CN113813225A - Portable beta-FeSi2Composite spray hydrogel and preparation method and application thereof - Google Patents

Portable beta-FeSi2Composite spray hydrogel and preparation method and application thereof Download PDF

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CN113813225A
CN113813225A CN202111106863.3A CN202111106863A CN113813225A CN 113813225 A CN113813225 A CN 113813225A CN 202111106863 A CN202111106863 A CN 202111106863A CN 113813225 A CN113813225 A CN 113813225A
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fesi
beta
hydrogel
sodium alginate
portable
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CN113813225B (en
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吴成铁
马文平
马红石
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Zhongke Sifukang Jining Medical Device Technology Co ltd
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Shanghai Institute of Ceramics of CAS
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    • A—HUMAN NECESSITIES
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    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/60—Materials for use in artificial skin
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
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    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus

Abstract

The invention relates to portable beta-FeSi2Composite spray hydrogel and a preparation method and application thereof. The portable beta-FeSi2The composite spray hydrogel comprises: sodium alginate hydrogel and beta-FeSi dispersed in sodium alginate hydrogel2And (3) granules.

Description

Portable beta-FeSi2Composite spray hydrogel and preparation method and application thereof
Technical Field
The invention relates to a skin tumor treatment material and a wound healing material, and relates to a portable beta-FeSi2A composite spray hydrogel, a preparation method thereof and application thereof in preparing a skin tumor treatment material and a wound healing material belong to the field of biological materials.
Background
Melanoma is one of the common malignancies in humans. Currently, the common clinical treatments for skin cancer are surgical resection and radio/chemotherapy. However, the large-area skin defect and residual tumor cells caused by the operation and the toxic and side effects of radiotherapy/chemotherapy severely limit the treatment effect of melanoma. Based on the limitations of these traditional therapeutic approaches, researchers have proposed a series of novel cancer treatment strategies. For example, photothermal therapy (PTT) can effectively kill tumor cells, and has the characteristics of high efficiency and small toxic and side effects. Furthermore, chemokinetic therapy (CDT) achieves specific and deep tumor ablation by generating highly aggressive hydroxyl radicals (· OH) to eliminate tumor cells. Meanwhile, the treatment of skin tumor is usually accompanied by large skin defect, which brings great pain and inconvenience to the postoperative recovery of patients. One of the key challenges in solving these problems is how to accomplish rapid treatment of skin wounds and provide the patient with the most convenient treatment options possible. Therefore, the development of a novel portable bifunctional biomaterial which can effectively remove residual tumor tissues and promote skin regeneration in time is of great significance.
The treatment of skin tumors is usually accompanied by major skin defects, which cause great pain and inconvenience to the postoperative recovery of the patient. Conventional skin wound dressings are often unsatisfactory due to their complex and slow manufacturing process. It is worth noting that the sprayed hydrogel can quickly form a protective layer on the wound to prevent bacteria invasion, has the advantages of simple operation and quick in-situ action, and is very suitable for on-site emergency wound treatment. For example, in sporting events, medical personnel often provide emergency treatment to injured athletes by spraying. Spray hydrogels are becoming an important component of home drug cabinets due to their convenience and portability. For patients after excision of skin tumors, the spray hydrogel can realize the purpose of home self-recovery treatment. Therefore, it is of great interest to develop an in situ cross-linked spray hydrogel that can be used immediately for skin tumor treatment and wound healing.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a portable beta-FeSi for the first time2Composite spray hydrogel, a preparation method thereof and application thereof in preparing tumor treatment materials and skin repair materials.
In a first aspect, the invention provides a portable beta-FeSi2Composite spray hydrogel, said portable beta-FeSi2The composite spray hydrogel comprises: sodium alginate hydrogel and beta-FeSi dispersed in sodium alginate hydrogel2And (3) granules.
