CN110590351A - Black bioactive ceramic powder and application thereof - Google Patents
Black bioactive ceramic powder and application thereof Download PDFInfo
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Abstract
The invention relates to black bioactive ceramic powder and application thereof, which is prepared by mixing white bioactive ceramic powder and Mg powder, placing the mixture in an inert atmosphere, carrying out a magnesiothermic reduction reaction for 1-12 hours at 500-800 ℃, and carrying out acid pickling on the mixture.
Description
Technical Field
The invention relates to black bioactive ceramic powder and application thereof in preparing a tumor treatment material and a tissue defect repair material, belonging to the field of biological materials.
Background
Malignant tumors have become the second cause of death in humans (second to cardiovascular disease), and the search for effective treatments has been a global problem that plagues modern medicine[1,2]. The current clinical treatment commonly used to treat solid tumors is surgical resection with the assistance of radiation therapy (radiotherapy) and chemotherapy (chemotherapy)[3]. Because the tumor cells are difficult to completely remove by surgical resection, the traditional chemotherapy and radiotherapy methods are usually adopted, and the radiotherapy and the chemotherapy cause great toxic and side effects on patients[4,5]. Compared with the traditional treatment mode, the photothermal treatment has the advantages of short treatment time, obvious treatment effect, low damage to normal tissues and the like[7 , 8]. In addition, large tissue defects are caused after the tumor is removed by operation, the body is difficult to self-heal, and foreign body tissues, artificial tissues or prosthesis are required to be implanted for defect repair and tissue function reconstruction[9]. The previous research shows that the nanometer material with the photothermal effect is combined with the tissue engineering material to prepare the bifunctional material with tumor treatment and tissue repair[10,11]However, these nanomaterials are generally not degradable and long-term safety after implantation in vivo remains to be investigated. In general, the tissue engineering matrix material (such as biopolymer material, bioactive ceramic powder, etc.) has the characteristics of biosafety and degradability.
Reference documents:
[1]Jemal A,Bray F,Center MM,Ferlay J,Ward E,Forman D.Global Cancer Statistics.CA-Cancer J Clin.2011；61:69-90.
[2]Fitzmaurice C,Dicker D,Pain A,Hamavid H,Moradi-Lakeh M,MacIntyre MF,et al.The global burden of cancer 2013.JAMA oncology.2015；1:505-27.
[3]Orentas R,Hodge JW,Johnson BD.Cancer vaccines and tumor immunity:John Wiley&Sons；2007.
[4]Goetz MP,Callstrom MR,Charboneau JW,Farrell MA,Maus TP,Welch TJ,et al.Percutaneous image-guided radiofrequency ablation of painful metastasesinvolving bone:a multicenter study.Journal of Clinical Oncology.2004；22:300-6.
[5]Meijer TW,Kaanders JH,Span PN,Bussink J.Targeting hypoxia,HIF-1,and tumor glucose metabolism to improve radiotherapy efficacy.Clinical CancerResearch.2012；18:5585-94.
[6]Chen Q,Ke H,Dai Z,Liu Z.Nanoscale theranostics for physical stimulus-responsive cancer therapies.Biomaterials.2015；73:214-30.
[7]Tian Q,Hu J,Zhu Y,Zou R,Chen Z,Yang S,et al.Sub-10nm Fe3O4@Cu2–xS Core–Shell Nanoparticles for Dual-Modal Imaging and PhotothermalTherapy.Journal of the American Chemical Society.2013；135:8571-7.
[8]Chen Z,Zhang L,Sun Y,Hu J,Wang D.980-nm Laser-Driven Photovoltaic Cells Based on Rare-Earth Up-Converting Phosphors for BiomedicalApplications.Advanced Functional Materials.2009；19:3815-20.
[9]Marques C,Ferreira JMF,Andronescu E,Ficai D,Sonmez M,Ficai A.Multifunctional materials for bone cancer treatment.International Journalof Nanomedicine.2014；9:2713-25.
[10]Xiaocheng Wang,Bing Ma,Jianmin Xue,Jinfu Wu,Jiang Chang and Chengtie Wu.Defective black nano-titania thermogels for cutaneous tumor-inducedtherapy and healing.Nano Letters,2019,19:2138-47.
[11]Xiaocheng Wang,Fang Lv,Tian Li,Yiming Han,Zhengfang Yi,Mingyao Liu,Jiang Chang and Chengtie Wu.Electrospun micropatterned nanocompositesincorporated with Cu2S nanoflowers for skin tumor therapy and woundhealing.ACS Nano,2017,11:11337-49.。
disclosure of Invention
Aiming at the problems, the invention provides black bioactive ceramic powder by using a magnesiothermic reduction method and application thereof in preparing a tumor treatment material and a tissue defect repairing material.
In a first aspect, the invention provides a black bioactive ceramic powder, which is prepared by mixing white bioactive ceramic powder and Mg powder, placing the mixture in an inert atmosphere, carrying out a magnesiothermic reduction reaction for 1-12 hours at 500-800 ℃, carrying out acid washing,obtaining black bioactive ceramic powder; the white bioactive ceramic powder is silicate bioactive ceramic powder or/and phosphate bioactive ceramic powder, preferably selected from CaSiO3、MgSiO3、Ca3(PO4)2And Ca5(PO4)3(OH).
In the disclosure, a magnesiothermic reduction method is used to perform a magnesiothermic reduction reaction on white bioactive ceramic powder (traditional silicate bioactive ceramic powder or/and phosphate bioactive ceramic powder) at 500-800 ℃ for 1-12 hours to prepare a novel black bioactive ceramic material. Specifically, in the magnesium thermal reduction reaction process, Mg reduces the Si element and the P element in a higher oxidation state to a lower oxidation state, so that a large number of oxygen vacancies and structural defects (fig. 3) exist in the crystal of the white bioactive ceramic powder, the Si element and the P element in a lower chemical valence state appear, and the degradation rate gradually slows down. The +4 Si or + 5P element in the silicate and phosphate ceramic powder subjected to magnesium thermal reaction is reduced by Mg, so that two atoms in the internal crystal lattice are in low valence state (shown in figures 17 and 18), and the atoms orderly arranged in the crystal are dislocated, so that the absorption of the crystal on visible light is increased, and the crystal is changed from white to dark color.
