RESUMEN

Minimally invasive transcatheter interventional therapy utilizing cardiac occluders represents the primary approach for addressing congenital heart defects and left atrial appendage (LAA) thrombosis. However, incomplete endothelialization and delayed tissue healing after occluder implantation collectively compromise clinical efficacy. In this study, we have customized a recombinant humanized collagen type I (rhCol I) and developed an rhCol I-based extracellular matrix (ECM)-mimetic coating. The innovative coating integrates metal-phenolic networks with anticoagulation and anti-inflammatory functions as a weak cross-linker, combining them with specifically engineered rhCol I that exhibits high cell adhesion activity and elicits a low inflammatory response. The amalgamation, driven by multiple forces, effectively serves to functionalize implantable materials, thereby responding positively to the microenvironment following occluder implantation. Experimental findings substantiate the coating's ability to sustain a prolonged anticoagulant effect, enhance the functionality of endothelial cells and cardiomyocyte, and modulate inflammatory responses by polarizing inflammatory cells into an anti-inflammatory phenotype. Notably, occluder implantation in a canine model confirms that the coating expedites reendothelialization process and promotes tissue healing. Collectively, this tailored ECM-mimetic coating presents a promising surface modification strategy for improving the clinical efficacy of cardiac occluders.

Asunto(s)

Materiales Biocompatibles Revestidos , Matriz Extracelular , Cicatrización de Heridas , Animales , Matriz Extracelular/metabolismo , Perros , Humanos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Cicatrización de Heridas/efectos de los fármacos , Colágeno Tipo I/metabolismo , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Células Endoteliales de la Vena Umbilical Humana , Repitelización/efectos de los fármacos , Adhesión Celular/efectos de los fármacos

RESUMEN

In order to properly satisfy biomedical constraints for cardiovascular applications, additively manufactured NiTi scaffolds required further process and metallurgical engineering. Additively manufactured NiTi materials for cardiovascular use will have to undergo surface finishing in order to minimize negative surface interactions within the artery. In this study, we sought to understand biocompatibility from chemically etched additively manufactured NiTi scaffolds by laser powder bed fusion (LPBF). Although two distinct oxide films were created in the surface etching process (labeled CP-A and CP-B), no qualitative changes in microroughness were seen between the two conditions. CP-A possessed significantly less Ni at the surface (0.19 at. %) than the CP-B group (3.30 at. %), via x-ray photoelectron spectroscopy, alongside a concomitant shift in the O1 s peak presentation alluding to a greater formation of a Ni based oxide in the CP-B group. Our live dead staining revealed significant toxicity and reduced cellular attachment for the CP-B group, in addition to inducing more cell lysis (20.9 ± 5.1%), which was significantly increased when compared to CP-A (P < 0.01). Future practices of manufacturing NiTi scaffolds using LPBF should focus on producing surface films that are not only smooth, but free of cytotoxic Ni based oxides.

Asunto(s)

Materiales Biocompatibles , Níquel , Propiedades de Superficie , Titanio , Titanio/química , Titanio/farmacología , Níquel/química , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Humanos , Óxidos/química , Óxidos/farmacología , Ensayo de Materiales , Supervivencia Celular/efectos de los fármacos , Espectroscopía de Fotoelectrones , Adhesión Celular/efectos de los fármacos , Andamios del Tejido/química

RESUMEN

Osteosarcoma is the most prevalent form of primary malignant bone tumor, primarily affecting children and adolescents. The nerve growth factors (NGF) referred to as neurotrophins have been associated with cancer-induced bone pain; however, the role of NGF in osteosarcoma has yet to be elucidated. In osteosarcoma samples from the Genomic Data Commons data portal, we detected higher levels of NGF and M2 macrophage markers, but not M1 macrophage markers. In cellular experiments, NGF-stimulated osteosarcoma conditional medium was shown to facilitate macrophage polarization from the M0 to the M2 phenotype. NGF also enhanced VCAM-1-dependent monocyte adhesion within the osteosarcoma microenvironment by down-regulating miR-513c-5p levels through the FAK and c-Src cascades. In in vivo xenograft models, the overexpression of NGF was shown to enhance tumor growth, while the oral administration of the TrK inhibitor larotrectinib markedly antagonized NGF-promoted M2 macrophage expression and tumor progression. These results suggest that larotrectinib could potentially be used as a therapeutic agent aimed at mitigating NGF-mediated osteosarcoma progression.

