RESUMO
Diabetic complications with high-glucose status (HGS) cause the dysregulated autophagy and excessive apoptosis of multiple-type cells, leading to the difficulty in wound self-healing. Herein, we firstly developed fiber-reinforced gelatin (GEL)/ß-cyclodextrin (ß-CD) therapeutic hydrogels by the modification of platelet-rich plasma exosomes (PRP-EXOs). The GEL fibers that were uniformly dispersed within the GEL/ß-CD hydrogels remarkably enhanced the compression strengths and viscoelasticity. The PRP-EXOs were encapsulated in the hydrogels via the covalent crosslinking between the PRP-EXOs and genipin. The diabetic rat models demonstrated that the GEL/ß-CD hydrogels and PRP-EXOs cooperatively promoted diabetic wound healing. On the one hand, the GEL/ß-CD hydrogels provided the biocompatible microenvironments and active components for cell adhesion, proliferation and skin tissue regeneration. On the other hand, the PRP-EXOs in the therapeutic hydrogels significantly activated the autophagy and inhibited the apoptosis of human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs). The activation of autophagy and inhibition of apoptosis in HUVECs and HSFs induced the blood vessel creation, collagen formation and re-epithelialization. Taken together, this work proved that the incorporation of PRP-EXOs in a wound dressing was an effective strategy to regulate autophagy and apoptosis, and provide a novel therapeutic platform for diabetic wound healing.
Assuntos
Complicações do Diabetes , Diabetes Mellitus , Exossomos , Plasma Rico em Plaquetas , Ratos , Humanos , Animais , Hidrogéis/farmacologia , Gelatina/farmacologia , Exossomos/metabolismo , Cicatrização , Complicações do Diabetes/metabolismo , Células Endoteliais da Veia Umbilical Humana , Plasma Rico em Plaquetas/metabolismo , Diabetes Mellitus/metabolismoRESUMO
Autogenous bone grafting has long been considered the gold standard for treating critical bone defects. However, its use is plagued by numerous drawbacks, such as limited supply, donor site morbidity, and restricted use for giant-sized defects. For this reason, there is an increasing need for effective bone substitutes to treat these defects. Mollusk nacre is a natural structure with outstanding mechanical property due to its notable "brick-and-mortar" architecture. Inspired by the nacre architecture, our team designed and fabricated a nacre-mimetic cerium-doped layered nano-hydroxyapatite/chitosan layered composite scaffold (CeHA/CS). Hydroxyapatite can provide a certain strength to the material like a brick. And as a polymer material, chitosan can slow down the force when the material is impacted, like an adhesive. As seen in natural nacre, the combination of these inorganic and organic components results in remarkable tensile strength and fracture toughness. Cerium ions have been demonstrated exceptional anti-osteoclastogenesis capabilities. Our scaffold featured a distinct layered HA/CS composite structure with intervals ranging from 50 to 200 µm, which provided a conducive environment for human bone marrow mesenchymal stem cell (hBMSC) adhesion and proliferation, allowing for in situ growth of newly formed bone tissue. In vitro, Western-blot and qPCR analyses showed that the CeHA/CS layered composite scaffolds significantly promoted the osteogenic process by upregulating the expressions of osteogenic-related genes such as RUNX2, OCN, and COL1, while inhibiting osteoclast differentiation, as indicated by reduced TRAP-positive osteoclasts and decreased bone resorption. In vivo, calvarial defects in rats demonstrated that the layered CeHA/CS scaffolds significantly accelerated bone regeneration at the defect site, and immunofluorescence indicated a lowered RANKL/OPG ratio. Overall, our results demonstrate that CeHA/CS scaffolds offer a promising platform for bone regeneration in critical defect management, as they promote osteogenesis and inhibit osteoclast activation.