Preferably, the mass ratio of the white bioactive ceramic powder to the Mg powder is 1 (0.1-1). In the present invention, by changing the amount of the reducing agent Mg powder, black bioactive ceramic powder with various colors can be prepared, wherein black refers to non-white relative to white (figure 1). For example, the CaSiO3 ceramic powder is kept at 1g, 0.1, 0.2, 0.4, 0.6 or 0.8g of Mg powder is weighed, mixed and placed in an Ar atmosphere furnace, and the mixture is kept at 650 ℃ for 4 hours to prepare the dark gray CaSiO3 ceramic powder. When the Mg powder mass is less than 0.4g, the color of the product gradually becomes darker with the increase of the Mg powder mass, the color becomes darkest with the Mg powder mass of 0.4g, and then the color becomes lighter with the increase of the Mg dose. Interestingly, for other ceramic powders, the color change also has a similar trend, and color turning points appear when the Mg powder is 0.4 g. For BCS4 treated at different temperaturesAnd BCS8 powder (FIG. 18), the main phase of the powder is wollastonite (CaSiO)3PDF #27-0088), with the temperature rise and the increase of the magnesium powder amount, the crystal crystallinity is gradually reduced, and phase (Si, CaSi) containing low-valence Si element appears2). Similarly, phase analysis was performed on magnesium silicate Black (BMS), tricalcium phosphate (BCP), and hydroxyapatite (BHAP), and it was found that the crystallinity of the powder decreased with the increase in the amount of magnesium powder, and a phase containing low-valent Si and P elements appeared (fig. 17). The XPS analysis results of BCS and BCP powders show that the peak positions of Si 2P and P2P are shifted to a low field, which indicates that Si and P obtain electrons, and further confirms the existence of low-valence Si and P elements (figure 2). The above results fully indicate that the + 4-valent Si or + 5-valent P element in the silicate and phosphate ceramic powder subjected to magnesium thermal reaction is reduced by Mg, so that two atoms in the internal crystal lattice are in low valence state, and the atoms orderly arranged in the crystal are dislocated, thereby increasing the absorption of visible light, and changing the white color into dark color.
Preferably, the temperature rise rate of the magnesiothermic reduction reaction is 1-10 ℃/min.
Preferably, the inert atmosphere is at least one of argon, nitrogen and helium.
In a second aspect, the invention provides a black bioactive ceramic composite membrane material, wherein the black bioactive ceramic powder, a binder and a solvent are mixed, and then subjected to vacuum filtration and drying to obtain the black bioactive ceramic composite membrane material; the binder is at least one of biopolymer materials such as chitosan, gelatin, sodium alginate, chitin, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol and polylactic acid.
Preferably, the mass ratio of the black bioactive ceramic powder to the binder is 1: (0.1-2). Along with the increase of the content of the ceramic powder, the color of the composite film gradually becomes dark, the surface roughness is increased, the photo-thermal effect is better, and the content of released ions is also increased.
Preferably, the solvent is at least one of acidic solutions such as acetic acid, hydrochloric acid, nitric acid, phosphoric acid, and the like.
Preferably, the acetic acid solution of chitosan is mixed with the water suspension of the black bioactive ceramic powder, ammonia water is added, the pH is adjusted to enable the chitosan to be settled, and the black bioactive ceramic composite membrane material is obtained after vacuum filtration and drying.
In a third aspect, the present invention provides a black bioactive ceramic bulk material, and a preparation method of the black bioactive ceramic bulk material comprises:
pressing and molding the black bioactive ceramic powder to obtain a blank;
and placing the obtained blank in an inert atmosphere, and sintering at 500-1000 ℃ for 1-24 hours to obtain the black bioactive ceramic block material.
Preferably, the blank body is further added with a binder, wherein the binder is at least one of biopolymer materials such as chitosan, chitin, gelatin, sodium alginate, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol and polylactic acid; preferably, the mass ratio of the black bioactive ceramic powder to the binder is 1: (0.1-1.2).
In a fourth aspect, the invention provides an application of the black bioactive ceramic powder in preparing a tumor treatment material and a tissue defect repair material.
In the present disclosure, in vivo and in vitro experiments prove that the obtained black bioactive ceramic powder has good effects in the aspects of superficial tumor treatment, chronic skin wound repair, bone tissue regeneration and the like. The design and development of the multifunctional biological tissue engineering material may have wide application prospect in the aspect of biomedical application.
In a fifth aspect, the invention provides an application of the black bioactive ceramic composite membrane material in preparation of a tumor treatment material and a tissue defect repair material.
In a sixth aspect, the invention provides an application of the black bioactive ceramic block material in preparation of a tumor treatment material and a tissue defect repair material.
In the disclosure, black bioactive ceramic powder is used as a main component, and the prepared black bioactive ceramic powder, ceramic composite membrane and ceramic block material have multiple functions of good biological safety, photo-thermal anti-tumor, wound repair, bone tissue regeneration and the like when used as a tumor tissue defect repair material.
Has the advantages that:
according to the invention, a series of black bioactive ceramic powder materials are obtained by a magnesiothermic reduction preparation method, and the preparation method has the advantages of simple preparation process, easily controlled conditions, stable material performance and the like;
the invention takes black bioactive ceramic powder as an active component to prepare a black bioactive ceramic composite film material and a black bioactive ceramic block material, so as to be convenient for the practical application of soft and hard tissues. The black bioactive ceramic material is systematically evaluated in vitro and in vivo anti-tumor effect, in vitro cell activity, in vivo tissue regeneration activity and other performances to determine whether the black bioactive ceramic material has multiple effects of tumor treatment, wound repair, bone tissue regeneration and the like, and is expected to be used as a multifunctional implant material for clinical application.