Asunto(s)

Monocitos , Factor de Crecimiento Nervioso , Osteosarcoma , Microambiente Tumoral , Molécula 1 de Adhesión Celular Vascular , Osteosarcoma/metabolismo , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/patología , Humanos , Factor de Crecimiento Nervioso/metabolismo , Animales , Microambiente Tumoral/efectos de los fármacos , Monocitos/metabolismo , Monocitos/efectos de los fármacos , Molécula 1 de Adhesión Celular Vascular/metabolismo , Ratones , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Óseas/metabolismo , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Macrófagos/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratones Desnudos

RESUMEN

Developing biomaterials with high osteogenic properties is crucial for achieving rapid bone repair and regeneration. This study focuses on the application of nanocrystal hydroxyapatite (nHAp) as a drug carrier to load Fu Yuan Huo Xue Decoction (FYHXD), a traditional Chinese medicine derived from Angelica sinensis, aiming to achieve improved efficacy in treating bone diseases such as osteoporosis. Through a facile physical adsorption approach, the FTIR result emerges new characteristic absorption peaks in the range of 1200-950 cm-1, proving the successful absorption of FYHXD onto the nHAp with a loading efficiency of 39.76 %. The modified nHAp exhibits a similar shape to the bone-derived hydroxyapatite nanocrystals, and their diameter increases slightly after modification. The drug release assay implies the rapid release of FYHXD in the first 10 h, followed by a continuously slow release within 70 h. The developed nHAp effectively enhances the adhesion, spreading, and proliferation of MC3T3-E1 cells in vitro, and significantly promotes their osteogenic differentiation, as indicated by increased alkaline phosphatase activity. Overall, the biocomposites hold great promise as active ingredients for integration into bone-associated biomaterials, offering the potential to stimulate spontaneous osteogenesis without requiring exogenous osteogenic factors.

Asunto(s)

Diferenciación Celular , Medicamentos Herbarios Chinos , Durapatita , Nanopartículas , Osteogénesis , Durapatita/química , Osteogénesis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Ratones , Animales , Nanopartículas/química , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Proliferación Celular/efectos de los fármacos , Medicina Tradicional China , Liberación de Fármacos , Fosfatasa Alcalina/metabolismo , Tamaño de la Partícula , Línea Celular , Adhesión Celular/efectos de los fármacos , Portadores de Fármacos/química

RESUMEN

Guided bone regeneration (GBR) technology has been demonstrated to be an effective method for reconstructing bone defects. A membrane is used to cover the bone defect to stop soft tissue from growing into it. The biosurface design of the barrier membrane is key to the technology. In this work, an asymmetric functional gradient Janus membrane was designed to address the bidirectional environment of the bone and soft tissue during bone reconstruction. The Janus membrane was simply and efficiently prepared by the multilayer self-assembly technique, and it was divided into the polycaprolactone isolation layer (PCL layer, GBR-A) and the nanohydroxyapatite/polycaprolactone/polyethylene glycol osteogenic layer (HAn/PCL/PEG layer, GBR-B). The morphology, composition, roughness, hydrophilicity, biocompatibility, cell attachment, and osteogenic mineralization ability of the double surfaces of the Janus membrane were systematically evaluated. The GBR-A layer was smooth, dense, and hydrophobic, which could inhibit cell adhesion and resist soft tissue invasion. The GBR-B layer was rough, porous, hydrophilic, and bioactive, promoting cell adhesion, proliferation, matrix mineralization, and expression of alkaline phosphatase and RUNX2. In vitro and in vivo results showed that the membrane could bind tightly to bone, maintain long-term space stability, and significantly promote new bone formation. Moreover, the membrane could fix the bone filling material in the defect for a better healing effect. This work presents a straightforward and viable methodology for the fabrication of GBR membranes with Janus-based bioactive surfaces. This work may provide insights for the design of biomaterial surfaces and treatment of bone defects.

Asunto(s)

Regeneración Ósea , Osteogénesis , Poliésteres , Regeneración Ósea/efectos de los fármacos , Animales , Poliésteres/química , Poliésteres/farmacología , Osteogénesis/efectos de los fármacos , Durapatita/química , Durapatita/farmacología , Polietilenglicoles/química , Membranas Artificiales , Adhesión Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Proliferación Celular/efectos de los fármacos , Humanos , Regeneración Tisular Dirigida/métodos , Conejos , Ratones

RESUMEN

In recent years, with the advent of a super-aged society, lifelong dental care has gained increasing emphasis, and implant therapy for patients with an edentulous jaw has become a significant option. However, for implant therapy to be suitable for elderly patients with reduced regenerative and immunological capabilities, higher osteoconductive and antimicrobial properties are required on the implant surfaces. Silicon nitride, a non-oxide ceramic known for its excellent mechanical properties and biocompatibility, has demonstrated high potential for inducing hard tissue differentiation and exhibiting antibacterial properties. In this study, silicon nitride was deposited on pure titanium metal surfaces and evaluated for its biocompatibility and antibacterial properties. The findings indicate that silicon nitride improves the hydrophilicity of the material surface, enhancing the initial adhesion of rat bone marrow cells and promoting hard tissue differentiation. Additionally, the antibacterial properties were assessed using Staphylococcus aureus, revealing that the silicon nitride-coated surfaces exhibited significant antibacterial activity. Importantly, no cytotoxicity was observed, suggesting that silicon nitride-coated titanium could serve as a novel implant material.