In the present disclosure, beta-FeSi is first introduced2Can be used as photo-thermal agent for tumor photo-thermal treatment under near infrared light excitation. Wherein, based on the weak acidic condition and high H of the tumor site2O2Feature, beta-FeSi2The released Fe ions can catalyze Fenton reaction to generate OH, so that the targeted chemical kinetic treatment of the tumor microenvironment is realized. And an external thermal field formed by near infrared light excitation can promote the Fenton reaction and improve the curative effect of CDT. Thus, beta-FeSi2Has the PTT and CDT synergistic anti-tumor capability and has great application potential.
Further, in order to promote skin regeneration, the present inventors have made an effective strategy to introduce bioactive ions to enhance the bioactivity of the composite hydrogel. The invention leads beta-FeSi to be2As a biological activator to improve the biological activity of the composite hydrogel. Furthermore, Sodium Alginate (SA) hydrogels have many advantages, being compatible with Ca2+The ions are quickly and simply crosslinked, and the biocompatibility is good. Of course, the lack of bioactivity of pure SA limits its use in tissue repair.
Preferably, the concentration of the sodium alginate in the sodium alginate hydrogel is 1.0-2.5 wt%; the beta-FeSi2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1.
preferably, the portable beta-FeSi2The composite spray hydrogel has a three-dimensional micron-sized pore structure, and the pore size distribution is 100-500 mu m.
Preferably, the beta-FeSi2The particles have a particle size of 15 μm or less, preferably 10 μm or less, more preferably 1 μm or less, and most preferably 500nm or less.
In a second aspect, the invention provides a portable beta-FeSi2The preparation method of the composite spray hydrogel comprises the step of mixing the beta-FeSi2Spraying the sodium alginate solution on the surface of the base material, and then spraying the calcium chloride solution to carry out in-situ crosslinking, thereby obtaining the portable beta-FeSi2And (3) compounding spray hydrogel.
Preferably, the concentration of the sodium alginate in the sodium alginate solution is 1.0-2.5 wt%; the beta-FeSi2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1.
preferably, the sodium alginate is added into the deionized water and stirred uniformly to obtain a sodium alginate solution; ultrasonically dispersing the beta-FeSi2Dispersing the particles in sodium alginate solution to obtain the product containing beta-FeSi2The sodium alginate solution of (1).
Preferably, calcium chloride is mixed with deionized water to obtain a calcium chloride solution; the concentration of the calcium chloride solution is 1.5-5.0 wt%.
Preferably, the spray coating contains beta-FeSi once2Spraying a calcium chloride solution for one time simultaneously with the sodium alginate solution; setting each spraying to contain beta-FeSi2The content of the sodium alginate solution is 0.01-0.05 mL/cm2And controlled to contain beta-FeSi2The spraying times of the sodium alginate solution are not more than 20.
In a third aspect, the present invention provides a portable deviceβ-FeSi2The application of the composite spray hydrogel in preparing skin tumor treatment materials and skin wound healing materials. When the beta-FeSi is used for preparing skin tumor treatment materials, the beta-FeSi is portable2The concentration of sodium alginate in the sodium alginate hydrogel in the composite spray hydrogel is 1.0-2.5 wt%, and the beta-FeSi is2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1. when the beta-FeSi is applied to preparing skin wound healing materials, the beta-FeSi is portable2The concentration of sodium alginate in the sodium alginate hydrogel in the composite spray hydrogel is 1.0-2.5 wt%, and the beta-FeSi is2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1.
has the advantages that:
the invention prepares the portable beta-FeSi2And (3) compounding spray hydrogel. Wherein, beta-FeSi2Has excellent photo-thermal performance and OH generation capacity, and can realize the synergistic and efficient treatment of tumors by PTT and CDT. Meanwhile, the evaluation of endothelial cell migration, in vitro angiogenesis-related gene expression and the therapeutic effect of burn skin in vivo proves that the beta-FeSi2Biological activity as novel biomaterials to promote wound healing and beta-FeSi2The convenience and timeliness of the composite spray hydrogel for skin regeneration. Importantly, the composite spray hydrogel prepared by the invention has the advantages of simplicity and convenience in use, and is suitable for wound treatment in emergency situations such as burns. Thus, due to portability and simplicity, as well as dual function of tumor therapy and skin wound healing, β -FeSi2The composite spray hydrogel provides a portable treatment method for patients after skin tumor excision.