Drawings
FIG. 1 shows the treatment of 1g of white bioactive ceramic (CaSiO) with different masses of magnesium powder (0g, 0.1g, 0.2g, 0.4g, 0.6g, 0.8g)3、MgSiO3、Ca3(PO4)2And Ca5(PO4)3(OH)) powder, and then carrying out magnesium thermal reaction to prepare black bioactive ceramic (CaSiO)3、MgSiO3、Ca3(PO4)2And Ca5(PO4)3(OH)) digital photograph of the powder; as can be seen from FIG. 1, after magnesiothermic reduction treatment, the originally white bioceramic powder is changed into black, and effective regulation and control of the appearance color of the bioceramic powder can be easily realized by changing the amount of Mg powder, so as to prepare black bioactive ceramic powder materials with various colors;
FIG. 2 is an XPS analysis of the black bioactive ceramic powder obtained in the present invention, which includes: XPS full spectrum analysis (a) of White Calcium Silicate (WCS) and Black Calcium Silicate (BCS) powders, XPS high resolution spectrum (B) of Si 2P electrons, XPS full spectrum analysis (C) of White Calcium Phosphate (WCP) and Black Calcium Phosphate (BCP) powders, and XPS high resolution spectrum (D) of P2P electrons. As can be seen from FIG. 2, the peak positions of Si 2P and P2P shift to a low field, which indicates that Si and P gain electrons, confirming the existence of the low valence Si and P elements;
FIG. 3 is a high resolution transmission electron micrograph and Geometric Phase Analysis (GPA) of WCS and BCS4 particles, where A is the high resolution transmission electron micrograph of WCS; b is a Geometric Phase Analysis (GPA) diagram of WCS; c is a high-resolution transmission electron micrograph of BCS4, D is a Geometric Phase Analysis (GPA) map of BCS 4; as can be seen from fig. 3, compared with WCS, BCS4 crystal has serious internal lattice distortion and a large number of structural defects;
FIG. 4 shows the cumulative amounts of Ca ions (A), Si ions (B) and Mg ions (C) released at specific time points when WCS, BCS1, BCS2, BCS4, BCS6 and BCS8 ceramic powders were immersed in Tris-HCl solution. As can be seen from fig. 4, after the amount of Mg is increased, the amount of Ca released from the BCS powder is decreased, the amount of Mg released is increased, and the amount of Si released is not significantly changed (although most of the reactant magnesium powder and the generated magnesium oxide are removed by acid washing, it is not excluded that a small amount of magnesium enters a calcium silicate lattice system to substitute for bonding of calcium ions and silicon oxygen);
FIG. 5 shows a graph of the sample at 0.20W/cm2The curve of the change of the temperature of the 808nm laser irradiated bioactive material surface along with time, A is the curve of the change of the temperature of the powder surface along with time within 5min after white or black bioactive ceramic powder (namely WCS, WMS, WCP and WHAP or BCS, BMS, BCP and BHAP powder (the amount of added Mg powder is 0.4g, and the sintering temperature is 650 ℃)) is irradiated; b is a temperature-time curve of BCS powder irradiation for 5min obtained by different magnesium powder amount treatment, and C is a temperature-time curve of BCS4 powder (the added Mg content respectively corresponds to 0.4g) laser irradiation for 5min obtained by different magnesium thermal reaction temperature treatment; d is different power (0.10, 0.15, 0.20, 0.25 and 0.30W/cm)2) Irradiating the BCS4 powder for 5min by using 808nm laser; as is clear from FIG. 5, the magnesiothermic reduction treatment can provide the bioactive ceramic powder having no photothermal property per se with excellent photothermal temperature increasing properties. The photo-thermal performance of the BCS powder can be effectively regulated and controlled by changing the using amount of Mg powder, the reaction temperature and the near-infrared laser power in the magnesium thermal reduction reaction;
FIG. 6 is a graph showing that skin cancer cells (B16F10 cells) are inoculated on the surfaces of the pure CTS, WCS-CTS and BCS-CTS composite films prepared in example 1 and irradiated with near infrared light (808nm, 0.50W/cm)215min), and co-culturing B16F10 cells with pure CTS, WCS-CTS and BCS-CTS composite membrane under near infrared irradiation (808nm, 0.50W/cm)215min) (B, green for cell survival and red for cell death). It can be seen from FIG. 6 that the BCS-CTS composite membrane under laser irradiation can also cause most of the tumor cells on the surface and nearby to die, and other groups have no such anti-tumor effect;
FIG. 7 shows the measured signal at 0.30W/cm2NIR laser (808nm) with power density is irradiated on the WCS-CTS and BCS-CTS composite film prepared in the example 1 and applied to the position of a tumor wound of B16F10 for 15min, and an infrared thermal imaging picture (A) for monitoring the temperature change of the tumor part in real time and a corresponding temperature-time relation curve (B) are obtained; ctrl (blank control group, wound without material cover), CTS, WCS-CTS, BCS-CTS, WCS-CTS + NIR and BCS-CTS + NIR groups digital photographs (C) of B16F10 nude mice at day 0 and day 15, tumor volume change curve (D) within day 15. From the results in fig. 7, it is shown that the experimental group (BCS-CTS + NIR) not only did the tumors not recur, but also the skin wound that was originally made at the tumor site was substantially healed. While the growth of the tumors in the other control groups was not controlled, and the wounds did not heal;
FIG. 8 is the result of H & E staining of microscopic tissue sections of B16F10 tumorous wound sites at different magnifications after different treatments for 15 days, and it can be seen that the epidermis of the BCS-CTS + NIR group is completely regenerated, the lower tissue is granulation tissue close to the normal skin healing proliferation period, while the incomplete epidermis of the control group is filled with vigorous tumor cells and rich vascular network;