Assuntos
Quitosana , Nácar , Ratos , Humanos , Animais , Quitosana/farmacologia , Quitosana/química , Durapatita/farmacologia , Durapatita/química , Alicerces Teciduais/química , Nácar/farmacologia , Regeneração Óssea , Osteogênese , Transdução de Sinais , Diferenciação Celular , Engenharia Tecidual/métodosRESUMO
Herein, we developed a multimodal antibacterial nanoplatform via synergism effect including knife-effect, photothermal, photocatalytic induced reactive oxygen species (ROS), and Cu2+ inherent attribute. Typically, 0.8-TC/Cu-NS possesses higher photothermal property with the higher photothermal conversion efficiency of 24% and the moderate temperature up to 97 °C. Meanwhile, 0.8-TC/Cu-NS exhibits the more active ROS, 1O2 and ·O2-. Hence, 0.8-TC/Cu-NS possesses best antibacterial properties against S. aureus and E. coli in vitro with efficiency of 99.94%/99.97% under near-infrared (NIR) light, respectively. In the therapeutic practical use for wound healing of Kunming mice, this system exhibits outstanding curing capacity and good biocompatibility. Based on the electron configuration measurement and density functional theory (DFT) simulation, it is confirmed that the electrons on CB of Cu-TCPP flow fleetingly to MXene trough the interface, with redistribution of charge and band upward bending over Cu-TCPP. As a result, the self-assembled 2D/2D interfacial Schottky junction have made great favor to accelerate photogenerated charges mobility, hamper charge recombination, and increases the photothermal/photocatalytic activity. This work gives us a hint to mostly design the multimodal synergistic nanoplatform under NIR light in biological applications without drug resistance.
Assuntos
Escherichia coli , Staphylococcus aureus , Camundongos , Animais , Teoria da Densidade Funcional , Espécies Reativas de Oxigênio/farmacologia , Antibacterianos/farmacologia , CicatrizaçãoRESUMO
In situ regeneration of large-segment bone defects is a difficult clinical problem. Here, we innovatively developed magnetically oriented micro-cellulose fibres using nano-hydroxyapatite/chitosan (CEF/Fe3O4/HA/CS) and loaded an NFκB pathway inhibitor on the surface of magnetically oriented cellulose fibres (CEF/Fe3O4/HA/CS/PQQ) prepared as a layered bioscaffold. CEF/Fe3O4/HA/CS/PQQ was constructed by layering HA/CS sheets. Nano-hydroxyapatite was deposited on the surface of cellulose fibres, then the magnetic nanoparticles on the cellulose fibres were aligned on the surface of chitosan under a magnetic field. Oriented cellulose fibres enhanced the compressive properties of the scaffold, with an average maximum compressive strength of 1.63 âMPa. The CEF/Fe3O4/HA/CS/PQQ layered scaffold was filled into the body, and the acute inflammatory response (IL-1ß and TNF-α) was suppressed through the early sustained release of PQQ. The CEF/Fe3O4/HA/CS/PQQ-layered scaffold further inhibited the osteoclasts differentiation. It was further found that the nano-hydroxyapatite on the surface of oriented cellulose fibres promoted the formation and migration of new blood vessels, accelerated the processing of collagen-I fibres to cartilage, and endochondral ossification. Hence, the development of the CEF/Fe3O4/HA/CS/PQQ layered scaffold with oriented fibres guides bone growth direction and pro-osteogenesis activity and provides a novel strategy for the in situ regeneration of large segmental bone defects.