Asunto(s)

Antibacterianos , Materiales Biocompatibles Revestidos , Compuestos de Silicona , Staphylococcus aureus , Propiedades de Superficie , Titanio , Titanio/química , Titanio/farmacología , Animales , Antibacterianos/farmacología , Antibacterianos/química , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Ratas , Staphylococcus aureus/efectos de los fármacos , Compuestos de Silicona/química , Compuestos de Silicona/farmacología , Ensayo de Materiales , Adhesión Celular/efectos de los fármacos , Células de la Médula Ósea/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos

RESUMEN

Strengthening tumor cellular adhesion through regulating the concentration of extracellular Ca2+ is highly challenging and promising for antimetastasis. Herein, a pH-responsive conjugated polymer-calcium composite nanoparticle (PFV/CaCO3/PDA@PEG) is developed for calcium-mediated cell adhesion enhancement-based antimetastasis and reactive oxygen species (ROS)-triggered calcium overload and photodynamic therapy (PDT) synergistic tumor treatment. PFV/CaCO3/PDA@PEG is mainly equipped with conjugated poly(fluorene-co-vinylene) (PFV-COOH)-composited CaCO3 nanoparticles, which can be rapidly decomposed under the tumor acidic microenvironment, effectively releasing Ca2+ and the photosensitizer PFV-COOH. The high extracellular Ca2+ concentration facilitates the generation of dimers between two adjacent cadherin ectodomains, which greatly enhances cell-cell adhesion and suppresses tumor metastasis. The inhibition rates are 97 and 87% for highly metastatic tumor cells 4T1 and MCF-7, respectively. Such a well-designed nanoparticle also contributes to realizing PDT, mitochondrial dysfunction, and ROS-triggered Ca2+ overload synergistic therapy. Furthermore, PFV/CaCO3/PDA@PEG displayed superior in vivo inhibition of 4T1 tumor growth and demonstrated a marked antimetastatic effect by both intravenous and intratumoral injection modes. Thus, this study provides a powerful strategy for calcium-mediated metastasis inhibition for tumor therapy.

Asunto(s)

Antineoplásicos , Calcio , Adhesión Celular , Nanopartículas , Fotoquimioterapia , Especies Reactivas de Oxígeno , Nanopartículas/química , Humanos , Animales , Calcio/metabolismo , Adhesión Celular/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Polímeros/química , Polímeros/farmacología , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/química , Femenino , Ratones Endogámicos BALB C , Células MCF-7 , Carbonato de Calcio/química , Carbonato de Calcio/farmacología , Proliferación Celular/efectos de los fármacos , Metástasis de la Neoplasia , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

PURPOSE: Uterine serous carcinoma (USC) is a highly aggressive and frequently recurring subtype of endometrial cancer with limited treatment options for advanced or recurrent stages. Sulindac, a classic non-steroidal anti-inflammatory drug, has demonstrated anti-tumor activity in several pre-clinical tumor models. This study aims to evaluate the effect of sulindac on cell proliferation and invasion in USC cells. METHODS: Human USC cell lines ARK-1 and SPEC2 were treated with different concentrations of sulindac. Cell proliferation was assessed using MTT and colony formation assays. ELISA assays measured cellular stress, cleaved caspase 3 activity, antioxidant ability, and adhesion. Cell cycle arrest was evaluated by Cellometer. The invasive capability was detected by wound healing assay. Western blotting was used to analyze the changes in protein expression induced by sulindac. RESULTS: Exposure to sulindac decreased cellular viability in a dose-dependent manner in ARK-1 and SPEC2 cells. Sulindac effectively inhibited cell cycle progression, increased cellular stress, caused apoptosis, and reduced cell adhesion and invasion in USC cells. Additionally, sulindac decreased the expression of COX-2 and blocked phosphorylation of NF-κB induced by TNF-α. CONCLUSION: Sulindac is a potential therapeutic agent for USC that deserves further exploration in pre-clinical studies and potentially future clinical trials.

Asunto(s)

Apoptosis , Proliferación Celular , Cistadenocarcinoma Seroso , Sulindac , Neoplasias Uterinas , Humanos , Femenino , Sulindac/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias Uterinas/tratamiento farmacológico , Neoplasias Uterinas/patología , Línea Celular Tumoral , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/metabolismo , Apoptosis/efectos de los fármacos , Invasividad Neoplásica , Adhesión Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos

