection of the bone tumor.
The purpose of the invention is realized by the following technical scheme:
the invention discloses a preparation method of a cross-scale multifunctional intelligent therapeutic and reparative system, which comprises the following steps:
step one, carrying out mirror polishing pretreatment on the surface of an original biomedical material, ultrasonically cleaning to remove surface residues, and drying to obtain a clean substrate to be processed with polished surface.
And step two, preparing a large-area and configuration-controllable three-dimensional multi-level micro/nano composite structure on the surface of the surface polishing material obtained in the step one by using femtosecond laser direct writing, and cleaning and drying the processed biomedical material by using deionized water and absolute ethyl alcohol.
And step three, modifying the black phosphorus nanosheet on the surface of the material obtained in the step two, and constructing a cross-scale heterostructure consisting of a three-dimensional multistage micro/nano composite structure and the nanosheets.
Step four, dropwise adding a solution of the chemotherapeutic drug adriamycin on the trans-scale heterostructure prepared in the step three, and performing vacuum drying treatment after the drug solution is uniformly spread on the surface of the material.
And step five, immersing the drug-loaded trans-scale heterostructure prepared in the step four into a dopamine hydrochloride solution at room temperature in a dark place, and uniformly coating the surface of the structure with a polydopamine coating through an autopolymerization reaction to obtain the trans-scale multifunctional intelligent repairing system.
The product prepared by the method has the functions of bone defect repair and tumor synergic photothermal-chemotherapy and bacterial infection eradication, and can be used for comprehensive biomedical tissue engineering and bone tumor multi-modal treatment.
The biomedical material of step one, comprising: medical metal materials, medical nonmetal materials, medical polymer materials and medical ceramic materials.
The concrete implementation steps of the second step are as follows:
(1) Fixing a clean substrate to be processed on a glass slide, and fixing the glass slide on a high-precision six-degree-of-freedom translation table;
(2) Focusing femtosecond laser pulses generated by a femtosecond laser to the surface of a base material by using an objective lens, and controlling a high-precision six-freedom-degree mobile platform by using a computer control system to enable a material to move relative to the laser; in the processing process, high-pressure nitrogen is used for blowing scraps, and various three-dimensional multistage micro/nano composite structures are prepared by controlling laser flux, processing speed and processing distance.
The third step is realized by the following steps:
(1) Preparing the block black phosphorus material into black phosphorus nanosheet dispersion liquid with different concentration gradients by using a physical stripping method;
(2) In a vacuum environment, the biomedical material with the surface having a three-dimensional multi-level micro/nano composite structure and prepared by femtosecond laser direct writing processing is placed at the bottom of a culture dish, and the prepared black phosphorus nanosheet dispersion liquid is added into the culture dish to carry out electrostatic adsorption reaction with the material. After reacting for a period of time at room temperature, taking out the material, drying, putting the material in a new culture dish again, adding the black phosphorus nanosheet dispersion liquid with the same concentration for secondary reaction, and circulating the process for a plurality of times to ensure that the black phosphorus nanosheets are uniformly and consistently decorated on the three-dimensional multilevel micro/nano composite structure;
(3) And (4) washing and drying the material subjected to the electrostatic adsorption reaction by using deionized water.
The concrete implementation steps of the fourth step are as follows:
(1) Preparing water solutions of chemotherapeutic adriamycin with different concentration gradients;
(2) In a vacuum environment, the femtosecond laser direct writing processing is combined with black phosphorus nanosheet modification to prepare a biomedical material with a cross-scale heterostructure, the surface of which is provided with a three-dimensional multi-level micro/nano composite structure and is composed of the nanosheets, the biomedical material is placed at the bottom of a culture dish, the prepared drug solution is dropwise added on the surface of the material, and drying treatment is carried out after the solution is uniformly spread. This process is cycled several times to ensure uniform, consistent loading of the drug on the trans-scale heterostructure;
(3) And washing the material loaded with the medicament by using deionized water and drying.