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Osteoporotic bone defects result from an imbalance in bone homeostasis, excessive osteoclast activity, and the weakening of osteogenic mineralization, resulting in impaired bone regeneration. Herein, inspired by the hierarchical structures of mollusk nacre, nacre exhibits outstanding high-strength mechanical properties, which are in part due to its delicate layered structure. SrFe12O19 nanoparticles and nano-layered double hydroxide (LDH) were incorporated into a bioactive chitosan (CS) matrix to form multifunctional layered nano-SrFe12O19-LDH/CS scaffolds. The compressive stress value of the internal ordered layer structure matches the trabecular bone (0.18 âMPa). The as-released Mg2+ ions from the nano-LDH can inhibit bone resorption in osteoclasts by inhibiting the NFκB signaling pathway. At the same time, the as-released Sr2+ ions promote the high expression of osteoblast collagen 1 proteins and accelerate bone mineralization by activating the BMP-2/SMAD signaling pathway. In vivo, the Mg2+ ions released from the SrFe12O19-LDH/CS scaffolds inhibited the release of pro-inflammatory factors (IL-1ß and TNF-α), while the as-released Sr2+ ions promoted osteoblastic proliferation and the mineralization of osteoblasts inside the layered SrFe12O19-LDH/CS scaffolds. Immunofluorescence for OPG, RANKL, and CD31, showed that stable vasculature could be formed inside the layered SrFe12O19-LDH/CS scaffolds. Hence, this study on multifunctional SrFe12O19-LDH/CS scaffolds clarifies the regulatory mechanism of osteoporotic bone regeneration and is expected to provide a theoretical basis for the research, development, and clinical application of this scaffold on osteoporotic bone defects.
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Natural polymer hydrogels are widely used as wound dressings, but they do not have enough bioactivity to accelerate angiogenesis and re-epithelialization. Herein, a therapeutic system was firstly constructed in which endothelin-1 (ET-1), as an endogenous vasoconstrictor peptide, was embedded in a photo-crosslinking gelatin methacryloyl (GelMA) hydrogel for full-thickness wound healing. The multifunctional GelMA-ET-1 hydrogels contained the arginine-glycine-aspartate (RGD) motifs of gelatin that provided adhesive sites for cell proliferation and migration. The ET-1 was wrapped within the network of crosslinked GelMA hydrogels via intermolecular hydrogen bonding interactions, effectively avoiding oxidization by atmospheric oxygen and in vivo enzymatic biodegradation. Notably, the ET-1 in the functional hydrogels significantly promoted the proliferation, migration and angiogenesis-related gene expression of human umbilical vein endothelial cells (HUVECs) and fibroblasts. The full-thickness skin defect model of rats further revealed that the GelMA-ET-1 hydrogels significantly accelerated new blood vessel formation, collagen deposition and re-epithelialization. After 14 days, the full-thickness skin defects almost closed and were filled with the newly formed tissue. Hence, the photo-crosslinking GelMA-ET-1 hydrogels functionalized with ET-1 can be employed as a promising therapeutic system for wound healing.
Assuntos
Endotelina-1/farmacologia , Gelatina/química , Hidrogéis/química , Neovascularização Fisiológica/efeitos dos fármacos , Animais , Humanos , RatosRESUMO
BACKGROUND: Breast cancer bone metastasis has become one of the most common complications; however, it may cause cancer recurrence and bone nonunion, as well as local bone defects. METHODS: Herein, In vitro, we verified the effect of bioscaffold materials on cell proliferation and apoptosis through a CCK8 trial, staining of live/dead cells, and flow cytometry. We used immunofluorescence technology and flow cytometry to verify whether bioscaffold materials regulate macrophage polarization, and we used ALP staining, alizarin red staining and PCR to verify whether bioscaffold material promotes bone regeneration. In vivo, we once again studied the effect of bioscaffold materials on tumors by measuring tumor volume in mice, Tunel staining, and caspase-3 immunofluorescence. We also constructed a mouse skull ultimate defect model to verify the effect on bone regeneration. RESULTS: Graphene oxide (GO) nanoparticles, hydrated CePO4 nanorods and bioactive chitosan (CS) are combined to form a bioactive multifunctional CePO4/CS/GO scaffold, with characteristics such as photothermal therapy to kill tumors, macrophage polarization to promote blood vessel formation, and induction of bone formation. CePO4/CS/GO scaffold activates the caspase-3 proteasein local tumor cells, thereby lysing the DNA between nucleosomes and causing apoptosis. On the one hand, the as-released Ce3+ ions promote M2 polarization of macrophages, which secretes vascular endothelial growth factor (VEGF) and Arginase-1 (Arg-1), which promotes angiogenesis. On the other hand, the as-released Ce3+ ions also activated the BMP-2/Smad signaling pathway which facilitated bone tissue regeneration. CONCLUSION: The multifunctional CePO4/CS/GO scaffolds may become a promising platform for therapy of breast cancer bone metastases.