RESUMEN

Teff (Eragrostis tef), a gluten-free cereal crop cultivated originally in Northeast Africa, is increasingly utilized due to its nutritional and health benefits. The aim of the present study was to investigate the effects of ethanol extract obtained from raw and thermally treated teff, referred to as RTE and TTE, respectively, on uncontrolled growth and activated metastasis using human cancer cell lines. Both RTE and TTE contained flavones, such as orientin (luteolin 8-C-glucoside) and vitexin (apigenin 8-C-glucoside), and phenolic acids, such as protocatechuic acid and p-coumaric acid. TTE showed higher total phenol, protocatechuic acid, and p-coumaric acid contents, but lower orientin content compared to RTE. RTE and TTE significantly suppressed cell growth of H1299 human lung cancer cells, with TTE exhibiting more pronounced effects than RTE, while both extracts had only minimal effects on the growth of non-malignant human umbilical vein endothelial cells. The growth-inhibitory activities of RTE and TTE in H1299 cells were associated with apoptosis induction and cell cycle arrest at the G2/M phase. TTE produced an additional effect on inducing cell cycle arrest at the S phase in H1299 cells, potentially contributing to its stronger growth-inhibitory effects. Moreover, both RTE and TTE effectively inhibited key events in metastasis, such as invasion, migration, and adhesion, in H1299 cells under non-cytotoxic conditions, with TTE showing stronger effects. In HCT116 human colon cancer cells, a similar pattern of inhibition was demonstrated against the metastatic events, accompanied by reduced levels of matrix metalloproteinase-2 and -9. Our results indicate that teff extracts exhibit in vitro anti-growth and anti-metastatic activities, which are enhanced by thermal treatment of teff.

Asunto(s)

Apoptosis , Movimiento Celular , Proliferación Celular , Extractos Vegetales , Humanos , Extractos Vegetales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Metástasis de la Neoplasia/prevención & control , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hidroxibenzoatos/farmacología , Adhesión Celular/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Calor , Metaloproteinasa 2 de la Matriz/metabolismo

RESUMEN

Background: Dental pulp stem cells (DPSCs) possess mesenchymal stem cell characteristics and have potential for cell-based therapy. Cell expansion is essential to achieve sufficient cell numbers. However, continuous cell replication causes cell aging in vitro, which usually accompanies and potentially affect DPSC characteristics and activities. Continuous passaging could alter susceptibility to external factors such as drug treatment. Therefore, this study sought to investigate potential outcome of in vitro passaging on DPSC morphology and activities in the absence or presence of external factor. Methods: Human DPSCs were subcultured until reaching early passages (P5), extended passages (P10), and late passages (P15). Cells were evaluated and compared for cell and nuclear morphologies, cell adhesion, proliferative capacity, alkaline phosphatase (ALP) activity, and gene expressions in the absence or presence of external factor. Alendronate (ALN) drug treatment was used as an external factor. Results: Continuous passaging of DPSCs gradually lost their normal spindle shape and increased in cell and nuclear sizes. DPSCs were vulnerable to ALN. The size and shape were altered, leading to morphological abnormality and inhomogeneity. Long-term culture and ALN interfered with cell adhesion. DPSCs were able to proliferate irrespective of cell passages but the rate of cell proliferation in late passages was slower. ALN at moderate dose inhibited cell growth. ALN caused reduction of ALP activity in early passage. In contrast, extended passage responded differently to ALN by increasing ALP activity. Late passage showed higher collagen but lower osteocalcin gene expressions compared with early passage in the presence of ALN. Conclusion: An increase in passage number played critical role in cell morphology and activities as well as responses to the addition of an external factor. The effects of cell passage should be considered when used in basic science research and clinical applications.

Asunto(s)

Alendronato , Adhesión Celular , Proliferación Celular , Pulpa Dental , Humanos , Pulpa Dental/citología , Pulpa Dental/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Alendronato/farmacología , Adhesión Celular/efectos de los fármacos , Fosfatasa Alcalina/metabolismo , Células Cultivadas , Células Madre Mesenquimatosas/efectos de los fármacos , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Técnicas de Cultivo de Célula/métodos , Células Madre/efectos de los fármacos , Células Madre/metabolismo , Células Madre/citología , Diferenciación Celular/efectos de los fármacos

RESUMEN

Doxorubicin, the most prescribed chemotherapeutic drug, causes dose-dependent cardiotoxicity and heart failure. However, our understanding of the immune response elicited by doxorubicin is limited. Here we show that an aberrant CD8+ T cell immune response following doxorubicin-induced cardiac injury drives adverse remodeling and cardiomyopathy. Doxorubicin treatment in non-tumor-bearing mice increased circulating and cardiac IFNγ+CD8+ T cells and activated effector CD8+ T cells in lymphoid tissues. Moreover, doxorubicin promoted cardiac CD8+ T cell infiltration and depletion of CD8+ T cells in doxorubicin-treated mice decreased cardiac fibrosis and improved systolic function. Doxorubicin treatment induced ICAM-1 expression by cardiac fibroblasts resulting in enhanced CD8+ T cell adhesion and transformation, contact-dependent CD8+ degranulation and release of granzyme B. Canine lymphoma patients and human patients with hematopoietic malignancies showed increased circulating CD8+ T cells after doxorubicin treatment. In human cancer patients, T cells expressed IFNγ and CXCR3, and plasma levels of the CXCR3 ligands CXCL9 and CXCL10 correlated with decreased systolic function.