Drawings
FIG. 1 shows beta-FeSi2A crystalline phase and microstructure of the particles, wherein (a) beta-FeSi2XRD pattern of (b) beta-FeSi2SEM image of (d). FIG. 1 shows that FeSi is synthesized2Is in the beta crystalline phase, consistent with expectations, and the crystallinity is good. The scanning electron microscope image shows that the particles are irregular and have a particle size of about 10 μm.
FIG. 2 shows beta-FeSi2The photothermal properties and the chemical kinetic properties of (a) withoutSame power density (0.30W/cm)2、0.45W/cm2And 0.60W/cm2) 808nm laser irradiation for 800s, and beta-FeSi was measured2Photothermal temperature profile of aqueous dispersion (2.5 mg/mL). (b) Different beta-FeSi2Content Tris-HCl extract (24h) was incubated with TMB (pH 6.0) for 24h and the UV-vis absorbance spectrum was low for the marker "4-7". In FIG. 2, it is shown that beta-FeSi2Has excellent photo-thermal performance and chemical kinetic property, and can be used as a novel antitumor agent.
FIG. 3 is a view showing β -FeSi2Preparation, shape and thickness control of composite spray hydrogel, wherein (a-d) beta-FeSi2Preparation of composite spray hydrogel, (e-h) different beta-FeSi2Appearance photos and micro-appearances of four groups of spray hydrogels with content (i-l) different beta-FeSi under high power2SEM images of four sets of spray hydrogels for content, (m) hydrogel thickness statistics. Shown in FIG. 3, beta-FeSi2The composite spray hydrogel has the characteristic of rapid in-situ gelation and is accompanied with beta-FeSi2The content of (a) increases, and the color of the hydrogel becomes darker. The scanning electron microscope image shows that the beta-FeSi has a micron-order pore structure2The shape of the porous material is not influenced by the addition of the (B), and the particles are distributed in the pore wall. In addition, the thickness of the hydrogel can be controlled by controlling the number of times of ejection.
FIGS. 4 and 5 are beta-FeSi2Photothermal performance testing of composite spray hydrogels, where FIG. 4 represents different β -FeSi2The content of the four groups of spray type composite hydrogel is measured at the laser power density (0.60W/cm)2) Temperature change curve of 10 minutes of irradiation (wet state: soaking in 300 μ L deionized water); FIG. 5 shows different laser power densities (0.30, 0.45, 0.60 and 0.75W/cm) for the SA-10FS group hydrogels2) Photothermal temperature profile of 10 min of irradiation. FIG. 6 shows β -FeSi2The chemical dynamic property test of the composite hydrogel shows that different beta-FeSi2Content of Tris-HCl extract of composite hydrogel (24h) and TMB (pH 6.0) after 24h incubation UV-vis absorption spectra with very low absorbance of the label "5-7". The results show that the composite hydrogel is prepared from beta-FeSi2Has good photo-thermal temperature rising characteristicAnd the ability to produce OH.
FIG. 7 shows β -FeSi2In vitro anti-tumor experiments with composite spray hydrogels, wherein (a) the survival rates of skin tumor cells B16F10 under different treatment conditions, (B) live-dead staining of B16F10 cells under different intervention conditions, (c) detection of OH within B16F10 cells. In FIG. 7, beta-FeSi is shown2The composite spray hydrogel has good effect of treating skin tumor in vitro, and can kill tumor cells through the cooperation of PTT and CDT.
FIG. 8 shows β -FeSi2The composite spray hydrogel is used for treating skin tumor in vivo, wherein (a) a mouse thermal imaging picture, (b) an optical picture of nude mice at day 0 and day 12, and (c) a relative tumor volume change curve within day 12. In FIG. 8, beta-FeSi is shown2The composite spray hydrogel can be used for synergistically treating skin tumors through PTT and CDT, and effectively inhibiting the growth of the tumors.