FIG. 9 is a diagram of the activity of CCK8 after 1, 3 and 5 days of co-culture of Human Dermal Fibroblasts (HDF) (A) and Human Umbilical Vein Endothelial Cells (HUVEC) (B) with the pure CTS, WCS-CTS or BCS-CTS composite membrane prepared in example 1, respectively, and the results from FIG. 9 indicate that the BCS-CTS composite membrane shows the effect of promoting the proliferation of both cells during 5 days of culture compared to the pure CTS and WCS-CTS composite membranes;
FIG. 10 is a photograph of confocal fluorescent staining after 24 hours of adhesion of HDF cells (A) and HUVEC cells (B) seeded on pure CTS, WCS-CTS or BCS-CTS composite membranes prepared in example 1 (red: cytoskeleton; blue: nucleus); as can be seen from FIG. 10, HDF cells and HUVEC cells can be adhered and spread on the surfaces of the three membrane materials, a large amount of cell pseudopodia is protruded, and the cells are vigorous;
fig. 11 representative photo optics of HDF cell scratch (cell purple) and corresponding statistics of relative wound area (/ p < 0.05,/p < 0.01 and/p < 0.001) (B) after 12h of example 1 preparation of pure CTS, WCS-CTS or BCS-CTS composite films; as can be seen from FIG. 11, the BCS-CTS composite membrane has an effect of accelerating cell migration;
figure 12 is a representative photograph of skin wounds (a) and statistical data for relative wound area (p < 0.05, p < 0.01 and p < 0.001) for the blank control group (Ctrl), pure CTS, WCS-CTS prepared in example 1, and BCS-CTS groups at days 0, 3, 6, 9, and 12 (B); as can be seen from fig. 12, the wound healing speed after the WCS-CTS and BCS-CTS composite films treatment was increased compared to the blank control group and the CTS group, and there was no significant difference between the two groups during the whole observation period;
FIG. 13 is a photograph of blank control (Ctrl), pure CTS, WCS-CTS prepared in example 1, and BCS-CTS group skin tissue sections on day 12 (A, B) H & E staining, (C) CD31 staining (neovasculature in brown pellet), and (D) alpha-SMA staining (mature vasculature in brown pellet). The results showed that under the scab layer of the BCS-CTS group, the epidermis in the neogenetic tissue was completely regenerated, inside a mature vascular network and cutaneous appendages in the developmental stage, while the epidermis of the other groups was incomplete and the number of vessels was small;
FIG. 14 shows rabbit bone marrow mesenchymal stem cells (RBMSC) and black CaSiO processed by different Mg calorimetric treatments3The CCK8 activity of the powder (A, BCS1, BCS2, BCS4, BCS6 and BCS8 powder) and the ceramic block (B) of WCS, BCS1, BCS2, BCS4, BCS6 or BCS8 is cultured for 1, 3 and 5 days; from FIG. 14, it is seen that the BCS material exhibits enhanced enhancementThe reproductive effect is the most obvious effect of BCS4 ceramic powder and ceramic block group;
FIG. 15 is a photograph of fluorescent staining of (A, C, E, G, I and K) low and (B, D, F, H, J and L) high power (red: cytoskeleton; blue: nucleus) after 3 days of culture by inoculating RBMSC on the surface of ceramic bulk material of (A, B) WCS, (C, D) BCS1, (E, F) BCS2, (G, H) BCS4, (I, J) BCS6 or (K, L) BCS 8; as can be seen from fig. 15, the cell density of all the bioceramic material surfaces is significantly increased, the cells are connected into bundles, and the cells on the surface of the BCS4 ceramic block are further stacked into multiple layers to completely cover the material;
FIG. 16 is a Micro-CT scan image (A) and a Van Giesen stained photograph (B) (red color is bone tissue and black color is implanted ceramic block material) of a WCS, BCS, WCP and BCP ceramic cylinder implanted into a femoral defect site of a rabbit at four (4W) and eight (8W) weeks, and it can be seen from FIG. 16 that the black bioactive ceramic block (BCS, BCP) is completely surrounded by new bone tissue, and the bonding between the two is tighter, especially the BCS group at 8 weeks, and the bone defect area is significantly smaller in volume than the other groups, thereby showing that the black bioactive ceramic material has better bone tissue regeneration inducing activity;
fig. 17 is XRD patterns of black calcium silicate (a), black magnesium silicate (B), black tricalcium phosphate (C) and black hydroxyapatite powder (D) prepared by magnesium thermal reaction after treatment with magnesium powder of different masses, from which it is known that as the amount of magnesium powder increases, the crystal crystallinity gradually decreases and a phase (Si) containing a low-valent Si element appears. Similarly, phase analysis was performed on magnesium silicate Black (BMS), tricalcium phosphate (BCP) and hydroxyapatite (BHAP), and it was found that the crystallinity of the powder decreased with the increase in the amount of magnesium powder;
FIG. 18 shows XRD patterns of BCS4 powder (A) and BCS8 powder (B) prepared by thermal reaction of magnesium at different temperatures (550 deg.C, 600 deg.C, 650 deg.C, 700 deg.C or 750 deg.C), from which it can be seen that the XRD phase analysis of BCS4 and BCS8 powder treated at different temperatures shows that the main phase of the powder is wollastonite (CaSiO) phase3PDF #27-0088), with increasing temperatureThe crystal crystallinity is gradually reduced due to the increase of the content of magnesium powder, and phase (Si, CaSi) containing low-valence Si element appears2)。
Detailed Description
The present invention is further illustrated by the following examples, which are to be understood as merely illustrative and not restrictive.
In the present disclosure, commercial white bioactive ceramic powders (including beta-calcium silicate (CaSiO) are used3) Magnesium silicate (MgSiO)3) Beta-tricalcium phosphate (Ca)3(PO4)2beta-TCP), hydroxyapatite (Ca)5(PO4)3(OH), HAP) and magnesium powder (Mg) are used as raw materials, and a series of black bioactive ceramic powder is prepared by a magnesiothermic reduction method.