Asunto(s)

Modelos Animales de Enfermedad , Doxorrubicina , Fibrosis , Interferón gamma , Linfocitos T Citotóxicos , Animales , Doxorrubicina/efectos adversos , Fibrosis/inducido químicamente , Humanos , Perros , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Interferón gamma/metabolismo , Antibióticos Antineoplásicos/efectos adversos , Antibióticos Antineoplásicos/toxicidad , Ratones Endogámicos C57BL , Cardiotoxicidad/etiología , Receptores CXCR3/metabolismo , Quimiocina CXCL10/metabolismo , Masculino , Granzimas/metabolismo , Cardiomiopatías/inducido químicamente , Cardiomiopatías/patología , Cardiomiopatías/inmunología , Miocardio/patología , Miocardio/metabolismo , Miocardio/inmunología , Degranulación de la Célula/efectos de los fármacos , Quimiocina CXCL9/metabolismo , Función Ventricular Izquierda/efectos de los fármacos , Sístole/efectos de los fármacos , Ratones , Femenino , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Adhesión Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos

RESUMEN

Skeletal muscle tissue can be severely damaged by disease or trauma beyond its ability to self-repair, necessitating the further development of biofabrication and tissue-engineering tools for reconstructive processes. Hence, in this study, a composite bioink of oxidized alginate (ADA) and gelatin (GEL) including cell-laden ribbon-shaped fillers is used for enhancing cell alignment and the formation of an anisotropic structure. Different plasma treatments combined with protein coatings were evaluated for the improvement of cell adhesion to poly(lactic-co-glycolic acid) (PLGA) ribbon surfaces. Oxygen plasma activation of 30 W for 5 min showed high immobilization of fibronectin as a protein coating on the PLGA ribbon surface, which resulted in enhanced cell adhesion and differentiation of muscle cells. Furthermore, the effect of various concentrations of CaCl2 solution, used for ionic cross-linking of ADA, on ADA-GEL physical and mechanical properties as well as encapsulated C2C12 cell viability and proliferation behavior was investigated. The pore area was measured via two approaches, cryofixation and lyophilization, which, in accordance with degradation tests and mechanical analysis, showed that 60 mM CaCl2 concentration is the optimum range for cross-linking of the formulation of ADA 2.5%w/v-GEL 3.75%w/v. These cross-linked hydrogels showed a compression modulus of 11.5 kPa (similar to the native skeletal muscle tissue), a high viability of C2C12 muscle cells (>80%), and a high proliferation rate during 7 days of culture. Rheological characterization of the ADA-GEL composite hydrogel containing short fillers (100 µm long) showed its suitability as a bioink with shear-thinning and flow behavior compared to ADA-GEL.

Asunto(s)

Alginatos , Gelatina , Hidrogeles , Músculo Esquelético , Ingeniería de Tejidos , Gelatina/química , Alginatos/química , Animales , Ratones , Hidrogeles/química , Hidrogeles/farmacología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/citología , Línea Celular , Andamios del Tejido/química , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/farmacología , Diferenciación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología

RESUMEN

The development of bioadhesives with strong adhesion and on-demand adhesion-detachment behavior is still critically important and challenging for facilitating painless and damage-free removal in clinical applications. In this work, for the first time, we report the easy fabrication of novel polyurethane-urea (PUU)-based bioadhesives with thermoresponsive on-demand adhesion and detachment behavior. The PUU copolymer was synthesized by a simple copolymerization of low-molecular-weight, hydrophilic, and biocompatible poly(ethylene glycol), glyceryl monolaurate (GML, a special chain extender with a long side hydrophobic alkyl group), and isophorone diisocyanate (IPDI). Here, GML was expected to not only adjust the temperature-dependent adhesion behavior but also act as an internal plasticizer. By simple adjustment of the water content, the adhesion strength of the 15 wt % water-containing PUU film toward porcine skin is as high as 55 kPa with an adhesion energy of 128 J/m2 at 37 °C. The adhesion strength dramatically decreases to only 3 kPa at 10 °C, exhibiting switching efficiency as high as 0.95. Furthermore, the present PUU-based adhesive also shows good on-demand underwater adhesion and detachment with a cell viability close to 100%. We propose that biomaterial research fields, especially novel PUU/polyurethane (PU)-based functional materials and bioadhesives, could benefit from such a novel thermoresponsive copolymer with outstanding mechanical and functional performances and an easy synthesis and scaled-up process as described in this article.

Asunto(s)

Poliuretanos , Poliuretanos/química , Poliuretanos/farmacología , Animales , Porcinos , Humanos , Temperatura , Urea/química , Urea/farmacología , Urea/análogos & derivados , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/síntesis química , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Adhesivos Tisulares/síntesis química , Adhesión Celular/efectos de los fármacos , Ratones , Adhesivos/química , Adhesivos/farmacología