FIG. 9 shows H of tumor tissues of different treatment groups&And E, dyeing results. In combination with FIG. 9, the synthesis shows β -FeSi2The composite spray hydrogel can be used for synergistically treating skin tumors through PTT and CDT, and effectively inhibiting the growth of the tumors.
FIG. 10 shows β -FeSi2In vitro bioactivity test of the composite spray hydrogel, wherein (a) the proliferation of HUVECs, (b) the proliferation of HDFs, (c) migration statistics of HUVECs, and (d) optical photographs of the migration of HUVECs. In FIG. 10, beta-FeSi is shown2The composite spray hydrogel has good biocompatibility, can obviously promote the migration of endothelial cells, and shows excellent bioactivity.
FIG. 11 is β -FeSi2In vitro angiogenesis promoting capability test of the composite spray hydrogel, wherein (a-d) is divided into HIF-1 alpha, VEGF, KDR and eNOS gene expression in endothelial cells, and (e) CD31 protein staining. Fig. 11 shows that the beta-FeSi 2 composite spray hydrogel can significantly promote the expression of angiogenesis-related genes, and the staining of CD31 protein also shows that the hydrogel has excellent in vitro angiogenesis capacity and is important for skin repair.
FIG. 12 is a test of scald treatment on the skin of a white mouse in vivo, wherein (a) the treatment process of the scald, (b) the statistics of wound closure rate, (c) the wound surface images at different time points,(d) newborn skin H&E staining, (E) neonatal intradermal angiogenesis. In FIG. 12, beta-FeSi is shown2The composite spray hydrogel can be quickly used for treating skin wounds, has the advantages of simple operation, convenient treatment, portability and the like, has good skin repair function according to the wound healing condition, and in addition, compared with a blank group and a pure sodium alginate group, the beta-FeSi group has the advantages of simple preparation, convenient preparation and the like2The composite spray hydrogel has remarkable angiogenesis promoting capability.
Detailed Description
The present invention is further illustrated by the following examples, which are to be understood as merely illustrative and not restrictive.
The inventor utilizes the photothermal conversion and chemical dynamic characteristics of a semiconductor iron-containing material and beta-FeSi for the first time2The elements contained are all bioactive ions, and the consideration is that the beta-FeSi2The composite spray hydrogel is used for treating skin tumor and healing wound surface.
In the present disclosure, a portable beta-FeSi2The composite spray hydrogel is a three-dimensional porous structure, and has the advantages of portability, simple operation and convenient use. The chemical composition of the sodium alginate-FeSi-beta-calcium alginate-sodium alginate-beta-FeSi-calcium phosphate-sodium alginate-calcium phosphate2. Among them, the beta-FeSi in the present invention2The specific synthesis method of the powder can be found in the literature (X.Du, P.Qiu, J.Chai, T.Mao, P.Hu, J.Y ang, Y.Y.Sun, X.Shi, L.Chen, double Thermoelectric Figure of Merit in p-Type beta-FeSi)2 via Synergistically Optimizing Electrical and Thermal Transports,ACS Appl.Mater.Interfaces 12(11)(2020)12901-12909)。
In an alternative embodiment, the concentration of sodium alginate in the sodium alginate hydrogel may be 1.0-2.5 wt%. The beta-FeSi2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1. as an example, the stoichiometric composition of the sodium alginate is pure sodium alginate (1.5 wt%), 2 wt% beta-FeSi2Sodium alginate, 5wt% beta-FeSi2Sodium alginate, 10 wt% beta-FeSi2Sodium alginate, abbreviated as SA, SA-2FS, SA-5FS, SA-10FS, respectively. beta-FeSi of the invention2The composite spray hydrogel has a three-dimensional micron-sized pore structure, beta-FeSi2The addition of (A) does not affect the morphology.
In the invention, the obtained beta-FeSi2The composite spray hydrogel can be quickly gelatinized at a target part; beta-FeSi2The composite spray hydrogel can be used as a novel bifunctional material, can be used for treating skin tumor, and can promote the healing of skin wound. In addition, the wound healing device can realize rapid treatment of the wound surface in emergency, and provides a portable therapy for wound treatment in families, fields and the like.
