CN114917340B - Oral mucosa repair material with photo-thermal function, preparation method and application - Google Patents
Oral mucosa repair material with photo-thermal function, preparation method and application Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Abstract
The invention belongs to the field of biomedical engineering, and particularly relates to an oral mucosa repair material with a photo-thermal function, and a preparation method and application thereof. The repairing material comprises the following components in parts by mass: 200-20000ppm of MXene, 0.01-5% of quercetin, 2-20% of collagen and 50-95% of silk fibroin. The invention uses two-dimensional inorganic photo-thermal material MXene as photo-thermal conversion agent, utilizes the inhibition effect of quercetin on HSP70 to enhance the killing effect of photo-thermal treatment on tumor cells, adopts collagen and silk fibroin to promote reconstruction and repair of mucous membrane defect, and adopts low-temperature 3D printing technology and freeze drying technology to prepare the MXene/quercetin/collagen/silk fibroin composite scaffold, and the prepared composite material has good photo-thermal performance and oral mucosa repair function.
Description
Technical Field
The invention belongs to the field of biomedical engineering, and particularly relates to an oral mucosa repair material with a photo-thermal function, and a preparation method and application thereof.
Background
Squamous cell carcinoma (squamous cell carcinoma, SCC) is abbreviated as squamous carcinoma, is the most common malignant tumor of the oral and maxillofacial region in China, and the occurrence position is the most common oral cancer and maxillary sinus cancer. Oral squamous cell carcinoma is still mainly treated by surgery and is assisted by radiotherapy and chemotherapy. Often leaving large mucous membrane defect after operation, tumor recurrence may be caused by residual tumor cells near the wound edge, and chemotherapy and radiotherapy bring about larger side effects. The gold standard of the oral mucosa defect repair accepted in clinic at present is still autologous tissue transplantation such as free skin graft transplantation, skin flap transplantation and the like, and the traditional repair method has the advantages of easy tissue survival, no rejection reaction and the like, but the corresponding defects are difficult to overcome, and a second operation area is required to be opened up when the skin flap repair is adopted; the transplanted tissue still maintains the characteristics of hair growth, epithelium keratinization and the like after years, and seriously influences the life quality of patients; the operation is complex, and the requirements on operators are high. Therefore, it is very necessary to develop a biomaterial that can eliminate tumor cells remaining near the wound margin and promote repair of oral mucosa defects.
Photothermal therapy (Photothermal therapy, PTT) has received increasing attention in the field of cancer treatment due to its minimally invasive, non-toxic, high selectivity characteristics. Photothermal therapy refers to the conversion of near infrared light into localized heat for ablating localized tumor tissue. Unlike traditional tumor treatment methods, photothermal treatment can effectively avoid damaging normal cells, tissues and the immune system. The mechanism by which photothermal therapy induces apoptosis is not yet known, and a number of experiments have shown that it is possible to correlate with the large expression of heat stress protein 70. Heat stress proteins (Heat shock proteins, HSPs) are a group of highly conserved stress proteins produced by organisms under adverse environmental factors, which are ubiquitous throughout the biological world, and almost all cells can synthesize, with heat stress protein 70 (HSP 70) being one of the most well studied. When the organism cells are subjected to various stresses such as high heat, oxidization and other harmful stresses, the produced HSP70 can enhance the tolerance degree of the cells to damage, maintain the normal function metabolism of the cells and improve the survival rate of the cells under the stress state. Different types of cells and species can improve the survival rate of the cells and species under high-temperature stress after synthesizing the HSP70 through heat induction, and inhibitors are added to inhibit the generation of the HSP70, so that the capability of the cells on tolerance of heat shock sources is obviously reduced.
In recent years, the application of tissue engineering in oromaxillofacial reconstruction has been widely focused by scholars, and there have been many studies on the construction of tissue engineering oral mucosa at home and abroad. The combination of photothermal therapy and tissue engineering can become a new idea for oral squamous cell carcinoma therapy and mucosa repair, a composite stent material is prepared, the composite stent material contains a compound capable of improving the photothermal therapy effect, residual tumor cells are killed by using the photothermal therapy, and meanwhile, the active high polymer material in the stent material can promote the repair of oral mucosa defects, so that the composite stent material is expected to provide a new treatment idea for oral squamous cell carcinoma therapy.