In one embodiment of the invention, the original white biological ceramic powder is changed into black after magnesiothermic reduction treatment, and effective regulation and control of the appearance color of the biological ceramic powder can be easily realized by changing the Mg powder amount and the heat treatment temperature, so that black biological active ceramic powder materials with various colors can be prepared. A large number of oxygen vacancies and structural defects exist in the crystal of the black bioactive ceramic powder (see figure 3), Si and P elements with lower chemical valence states appear (see figures 17 and 18), and the black bioactive ceramic powder has the characteristic of photo-thermal temperature rise under the irradiation of near-infrared laser (see figure 5). Can cause death of skin cancer cells and bone tumor cells around the material, thereby effectively inhibiting the growth of tumors in vivo (figures 6-8). On the other hand, after the magnesium thermal reduction treatment, the degradation rate of the black bioactive ceramic material is reduced (figure 4), which is more beneficial to the adhesion, proliferation and migration of normal skin cells and osteoblasts, and has certain promotion effect on the regeneration of skin tissues and bone tissues in vivo (figures 9-16). The multifunctional novel bioactive material has wide development prospect in the fields of tumor treatment, tissue engineering and regenerative medicine application.
In one embodiment of the present invention, white bioactive ceramic powder (CaSiO)3、MgSiO3、Ca3(PO4)2、Ca5(PO4)3(OH) etc.) and Mg powder, and introduced into the crucible boat. Then placing the mixture in an inert atmosphere furnace, heating to a certain temperature (500-. The mass ratio of the white bioactive ceramic powder to the Mg powder is 1 (0.1-1). The crystal crystallinity gradually decreases with an increase in the amount of magnesium powder, and a phase (Si) containing a lower-valence Si element appears. Similarly, phase analysis was performed on magnesium silicate Black (BMS), tricalcium phosphate (BCP) and hydroxyapatite (BHAP), and it was found that the crystallinity of the powder decreased with the increase in the amount of magnesium powder. Wherein the rate of temperature rise is 1-10 ℃/min.
In another embodiment of the invention, the black bioactive ceramic powder is used as a main component to prepare two tissue engineering materials suitable for soft and hard tissues, namely a black bioactive ceramic composite membrane and a block material, which are respectively applied to the soft and hard tissue repair.
And (3) preparing a black bioactive ceramic composite membrane. Mixing black bioactive ceramic powder, a binder, a solvent and the like serving as raw materials, and performing vacuum filtration and drying to obtain the black bioactive ceramic composite membrane material. Wherein the binder can be Chitosan (CTS), gelatin, sodium alginate, chitin, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol, polylactic acid, and other biopolymer materials. Wherein, the mass ratio of the black bioactive ceramic powder to the binder can be 1: (0.1-2). The solvent can be acid solution such as acetic acid, hydrochloric acid, phosphoric acid, nitric acid, etc.
As an example of the preparation of the black bioactive ceramic composite membrane, the method includes: dispersing black bioactive ceramic powder in an acid solution of chitosan, and controlling the mass ratio of the black bioactive ceramic powder to the chitosan to be 1: 0.1-2, and performing vacuum filtration after uniform stirring. Wherein the vacuum filtration time is 1-10 min. And then drying to prepare the black bioactive ceramic composite membrane material. The drying method can be freeze drying for 6-48 h.
And (3) preparing a black bioactive ceramic block material. And tabletting the black bioactive ceramic powder to obtain a blank. Wherein the pressure is 0.1-10 MPa. And then, putting the blank into an inert atmosphere furnace for calcining and forming to obtain the black bioactive ceramic block material. The sintering (calcining) temperature can be 500-1000 ℃, and the heat preservation time is 1-24 h. The resulting bulk material may be in the shape of a cylinder, cube, or the like. The ceramic block material may also be added with a binder. The binder can be biological polymer material such as Chitosan (CTS), gelatin, sodium alginate, chitin, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol and polylactic acid. Wherein, the mass ratio of the black bioactive ceramic powder to the binder can be 1: (0.1-2).
In the present disclosure, black bioactive ceramic materials are characterized by means of optical microscopy, SEM, EDS, XRD, XPS, ICP, etc.
In the disclosure, the obtained black bioactive ceramic material (including black bioactive ceramic powder, black bioactive composite membrane material and black bioactive ceramic block material) has the characteristics of photo-thermal temperature rise under the irradiation of near-infrared laser and has a lower power (0.1-0.5W/cm)2) Under the irradiation of near infrared light, the black bioactive ceramic material shows obvious photothermal effect, can cause skin cancer cells and bone tumor cells around the material to die, and inhibits the growth of tumor tissues in vivo. The two tumor skin wound models of skin cancer and bone tumor in vivo prove that the black bioactive ceramic composite membrane material can completely remove tumor cells by combining near infrared light irradiation in the early treatment stage, the tumor does not relapse in the later treatment stage, and the originally manufactured wound is gradually healed. In addition, the material can play a certain role in promoting the adhesion, proliferation and migration of normal skin cells, and improves the healing speed and the healing quality of the chronic skin wound. The black biological ceramic block material can promote the activity of osteoblasts and has certain promotion effect on the repair of large bone tissue defect in vivo. Therefore, the black bioactive ceramic material has dual effects of photo-thermal anti-tumor and tissue regeneration promotion, and shows the effects of treating superficial tumor, repairing chronic skin wound, regenerating bone tissue and the likeGood effect. The design and development of the multifunctional biological tissue engineering material may have wide application prospect in the aspect of biomedical application.
And (3) evaluating the performance of the black bioactive ceramic material.
2.1 photo-thermal Properties of Black bioactive ceramic Material
The black bioactive ceramic material with different chemical compositions is irradiated by near infrared light with wavelength of 808nm, and the temperature change is monitored in real time by a thermal imager. The photo-thermal property of the black bioactive ceramic material can be regulated and controlled by changing the using amount of Mg powder, the reaction temperature and the near-infrared laser power. The result shows that the black bioactive ceramic material has obviously raised temperature and excellent photo-thermal performance at relatively low power and in very short time.