In one embodiment of the present invention, the portable beta-FeSi2The preparation method of the composite spray hydrogel has the advantages of simple operation and convenient preparation. The following is an exemplary illustration of β -FeSi2A preparation method of composite spray hydrogel.
Dispersing beta-FeSi by using ultrasonic2Dispersing in sodium alginate solution to obtain the product containing beta-FeSi2The sodium alginate solution of (1). As an example, a mass of sodium alginate is added to deionized water and stirred overnight to give a 1.5 wt.% sodium alginate solution; then dispersing the beta-FeSi with different mass fractions by using ultrasound2Dispersed in sodium alginate solution as solution A. The sodium alginate is high in viscosity, and the molecular weight is generally selected from 30000-210000.
Mixing calcium chloride and deionized water to obtain a calcium chloride solution. As an example, calcium chloride and deionized water were mixed in a mass ratio of 3: 97, and stirred to obtain a 3 wt.% calcium chloride solution as solution B. The calcium chloride can be anhydrous calcium chloride.
By separately ejecting a liquid containing beta-FeSi2The sodium alginate solution and the calcium chloride solution are subjected to in-situ rapid crosslinking to form hydrogel. As an example, solution A is sprayed on a glass sheet, and then solution B is sprayed to form hydrogel in situ through rapid crosslinking.
In alternative embodiments, the thickness of the composite hydrogel can be controlled by controlling the number of ejections (e.g., can be 200 μm to 1.5 mm). In addition, hydrogel materials with uniform thickness and size were prepared with the aid of a punch. Setting each spraying to contain beta-FeSi2Content of sodium alginate solution0.01-0.05 mL/cm2The number of ejection times is controlled to be 20 or less, and the calcium ion diffusion crosslinking limit is prevented from being exceeded.
In the invention, the obtained beta-FeSi2The composite spray hydrogel is used for preparing skin tumor treatment and wound healing materials which are simple to operate, portable and convenient to use.
beta-FeSi of the invention2The composite spray hydrogel has the characteristic of rapid gelation, excellent in-vitro anti-tumor effect and good biological activity, and animal experiments prove that the beta-FeSi2The composite spray hydrogel has excellent double functions of treating skin tumors and promoting skin wound healing. Thus, beta-FeSi2The composite spray hydrogel is a novel bifunctional biological material, and the spraying method has the advantages of simple operation, portability and the like, and provides a new idea and a new method for rapidly treating emergency wounds in families, fields and the like.
β-FeSi2The crystal form and the appearance are characterized:
according to the invention, the beta-FeSi in the invention can be known through Scanning Electron Microscope (SEM) and X-ray diffraction (XRD)2The beta phase has good crystallinity and has a particle size of about 10 μm (see, for example, FIG. 1).
β-FeSi2The performance characterization of (2):
the beta-FeSi in the invention can be known by means of photo-thermal performance test, OH generation detection and the like2Has good photo-thermal and chemical dynamic properties, and can be used as a novel antitumor agent (see, for example, FIG. 2).
β-FeSi2Preparation of the composite spray hydrogel:
the invention comprises beta-FeSi by respectively spraying2And calcium chloride solution to rapidly crosslink in situ to form a hydrogel (see, e.g., figure 3).
p-beta-FeSi2The morphology and thickness control research of the composite spray hydrogel comprises the following steps:
the invention researches different beta-FeSi2The micro-morphology of the composite hydrogel. The result shows that the material has a porous three-dimensional network structure, beta-FeSi2The addition of the additive does not affect theMorphology, and beta-FeSi 2 particles are dispersed inside the pore walls. In addition, by controlling the number of times of ejection, the thickness of the hydrogel can be adjusted, the number of times of ejection is less than 15, the thickness is almost linear with the number of times, and when the number of times of ejection is more than 15, the thickness is slightly reduced because of Ca2+Limited diffusion limits cross-linking (see, e.g., fig. 3).