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Cério/química , Grafite/farmacologia , Nanotubos/química , Fosfatos/química , Células 3T3 , Animais , Materiais Biocompatíveis , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/metabolismo , Regeneração Óssea , Osso e Ossos , Neoplasias da Mama/metabolismo , Proliferação de Células , Quitosana , Modelos Animais de Doenças , Feminino , Macrófagos , Camundongos , Metástase Neoplásica , Osteogênese , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio VascularRESUMO
Electret melt-blown nonwovens are widely used for air purification due to their low pressure drop and high filtration efficiency. However, the charge stability could be affected by the ambient temperature and humidity, reducing the filtration efficiency, resulting in the electret melt blown filter not providing effective protection. Herein, we used corona charge to prepare electret melt-blown nonwovens and systematically studied the effects of different temperature and humidity on the structure, morphology, filtration performance, and surface potential within 24 h. The effect of treatment temperature and humidity on pressure drop was minimal because the fiber morphology and web structure of melt-blown nonwovens were not damaged. When the treatment temperature was lower than 70 °C, the effect on the filtration efficiency of the sample was small, but when the temperature increased to 90 or 110 °C, the filtration efficiency decreased significantly with the increase of the treatment time, and the surface potential also declined similarly. In conclusion, high temperatures will lead to charge escape and reduce the electrostatic adsorption effect. Furthermore, at the same temperature, increasing relative humidity can accelerate the charge release and make the filtration efficiency drop more. After the sample was treated at 110 °C and 90% relative humidity for 24 h, the filtration efficiency decreased from 95.49% to 38.16% at a flow rate of 14.16 cm s-1, and the surface potential dropped to the lowest value of -1.01 kV. This result shows that all links of electret melt-blown filter material from raw material to final use should be avoided in high temperature and high humidity conditions to ensure the protection effect.
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Design and fabrication of novel adsorbents to remove heavy metal ions in continuous-flow wastewater remained a great challenge. Inspired by the hierarchical architecture and biomineralization process of nacre, we firstly constructed hydroxyapatite/chitosan (HA/CH) layered composites. The brick-and-mortar characteristics of HA/CH layered composites improved their flexure strengths up to 3.08 MPa so that the hierarchical architectures could not be destroyed even under high-pressure drop. HA/CH layered composites had the hierarchical microstructures analogous to plate towers, facilitating the separation of adsorbents from water. The interlaminar macropores in the layered composites contributed to the transfer of continuous-flow wastewater. The Pb(II), Cd(II) and Hg(II) ions in wastewater showed similar adsorption trends, and their adsorption amounts arrived at 295.96, 192.37 and 127.38 mgâ¯g-1 after 6 days, respectively. Among the above heavy metal ions, the HA/CH layered composites possessed the best Pb(II) adsorption ability due to forming lead hydroxyapatite rods and CH-Pb complexes. The Pb(II) adsorption performances of HA/CH layered composites matched well with Elovich equation, pseudo-first-order and pseudo-second-order kinetics models, revealing the heterogeneous chemisorption mechanism at adsorbent/wastewater interfaces. Therefore, the nacre-like HA/CH layered composites with appropriate mechanical property and excellent adsorption capacity are a novel platform for heavy metal removal in continuous-flow wastewater.