The concrete implementation steps of the fifth step are as follows:
(1) Pouring a predetermined volume of Tris-HCl buffer solution with the pH =8.5 into a beaker, weighing a certain amount of dopamine hydrochloride powder, adding the dopamine hydrochloride powder into the buffer solution, stirring to completely dissolve the dopamine hydrochloride powder, and preparing dopamine hydrochloride solutions with different concentration gradients;
(2) Soaking the material with the drug-loaded trans-scale heterostructure into 10mL of dopamine hydrochloride solution at room temperature in a dark condition for a period of time;
(3) And (3) washing the material subjected to the self-polymerization reaction by using deionized water, and drying.
The multiple of the processed objective lens, the laser flux, the processing speed and the processing distance in the step two (2) are respectively 5 times, 10 times or 20 times and 1-200J/cm 2 5-2000 μm/s and 1-50 μm.
And (2) the concentration of the black phosphorus nanosheet dispersion liquid in the third step (1) is 0.2-1mg/mL.
The room-temperature reaction time of the step three (2) is 0.5-2h, the drying time is 1-3h, and the cycle reaction times are 3-5.
The concentration of the adriamycin aqueous solution in the step four (1) is 200-800 mug/mL.
And (3) drying at 20-30 ℃ for 1-3h for 2-6 times.
And (2) the concentration of the dopamine hydrochloride solution in the step five (1) is 2-6mg/mL.
The standing time in the step five (2) is 16-24h.
Has the advantages that:
(1) The cross-scale multifunctional intelligent therapeutic and reparative system has the functions of bone defect repair, tumor synergistic photothermal-chemotherapy and bacterial infection eradication, and can be used for comprehensive biomedical tissue engineering and bone tumor multi-modal treatment.
(2) The preparation method of the cross-scale multifunctional intelligent therapeutic and reparative system provided by the invention has patterning processing capacity and can be used for biomedical materials with various sizes, shapes and types.
(3) The cross-scale multifunctional intelligent therapeutic and repair system and the preparation method thereof have excellent photo-thermal conversion characteristics in vitro and in animal bodies.
(4) The invention relates to a cross-scale multifunctional intelligent therapeutic and modification system and a preparation method thereof.
(5) The invention relates to a cross-scale multifunctional intelligent therapeutic and reparative system and a preparation method thereof.
(6) The cross-scale multifunctional intelligent therapeutic and repairing system and the preparation method thereof have excellent cell compatibility in vitro and no cytotoxicity.
(7) The invention relates to a cross-scale multifunctional intelligent therapeutic system and a preparation method thereof, wherein the multifunctional intelligent therapeutic system can remarkably induce human osteosarcoma cells (Saos-2) and human breast cancer cells (MDA-MB-231, cancer cells which are very easy to generate bone metastasis) to die by cooperating with photothermal-chemotherapy in vitro.
(8) The invention relates to a cross-scale multifunctional intelligent therapeutic and reparative system and a preparation method thereof.
(9) The invention relates to a cross-scale multifunctional intelligent therapeutic and reparative system and a preparation method thereof.
(10) According to the cross-scale multifunctional intelligent therapeutic and repair system and the preparation method thereof, the survival rate of tumor-bearing mice treated by the multifunctional intelligent therapeutic and repair system is kept 100% after the mice are raised for 60 days, and no tumor recurs.
(11) According to the cross-scale multifunctional intelligent therapeutic and prosthetic system and the preparation method thereof, the multifunctional intelligent therapeutic and prosthetic system remarkably promotes bone regeneration.
(12) The multi-functional intelligent therapeutic system can effectively inhibit the formation of a biological membrane, remarkably kill various bacteria adhered to the surface of a material through a photothermal effect and has excellent capability of eradicating bacterial infection.
(13) The cross-scale multifunctional intelligent therapeutic and repair system and the preparation method thereof have the advantages of flexibility and simplicity, easily controlled process parameters, extremely high repeatability and easiness in realizing application in the technical field of laser. It is worth noting that the method does not need to introduce any other auxiliary chemical reagent in the preparation process, and has no pollution.