In the research of oral mucosa repair materials, silk fibroin and collagen are two materials with more applications. Silk fibroin is a natural polymer produced by various silk producing limbs, with silk fibroin isolated from silk being one of the most representative. As a natural macromolecular material, silk fibroin contains a special tripeptide structure which is closely related to cell adhesion, namely a fine-glycine-aspartic acid (Arg-Gly-Asp, RGD) peptide structure, and can promote migration, adhesion and proliferation of cells on the surface of the material. It was found that silk fibroin promotes adhesion of human fibroblasts to the surface of the material, and increases by about 2.2 times compared to normal uncoated cells. Collagen is the most abundant protein in extracellular matrix, and is about 30% of the total protein in mammals, and is widely distributed on skin, bones, viscera, etc. of animals. Collagen has good biodegradability and low antigenicity, and its microstructure can affect cell adhesion, proliferation, migration, and can induce cell differentiation and maintain the differentiation phenotype of certain cells. The regularly arranged collagen can also specifically initiate the adhesion and chemotaxis of platelets, thereby enabling thrombosis, and simultaneously promoting the proliferation of fibroblasts and capillaries, which plays an important role in the initial healing of tissue wounds.
Various near infrared light responsive materials have been developed and applied to photothermal therapy, including carbon nanotubes, graphene, gold nanostructures, and the like. In 2011, MXene (the chemical formula is M n+1AXn, M represents a transition metal element, and X represents a C or N element) is successfully stripped from a three-dimensional ternary nitride or carbide (MAX) phase ceramic material by a special etching method through NAGUIB, YURY, and the like. The crystal is an ordered crystal with alternating arrangement of transition metal layers and nitrogen element or carbon element layers, and has an adjustable accordion structure, excellent thermal stability and higher specific surface area. Wherein Ti 3C2 MXene has high-efficiency photo-thermal conversion capability and shows good biocompatibility in-vitro and in-vivo tests.
Quercetin is a bioflavonoid that is widely found in nature and in the daily diet, such as grape, berry, cherry, apple, mango, etc. Quercetin has various pharmacological activities, and has antitumor effect on various solid tumors and blood tumors. In 2010, the U.S. food and drug administration officially approved quercetin as a pharmaceutical and food additive.
Therefore, how to effectively combine photothermal treatment and tissue engineering becomes a key of the problem, and the mucosa repair effect is not influenced while the material has good photothermal effect.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides an oral mucosa repair material with a photo-thermal function and a preparation method thereof.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an oral mucosa repair material with a photo-thermal function comprises the following components in parts by mass: 200-20000ppm of MXene, 0.01-5% of quercetin, 2-20% of collagen and 50-95% of silk fibroin.
Preferably, the composition comprises the following components in parts by mass: 0.37-1.19% of MXene, 0.22% of quercetin, 10.07-10.16% of collagen and 88.52-89.25% of silk fibroin.
Preferably, the composition comprises the following components in parts by mass: 0.37% of MXene, 0.22% of quercetin, 10.16% of collagen and 89.25% of silk fibroin.
Specifically, the MXene is Ti 3C2.
The invention also discloses a preparation method of the oral mucosa repair material with the photo-thermal function, which comprises the following steps:
a. Ultrasound is carried out on MXene in a certain amount of water to prepare MXene suspension;
b. Blending the MXene suspension with quercetin, a silk fibroin solution and collagen gel to prepare mixed gel;
c. Designing a three-dimensional printing model, and importing the model into low-temperature 3D printer software;
d. putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters;
And (3) curing the extruded composite gel silk at low temperature, preserving the cured composite gel at-20 ℃ overnight, and then performing freeze drying and post-treatment to obtain the oral mucosa repair material with the photo-thermal function.
Specifically, the travelling distance of the printing needle heads is set to be 200-1800 mu m, and the temperature of the receiving device is controlled to be-20 ℃ to-4 ℃.
Specifically, in the step d, the freeze-drying treatment conditions are as follows: condensing temperature is minus 50 ℃ and vacuum degree is less than 20Pa.
Specifically, in the step d, the post-treatment is to soak with absolute ethyl alcohol firstly, then soak with NaOH solution with the mass percent of 0.1-0.5%, and finally rinse the residual ethyl alcohol and NaOH with water.