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Chitosan (CTS) and mesoporous calcium silicate (MCS) have been developed for bone defect healing; however, their bone regeneration capacity still does not satisfy the patients with bone diseases. Gadolinium (Gd) is accumulated in human bones, and plays a beneficial role in regulating cell performance and bone regeneration. We firstly constructed Gd-doped MCS/CTS (Gd-MCS/CTS) scaffolds by a lyophilization technology. The interconnected arrangement of CTS films lead to forming macropores by using ice crystals as templates during the lyophilization procedure, and the Gd-MCS nanoparticles dispersed uniformly on the macropore walls. The biocompatible chemical components and hierarchical pores facilitated the attachment and spreading of rat bone marrow-derived mesenchymal stem cells (rBMSCs). Interestingly, the Gd dopants in the scaffolds effectively activated the Wnt/ß-catenin signaling pathway, resulting in excellent cell proliferation and osteogenic differentiation capacities. The osteogenic-related genes such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2) and collagen type1 (COL-1) were remarkably up-regulated by Gd-MCS scaffolds as compared with MCS scaffolds, and their expression levels increased in a positive correlation with Gd doping amounts. Moreover, in vivo rat cranial defect tests further confirmed that Gd-MCS/CTS scaffolds significantly stimulated collagen deposition and new bone formation. The exciting finding suggested the beneficial effects of Gd3+ ions on osteogenic differentiation and new bone regeneration, and Gd-MCS/CTS scaffolds can be employed as a novel platform for bone defect healing.
Assuntos
Regeneração Óssea/efeitos dos fármacos , Compostos de Cálcio/química , Compostos de Cálcio/farmacologia , Quitosana/química , Gadolínio/química , Gadolínio/farmacologia , Silicatos/química , Silicatos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Materiais Biocompatíveis/química , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Engenharia Tecidual/métodos , Alicerces Teciduais/química , Regulação para Cima/efeitos dos fármacosRESUMO
Hierarchically porous structures and bioactive compositions of artificial biomaterials play a positive role in bone defect healing and new bone regeneration. Herein, cerium oxide nanoparticles-modified bioglass (Ce-BG) scaffolds were firstly constructed by the incorporation of hollow mesoporous Ce-BG microspheres in CTS via a freeze-drying technology. The interconnected macropores in Ce-BG scaffolds facilitated the in-growth of bone cells/tissues from material surfaces into the interiors, while the hollow cores and mesopore shells in Ce-BG microspheres provides more active sites for bone mineralization. The cerium oxide nanoparticles in the scaffolds rapidly promoted the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs), as confirmed by the up-regulation of osteogenesis-related markers such as OCN, ALP and COL-1. The enhanced osteoinductivity of Ce-BG scaffolds was mainly related to the activated ERK pathway, and it was blocked by adding a selective ERK1/2 inhibitor (SCH772984). In vivo rat cranial defect models revealed that Ce-BG scaffolds accelerated collagen deposition, osteoblast formation and bone regeneration as compared to BG scaffolds. The exciting results demonstrated that the synergistic effects between hierarchically porous structures and cerium oxide nanoparticles contributed to osteogenic ability, and hollow mesoporous Ce-BG scaffolds would be a novel platform for bone regeneration.
Assuntos
Regeneração Óssea/efeitos dos fármacos , Cerâmica/farmacologia , Cério/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Alicerces Teciduais/química , Animais , Materiais Biocompatíveis/farmacologia , Células Cultivadas , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/ultraestrutura , Osteogênese/efeitos dos fármacos , Porosidade , Ratos Sprague-DawleyRESUMO
BACKGROUND: Biomaterial-induced osteogenesis is mainly related to hierarchically porous structures and bioactive components. Rare earth elements are well known to promote osteogenesis and stimulate bone repair; however, the underlying biological effects of gadolinium (Gd) element on bone regeneration are not yet known. METHODS: In this study, we successfully fabricated gadolinium-doped bioglass (Gd-BG) scaffolds by combining hollow mesoporous Gd-BG microspheres with chitosan and evaluated in vitro effects and underlying mechanisms with Cell Counting Kit-8, scanning electron microscopy, alkaline phosphatase, Alizarin red staining, and polymerase chain reaction. Cranial defect model of rats was constructed to evaluate their in vivo effects. RESULTS: The results indicated that Gd-BG scaffolds could promote the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Mechanistically, the Akt/GSK3ß signaling pathway was activated by the Gd-BG scaffolds. The enhancing effect of Gd-BG scaffolds on the osteogenic differentiation of hBMSCs was inhibited by the addition of LY294002, an inhibitor of Akt. Moreover, the in vivo cranial defect model of rats indicated that the Gd-BG scaffolds could effectively promote bone regeneration. CONCLUSION: Both in vitro and in vivo results suggested that Gd-BG scaffolds have promising applications in bone tissue engineering.