Drawings
FIG. 1 is a process flow diagram for preparing a cross-scale multifunctional intelligent remedial system according to an embodiment of the present invention; wherein (a) is the preparation of black phosphorus nanosheets; (b) Preparing a three-dimensional multi-level micro/nano composite structure on the surface of the biomedical material by femtosecond laser direct writing; (c) preparation of a cross-scale heterostructure; (d) preparation of drug-loaded trans-scale heterostructures; and (e) preparing a polydopamine coating.
Fig. 2 is an Ultraviolet (UV) -visible (vis) -Near Infrared (NIR) absorption spectrum of a cross-scale multifunctional intelligent remedial system prepared by an embodiment of the present invention.
FIG. 3 is a photo-thermal property and stability of a trans-scale multifunctional intelligent remedial system prepared by an embodiment of the present invention using NIR (808 nm) laser irradiation in vitro (4 cycle experiments); wherein (a) is a dry (air) environment; and (b) is a liquid (phosphate buffered saline, PBS) environment.
FIG. 4 is a graph of drug loading and release behavior of a cross-scale multifunctional intelligent remedial system prepared according to the present invention; wherein (a) is the drug loading capacity of various types of surfaces; (b) The intelligent NIR/pH response drug release capability of the cross-scale multifunctional intelligent therapeutic system is realized.
FIG. 5 is a graph showing the blood compatibility (hemolysis rate) of a multi-functional, cross-scale, intelligent, remedial system prepared according to an embodiment of the present invention.
FIG. 6 is a graph of the in vitro synergistic photothermal-chemotherapy anti-cancer properties of a cross-scale multifunctional intelligent remedial system prepared by an embodiment of the present invention; wherein, (a) is relative cell activity of human osteosarcoma cells (Saos-2) under the condition of NIR laser irradiation/non-NIR laser irradiation (continuous irradiation for 10 min); (b) Relative cellular activity of human breast cancer cells (MDA-MB-231) with/without NIR laser irradiation (continuous irradiation for 10 min).
FIG. 7 is a toxicity and safety test of the cross-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in animals (nude mice).
FIG. 8 shows the photothermal properties (laser power of 1W/cm) of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in the animal (nude mouse) 2 )。
FIG. 9 shows the tumor treatment ability of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in cooperation with photothermal-chemotherapy in animals (nude mice).
FIG. 10 is an image of osteoblast (MC 3T3-E1, after 7 days of co-culture) adhesion in a trans-scale multifunctional intelligent theranostic system prepared in accordance with an embodiment of the present invention; wherein, (a) a fluorescence microscopy image; (b) Are scanning electron microscope (scanning electron microscope) images.
FIG. 11 is a graph of NIR laser power density of 1W/cm for a multi-functional, cross-scale, intelligent, remedial system made in accordance with embodiments of the present invention 2 Continuously irradiating for 10min to obtain antibacterial efficiency; wherein (a) is staphylococcus aureus (s. Aureus); (b) Pseudomonas aeruginosa.
Detailed Description
In order to better understand the present invention, the following detailed description of the technical solution of the present invention is provided with reference to specific embodiments.
The experimental procedures used in the following examples were carried out by a conventional method unless otherwise specified.
