RESUMEN
Inorganic materials have essential roles in society, including in building construction, optical devices, mechanical engineering and as biomaterials1-4. However, the manufacture of inorganic materials is limited by classical crystallization5, which often produces powders rather than monoliths with continuous structures. Several precursors that enable non-classical crystallization-such as pre-nucleation clusters6-8, dense liquid droplets9,10, polymer-induced liquid precursor phases11-13 and nanoparticles14-have been proposed to improve the construction of inorganic materials, but the large-scale application of these precursors in monolith preparations is limited by availability and by practical considerations. Inspired by the processability of polymeric materials that can be manufactured by crosslinking monomers or oligomers15, here we demonstrate the construction of continuously structured inorganic materials by crosslinking ionic oligomers. Using calcium carbonate as a model, we obtain a large quantity of its oligomers (CaCO3)n with controllable molecular weights, in which triethylamine acts as a capping agent to stabilize the oligomers. The removal of triethylamine initiates crosslinking of the (CaCO3)n oligomers, and thus the rapid construction of pure monolithic calcium carbonate and even single crystals with a continuous internal structure. The fluid-like behaviour of the oligomer precursor enables it to be readily processed or moulded into shapes, even for materials with structural complexity and variable morphologies. The material construction strategy that we introduce here arises from a fusion of classic inorganic and polymer chemistry, and uses the same cross-linking process for the manufacture the materials.
Asunto(s)
Carbonato de Calcio/química , Química Inorgánica , Ciencia de los Materiales/métodos , Polímeros/químicaRESUMEN
Osteoporosis is a global chronic disease characterized by severe bone loss and high susceptibility to fragile fracture. It is widely accepted that the origin acidified microenvironment created by excessive osteoclasts causes irreversible bone mineral dissolution and organic degradation during osteoclastic resorption. However, current clinically available approaches are mainly developed from the perspective of osteoclast biology rather than the critical acidified niche. Here, we developed a smart "nanosacrificial layer" consisting of sodium bicarbonate (NaHCO3)-containing and tetracycline-functionalized nanoliposomes (NaHCO3-TNLs) that can target bone surfaces and respond to external secreted acidification from osteoclasts, preventing osteoporosis. In vitro and in vivo results prove that this nanosacrificial layer precisely inhibits the initial acidification of osteoclasts and initiates a chemically regulated biocascade to remodel the bone microenvironment and realize bone protection: extracellular acid-base neutralization first inhibits osteoclast function and also promotes its apoptosis, in which the apoptosis-derived extracellular vesicles containing RANK (receptor activator of nuclear factor-κ B) further consume RANKL (RANK ligand) in serum, achieving comprehensive osteoclast inhibition. Our therapeutic strategy for osteoporosis is based on original and precise acid-base neutralization, aiming to reestablish bone homeostasis by using a smart nanosacrificial layer that is able to induce chemically regulated biocascade effects. This study also provides a novel understanding of osteoporosis therapy in biomedicine and clinical treatments.
Asunto(s)
Huesos/metabolismo , Nanoestructuras/química , Osteoclastos/metabolismo , Osteoporosis/prevención & control , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Animales , Resorción Ósea/metabolismo , Dióxido de Carbono/química , Colesterol/química , Femenino , Humanos , Lecitinas/química , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Fosfatidiletanolaminas/metabolismo , Polietilenglicoles/metabolismo , Ligando RANK/metabolismo , Bicarbonato de Sodio/química , Propiedades de Superficie , Tetraciclina/químicaRESUMEN
Bone is the most common site of metastasis, and although low proliferation and immunoediting at the early stage make existing treatment modalities less effective, the microenvironment-inducing behaviour could be a target for early intervention. Here we report on a spatiotemporal coupling interaction between tumour cells and osteoclasts, and named the tumour-associated osteoclast 'tumasteoclast'-a subtype of osteoclasts in bone metastases induced by tumour-migrasome-mediated cytoplasmic transfer. We subsequently propose an in situ decoupling-killing strategy in which tetracycline-modified nanoliposomes encapsulating sodium bicarbonate and sodium hydrogen phosphate are designed to specifically release high concentrations of hydrogen phosphate ions triggered by tumasteoclasts, which depletes calcium ions and forms calcium-phosphorus crystals. This can inhibit the formation of migrasomes for decoupling and disrupt cell membrane for killing, thereby achieving early prevention of bone metastasis. This study provides a research model for exploring tumour cell behaviour in detail and a proof-of-concept for behaviour-targeting strategy.