Assuntos
Osso e Ossos/patologia , Diferenciação Celular/efeitos dos fármacos , Cerâmica/farmacologia , Gadolínio/farmacologia , Células-Tronco Mesenquimais/citologia , Osteogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Alicerces Teciduais/química , Cicatrização/efeitos dos fármacos , Animais , Regeneração Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Masculino , Modelos Biológicos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Crânio/diagnóstico por imagem , Crânio/patologia , Microtomografia por Raio-XRESUMO
Trace rare earth elements such as lanthanum (La) regulated effectively bone tissue performances; however, the underlying mechanism remains unknown. In order to accelerate bone defects especially in patients with osteoporosis or other metabolic diseases, we firstly constructed lanthanum-doped mesoporous calcium silicate/chitosan (La-MCS/CTS) scaffolds by freeze-drying technology. During the freeze-drying procedure, three-dimensional macropores were produced within the La-MCS/CTS scaffolds by using ice crystals as templates, and the La-MCS nanoparticles were distributed on the macropore walls. The hierarchically porous structures and biocompatible components contributed to the adhesion, spreading and proliferation of rat bone marrow-derived mesenchymal stem cells (rBMSCs), and accelerated the in-growth of new bone tissues. Particularly, the La3+ ions in the bone scaffolds remarkably induced the osteogenic differentiation of rBMSCs via the activation of the TGF signal pathway. A critical-sized calvarial-defect rat model further revealed that the La-MCS/CTS scaffolds significantly promoted new bone regeneration as compared with pure MCS/CTS scaffolds. In conclusion, the La-MCS/CTS scaffold showed the prominent ability in osteogenesis and bone regeneration, which showed its application potential for bone defect therapy.
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Osso e Ossos/efeitos dos fármacos , Compostos de Cálcio/farmacologia , Quitosana/farmacologia , Lantânio/farmacologia , Silicatos/farmacologia , Engenharia Tecidual , Animais , Compostos de Cálcio/química , Quitosana/química , Lantânio/química , Tamanho da Partícula , Porosidade , Ratos , Silicatos/química , Propriedades de SuperfícieRESUMO
Bioglass scaffolds have great application potentials in orthopedics, and Ursolic acid (UA) can effectively promote in vivo new bone formation. Herein, we for the first time developed the mesoporous bioglass/chitosan porous scaffolds loaded with UA (MBG/CS/UA) for enhanced bone regeneration. The MBG microspheres with particle sizes of ~300â¯nm and pore sizes of ~3.9â¯nm were uniformly dispersed on the CS films. The mesoporous structure within the MBG microspheres and the hydrogen bonding between the scaffolds and UA drugs made the MBG/CS/UA scaffolds have controlled drug release performances. The as-released UA drugs from the scaffolds increased remarkably the alkaline phosphatase activity, osteogenic differentiation related gene type I collagen, runt-related transcription factor 2 expression, and osteoblast-associated protein expression. Moreover, the results of micro-CT images, histomorphological observations demonstrated that the MBG/CS/UA scaffolds improved new bone formation ability. Therefore, the MBG/CS/UA porous scaffolds can be used as novel bone tissue engineering materials.