Example 1
As shown in fig. 1, the cross-scale multifunctional intelligent therapeutic system and the preparation method thereof of the present embodiment includes the following specific steps:
firstly, performing optical-level polishing on the surface of a medical nickel titanium (NiTi) alloy with a nearly equal atomic ratio to obtain a NiTi alloy material with a mirror surface polished, wherein the surface roughness is less than 5 angstroms;
step two, cleaning the titanium alloy material subjected to mirror polishing in the step one by using an ultrasonic cleaning instrument, wherein the ultrasonic frequency of the ultrasonic cleaning instrument is 60KHZ, submerging the surface of the material by using deionized water and absolute ethyl alcohol solution respectively, and cleaning for 5min at room temperature respectively;
step three, drying the cleaned titanium alloy material in the step two by cold air to obtain a clean titanium alloy material;
step four, preparing the block black phosphorus material into black phosphorus nanosheet dispersion liquid with different concentration gradients by using a physical stripping method for later use, wherein the result is shown in fig. 1 (a);
step five, performing laser-induced three-dimensional multi-level micro/nano composite structure processing on the surface of the titanium alloy by using the femtosecond laser direct writing processing technology shown in fig. 1 (b), wherein the laser processing parameters are specifically set as follows: the femtosecond laser has wavelength of 800nm, pulse duration of 35fs, repetition frequency of 1KHZ, 5 times of objective lens for processing, and laser flux of 22.68J/cm 2 The scanning speed is 1300 mu m/s, the scanning interval is 5 mu m, and high-pressure nitrogen is used for blowing scraps in the whole processing process so as to process a large-area and consistent three-dimensional groove array micro/nano composite structure;
step six, in a vacuum environment, putting the titanium alloy material which is prepared by femtosecond laser direct writing processing and has the three-dimensional groove array micro/nano composite structure on the surface in the step five into the bottom of a culture dish, adding the prepared black phosphorus nanosheet dispersion liquid into the culture dish, further uniformly modifying the black phosphorus nanosheets on the three-dimensional groove array micro/nano composite structure by adopting an electrostatic adsorption method, and constructing a cross-scale heterostructure consisting of the three-dimensional groove array micro/nano composite structure and the nanosheets, wherein the result is shown in fig. 1 (c). Notably, the cross-scale heterostructure related by the invention does not need any auxiliary chemical reagent in the preparation process, and skillfully utilizes the typical technical characteristic that the femtosecond laser can process metal materials in the air to fully oxidize the surface of the metal materials, so that the processed titanium alloy surface presents strong oxidation characteristic, the surface of the titanium alloy has electropositivity, and black phosphorus nanosheets with electronegative performance on the surface are efficiently adsorbed;
and step seven, in a vacuum environment, placing the titanium alloy material with the cross-scale heterostructure on the surface prepared in the step six into the bottom of a culture dish, dropwise adding the prepared water solution of the chemotherapeutic drug adriamycin onto the surface of the material by adopting a vacuum physical adsorption method, and drying after the solution is uniformly spread. This process is cycled several times to ensure that the drug is uniformly and consistently loaded on the cross-scale heterostructure, thereby producing a drug-loaded cross-scale heterostructure, the results of which are shown in fig. 1 (d). The surface of the black phosphorus nanosheet is negatively charged, and the surface of the adriamycin medicine is positively charged, so that the medicine can be effectively and firmly locked on the cross-scale heterostructure by utilizing the electrostatic adsorption effect;
step eight, immersing the titanium alloy material with the drug-loaded trans-scale heterostructure on the surface prepared in the step seven into a dopamine hydrochloride solution at room temperature in a dark place, and uniformly coating the surface of the titanium alloy material with a poly-dopamine coating through auto-polymerization reaction to obtain the trans-scale multifunctional intelligent repairing system, wherein the result is shown in fig. 1 (e).
The electrostatic adsorption method in the sixth step comprises the following steps:
(1) Preparing 6mL of black phosphorus nanosheet dispersion liquid with the concentration of 0.2 mg/mL;
(2) In a vacuum environment, placing a titanium alloy material which is prepared by femtosecond laser direct writing and has a three-dimensional groove array micro/nano composite structure on the surface into the bottom of a culture dish, slowly adding prepared 2mL of black phosphorus nanosheet dispersion liquid into the culture dish, ensuring that the material is immersed in the dispersion liquid, and standing the culture dish for 30min at room temperature;
(3) After the first standing, taking out the material, drying the material in vacuum at room temperature for 1h, then placing the material in a new culture dish again, and adding 2mL of black phosphorus nanosheet dispersion liquid for the second time, and standing for 30min;
(4) After standing for the second time, similarly taking out the material, drying the material in vacuum at room temperature for 1h, then placing the material in a new culture dish again, and adding 2mL of black phosphorus nanosheet dispersion liquid for three times, and standing for 30min;
(5) And after standing for the third time, taking out the titanium alloy material, drying the titanium alloy material in vacuum for 1 hour at room temperature, washing the titanium alloy material by using deionized water, and drying the titanium alloy material to obtain the trans-scale heterostructure consisting of the three-dimensional groove array micro/nano composite structure and the black phosphorus nanosheets.