RESUMEN

OBJECTIVES: To synthesize casein enzymatic hydrolysate (CEH)-laden gelatin methacryloyl (GelMA) fibrous scaffolds and evaluate the cytocompatibility and anti-inflammatory effects on dental pulp stem cells (DPSCs). MATERIALS AND METHODS: GelMA fibrous scaffolds with 10%, 20%, and 30% CEH (w/w) and without CEH (control) were obtained via electrospinning. Chemo-morphological, degradation, and mechanical analyses were conducted to evaluate the morphology and composition of the fibers, mass loss, and mechanical properties, respectively. Adhesion/spreading and viability of DPSCs seeded on the scaffolds were also assessed. The anti-inflammatory potential on DPSCs was tested after the chronic challenge of cells with lipopolysaccharides (LPS), followed by treatment with extracts obtained after immersing the scaffolds in α-MEM. The synthesis of the pro-inflammatory cytokines IL-6, IL-1α, and TNF-α was measured by ELISA. Data were analyzed by ANOVA/post-hoc tests (α = 5%). RESULTS: CEH-laden electrospun fibers had a larger diameter than pure GelMA (p ≤ 0.036). GelMA scaffolds laden with 20% and 30% CEH had a greater mass loss. Tensile strength was reduced for the 10% CEH fibers (p = 0.0052), whereas no difference was observed for the 20% and 30% fibers (p ≥ 0.6736) compared to the control. Young's modulus decreased with CEH (p < 0.0001). Elongation at break increased for the 20% and 30% CEH scaffolds (p ≤ 0.0038). Over time, DPSCs viability increased across all groups, indicating cytocompatibility, with CEH-laden scaffolds exhibiting greater cell viability after seven days (p ≤ 0.0166). Also, 10% CEH-GelMA scaffolds decreased the IL-6, IL-1α, and TNF-α synthesis (p ≤ 0.035). CONCLUSION: CEH-laden GelMA scaffolds facilitated both adhesion and proliferation of DPSCs, and 10% CEH provided anti-inflammatory potential after chronic LPS challenge. CLINICAL RELEVANCE: CEH incorporated in GelMA fibrous scaffolds demonstrated the potential to be used as a cytocompatible and anti-inflammatory biomaterial for vital pulp therapy.

Asunto(s)

Antiinflamatorios , Caseínas , Supervivencia Celular , Pulpa Dental , Gelatina , Andamios del Tejido , Gelatina/química , Pulpa Dental/citología , Pulpa Dental/efectos de los fármacos , Andamios del Tejido/química , Humanos , Antiinflamatorios/farmacología , Supervivencia Celular/efectos de los fármacos , Metacrilatos/química , Ensayo de Materiales , Ensayo de Inmunoadsorción Enzimática , Resistencia a la Tracción , Células Cultivadas , Células Madre/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Materiales Biocompatibles/farmacología , Materiales Biocompatibles/química , Citocinas/metabolismo , Propiedades de Superficie

RESUMEN

As a prominent complication of diabetes mellitus (DM) affecting microvasculature, diabetic retinopathy (DR) originates from blood-retinal barrier (BRB) damage. Natural polyphenolic compound chlorogenic acid (CGA) has already been reported to alleviate DR. This study delves into the concrete mechanism of the CGA-supplied protection against DR and elucidates its key target in retinal endothelial cells. DM in mice was induced using streptozotocin (STZ). CGA mitigated BRB dysfunction, leukocytes adhesion and the formation of acellular vessels in vivo. CGA suppressed retinal inflammation and the release of tumor necrosis factor-α (TNFα) by inhibiting nuclear factor kappa-B (NFκB). Furthermore, CGA reduced the TNFα-initiated adhesion of peripheral blood mononuclear cell (PBMC) to human retinal endothelial cell (HREC). CGA obviously decreased the TNFα-upregulated expression of vascular cell adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1), and abrogated the TNFα-induced NFκB activation in HRECs. All these phenomena were reversed by overexpressing type 1 TNF receptor (TNFR1) in HRECs. The CGA-provided improvement on leukocytes adhesion and retinal inflammation was disappeared in mice injected with an endothelial-specific TNFR1 overexpression adeno-associated virus (AAV). CGA reduced the interaction between TNFα and TNFR1 through binding to TNFR1 in retinal endothelial cells. In summary, excepting reducing TNFα expression via inhibiting retinal inflammation, CGA also reduced the adhesion of leukocytes to retinal vessels through decreasing VCAM1 and ICAM1 expression via blocking the TNFα-initiated NFκB activation by targeting TNFR1 in retinal endothelial cells. All of those mitigated retinal inflammation, ultimately alleviating BRB breakdown in DR.

Asunto(s)

Ácido Clorogénico , Retinopatía Diabética , Células Endoteliales , Ratones Endogámicos C57BL , FN-kappa B , Receptores Tipo I de Factores de Necrosis Tumoral , Retina , Factor de Necrosis Tumoral alfa , Animales , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Retinopatía Diabética/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Ácido Clorogénico/farmacología , Ácido Clorogénico/uso terapéutico , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Masculino , FN-kappa B/metabolismo , Ratones , Retina/efectos de los fármacos , Retina/patología , Retina/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Adhesión Celular/efectos de los fármacos , Barrera Hematorretinal/efectos de los fármacos , Barrera Hematorretinal/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Células Cultivadas , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo

RESUMEN

Controlling biomolecular-cell interactions is crucial for the design of scaffolds for tissue engineering (TE). Regenerated silk fibroin (RSF) has been extensively used as TE scaffolds, however, RSF showed poor attachment of neuronal cells, such as rat pheochromocytoma (PC12) cells. In this work, amphiphilic peptides containing a hydrophobic isoleucine tail (I3) and laminin or fibronectin derived peptides (IKVAV, PDSGR, YIGSR, RGDS and PHSRN) were designed for promoting scaffold-cell interaction. Three of them (I3KVAV, I3RGDS and I3YIGSR) can self-assemble into nanofibers, therefore, were used to enhance the application of RSF in neuron TE. Live / dead assays revealed that the peptides exhibited negligible cytotoxicity against PC12 cells. The specific interaction between PC12 cells and the peptides were investigate using atomic force microscopy (AFM). The results indicated a synergistic effect in the designed peptides, promoting cellular attachment, proliferation and morphology changes. In addition, AFM results showed that co-assembling peptides I3KVAV and I3YIGSR possesses the best regulation of proliferation and attachment of PC12 cells, consistent with immunofluorescence staining results. Moreover, cell culture with hydrogels revealed that a mixture of peptides I3KVAV and I3YIGSR can also promote 3D neurites outgrowth. The approach of combining two different self-assembling peptides shows great potential for nerve regeneration applications.

Asunto(s)

Nanofibras , Proyección Neuronal , Péptidos , Seda , Andamios del Tejido , Animales , Células PC12 , Ratas , Nanofibras/química , Andamios del Tejido/química , Proyección Neuronal/efectos de los fármacos , Péptidos/química , Péptidos/farmacología , Seda/química , Proliferación Celular/efectos de los fármacos , Fibroínas/química , Fibroínas/farmacología , Ingeniería de Tejidos/métodos , Adhesión Celular/efectos de los fármacos

RESUMEN

Scaffolds with multiphasic structures are considered to be superior for guided tissue regeneration. Two types of tilapia skin collagen gradient membranes (stepped gradient and linear gradient) with multiphasic structures were prepared by controlling the collagen concentrations and the freezing rates. The results revealed that collagen gradient membranes were more capable of guiding tissue regeneration compared to homogeneous membranes. These two gradient membranes featured a dense outer layer and a loose inner layer, with good mechanical properties as indicated by tensile strengths of more than 250 Kpa and porosities exceeding 85 %. Additionally, these membranes also showed good hydrophilicity and water absorption, with an inner layer contact angle of less than 91° and a water absorption ratio greater than 40 times. Furthermore, the multiphasic scaffolds were proved to be biocompatible by the acute toxicity assay, the intradermal irritation test and so on. Gradient membranes could effectively promote the adhesion and proliferation of fibroblasts and osteoblasts, through elevating the TGF-ß/Smad signaling pathway by TGF-ß and Smads, and activating the Wnt/ß-catenin signaling pathway by LRP5 and ß-catenin, similar to homogenous membranes. Therefore, collagen gradient membranes from tilapia skin show important application value in guiding tissue regeneration.

Asunto(s)

Materiales Biocompatibles , Colágeno , Animales , Colágeno/química , Colágeno/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Andamios del Tejido/química , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/citología , Proliferación Celular/efectos de los fármacos , Membranas Artificiales , Tilapia/metabolismo , Osteoblastos/efectos de los fármacos , Osteoblastos/citología , Osteoblastos/metabolismo , Ratones , Ensayo de Materiales , Piel/metabolismo , Adhesión Celular/efectos de los fármacos , Resistencia a la Tracción

RESUMEN

Artificial periosteum is deemed a novel strategy for inducing endogenous bone regeneration, but ideal periosteum substitutes achieved by orchestrating a biomimetic microenvironment for bone regeneration remain a significant challenge. Here, we design and fabricate a hybridized nanofiber-based artificial periosteum with boosted osteoinduction properties. Via a "molecular cage" biomineralization strategy, nano-hydroxyapatite (nano-HAp) with a controllable size (∼22 nm) and excellent dispersion serves as unique nano-additives for water-soluble polyvinyl-alcohol (PVA)-based artificial periosteum. The PVA/HAp composite is electrospun into nanofibers to replicate the extracellular-matrix-inspired nanostructure for inducing cell adhesion, proliferation, and fate manipulation. A simple post-crosslinking treatment is subsequently applied to further booster its mechanical strength (6.6 MPa) and swelling stability. The optimized sample of C-PVA/HAp (10 wt% nano-HAp) artificial periosteum features excellent biocompatibility and remarkable in vitro mineralization. Cell experiments demonstrate that its effectively boasted cell modulation for enhanced osteogenesis without the aid of growth factors, showing a possible activation of the ERK/MAPK signaling pathway. This work provides an effective strategy for designing novel HAp nano-additives and expands the possibility of biomimetic fabrication for more advanced nanofiber-based artificial periosteum.