2.2 in vitro antitumor ability of Black bioactive ceramic Material
Murine skin melanocyte B16F10 and murine osteosarcoma cell LM8 are planted on pure polymer membrane (CTS), white (WCS-CTS) and black bioactive ceramic composite membrane (BCS-CTS) materials, and after the cells are basically fully paved, the three membrane materials are irradiated for 15 minutes by near infrared light of 808 nm. And (3) carrying out fluorescent staining on the cells, observing the change of the appearance of the cells on the surface of the material before and after illumination under a confocal microscope, and detecting the change of the survival rate of the cells by adopting a CCK8 method. The results show that tumor cells were significantly reduced after illumination in the BCS-CTS group, while the number of cells did not significantly change before and after illumination in the CTS and WCS-CTS groups. The excellent photo-thermal property of the composite black bioactive ceramic is utilized to effectively kill skin and bone tumor cells.
2.3 in vivo antitumor and repairing tumorous wound surface effects of Black bioactive ceramic Material
Constructing a nude mouse subcutaneous melanoma and osteosarcoma model, after the tumor grows to a certain size, making a 10mm full-skin wound at the tumor part, and attaching CTS, WCS-CTS and BCS-CTS membrane materials for photothermal therapy. The first four days are irradiated for 15min every day, the later period is not irradiated, the change of the tumor volume within 15 days is recorded, and the tumor and the surrounding skin tissues are taken out for analysis after the treatment is finished. The results show that not only does the BCS-CTS group show no recurrence of the tumor, but the skin wound originally made at the tumor site is also substantially healed. Whereas tumor growth was uncontrolled in the CTS and WCS-CTS groups, the wound did not heal. The BCS-CTS composite membrane under near infrared light irradiation has excellent in-vivo anti-tumor effect, and the feasibility of the black bioactive ceramic material for treating and repairing the tumor skin wound surface is proved.
2.4 in vitro skin repair Activity of Black bioactive ceramic Material
Skin fibroblasts (HDF) and umbilical vein endothelial cells (HUVEC) are respectively planted on the surfaces of CTS, WCS-CTS and BCS-CTS membrane materials, and after 24-hour culture, staining is carried out to observe the cell morphology and the adhesion condition. Cells were co-cultured with membrane material and tested for proliferation on days 1, 3, and 5. To determine the effect of black bioactive ceramic material on normal cell migration, HDF and HUVEC cell scratch experiments were performed. The results show that HDF and HUVEC cells can be well adhered and spread on the membrane material, and compared with pure CTS and WCS-CTS composite membranes, the BCS-CTS composite membrane has the function of promoting the proliferation and migration of the two cells. The results show that the black calcium silicate powder and chitosan composite membrane material support the actions of adhesion, proliferation, migration and the like of normal skin cells and show better in-vitro tissue regeneration activity.
2.5 in vivo skin repair Activity of Black bioactive ceramic Material
The invention proves that the black bioactive ceramic material has the capability of promoting the healing of chronic wound in vivo. In order to explore the effect of the BCS-CTS composite membrane on the chronic skin repair and healing, the composite membrane is directly pasted on a wound part, and a mouse wound surface repair experiment with the time period of 12 days is carried out. On day 12, the relative wound area of the placebo, CTS, WCS-CTS and BCS-CTS groups were 15.6%, 7.9%, 4.6% and 4.8%, respectively. The sections of neogenetic skin tissues were subjected to staining analysis, and the results showed that the epidermis in the neogenetic tissues was completely regenerated under the scab layer of the BCS-CTS group, a mature vascular network and skin appendages in the developmental stage appeared inside, while the epidermis in the other groups was incomplete and the number of blood vessels was small. Therefore, the BCS-CTS composite membrane can accelerate the healing speed of the chronic skin wound surface, can improve the healing quality, and has wide application prospect in the field of skin tissue regeneration.
2.6 in vitro osteogenesis Activity of Black bioactive ceramic Material
In order to research the osteogenic activity of the black calcium silicate ceramic material, rabbit-derived mesenchymal stem cells (RBMSC) and calcium silicate powder or ceramic blocks ((BCS1, BCS2, BCS4, BCS6 and BCS8) treated by different Mg amounts are cultured together for 5 days, and the result shows that the black ceramic material group (BCS) shows an effect of promoting proliferation, wherein the effect of the BCS4 ceramic powder and the ceramic block group is most obvious, RBMSC is directly inoculated on the surface of the BCS4 ceramic block body for culturing for 1 day, the number of cells adhered on all BCS block body materials is more than that of the WCS, the cells are tightly adhered on the surface of the materials and extend out longer pseudo feet to deep pores of the materials, wherein the number of the cells on the surface of the BCS4 ceramic block body is the most and the cell extension state is better, after 3 days, the cell densities on the surface of all the materials are obviously increased, the cells are connected with each other and are connected into bundles, and the cells on the surface of the BCS4 ceramic block body are further stacked into, completely covering the material. Therefore, the BCS material prepared by the experiment can provide a more ideal living environment for osteoblasts.
2.7 in vivo osteogenesis Activity of Black bioactive ceramic Material
The invention proves that the black bioactive ceramic material has the capability of promoting in-vivo osteogenesis. To evaluate the in vivo osteogenic activity of the black bioactive ceramic material, black ceramic blocks were implanted into femoral defect sites of new zealand white rabbits. The tissues are taken out at 4 and 8 weeks and subjected to Micro-CT analysis and Van Gieson staining analysis, and it can be seen that the black bioactive ceramic blocks (BCS and BCP) are completely surrounded by new bone tissues and are combined more tightly compared with the white bioactive ceramic blocks (WCS and WCP), particularly, the bone defect area volume of the BCS group at 8 weeks is obviously smaller than that of other groups, so that the black bioactive ceramic material has better bone tissue regeneration inducing activity. In addition, the degradation rate of each biological ceramic block material is different, and the degradation rate of the black biological active ceramic material is slowed down, which suggests that the magnesiothermic reduction treatment has the function of adjusting the degradation rate of the ceramic material.
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.