The vacuum physical adsorption method comprises the following steps:
(1) Preparing 30 mu L of chemotherapeutic drug adriamycin aqueous solution with the concentration of 600 mu g/mL;
(2) In a vacuum environment, placing a titanium alloy material which is prepared by combining femtosecond laser direct writing processing with black phosphorus nanosheet modification and has a cross-scale heterostructure composed of a three-dimensional groove array micro/nano composite structure and nanosheets on the surface into the bottom of a culture dish, dropwise adding a prepared 10 mu L adriamycin aqueous solution on the surface of the material, and after the solution is uniformly spread on the surface of the material, carrying out vacuum drying on the culture dish for 2 hours at 30 ℃;
(3) After the first drug loading, 10 mu L of adriamycin aqueous solution is dropwise added on the surface of the material for the second time, and after the solution is uniformly spread on the surface of the material, the material is dried in vacuum for 2 hours at the temperature of 30 ℃;
(4) After the second drug loading, dropwise adding 10 mu L of adriamycin aqueous solution on the surface of the material for three times, and continuing to perform vacuum drying for 2 hours at 30 ℃ after the solution is uniformly spread on the surface of the material;
(5) And after carrying out the drug for three times, washing and drying the titanium alloy material by using deionized water to obtain the drug-loaded trans-scale heterostructure.
Wherein, the self-polymerization reaction of the step eight comprises the following steps:
(1) Weighing 10mL,10mM Tris-HCl buffer solution with the pH =8.5, pouring the buffer solution into a beaker, adding 20mg of dopamine hydrochloride powder into the buffer solution, stirring the buffer solution to be completely dissolved, and preparing a dopamine hydrochloride solution with the concentration of 2 mg/mL;
(2) Immersing the titanium alloy material with the drug-loaded trans-scale heterostructure on the surface into 10mL of dopamine hydrochloride solution at room temperature in a dark condition for carrying out self-polymerization reaction for 24 hours;
(3) After the reaction is finished, the titanium alloy material is washed and dried by deionized water, and the trans-scale multifunctional intelligent therapeutic and repairing system is obtained.
In the corresponding reaction process of the sixth, seventh and eighth steps, the titanium alloy material and various solutions can be placed in a plastic or glass culture dish and a beaker. Any application of this method to carry out the corresponding reaction processes in different containers is within the scope of this patent.
The product prepared by the method has excellent functions of bone defect repair, tumor synergistic photothermal-chemotherapy and bacterial infection eradication, and can be used for comprehensive biomedical tissue engineering and bone tumor multi-modal treatment.
Fig. 2 shows the absorption spectrum of Ultraviolet (UV) -visible (vis) -Near Infrared (NIR) of the multi-functional smart remedial system across scales prepared in this example. As can be seen from the figure, the black phosphorus nanosheet has a wide absorption characteristic in the whole visible light and near infrared region, so that the trans-scale heterostructure has an excellent light absorption characteristic in the near infrared band compared with a three-dimensional multilevel micro/nano composite structure and a surface polishing material. After the polydopamine coating is coated, the light absorption property of the polydopamine coating in a near infrared band is further improved. In conclusion, the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment can be used for NIR laser (808 nm) assisted photothermal therapy.
Fig. 3 shows the photothermal properties and stability (4 cycle experiments) of the trans-scale multifunctional intelligent therapeutic system prepared in this example in vitro. Graph (a) is a cross-scale multifunctional intelligent therapeutic system utilizing a power density of 1.0W/cm in a dry (in air) environment 2 The NIR laser of (a) was irradiated, and it can be seen from the figure that its surface temperature rapidly increased to 76.8 ℃ within 5min, and had a stable photothermal conversion effect under 4 cycles of experiments; panel (b) is a multifunctional therapeutic biomaterial in a liquid (phosphate buffered saline, PBS) environment using a power density of 1.0W/cm 2 The NIR laser of (a) was irradiated, it was seen that its surface temperature rapidly increased to 56.3 ℃ within 5min, and had a stable photothermal conversion effect under 4-cycle experiments. In conclusion, the trans-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention has controllable, excellent and stable photothermal conversion effect in dry and liquid environments.