The invention also comprises application of the oral mucosa repair material with the photo-thermal function, which is characterized in that the material is applied to preparation of the material for promoting repair of squamous cell carcinoma postoperative mucosa defects.
Compared with the prior art, the invention has the beneficial effects that:
The application uses two-dimensional inorganic photo-thermal material MXene as photo-thermal conversion agent, utilizes the inhibition effect of quercetin on HSP70 to enhance the killing effect of photo-thermal treatment on tumor cells, adopts collagen and silk fibroin to promote the reconstruction and repair of mucous membrane defect, and adopts low-temperature 3D printing technology and freeze-drying technology to prepare the MXene/quercetin/collagen/silk fibroin composite scaffold. The low-temperature 3D printing combined freeze-drying method can keep the bioactivity of the printing material to the greatest extent. The prepared composite material has good photo-thermal performance and an oral mucosa repair function.
Drawings
FIG. 1 is a scanning electron microscope photograph 1 (B) at 2000 times showing the appearance of a material according to an embodiment of the present invention.
FIG. 2 is a graph showing the comparison of the first, second and third porosities 2 (A) and the water-swelling capacities 2 (B) of the first and second comparative examples.
FIG. 3 is a graph showing the temperature change of the first, second, third and fourth embodiments of the present invention when the laser (808 nm) is irradiated at 1.0W/cm 2 for 5min and the switching cycle is 5;
FIG. 4 is a real-time temperature image of the first, second and third examples of the present invention after laser (808 nm) irradiation of 1.0W/cm 2 min.
FIG. 5 is a diagram showing morphological changes of human tongue squamous carcinoma cells CAL27 inoculated on the first embodiment of the present invention before and after 5min of laser (808 nm) irradiation at 1.0W/cm 2.
FIG. 6 is a graph showing the proliferation of SD rat buccal mucosa fibroblasts inoculated on the first, second and third examples of the present invention within 10 days according to the CCK8 method.
FIG. 7 is a graph showing the measurement of cell viability of human tongue squamous carcinoma cells CAL27 inoculated onto first, second and third examples of the present invention at different time points under irradiation of 1.0W/cm 2 laser (808 nm) by CCK8 method.
Detailed Description
The present invention will be described in further detail below with reference to the drawings and preferred embodiments, so that those skilled in the art can better understand the technical solutions of the present invention.
Example 1: the MXene powder is dispersed in water by ultrasonic to prepare a suspension, and then the suspension is fully mixed with quercetin, collagen gel and silk fibroin solution to prepare a blend gel (the weight ratio of the four substances of MXene (Ti 3C2, the same applies below), quercetin, collagen and silk fibroin to the final finished composite material is 0.37%, 0.22%, 10.16% and 89.25%). Putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters: the diameter of the printing needle is 260 mu m, the running distance of the needle is 1304 mu m, the temperature of a receiving device is 13 ℃ below zero, the extruded composite gel silk is solidified at low temperature, the solidified composite gel is preserved overnight at 20 ℃ below zero, then freeze drying (the condensation temperature is minus 50 ℃ and the vacuum degree is less than 20 Pa) and post treatment are carried out, the post treatment is that absolute ethyl alcohol is firstly used for soaking, then NaOH solution with the mass percent of 0.1-0.5% is used for soaking, and finally residual ethanol and NaOH are washed clean by water, so that the oral mucosa repair material with the photo-thermal function is obtained. FIG. 1 is an external view of the repair material of the present embodiment (FIG. 1 (A)) and a scanning electron micrograph at 2000 times (FIG. 1 (B)); as can be seen from FIG. 1, in the embodiment of the invention, the aperture of the bracket is uniform, and the MXene particles are embedded on the surface of the bracket under a scanning electron microscope.
Comparative example one: the first comparative example differs from the first example only in that MXene and quercetin are not contained.
Control II: the second comparative example differs from the first example only in that MXene is not contained.
Control three: the difference between the third comparative example and the first experimental example is that the sample does not contain quercetin.