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Regeneração Óssea/efeitos dos fármacos , Cerâmica/química , Quitosana/química , Sistemas de Liberação de Medicamentos , Alicerces Teciduais/química , Triterpenos/farmacologia , Animais , Linhagem Celular , Colágeno Tipo I/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos , Microesferas , Osseointegração/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Porosidade , Ratos Sprague-Dawley , Ácido UrsólicoRESUMO
Oral or intravenous chemotherapy is an important strategy to treat metastatic cancer, but it may cause systemic toxicity for healthy tissue. Herein, we for the first time fabricated mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin (ZSM-5/CS/DOX) as drug delivery systems against osteosarcoma. The mesoporous ZSM-5 zeolites exhibited disk-like shapes with thicknesses of 100nm and diameters of 300nm, and the mesopores with pore sizes of 3.75nm were originated from desilication treatment. The pH-responsive ZSM-5/CS/DOX nanodisks possessed a great drug loading efficiency of 97.7%, and their controlled release trends of DOX were fitted well with the Korsmeyer-Peppas model. The DOX could be efficiently released the ZSM-5/CS/DOX nanodisks after cellular endocytosis and induced cancer cells apoptosis. Moreover, the pH-responsive drug carriers led to efficient tumor inhibition with low side effects, especially cardiac toxicity, as confirmed by pharmacokinetic study, serological examination and H&E staining assays. Therefore, the ZSM-5/CS/DOX nanodisks are a promising pH-responsive drug carrier for targeted cancer therapy.
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Quitosana/química , Doxorrubicina/uso terapêutico , Nanopartículas/química , Osteossarcoma/tratamento farmacológico , Zeolitas/química , Adulto , Animais , Biomarcadores/metabolismo , Morte Celular , Linhagem Celular Tumoral , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , L-Lactato Desidrogenase/metabolismo , Masculino , Malondialdeído/metabolismo , Células-Tronco Mesenquimais/citologia , Modelos Biológicos , Nanopartículas/ultraestrutura , Nitrogênio/química , Porosidade , Ratos Sprague-Dawley , Temperatura , Distribuição Tecidual , Difração de Raios XRESUMO
For effectively treating tumor related-bone defects, design and fabrication of multifunctional biomaterials still remain a great challenge. Herein, we firstly fabricated magnetic SrFe12O19 nanoparticles modified-mesoporous bioglass (BG)/chitosan (CS) porous scaffold (MBCS) with excellent bone regeneration and antitumor function. The as-produced magnetic field from MBCS promoted the expression levels of osteogenic-related genes (OCN, COL1, Runx2 and ALP) and the new bone regeneration by activated BMP-2/Smad/Runx2 pathway. Moreover, the SrFe12O19 nanoparticles in MBCS improved the photothermal conversion property. Under the irradiation of near-infrared (NIR) laser, the elevated temperatures of tumors co-cultured with MBCS triggered tumor apoptosis and ablation. As compared with the pure scaffold group, MBCS/NIR group possessed the excellent antitumor efficacy against osteosarcoma via the hyperthermia ablation. Therefore, the multifunctional MBCS with excellent bone regeneration and photothermal therapy functions has a great application for treating the tumor-related bone defects.
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Neoplasias Ósseas/terapia , Regeneração Óssea , Hipertermia Induzida , Nanopartículas de Magnetita/administração & dosagem , Osteossarcoma/terapia , Fototerapia , Alicerces Teciduais , Animais , Neoplasias Ósseas/patologia , Proliferação de Células , Humanos , Lasers , Nanopartículas de Magnetita/química , Masculino , Osteossarcoma/patologia , Porosidade , Ratos , Ratos Sprague-Dawley , Células Tumorais CultivadasRESUMO
The surgical resection of melanoma may cause skin wounds, and the remaining melanoma cells bring a great risk of tumor recurrence. To overcome the above problem, we for the first time constructed lanthanum-doped chitosan (La-CS) hydrogels with excellent wound healing and antitumor functions. The La element was uniformly dispersed within whole hydrogels, and part of La3+ ions reacted with CS to form La-CS complex. The complexation interaction between La3+ ions and CS significantly improve the La3+ release performances of La-CS hydrogels. The as-released La3+ ions from the composite hydrogels selectively inhibited the proliferation of B-16 melanoma cells, but showed lower toxic side effects to L929 skin fibroblast cells. Moreover, the La3+ ions triggered the apoptosis of B-16 cells through Bcl-2/Bax pathway, as confirmed by the Annexin Vand PI double staining, flow cytometry, and Western blot results. The in vivo tumor models of C57 mice revealed that the La-CS hydrogels had more significant relapse-inhibition effects on B-16 melanoma cells than the pure CS hydrogels. At the same time, the in vivo wound healing was accelerated by the multifunctional hydrogels. The exciting finding provides a critical and promising strategy in the construction of La-doped hydrogels for oncotherapy.
