Multifunctional Silicate Bioactive Materials For Melanoma Therapy And Skin Healing

Melanoma is a kind of skin tumor with a high mortality rate.At present,surgical resection is one of the most common methods to treat melanomas.However,the tumor is easy to relapse,and the large area of skin wound has limited self-heal ability.Therefore,it is quite important to develop multifunctional bioactive materials,which can not only treat melanomas,but also rapidly repair damaged skin tissues.Photothermal therapy kills tumor cells with high efficiency and little side effect via photothermal materials converting light energy into heat energy,and has attracted extensive attention.It was found that the ions with photothermal conversion properties could induce photothermal effect.It is worth noting that some of these ions could have a positive effect on skin healing.Silicate biomaterials,composed of silicon,oxygen and other bioactive ions,could promote tissue regeneration by releasing Si and other bioactive ions.Therefore,in this dissertation,the ions with both photothermal and wound healing properties were firstly incorporated into silicate materials to create silicate biomaterials with photothermal property,which were further combined with three-dimensional tissue engineering scaffolds.The potential application of the composite scaffolds in the field of melanoma treatment and wound healing was finally explored.It may be of great clinical significance for the study of cancer-induced wound healing and tissue regeneration.The main results are described as follows:?1?Considering the photothermal effect and the activity of inducing angiogenesis of Cu ions,the CaCuSi₄O₁₀nanoparticles?NPs?were firstly prepared by sol-gel methods.Inspired by the designing strategy and fabrication method of Chinese sesame sticks,the 3C-PP scaffolds were then developed by spin coating of CaCuSi₄O₁₀ NPs on the surface of polycaprolactone/poly?lactic acid?electrospun fibers?PP?.The results showed that the photothermal conversion efficiency of the CaCuSi₄O₁₀NPs was 33.8%.After coating of the CaCuSi₄O₁₀ NPs on the fibers,the nanoparticles?sesame?were uniformly and stably distributed on the surface of the fibers?sugar sticks?,endowing the composite scaffolds with the sesame stick-like structure.Similar to the concept that sesame seeds offer sugar sticks flavor and nutrition,the CaCuSi₄O₁₀ NPs not only endowed the composite scaffolds with excellent photothermal properties,but also enabled them to have the wound healing ability.The in vitro anti-tumor results showed that the death rate of tumor cells increased with increasing irradiation time and power density of NIR laser.The in vivo anti-tumor results showed hyperthermia induced by 3C-PP scaffolds inhibited the tumor growth and the CaCuSi₄O₁₀ NPs could accelerate the re-epithelization of damaged skin above the tumors.At the same time,3C-PP scaffolds supported the growth and adhesion of fibroblasts,and accelerated diabetic wound healing by improving the angiogenesis and collagen deposition,which were mainly ascribed to the released bioactive Si O₄^4-and Cu ions from CaCuSi₄O₁₀NPs.Therefore,the sesame stick-inspired composite scaffolds with CaCuSi₄O₁₀NPs and electrospun fibers may provide a new strategy for the development of multifunctional bioactive materials for the treatment and repair of melanoma skin.?2?Based on the multifunctions of copper-containing silicate photothermal conversion materials and the concept of NIR laser-controlled chemotherapy,the copper silicate hollow microspheres?CSO HMSs?were firstly prepared by hydrothermal synthesis.After loading chemotherapeutic drugs,the Tra-CSO-PP scaffolds were finally developed by incorporating drug-loaded CSO HMSs into the PP fibers.The results showed that the photothermal conversion efficiency of the CSO HMSs was 48.3%.The CSO HMSs had interior hollow and external nanoneedle and drug loading efficiency could reach 26.9%.The Tra-CSO-PP scaffolds retained the excellent photothermal properties of the CSO HMSs and heated up rapidly under the NIR light.The release rate of drug molecules gradually increased with the increase of temperature,showing a NIR-triggered drug release.The in vitro and in vivo anti-tumor results showed that the tumor growth of the Tra-CSO-PP+Laser group was continuously inhibited under the synergistic hyperthermia and drugs,and the treatment effect was much better than that of single treatment mode.Moreover,the damaged skin in the tumor bed healed well without tumor cells.The in vitro wound healing results showed that the CSO HMSs promoted the expression of angiogenesis-related genes of endothelial cells,as well as the proliferation and adhesion of fibroblasts on the scaffolds.The diabetic wound healing results showed that CSO HMSs composite fibers significantly accelerated the wound healing rate by releasing Si O₄^4-and Cu ions,and improved the wound healing quality by promoting the neovascularization,the expression of collagen I and collagen III,as well as re-epithelialization.Herein,CSO HMSs-incorporated bioactive scaffolds may have a great potential in the fields of photothermal treatment,hyperthermia-controlled chemotherapy and healing of melanoma-caused skin defects.?3?Based on the applications of Mn ions in accelerating keratinocyte migration,photothermal therapy and starvation therapy,the manganese silicate hollow nanospheres?MS HNPs?were prepared by hydrothermal methods combining Mn ions with silicates.After loading glucose oxidase?GOx?,the MS HNPs were subsequently incorporated into sodium alginate?SA?hydrogel to develop composite hydrogels?G/MS-5SA?.The results showed that the MS HNPs had hollow vesicle structures.The contents of GOx absorbed on the MS HNPs reached?81?g/mg.The photothermal conversion efficiency of MS HNPs was 38.5%.After the incorporation of MS HNPs,the composite hydrogels exhibited great photothermal properties.Under the NIR laser,with the temperature of G/MS-5SA hydrogel increasing to 42°C,the rate of glucose consumption increased.However,when the temperature further increased,the activity of GOx was inhibited.The G/MS-5SA hydrogels showed excellent biocompatibility when co-cultured with fibroblasts.The in vitro anti-tumor results showed that the synergistic effect of photothermal and starvation therapy led to the highest death rate of tumor cells.Compared with SA hydrogel,the introduction of MS HNPs into hydrogels could obviously promote the epithelialization process of the new skin wounds,while the GOx and hyperthermia from G/MS-5SA hydrogels decreased the quality of wound healing.In summary,silicate photothermal materials were designed by incorporating the ions?Cu and Mn ions?with both photothermal and wound healing properties into the silicate system and further combined with three-dimensional scaffolds to construct multifunctional bioactive scaffolds.The anti-tumor elements were loaded on the hollow silicate photothermal materials and intelligent anti-tumor modes were created by using photothermal heating to regulate anti-tumor process of the carriers.The composite scaffolds successfully acted as a multifunctional platform,which could remove the melanoma cells by photothermal therapy or photothermal/chemotherapy or photothermal/starvation therapy,meanwhile,could promote wound healing by releasing bioactive ions.The multifunctional bioactive silicate materials may offer a new strategy and direction for tumor treatment and postoperative wound management.