FIG. 2 shows the comparison of the first, second and third porosities (FIG. 2 (A)) and the water-swelling rate (FIG. 2 (B)) of the present invention with those of the comparative examples. And (3) injection: the CS stent is the first control, the CSQ stent is the second control, the MCS stent is the third control, and MCSQ is the first control. As can be seen from fig. 2, the incorporation of MXene and quercetin did not affect the porosity and water expansion of the photothermal scaffolds of the present invention, and the measurement results were not statistically different.
Embodiment two: the MXene powder is added with ultrapure water to prepare dispersion liquid, ultrasonic oscillation is carried out, and then the dispersion liquid is mixed with collagen, silk fibroin and quercetin gel to obtain blended gel (the weight ratio of the MXene, the quercetin, the collagen and the silk fibroin to the final finished composite material is 0.64%, 0.22%, 10.13% and 89.01%). Putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters: the diameter of the printing needle is 260 mu m, the running distance of the needle is 1304 mu m, the temperature of a receiving device is 13 ℃ below zero, the extruded composite gel silk is solidified at low temperature, the solidified composite gel is preserved overnight at 20 ℃ below zero, then freeze drying (the condensation temperature is minus 50 ℃ and the vacuum degree is less than 20 Pa) and post treatment are carried out, the post treatment is that absolute ethyl alcohol is firstly used for soaking, then NaOH solution with the mass percent of 0.1-0.5% is used for soaking, and finally residual ethanol and NaOH are washed clean by water, so that the oral mucosa repair material with the photo-thermal function is obtained.
Embodiment III: the MXene powder is added with ultrapure water to prepare dispersion liquid, ultrasonic oscillation is carried out, and then the dispersion liquid is mixed with collagen, silk fibroin and quercetin gel to obtain blended gel (the weight ratio of the MXene, the quercetin, the collagen and the silk fibroin to the final finished composite material is 0.92%, 0.22%, 10.10% and 88.76% respectively). Putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters: the diameter of the printing needle is 260 mu m, the running distance of the needle is 1304 mu m, the temperature of a receiving device is 13 ℃ below zero, the extruded composite gel silk is solidified at low temperature, the solidified composite gel is preserved overnight at 20 ℃ below zero, then freeze drying (the condensation temperature is minus 50 ℃ and the vacuum degree is less than 20 Pa) and post treatment are carried out, the post treatment is that absolute ethyl alcohol is firstly used for soaking, then NaOH solution with the mass percent of 0.1-0.5% is used for soaking, and finally residual ethanol and NaOH are washed clean by water, so that the oral mucosa repair material with the photo-thermal function is obtained.
Embodiment four: the MXene powder is added with ultrapure water to prepare dispersion liquid, ultrasonic oscillation is carried out, and then the dispersion liquid is mixed with collagen, silk fibroin and quercetin gel to obtain blended gel (the weight ratio of the MXene, the quercetin, the collagen and the silk fibroin to the final finished composite material is 1.19%, 0.22%, 10.07% and 88.52% respectively). Putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters: the diameter of the printing needle is 260 mu m, the running distance of the needle is 1304 mu m, the temperature of a receiving device is 13 ℃ below zero, the extruded composite gel silk is solidified at low temperature, the solidified composite gel is preserved overnight at 20 ℃ below zero, then freeze drying (the condensation temperature is minus 50 ℃ and the vacuum degree is less than 20 Pa) and post treatment are carried out, the post treatment is that absolute ethyl alcohol is firstly used for soaking, then NaOH solution with the mass percent of 0.1-0.5% is used for soaking, and finally residual ethanol and NaOH are washed clean by water, so that the oral mucosa repair material with the photo-thermal function is obtained.
FIG. 3 shows the temperature change of the first and third examples of the present application when the first, second, third and fourth examples were irradiated with 1.0W/cm 2 laser (808 nm) for 5min and 5 switching cycles; as can be seen from fig. 3A, the temperature of the photothermal scaffold gradually increased as the concentration of MXene increased. An increase in the MXene content will enhance the photothermal conversion properties of the scaffold, but an excessive temperature will affect the effect of tissue repair. Therefore, the first embodiment of the present application is suitable in temperature, which is the most preferred embodiment, relative to the second, third and fourth embodiments. As can be seen from fig. 3B, the addition of quercetin did not affect the stability of the photothermal properties of the stent, compared to the third control.