Asunto(s)
Neoplasias Óseas , Osteoclastos , Neoplasias Óseas/secundario , Neoplasias Óseas/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/prevención & control , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Osteoclastos/patología , Animales , Humanos , Ratones , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Liposomas/química , FemeninoRESUMEN
Nanomaterials with intrinsic enzyme-like activity have gained substantial scientific attention as viable substitutes to natural biological enzymes owing to their cheap price and great stability. Numerous artificial enzyme mimics have been employed effectively in sectors such as sensing, environmental processing, and cancer treatment. In this study, novel nitrogen-doped porous carbon nanomaterials (CPs) were produced by modifying polypyrrole with magadiite using chemical oxidative polymerization and calcination methods. The obtained nitrogen-doped porous carbon nanomaterials exhibited improved peroxidase-like activity, which catalyzed the oxidation of 3,3,5,5-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2) to produce colorful compounds. Kinetic investigation revealed that the affinity for TMB of nitrogen-doped porous carbon peroxidase mimics was higher than that of genuine horseradish peroxidase (HRP). In addition, a sensitive assay with encouraging performance for the colorimetric detection of ascorbic acid (AA) was successfully fabricated employing nitrogen-doped porous carbon nanomaterials as peroxidase mimics. The results were satisfactory and demonstrated its potential application in antioxidant detection.
Asunto(s)
Nanoestructuras , Peroxidasa , Peroxidasa/química , Antioxidantes , Polímeros , Ácido Ascórbico , Carbono/química , Nitrógeno , Glucosa , Colorimetría/métodos , Peróxido de Hidrógeno/química , Porosidad , Pirroles , Peroxidasas , Nanoestructuras/química , ColorantesRESUMEN
Biomineralization is a process in which natural organisms regulate the crystal growth of inorganic minerals, resulting in hierarchical structured biominerals with excellent properties. Typical biominerals in the human body are the bones and teeth, and damage to these hard tissues directly affect our daily lives. The repair of bones and teeth in a biomimetic way, either by using a biomimetic mineralization strategy or biomimetic materials, is the key for hard tissue regeneration. In this review, we briefly introduce the structure of bone and tooth, and highlight the fundamental role of collagen mineralization in tissue repair. The recent progress on intra-/extrafibrillar collagen mineralization by a biomimetic strategy or materials is presented, and their potential for tissue regeneration is discussed. Then, recent achievements on bone and tooth repair are summarized, and these works are discussed in the view of materials science and biological science, providing a broader vision for the future research of hard tissue repair techniques. Lastly, recent progress on hard tissue regeneration is concluded, and existing problems and future directions are prospected.
Asunto(s)
Materiales Biomiméticos , Diente , Humanos , Biomimética , Colágeno , Huesos , Materiales Biomiméticos/farmacología , Materiales Biomiméticos/químicaRESUMEN
The nacre-inspired laminates are promising materials for their excellent mechanics. However, the interfacial defects between organic-inorganic phases commonly lead to the crack propagation and fracture failure of these materials under stress. A natural biomineral, bone, has much higher bending toughness than the nacre. The small size of inorganic building units in bone improves the organic-inorganic interaction, which optimizes the material toughness. Inspired by these biological structures, here, an ultratough nanocomposite laminate is prepared by the integration of ultrasmall calcium phosphate oligomers (CPO, 1 nm in diameter) within poly(vinyl alcohol) (PVA) and sodium alginate (Alg) networks through a simple three-step strategy. Owing to the small size of inorganic building units, strong multiple molecular interactions within integrated organic-inorganic hierarchical structure are built. The resulting laminates exhibit ultrahigh bending strain (>50% without fracture) and toughness (21.5-31.0 MJ m-3), which surpass natural nacre and almost all of the synthetic laminate materials that have been reported so far. Moreover, the mechanics of this laminate is tunable by changing the water content within the bulk structure. This work provides a way for the development of organic-inorganic nanocomposites with ultrahigh bending toughness by using inorganic ionic oligomers, which can be useful in the fields of tough protective materials and energy absorbing materials.