β-FeSi2Performance study of the composite spray hydrogel:
the invention researches four groups of different beta-FeSi2The content of the hydrogel has the photo-thermal property and the chemical-dynamic property. The results show that the final temperature of the hydrogel gradually increases with increasing FS content under the same laser power irradiation. However, the pure SA group had no significant photothermal effect. The temperature change of the composite hydrogel in the same group can be controlled by the power density of the near infrared laser. At 0.30-0.75W/cm2After 10 minutes of irradiation at the laser power of (2), there was a significant difference in the maximum temperature of the SA-10FS hydrogel. Furthermore, the generation of OH in four groups of SA, SA-2FS, SA-5FS and SA-10FS was examined with TMB. Three groups of SA-2FS, SA-5FS and SA-10FS all have obvious absorption peaks near 652 nm. SA-10FS has the greatest absorbance due to the highest iron content, indicating the strongest ability to produce OH (see, e.g., FIGS. 4-6).
β-FeSi2The in vitro anti-tumor effect of the composite spray hydrogel is as follows:
the invention proves that the beta-FeSi is firstly2The composite spray hydrogel has excellent performance of treating skin tumor in vitro through the cooperation of PTT and CDT. Cell viability of B16F10 cells under different conditions of pH 7.4 and pH 6.0 showed that, first, survival rates of B16F10 cells were 97.7% and 31.2% at pH 7.4 in the SA-10FS group and the SA-10FS +47 ℃ group, respectively, demonstrating that the SA-10FS hydrogel in vitro photothermal therapy was effective. Second, at pH 6.0, SA-10FS +47 ℃ + H compared to the SA-10FS +47 ℃ group2O2The group B16F10 cell viability was reduced to 12.5% due to the significant synergistic efficiency of CDT and PTT in vitro, and the high temperature was shown to significantly increase the effectiveness of CDT. As a control, pure CDT group (SA-10FS + H)2O2Group, pH 6.0) cell survival was normal (99.3%), indicating that CDT alone was essentially absentHas therapeutic effect. To further enhance the synergistic effect of PTT and CDT, the temperature was increased to 52 ℃ by adjusting the laser power density. The results showed that the co-treatment group had 52 ℃ (SA-10FS +52 ℃ + H)2O2pH 6.0) as compared with 47 ℃ co-treatment group (SA-10FS + H)2O2pH 6.0) was significantly reduced, determining the most effective treatment temperature. Subsequently, live/dead staining images visually confirmed that the co-treatment of CDT and PTT was significantly effective. Next, the SA-10FS hydrogel was further evaluated for intracellular OH production. At pH 6.0 with SA-10FS + H2O2The incubated B16F10 cells showed strong green luminescence. In contrast, the high temperature group (SA-10FS +47 ℃ + H)2O2And SA-10FS +52 ℃ + H2O2) More pronounced green luminescence occurs, demonstrating that increasing temperature favors intracellular OH production (see, e.g., FIG. 7).
β-FeSi2Study of skin tumor treatment in composite spray hydrogel:
nude mice with B16F10 tumor were selected to evaluate the in vivo therapeutic potential of the composite hydrogel. The mouse thermographic photographs show that the tumor site temperature of the SA-10FS + NIR group can quickly reach about 52 ℃ under the laser irradiation, while the temperature of the SA + NIR group is only kept below 37 ℃ under the same laser irradiation, which shows the feasibility of PTT. Statistics of relative tumor volumes during 12 days and photographs of mice after 12 days all show that tumor growth is severely inhibited in the SA-10FS + NIR group only, skin wounds have nearly healed, validating the high efficiency of PTT and CDT. However, tumors grew rapidly in all four other groups. Tumor tissue H & E staining further indicated that tumor growth was significantly inhibited in the SA-10FS + NIR group, and the tumor internal structure was already incomplete, showing evidence of significant tumor cell necrosis. In contrast, four other groups of tumors were intact with extremely dense and intact nuclear structures (see, e.g., fig. 8, fig. 9).