FIG. 4 is a real-time temperature image of the first, second and third examples of the present invention after laser (808 nm) irradiation of 1.0W/cm 2 min. As can be seen from fig. 4, the photo-thermal bracket of the invention has the highest center temperature, gradually decreases to the ambient temperature, and has good photo-thermal conversion effect.
FIG. 5 shows the morphological changes of human tongue squamous carcinoma cells CAL27 inoculated on the first embodiment of the present invention before and after 5min of laser (808 nm) irradiation at 1.0W/cm 2. (scanning electron microscope observation, 2000 times). As can be seen from FIG. 5, the squamous carcinoma cells seeded on the first embodiment of the photothermal support of the present invention are synaptic shrunk in morphology after laser irradiation.
FIG. 6 shows the proliferation of SD rat buccal mucosa fibroblasts inoculated on the first, second and third examples of the present invention within 10 days by CCK8 assay. From fig. 6 it can be seen that SD rat buccal mucosa fibroblasts grew well on the photothermal scaffolds of the present invention.
FIG. 7 is a graph showing the measurement of cell viability of human tongue squamous carcinoma cells CAL27 inoculated onto first, second and third examples of the present invention at different time points under irradiation of 1.0W/cm 2 laser (808 nm) by CCK8 method. As can be seen from FIG. 7A, CAL27 cells inoculated on the first and second control examples survived in large amounts at 5min of laser irradiation, with cell viability rates of 98.12% and 96.45%, respectively. As can be seen from fig. 7B, quercetin can significantly enhance the killing effect of photothermal treatment on CAL27 cells, and the cell viability of example one and comparative example three at different time points has a statistical difference.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (5)
1. The oral mucosa repair material with the photo-thermal function is characterized by comprising the following components in parts by weight: 200-20000ppm of MXene 0.37%, quercetin 0.22%, collagen 10.16%, and silk fibroin 89.25%;
The preparation method of the oral mucosa repair material with the photo-thermal function comprises the following steps:
a. ultrasound is carried out on MXene in a certain amount of water to prepare MXene suspension;
b. blending the MXene suspension with quercetin, a silk fibroin solution and collagen gel to prepare mixed gel;
c. Designing a three-dimensional printing model, and importing the model into low-temperature 3D printer software;
d. putting the co-coagulation glue into a charging barrel of a low-temperature 3D printer, and setting printing parameters;
the low temperature in the steps c and d is that the temperature of the receiving device is controlled between minus 20 ℃ and minus 4 ℃;
And (3) curing the extruded composite gel silk at low temperature, preserving the cured composite gel at-20 ℃ overnight, and then performing freeze drying and post-treatment to obtain the oral mucosa repair material with the photo-thermal function.
2. The oral mucosa repair material with photo-thermal function according to claim 1, wherein in step D, the setting parameters of the 3D printing are: the travelling distance of the printing needle heads is set to be 200-1800 mu m.
3. The oral mucosa repair material with photo-thermal function according to claim 1, wherein in step d, the treatment conditions of freeze drying are: condensing temperature is minus 50 ℃ and vacuum degree is less than 20Pa.
4. The oral mucosa repair material with photo-thermal function according to claim 1, wherein in the step d, the post treatment is to soak with absolute ethanol, then soak with 0.1-0.5% NaOH solution by mass percent, and finally rinse the residual ethanol and NaOH with water.
5. The use of the oral mucosa repair material with photo-thermal function as claimed in claim 1, for preparing a material for promoting repair of squamous cell carcinoma postoperative mucosa defects.
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| CN110935059A (en) * | 2019-11-07 | 2020-03-31 | 天津市口腔医院 | MXene composite bone repair material with photothermal function and preparation method thereof |
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| CN110935059A (en) * | 2019-11-07 | 2020-03-31 | 天津市口腔医院 | MXene composite bone repair material with photothermal function and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| Photothermal effect of indocyanine green modified scaffold inhibits oral squamous cell carcinoma and promotes wound heali;Yaru Fan等;《Biomaterials Advance》;第137卷;1-14 * |
| 头颈部鳞状细胞癌细胞热疗后HSP70／HSP90的表达规律及其抑制对热疗疗效的影响;崔晓波等;《中国耳鼻咽喉头颈外科》;第17卷(第8期);396-398 * |
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