Asunto(s)
Nácar , Nanocompuestos , Polímeros , Nácar/química , Nanocompuestos/química , Iones , Alcohol PolivinílicoRESUMEN
The organic-inorganic structure in biological hard tissues ensures their marvelous characteristics but these hybrids are easily destroyed by the demineralization of inorganic components, e.g., the damage of dentin. Current clinical materials for hard tissue regeneration commonly act as "fillers" and their therapeutic effect is limited by the failures of biological-linked organic-inorganic interface reconstruction. Herein, a fast in situ crosslinking of calcium phosphate oligomers (CPOs) on collagen matrixes for efficient organic-inorganic interface re-construction, which can result in a biomimetic hybrid, is demonstrated. By using damaged dentin as an example, the inorganic ionic crosslinking can instantly infiltrate into the dentin matrix to rebuild a dense and continuous calcium phosphate-collagen hybrid within only 5 min, where the structurally integrated organic-inorganic interface is identical to natural dentin. As a result, the damaged dentin can be fully recovered to a healthy one, which is superior to any current dentin treatments. The fast construction of biomimetic hybrid by inorganic ionic crosslinking provides a promising strategy for hard tissue repair and follows great potentials of CPOs as advanced biomedical materials in future.
Asunto(s)
Biomimética , Fosfatos de Calcio , Fosfatos de Calcio/farmacología , ColágenoRESUMEN
Inducible expression systems are indispensable for precise regulation and in-depth analysis of biological process. Binary Tet-On system has been widely employed to regulate transgenic expression by doxycycline. Previous pig models with tetracycline regulatory elements were generated through random integration. This process often resulted in uncertain expression and unpredictable phenotypes, thus hindering their applications. Here, by precise knock-in of binary Tet-On 3G elements into Rosa26 and Hipp11 locus, respectively, a double knock-in reporter pig model was generated. We characterized excellent properties of this system for controllable transgenic expression both in vitro and in vivo. Two attP sites were arranged to flank the tdTomato to switch reporter gene. Single or multiple gene replacement was efficiently and faithfully achieved in fetal fibroblasts and nuclear transfer embryos. To display the flexible application of this system, we generated a pig strain with Dox-inducing hKRASG12D expression through phiC31 integrase-mediated cassette exchange. After eight months of Dox administration, squamous cell carcinoma developed in the nose, mouth, and scrotum, which indicated this pig strain could serve as an ideal large animal model to study tumorigenesis. Overall, the established pig models with controllable and switchable transgene expression system will provide a facilitating platform for transgenic and biomedical research.
Asunto(s)
Terapia Genética , Integrasas , Masculino , Animales , Porcinos , Integrasas/genética , Integrasas/metabolismo , Transgenes , Animales Modificados Genéticamente , Expresión GénicaRESUMEN
The regeneration of tooth enamel, the hardest biological tissue, remains a considerable challenge because its complicated and well-aligned apatite structure has not been duplicated artificially. We herein reveal that a rationally designed material composed of calcium phosphate ion clusters can be used to produce a precursor layer to induce the epitaxial crystal growth of enamel apatite, which mimics the biomineralization crystalline-amorphous frontier of hard tissue development in nature. After repair, the damaged enamel can be recovered completely because its hierarchical structure and mechanical properties are identical to those of natural enamel. The suggested phase transformation-based epitaxial growth follows a promising strategy for enamel regeneration and, more generally, for biomimetic reproduction of materials with complicated structure.
Asunto(s)
Apatitas/química , Materiales Biomiméticos/química , Esmalte Dental/química , Animales , Cristalización , HumanosRESUMEN
Multidrug resistance is one of major obstacles to the effective cancer chemotherapy. To address this issue, we developed the effective circumvention of multidrug resistance in cancer cells by a yolk-shell Fe3O4@MgSiO3 nanoplatform with the polymerpoly(ethylene glycol) and folic acid modifications can achieve active targeted delivery of anti-cancer drug by using combined magnetic and ligand targeting. The direct intracellular drug delivery of doxorubicin by nanocarrier was much more effectively than free DOX for multidrug resistant Hep-G2/MDR cancer cells. Besides the excellent biocompatibility, high drug loading efficiency, dual-targeting delivery, and controlled releasing behavior, in vivo experiments demonstrate that this nanocarrier can specifically deliver and concentrate doxorubicin hydrochloride in tumor sites to overcome drug resistance. It follows an alternative strategy for effective chemotherapy against drug resistant cancers by using rationally designed nanomaterial.