Fig. 4 shows the drug loading capacity and release behavior of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention. The drug loading capacity of the graph (a) shows that due to the multi-fold structure and the negative charge characteristic of the black phosphorus nanosheet, the cross-scale heterostructure has the capacity of efficiently loading the chemotherapeutic drug, and the loading efficiency is 93.2%, which is significantly higher than that of the three-dimensional multilevel micro/nano composite structure (35.2%) and the surface polishing material (13.3%). The drug release capacity of the trans-scale multifunctional intelligent therapeutic system is shown in the graph (b), and the intelligent and controllable drug release behavior with obvious NIR/pH dual trigger can be seen from the graph. In conclusion, the cross-scale multifunctional intelligent therapeutic and reparative system prepared by the embodiment of the invention can be used for the cooperative photothermal-chemotherapy of tumors.
Fig. 5 shows the blood compatibility (hemolysis rate) test of the cross-scale multifunctional intelligent therapeutic system prepared by the embodiment of the present invention. As can be seen from the figure, the value of the hemolysis rate of the trans-scale multifunctional intelligent therapeutic system is only 0.52%, which is significantly lower than the internationally recognized standard value (5%), demonstrating that the trans-scale multifunctional intelligent therapeutic system hardly has any damage to red blood cells. In conclusion, the trans-scale multifunctional intelligent therapeutic and prosthetic system prepared by the embodiment of the invention can be reliably applied to a wide medical field.
Fig. 6 shows the in vitro synergistic photothermal-chemotherapy anticancer properties of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention. FIG. (a) is the relative cell activity of human osteosarcoma cells (Saos-2) with/without NIR laser irradiation (10 min continuous irradiation); panel (b) relative cell viability of human breast cancer cells (MDA-MB-231) with/without NIR laser irradiation (10 min continuous irradiation). As can be seen from the figure, in the absence of NIR laser irradiation, the trans-scale multifunctional intelligent remedial system can induce death of both cancer cells due to the effective cumulative release of chemotherapeutic drugs, but relying on chemotherapeutic action alone is difficult to kill tumor cells substantially. In the case of NIR laser irradiation, the trans-scale heterostructure clearly induces death of both cancer cells due to its excellent photothermal effect (provided by black phosphorus nanoplates), with relative activities reduced to 15.3% and 17.8%, respectively. Particularly, the cross-scale multifunctional intelligent therapeutic and repair system can remarkably kill the two cancer cells due to excellent photothermal effect and intelligent and controllable drug release capacity, and the relative activities of the two cancer cells are respectively reduced to 9.6% and 11.5%. In conclusion, the trans-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention has excellent synergistic photothermal-chemotherapy anticancer characteristics in vitro, and the anticancer capability of the system is obviously superior to that of separate chemotherapy and photothermal therapy.
Fig. 7 shows toxicity and safety tests of the cross-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in animals (nude mice). After the material with the cross-scale multifunctional intelligent therapeutic and repair system on the surface is implanted into the nude mice and further raised for 14 days and 28 days, the main organs (heart, liver, spleen, lung and kidney) of the nude mice are taken out for sectioning, and histological analysis is carried out after H & E staining. As can be seen from the figure, no obvious histomorphosis, pathological toxicity and adverse reaction are seen in each organ no matter the organs are raised for 14 days or 28 days. In conclusion, the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention has satisfactory biocompatibility in the animal body.
FIG. 8 shows the photothermal properties (laser power of 1W/cm) of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in the animal (nude mouse) 2 ). As can be seen from the figure, the local temperature of the tumor site after the implantation of the material with the trans-scale multifunctional intelligent therapeutic system on the surface is rapidly increased to 54.3 ℃ within 10min of NIR laser irradiation, and the temperature distribution is uniform. In conclusion, the cross-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention has excellent, controllable and stable photo-thermal characteristics in an animal body.