β-FeSi2The in vitro biological activity and angiogenesis promoting capability of the composite spray hydrogel are researched:
HUVECs and HDFs were treated with four different sets of beta-FeSi2Culturing the hydrogel leaching liquor for 1, 3 and 5 days. CCK-8 analysisAs a result, it was confirmed that beta-FeSi was present2The released ions have no cytotoxicity on HUVECs and HDFs, and the composite hydrogel has good biocompatibility. Subsequently, from the results of the migration of endothelial cells, it was found that a certain amount of β -FeSi was contained2The hydrogel leaching liquor has obvious promotion effect on the migration of HUVECs. Furthermore, beta-FeSi2The composite hydrogel leaching liquor can remarkably up-regulate the expression of HUVECs angiogenesis related genes VEGF, HIF-1 alpha, KDR and eNOS, which indicates that beta-FeSi2The released ions have a certain in vitro pro-angiogenic capacity. To further demonstrate their ability to vascularize, we performed CD31 immunofluorescent protein staining of cells cultured for 3 days with SA-10FS hydrogel extracts, and the SA-10FS group showed significantly high expression of CD31 protein compared to the blank and SA groups (see, e.g., fig. 10, fig. 11).
β-FeSi2The compound spray hydrogel has the following effects of treating the skin scald of the white mouse in vivo:
further confirmation of beta-FeSi by creating an in vivo skin scald model2The in vivo bioactivity of the composite spray hydrogel. The characteristics of simple operation, convenient use and timeliness of the spraying method are shown in the treatment process of the scald. The change result of the wound size within 14 days shows that the SA-10FS hydrogel has obvious promotion effect on wound healing compared with the blank group and the SA group. In addition, skin samples after 14 days passed H&E and CD31 staining for analysis. From H&E staining it can be seen that SA-10FS has healed completely, showing good re-epithelialization, while the blanks and SA groups still have scars. As can be seen from the result of immunofluorescent staining with CD31, the positive expression of CD31 in the wound surface tissue of the SA-10FS group is obviously higher than that of the other two groups. In addition, statistics of new blood vessels in three groups of dermis also show that beta-FeSi2The addition of (A) has a significant effect on promoting angiogenesis in the wound healing process (see, for example, FIG. 12).
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below. The spraying equipment used in the invention is a 5mL throat spray bottle (short rocker, outlet diameter: 0.5 mm); 20mL of a conventional side spray bottle (outlet diameter: 0.75 mm).
Example 1
(1) On the surface of the glass substrate, the mixture is sprayed by the spray nozzle containing beta-FeSi2Sodium alginate solution (beta-FeSi)2The mass ratio of particles and sodium alginate is 5 wt.%) and 3 wt.% calcium chloride solution, which are cross-linked in situ to form a hydrogel (SA-5 FS). Each spray coating contains beta-FeSi2The content of the sodium alginate solution is 0.025mL/cm2The thickness of the ink is 1mm by regulating and controlling the spraying times (10-12 times);
(2) the prepared composite hydrogel is subjected to morphology analysis, and the influence of the spraying times on the thickness of the hydrogel is researched, and the result is shown in FIG. 3;
(3) p-beta-FeSi2The photothermal and chemical dynamic properties of the composite spray hydrogel (SA-5FS) were investigated as described above, and the results are shown in FIGS. 4 to 6.
Example 2
(1) On the surface of the glass substrate, the mixture is sprayed by the spray nozzle containing beta-FeSi2Sodium alginate solution (beta-FeSi)210 wt.% of particles and sodium alginate) and 3 wt.% of calcium chloride solution, and crosslinking the particles in situ to form a hydrogel (SA-10 FS). Each spray coating contains beta-FeSi2The content of the sodium alginate solution is 0.02mL/cm2The thickness of the ink is 1mm by regulating and controlling the spraying times (11-13 times);
(2) the capacity of the prepared composite hydrogel for removing tumor cells in vitro through PTT and CDT is researched, and the result is shown in figure 7;
(3) exploration of beta-FeSi2The in vivo tumor treatment effect of the composite spray hydrogel (SA-10FS) was shown in FIG. 8 and FIG. 9.