Example 1:
1g of white CaSiO3Respectively and uniformly mixing ceramic powder (WCS) with Mg powder (0.1g, 0.4g, 0.6g, 0.8g) with different masses, and then introducing into an alumina crucible boat;
the crucible boat is placed in an argon atmosphere furnace, and is heated to a certain temperature of 550 ℃, 600 ℃, 650 ℃, 700 ℃ or 750 ℃ at a speed of 2 ℃/min respectively, and is insulated for 4 hours. Naturally cooling to room temperature, and then carrying out acid washing and vacuum drying to obtain black calcium silicate ceramic powder. Wherein, the black calcium silicate ceramic powder obtained by reaction at 650 ℃ can be marked as BCS1, BCS4, BCS6 and BCS8 powder respectively;
dissolving 250mg of chitosan powder in 50mL of acetic acid solution to obtain an acidic CTS solution (5 wt.%);
250mg of BCS4 powder is weighed and dispersed in 10mL of H2Obtaining BCS suspension in the O solution; (3) mixing 50mL of CTS solution with 10mL of BCS suspension, stirring continuously, and dropwise adding 2mL of ammonia water to obtain BCS-CTS suspension;
sucking 6mL of BCS-CTS suspension, selecting filter paper with the diameter of 5cm, and carrying out vacuum filtration for 2 min;
and (5) carrying out freeze vacuum drying for 24 hours to prepare the BCS-CTS composite membrane.
Similarly, a pure CTS film (pure chitosan film) and a white calcium silicate composite chitosan film (WCS-CTS) were prepared as controls.
Pure CTS film, WCS-CTS and BCSExposing the CTS composite film to NIR light of 808nm, and adjusting the laser power to be 0.30W/cm2Keeping the distance between a laser head and the composite film at 20cm, irradiating for 5min, monitoring the temperature change condition of the surface of the material in real time through an infrared thermal imager, intercepting infrared thermal imaging pictures corresponding to the surface temperature of the film at different moments, and drawing a temperature-time change curve in a dry state.
Placing pure CTS film, WCS-CTS and BCS-CTS composite film into 48-well plate, adding 200 μ L H2O submerged material, and performing laser irradiation (808nm, 0.30W/cm)2And 10min), recording the temperature change along with the time by using a thermal imager, intercepting the infrared thermal imaging pictures at different moments, and drawing a temperature-time change curve.
Then, the evaluation of the in vivo and in vitro biological performances such as anti-tumor and skin tissue regeneration is carried out, and the performance evaluation in the invention is the same as the performance evaluation in the invention content.
Example 2:
1g of white CaSiO3Ceramic powder (WCS) and Mg powder (0.2g) are uniformly mixed and then are introduced into an alumina crucible boat;
the crucible boat is placed in an argon atmosphere furnace, and the temperature is raised to a certain temperature of 550 ℃, 600 ℃, 650 ℃, 700 ℃ or 750 ℃ at the speed of 2 ℃/min, and the temperature is kept for 4 hours. Naturally cooling to room temperature, and then carrying out acid pickling and vacuum drying to obtain black calcium silicate ceramic powder;
0.2g of Mg powder is adopted to react at 650 ℃ to obtain black calcium silicate ceramic powder which is marked as BCS2 powder;
dissolving 250mg of chitosan powder in 50mL of acetic acid solution to obtain an acidic CTS solution (5 wt.%);
250mg of BCS2 powder is weighed and dispersed in 10mL of H2Obtaining BCS suspension in the O solution; (3) mixing 50mL of CTS solution with 10mL of BCS suspension, stirring continuously, and dropwise adding 2mL of ammonia water to obtain BCS-CTS suspension;
sucking 6mL of BCS-CTS suspension, selecting filter paper with the diameter of 5cm, and carrying out vacuum filtration for 2 min;
and (5) carrying out freeze vacuum drying for 24 hours to prepare the BCS-CTS composite membrane.
Similarly, a pure CTS film and a white calcium silicate composite chitosan film (WCS-CTS) were prepared as controls.
Exposing pure CTS film, WCS-CTS and BCS-CTS composite film to NIR light of 808nm, and adjusting laser power to 0.20W/cm2Keeping the distance between a laser head and the composite film at 20cm, irradiating for 5min, monitoring the temperature change condition of the surface of the material in real time through an infrared thermal imager, intercepting infrared thermal imaging pictures corresponding to the surface temperature of the film at different moments, and drawing a temperature-time change curve in a dry state;
placing pure CTS film, WCS-CTS and BCS-CTS composite film into 48-well plate, adding 200 μ L H2O submerged material, and performing laser irradiation (808nm, 0.20W/cm)2And 10min), recording the temperature change along with the time by using a thermal imager, intercepting the infrared thermal imaging pictures at different moments, and drawing a temperature-time change curve.
Then, the evaluation of the in vivo and in vitro biological performances such as anti-tumor and skin tissue regeneration is carried out, and the performance evaluation in the invention is the same as the performance evaluation in the invention content.
Example 3:
1g of white Ca is taken3(PO3)2Respectively and uniformly mixing ceramic powder (WCP) with Mg powder (0g, 0.1g, 0.2g, 0.4g, 0.6g and 0.8g) with different masses, and then introducing into an alumina crucible boat;
the crucible boat is placed in an argon atmosphere furnace, and the temperature is raised to a certain temperature of 550 ℃, 600 ℃, 650 ℃, 700 ℃ or 750 ℃ at the speed of 2 ℃/min, and the temperature is kept for 4 hours. Naturally cooling to room temperature, and then carrying out acid washing and vacuum drying to obtain the black calcium phosphate ceramic powder.
Marking the black calcium phosphate ceramic powder obtained by adopting 0.4g of Mg powder as BCP4 powder;
a certain amount of BCP4 powder is weighed and pressed into a cylinder with the diameter of 6mm by using a tablet press. Calcining for 5 hours in an argon furnace at 800 ℃ to ensure that the ceramic block has certain strength, thereby obtaining the BCP4 ceramic block material.
And weighing white ceramic powder (BCP) with equal mass as a reference, tabletting, and calcining and molding in an argon furnace at 800 ℃ to obtain the BCP ceramic block material.
Then, evaluation of the in vivo and in vitro bone tissue regeneration activity was carried out, as in the performance evaluation in the summary of the invention.