Fig. 9 shows the tumor treatment ability of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention in cooperation with photothermal-chemotherapy in animals (nude mice). Firstly, establishing an ectopic bone tumor model on the right side of the back of a nude mouse, implanting a material at the bottom of a tumor when the diameter of the tumor is about 10mm, then dividing the nude mouse into an NIR laser-free irradiation group and an NIR laser-free irradiation group, continuously feeding the nude mouse for 14 days after the material is implanted, irradiating the tumor part by the NIR laser-free irradiation group after the material is implanted, wherein the laser power density is 1W/cm 2 Irradiating for 10min every day, continuously irradiating for 3 days, and continuously feeding nude mice for 14 days. As can be seen from the figure, the surface polishing material, the surface, after 14 days of rearing without NIR laser irradiationThe material with a three-dimensional multi-level micro/nano composite structure and the material with a cross-scale heterostructure on the surface do not have the treatment capacity in a nude mouse body, and the tumor volume is increased crazy. The material with the cross-scale multifunctional intelligent therapeutic and repair system on the surface has certain tumor growth inhibition capacity due to the single chemotherapy effect, but the tumor cannot be effectively eliminated only by using chemotherapy. When the NIR laser is adopted for irradiation, the surface polishing material and the material with the three-dimensional multi-level micro/nano composite structure on the surface do not have photothermal characteristics in a nude mouse body, so that the volume of the tumor still shows obvious increase even after photothermal treatment. However, materials with a trans-scale heterostructure on the surface almost disappeared on day 14 after photothermal treatment. In addition, the material with the cross-scale multifunctional intelligent therapeutic and repair system on the surface completely disappears on the 14 th day after the cooperation of photothermal-chemotherapy, thereby achieving the purpose of completely treating the tumor. In conclusion, the trans-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention has excellent tumor treatment capability of cooperating photothermal-chemotherapy in an animal body.
Fig. 10 shows the bone regeneration induction characteristics of the trans-scale multifunctional intelligent therapeutic system prepared by the embodiment of the invention. FIG. (a) is a fluorescence microscopy image of the material after 7 days of co-culture with osteoblasts (MC 3T 3-E1); FIG. b is a scanning electron microscope (scanning electron microscope) image of the material after co-culturing with osteoblasts (MC 3T 3-E1) for 7 days. As can be seen from the figure, osteoblasts with abundant pseudo-sufficiency almost completely spread out the whole material surface, and the cells grow along the micro/nano composite structure of the three-dimensional groove array in a directional arrangement, and show obvious contact guiding effect. In conclusion, the cross-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention can obviously induce the adhesion and proliferation of osteoblasts and has excellent osteogenesis characteristics.
FIG. 11 shows the NIR laser power density of 1W/cm for the multi-functional intelligent therapy system prepared by the embodiment of the invention 2 And (3) continuously irradiating for 10 min. Graph (a) shows the antibacterial efficiency of staphylococcus aureus (s. Aureus); drawing (b) is AerugoAntibacterial efficiency of pseudomonas (p. Aeruginosa). As can be obtained from the figure, the photothermal antibacterial efficiency against Staphylococcus aureus can reach 99.2%, and the photothermal antibacterial efficiency against Pseudomonas aeruginosa can reach 99.6%. In conclusion, the cross-scale multifunctional intelligent therapeutic and repair system prepared by the embodiment of the invention can effectively eradicate the infection of various bacteria.
The above detailed description is provided for further explaining the objects, technical solutions and advantages of the present invention, and it should be understood that the above are only exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention.

Claims (8)

1. A preparation method of a cross-scale multifunctional intelligent therapeutic and reparative system is characterized by comprising the following steps: the method comprises the following steps:
step one, carrying out mirror polishing pretreatment on the surface of an original biomedical material, ultrasonically cleaning to remove surface residues, and drying to obtain a clean surface-polished substrate to be processed; the biomedical material is medical NiTi alloy;
step two, preparing a large-area and configuration-controllable three-dimensional multi-stage micro/nano composite structure on the surface of the surface polishing material obtained in the step one by utilizing femtosecond laser direct writing, and cleaning and drying the processed biomedical material by using deionized water and absolute ethyl alcohol;
step three, modifying the black phosphorus nanosheets on the surface of the material obtained in the step two, and constructing a cross-scale heterostructure;
step four, dropwise adding a solution of chemotherapeutic drug adriamycin on the trans-scale heterostructure prepared in the step three, and performing vacuum drying treatment after the drug solution is uniformly spread on the surface of the material;
and step five, immersing the drug-loaded trans-scale heterostructure prepared in the step four into a dopamine hydrochloride solution at room temperature in a dark place, and uniformly coating the surface of the structure with a polydopamine coating through self-polymerization reaction to obtain the trans-scale multifunctional intelligent therapeutic system.