Asunto(s)

Durapatita , Nanofibras , Osteogénesis , Periostio , Alcohol Polivinílico , Nanofibras/química , Alcohol Polivinílico/química , Durapatita/química , Durapatita/farmacología , Osteogénesis/efectos de los fármacos , Humanos , Ingeniería de Tejidos/métodos , Andamios del Tejido/química , Regeneración Ósea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Animales , Materiales Biocompatibles/química , Adhesión Celular/efectos de los fármacos , Sustitutos de Huesos/química

RESUMEN

The cell (plasma) membrane is enriched with numerous receptors, ligands, enzymes, and phospholipids that play important roles in cell-cell and cell-extracellular matrix interactions governing, for instance, tissue development and repair. We previously showed that plasma membrane nanofragments (PMNFs) act as nucleation sites for bone formation in vivo, and induce in vitro mineralization within 1 day. In this study, we optimized the methods for generating, isolating, and applying PMNFs as a cell-free therapeutic to expedite bone defect repair. The PMNFs were isolated from different mouse cell lines (chondrocytes, osteoblasts, and fibroblasts), pre-conditioned, lyophilized, and subsequently transplanted into 2 mm critical-sized calvarial defects in mice (n = 75). The PMNFs from chondrocytes, following a 3-day pre-incubation, significantly accelerated bone repair within 2 weeks, through a coordinated attraction of macrophages, endothelial cells, and osteoblasts to the healing site. In vitro experiments confirmed that PMNFs enhanced cell adhesion. Comparison of the PMNF efficacy with phosphatidylserine, amorphous calcium phosphate (ACP), and living cells confirmed the unique ability of PMNFs to promote accelerated bone repair. Importantly, PMNFs promoted nearly complete integration of the regenerated bone with native tissue after 6 weeks (% non-integrated bone area = 15.02), contrasting with the partial integration (% non-integrated bone area = 56.10; p < 0.01, Student's test) with transplantation of ACP. Vickers microhardness tests demonstrated that the regenerated bone after 6 weeks (30.10 ± 1.75) exhibited hardness similar to native bone (31.07 ± 2.46). In conclusion, this is the first study to demonstrate that cell membrane can be a promising cell-free material with multifaceted biofunctional properties that promote accelerated bone repair. STATEMENT OF SIGNIFICANCE.

Asunto(s)

Regeneración Ósea , Membrana Celular , Animales , Ratones , Regeneración Ósea/efectos de los fármacos , Membrana Celular/metabolismo , Osteoblastos/metabolismo , Osteoblastos/citología , Cráneo/patología , Cráneo/lesiones , Condrocitos/metabolismo , Condrocitos/citología , Línea Celular , Osteogénesis/efectos de los fármacos , Adhesión Celular/efectos de los fármacos

RESUMEN

Bioresorbable shape memory polymers (SMP) are an emerging class of polymers that can help address several challenges associated with minimally invasive surgery by providing a solution for structural tissue repair. Like most synthetic polymer networks, SMPs require additional biorelevance and modification for biomedical applications. Methodologies used to incorporate bioactive ligands must preserve SMP thermomechanics and ensure biofunctionality following in vivo delivery. We have previously described the development of a novel thermoresponsive bioresorbable SMP, poly (glycerol dodecanedioate) (PGD). In this study, cell-adhesive peptide sequences RGD and YIGSR were conjugated with PGD. We investigated 1) the impact of conjugated peptides on the fixity (Rf), recovery (Rr), and recovery rate (dRr/dT), 2) the impact of conjugated peptides on cell binding, and 3) the impact of the shape memory cycle (Tprog) on conjugated peptide functionality towards binding human bone marrow stromal cells (BMSC). Peptide conjugation conditions impact fixity but not the recovery or recovery rate (p < 0.01). Peptide-conjugated substrates increased cell attachment and proliferation compared with controls (p < 0.001). Using complementary integrin binding cell-adhesive peptides increased proliferation compared with using single peptides (p < 0.05). Peptides bound to PGD substrates exhibited specificity to their respective integrin targets. Following the shape memory cycle, peptides maintained functionality and specificity depending on the shape memory cycle conditions (p < 0.001). The dissipation of strain energy during recovery can drive differential arrangement of conjugated sequences impacting functionality, an important design consideration for functionalized SMPs. STATEMENT OF SIGNIFICANCE: Shape memory elastomers are an emerging class of polymers that are well-suited for minimally invasive repair of soft tissues. Tissue engineering approaches commonly utilize biodegradable scaffolds to deliver instructive cues, including cells and bioactive signals. Delivering these instructive cues on biodegradable shape memory elastomers requires modification with bioactive ligands. Furthermore, it is necessary to ensure the specificity of the ligands to their biological targets when conjugated to the polymer. Moreover, the bioactive ligand functionality must be conserved after completing the shape memory cycle, for applications in tissue engineering.

Asunto(s)

Adhesión Celular , Células Madre Mesenquimatosas , Oligopéptidos , Humanos , Oligopéptidos/química , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Adhesión Celular/efectos de los fármacos , Polímeros/química , Materiales Inteligentes/química , Glicerol/química , Glicerol/análogos & derivados