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Poor bone formation remains a key risk factor associated with acellular scaffolds that occurs in some bone defects, particularly in patients with metabolic bone disorders and local osteoporosis. We herein fabricated for the first time layered double hydroxide-chitosan porous scaffolds loaded with PFTα (LDH-CS-PFTα scaffolds) as therapeutic bone scaffolds for the controlled release of PFTα to enhance stem cell osteogenic differentiation and bone regeneration. The LDH-CS scaffolds had three-dimensional interconnected macropores, and plate-like LDH nanoparticles were uniformly dispersed within or on the CS films. The LDH-CS scaffolds exhibited appropriate PFTα drug delivery due to hydrogen bonding among LDH, CS and PFTα. In vitro functional studies demonstrated that the PFTα molecules exhibited potent ability to induce osteogenesis of hBMSCs via the GSK3ß/ß-catenin pathway, and the LDH-CS-PFTα scaffolds significantly enhanced the osteogenic differentiation of hBMSCs. In vivo studies revealed significantly increased repair and regeneration of bone tissue in cranial defect model rats compared to control rats at 12 weeks post-implantation. In conclusion, the LDH-CS-PFTα scaffolds exhibited excellent osteogenic differentiation and bone regeneration capability and hold great potential for applications in defined local bone regeneration.
Assuntos
Compostos de Alumínio/química , Benzotiazóis/química , Regeneração Óssea , Quitosana/química , Hidróxidos/química , Compostos de Magnésio/química , Osteogênese , Alicerces Teciduais , Tolueno/análogos & derivados , Animais , Diferenciação Celular , Células Cultivadas , Humanos , Masculino , Células-Tronco Mesenquimais , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Engenharia Tecidual , Tolueno/químicaRESUMO
There is a need to find better strategies to promote wound healing, especially of chronic wounds, which remain a challenge. We found that synovium mesenchymal stem cells (SMSCs) have the ability to strongly promote cell proliferation of fibroblasts; however, they are ineffective at promoting angiogenesis. Using gene overexpression technology, we overexpressed microRNA-126-3p (miR-126-3p) and transferred the angiogenic ability of endothelial progenitor cells to SMSCs, promoting angiogenesis. We tested a therapeutic strategy involving controlled-release exosomes derived from miR-126-3p-overexpressing SMSCs combined with chitosan. Our in vitro results showed that exosomes derived from miR-126-3p-overexpressing SMSCs (SMSC-126-Exos) stimulated the proliferation of human dermal fibroblasts and human dermal microvascular endothelial cells (HMEC-1) in a dose-dependent manner. Furthermore, SMSC-126-Exos also promoted migration and tube formation of HMEC-1. Testing this system in a diabetic rat model, we found that this approach resulted in accelerated re-epithelialization, activated angiogenesis, and promotion of collagen maturity in vivo. These data provide the first evidence of the potential of SMSC-126-Exos in treating cutaneous wounds and indicate that modifying the cells-for example, by gene overexpression-and using the exosomes derived from these modified cells provides a potential drug delivery system and could have infinite possibilities for future therapy. Stem Cells Translational Medicine 2017;6:736-747.