2. The product of the process of claim 1, wherein: the product has the functions of bone defect repair, tumor synergistic photothermal-chemotherapy and bacterial infection eradication, and can be used for comprehensive biomedical tissue engineering and bone tumor multi-modal treatment.
3. The method of claim 1, wherein: the third step is realized by the following steps:
(1) Preparing the block black phosphorus material into black phosphorus nanosheet dispersion liquid with different concentration gradients by using a physical stripping method;
(2) In a vacuum environment, placing a biomedical material with a three-dimensional multi-level micro/nano composite structure on the surface, which is prepared by femtosecond laser direct writing processing, at the bottom of a culture dish, adding the prepared black phosphorus nanosheet dispersion liquid into the culture dish at room temperature to perform electrostatic adsorption reaction with the material; after reacting for a period of time, taking out the material, drying the material in vacuum at room temperature, putting the material into a new culture dish again, adding the black phosphorus nanosheet dispersion liquid with the same concentration to carry out secondary reaction, and circulating the process for a plurality of times to ensure that the black phosphorus nanosheets are uniformly and consistently modified on the three-dimensional multilevel micro/nano composite structure;
(3) And washing the material subjected to the electrostatic adsorption reaction by using deionized water, and drying.
4. The method of claim 1, wherein: the concrete implementation steps of the fourth step are as follows:
(1) Preparing water solutions of chemotherapeutic adriamycin with different concentration gradients;
(2) In a vacuum environment, a biomedical material with a three-dimensional multi-level micro/nano composite structure on the surface and a cross-scale heterostructure consisting of nano sheets is prepared by combining femtosecond laser direct writing processing with black phosphorus nano sheet modification and is placed at the bottom of a culture dish, then a prepared drug solution is dropwise added on the surface of the material, and drying treatment is carried out after the solution is uniformly spread; this process is cycled several times to ensure uniform, consistent loading of the drug on the trans-scale heterostructure;
(3) And washing the material loaded with the medicament by using deionized water and drying.
5. The method of claim 1, wherein: the concrete implementation steps of the fifth step are as follows:
(1) Pouring a predetermined volume of Tris-HCl buffer solution into a beaker, weighing a certain amount of dopamine hydrochloride powder, adding the dopamine hydrochloride powder into the buffer solution, and stirring to completely dissolve the dopamine hydrochloride powder to prepare a dopamine hydrochloride solution;
(2) Immersing the material with the drug-loaded trans-scale heterostructure into a dopamine hydrochloride solution with a certain volume under the condition of room temperature and light shielding for placing;
(3) And (3) washing the material subjected to the self-polymerization reaction by using deionized water, and drying.
6. The method of claim 3, wherein: the concentration of the black phosphorus nanosheet dispersion liquid in the step (1) is 0.2-1mg/mL; in the step (2), the room temperature reaction time is 0.5-2h, the drying time is 1-3h, and the circulating reaction times are 3-5.
7. The method of claim 4, wherein: the concentration of the adriamycin aqueous solution in the step (1) is 200-800 mug/mL; the drying treatment temperature in the step (2) is 20-30 ℃, the drying time is 1-3h, and the cyclic loading times are 2-6.
8. The method of claim 5, wherein: the pH value of the Tris-HCl buffer solution in the step (1) is 8.5, and the concentration of the dopamine hydrochloride solution is 2-6mg/mL; the volume of the dopamine hydrochloride solution in the step (2) is 10-20/mL, and the standing time is 16-24h.
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