Example 4:
the powders of BCS1, BCS2, BCS4, BCS6 and BCS8 were used as raw materials, and pressed into a cylindrical green body having a diameter of 6mm under 2 MPa. Then, the ceramic block material (BCS1, BCS2, BCS4, BCS6 and BCS8 respectively) with certain strength was calcined in an argon furnace at 800 ℃ for 5 hours. As a comparison, white ceramic powder (WCS) with equal mass is weighed, and is calcined and molded by an argon furnace at 800 ℃ after being tableted. The samples were stored in a sealed sample box, and care was taken for light handling (in WCS). Similarly, WCP and BCP ceramic blocks were prepared for in vitro bone tissue regeneration experiments.
Example 5:
1g of white MgSiO was taken3Respectively and uniformly mixing ceramic powder (WMS) with Mg powder (0g, 0.1g, 0.2g, 0.4g, 0.6g and 0.8g) with different masses, and then introducing into an alumina crucible boat;
the crucible boat is placed in an argon atmosphere furnace, and the temperature is raised to a certain temperature of 550 ℃, 600 ℃, 650 ℃, 700 ℃ or 750 ℃ at the speed of 2 ℃/min, and the temperature is kept for 4 hours. Naturally cooling to room temperature, and then carrying out acid washing and vacuum drying to obtain the black magnesium silicate ceramic powder. In FIG. 1, the color change of the obtained magnesium silicate black ceramic powder is shown, and in FIG. 17, B is the phase change of the magnesium silicate black ceramic powder.
Example 6:
1g of white Ca is taken5(PO4)3Respectively and uniformly mixing (OH) ceramic powder (WHAP) with Mg powder (0g, 0.1g, 0.2g, 0.4g, 0.6g, 0.8g) with different masses, and then introducing into an alumina crucible boat;
the crucible boat is placed in an argon atmosphere furnace, and the temperature is raised to a certain temperature of 550 ℃, 600 ℃, 650 ℃, 700 ℃ or 750 ℃ at the speed of 2 ℃/min, and the temperature is kept for 4 hours. Naturally cooling to room temperature, and then carrying out acid washing and vacuum drying to obtain the black hydroxyapatite ceramic powder. Fig. 1 shows the color change of the black hydroxyapatite ceramic powder, and fig. 17 shows the color change of the black hydroxyapatite ceramic powder.
Claims (13)
1. A black bioactive ceramic powder is prepared from white living thingsMixing the active ceramic powder and Mg powder, placing the mixture in an inert atmosphere, carrying out a magnesiothermic reduction reaction for 1-12 hours at 500-800 ℃, and carrying out acid pickling to obtain black bioactive ceramic powder; the white bioactive ceramic powder is silicate bioactive ceramic powder or/and phosphate bioactive ceramic powder, preferably selected from CaSiO3、MgSiO3、Ca3(PO4)2And Ca5(PO4)3(OH).
2. The black bioactive ceramic powder according to claim 1, wherein the mass ratio of the white bioactive ceramic powder to the Mg powder is 1 (0.1-1).
3. The black bioactive ceramic powder according to claim 1 or 2, wherein the temperature rise rate of the magnesiothermic reduction reaction is 1-10 ℃/min.
4. The black bioactive ceramic powder according to any of claims 1 to 3, wherein the inert atmosphere is at least one of argon, nitrogen and helium.
5. A black biological ceramic composite membrane material is characterized in that the black biological ceramic composite membrane material is obtained by mixing the black biological active ceramic powder body of any one of claims 1 to 4, a binder and a solvent, and then carrying out vacuum filtration and vacuum drying; the binder is at least one of chitosan, chitin, gelatin, sodium alginate, chitin, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol and polylactic acid.
6. The black bioceramic composite film material as claimed in claim 5, wherein the mass ratio of the black bioactive ceramic powder to the binder is 1: (0.1-2).
7. The black bioceramic composite film material according to claim 5 or 6, wherein the solvent is at least one of an acetic acid solution, a hydrochloric acid solution, a nitric acid solution and a phosphoric acid solution.
8. The black bioceramic composite film material according to claim 7, wherein the black bioceramic composite film material is obtained by mixing an acetic acid solution of chitosan with an aqueous suspension of black bioactive ceramic powder, adding ammonia water, and performing vacuum filtration and vacuum drying.
9. The black bioactive ceramic block material is characterized in that the preparation method of the black bioactive ceramic block material comprises the following steps: pressing the black bioactive ceramic powder of any one of claims 1-4 to form a green body; and placing the obtained blank in an inert atmosphere, and sintering at 500-1000 ℃ for 1-24 hours to obtain the black bioactive ceramic block material.
10. The black bioactive ceramic block material according to claim 9, wherein a binder is further added into the green body, wherein the binder is at least one of chitosan, chitin, gelatin, sodium alginate, chitin, hyaluronic acid, collagen, polyvinyl alcohol, polyethylene glycol and polylactic acid; preferably, the mass ratio of the black bioactive ceramic powder to the binder is 1: (0.1-2).
11. The use of the black bioactive ceramic powder according to any one of claims 1 to 4 in the preparation of a tumor treatment material and a tissue defect repair material.
12. Use of the black bioceramic composite membrane material according to any one of claims 5 to 8 in preparation of tumor treatment materials and tissue defect repair materials.
13. Use of the black bioactive ceramic block material according to claim 9 or 10 in the preparation of tumor treatment materials and tissue defect repair materials.
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| CN112843322A (en) * | 2021-01-11 | 2021-05-28 | 苏州汇涵医用科技发展有限公司 | Preparation method of black bioactive ceramic dressing |
| CN112794709A (en) * | 2021-02-02 | 2021-05-14 | 中国科学院上海硅酸盐研究所 | Bioactive ceramic scaffold for bone tissue repair and tumor treatment and preparation method thereof |
| CN112794709B (en) * | 2021-02-02 | 2022-06-14 | 中国科学院上海硅酸盐研究所 | Bioactive ceramic scaffold for bone tissue repair and tumor treatment and preparation method thereof |
| CN114621003A (en) * | 2021-11-04 | 2022-06-14 | 上海市第八人民医院 | Modified hydroxyapatite, composite bone cement, and preparation methods and applications thereof |
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