Example 3
(1) On the surface of the glass substrate byThe ejection contains beta-FeSi2Sodium alginate solution (beta-FeSi)210 wt.% of particles and sodium alginate) and 3 wt.% of calcium chloride solution, and crosslinking the particles in situ to form a hydrogel (SA-10 FS). Each spray coating contains beta-FeSi2The content of the sodium alginate solution is 0.02mL/cm2The thickness of the ink is 1mm by the number of times of spraying (11-13 times);
(2) the prepared composite hydrogel was evaluated for in vitro bioactivity, and the results are shown in fig. 10;
(3) p-beta-FeSi2The in vitro angiogenesis promoting capacity of the composite spray hydrogel was investigated, and the results are shown in fig. 11;
(4) explores beta-FeSi2The in vivo skin scald treatment effect of the composite spray hydrogel (SA-10FS) was shown in FIG. 12.
Example 4
On the surface of the glass substrate, the mixture is sprayed by the spray nozzle containing beta-FeSi2Sodium alginate solution (beta-FeSi)2The mass ratio of particles and sodium alginate was 2 wt.%) and 3 wt.% calcium chloride solution, which were cross-linked in situ to form a hydrogel (SA-2 FS). Each spray coating contains beta-FeSi2The content of the sodium alginate solution is 0.03mL/cm2The thickness of the ink is 1mm by regulating and controlling the spraying times (8-10 times).
Comparative example 1
Pure sodium alginate hydrogel was used as a control: on the surface of the glass substrate, 1.5 wt.% pure sodium alginate solution and 3 wt.% calcium chloride solution are respectively sprayed out to be rapidly crosslinked in situ to form hydrogel (SA).

Claims (10)

1. Portable beta-FeSi2The composite spray hydrogel is characterized in that the portable beta-FeSi2The composite spray hydrogel comprises: sodium alginate hydrogel and beta-FeSi dispersed in sodium alginate hydrogel2And (3) granules.
2. The portable β -FeSi according to claim 12The composite spray hydrogel is characterized in that the concentration of sodium alginate in the sodium alginate solution is 1.0-2.5 wt%; the beta-FeSi2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1.
3. the portable β -FeSi according to claim 1 or 22The composite spray hydrogel is characterized in that the portable beta-FeSi2The composite spray hydrogel has a three-dimensional micron-sized pore structure, and the pore size distribution is 100-500 mu m.
4. The portable β -FeSi according to any one of claims 1-32Composite spray hydrogel, characterized in that the beta-FeSi2The particles have a particle size of 15 μm or less, preferably 10 μm or less, more preferably 1 μm or less, and most preferably 500nm or less.
5. The portable beta-FeSi of any one of claims 1-42The preparation method of the composite spray hydrogel is characterized in that the hydrogel contains beta-FeSi2Spraying the sodium alginate solution on the surface of the base material, and then spraying the calcium chloride solution to carry out in-situ crosslinking, thereby obtaining the portable beta-FeSi2And (3) compounding spray hydrogel.
6. The preparation method of claim 5, wherein the concentration of sodium alginate in the sodium alginate solution is 1.0-2.5 wt%; the beta-FeSi2The mass ratio of the particles to the sodium alginate is (0.01-0.2): 1.
7. the preparation method of claim 5 or 6, wherein sodium alginate is added into deionized water and stirred uniformly to obtain a sodium alginate solution; ultrasonically dispersing the beta-FeSi2Dispersing the particles in sodium alginate solution to obtain the product containing beta-FeSi2The sodium alginate solution of (1).
8. The method according to any one of claims 5 to 7, wherein calcium chloride and deionized water are mixed to obtain a calcium chloride solution; the concentration of the calcium chloride solution is 1.5-5.0 wt%.
9. The production method according to any one of claims 5 to 8, wherein β -FeSi is contained per one time of spraying2Spraying a calcium chloride solution for one time simultaneously with the sodium alginate solution; setting each spraying to contain beta-FeSi2The content of the sodium alginate solution is 0.01-0.05 mL/cm2And controlled to contain beta-FeSi2The spraying times of the sodium alginate solution are not more than 20.
10. A portable β -FeSi according to any one of claims 1 to 42The application of the composite spray hydrogel in preparing skin tumor treatment materials and skin wound healing materials.
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