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PDF file - 427K, Effects of the combination cetuximab plus fingolimod on tumor growth of mice xenografted with GEO-CR resistant tumors

PDF file - 5320K, Validation of antibodies for analysis of SphK1 expression on FFPE colorectal cancer tissues

PDF file - 503K, Effects of SphK1 modulation on cetuximab sensitivity in resistant colorectal cancer cell lines

PDF file - 1047K, Effects of the combination cetuximab plus fingolimod on apoptosis of GEO-CR tumor xenografts

PDF file - 2068K, Correlation of SphK1 expression with clinical data in colorectal cancer patients

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PDF file - 483K, Effects of SphK1 inhibition by DMS on cetuximab sensitivity in resistant colorectal cancer cell lines

PDF file - 357K, Sensitivity to cetuximab of a panel of human colorectal cancer cell lines

Purpose: Although the anti–EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the “sphingolipid rheostat”—the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)—due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described.Experimental design: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients.Results: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients. Clin Cancer Res; 19(1); 138–47. ©2012 AACR.

PDF file - 908K, Multivariate analysis correlating the response to cetuximab-based regimens to different factors

Three-dimensional bioprinting is a powerful technique for manufacturing improved engineered tissues. Three-dimensional bioprinted hydrogels have significantly advanced the medical field to repair cartilage tissue, allowing for such constructs to be loaded with different components, such as cells, nanoparticles, and/or drugs. Cartilage, as an avascular tissue, presents extreme difficulty in self-repair when it has been damaged. In this way, hydrogels with optimal chemical and physical properties have been researched to respond to external stimuli and release various bioactive agents to further promote a desired tissue response. For instance, methacryloyl gelatin (GelMA) is a type of modified hydrogel that allows for the encapsulation of cells, as well as oxygen-releasing nanoparticles that, in the presence of an aqueous medium and through controlled porosity and swelling, allow for internal and external environmental exchanges. This review explores the 3D bioprinting of hydrogels, with a particular focus on GelMA hydrogels, to repair cartilage tissue. Recent advances and future perspectives are described.

Aim: Comparison of first-line FOLFIRINOX (FFN) and nab-paclitaxel plus gemcitabine (NabGem) in patients with metastatic pancreatic ductal adenocarcinoma. Patients & methods: The authors analyzed data from 160 patients with metastatic pancreatic adenocarcinoma receiving first-line FFN (n=43) or NabGem (n=117). Results: FFN and NabGem were similar in median progression-free survival (24.43 vs 26.28weeks; hazard ratio [HR]: 0.88) and medial overall survival (47.43 vs 42.86weeks; HR: 0.90). Of the 43 patients receiving FFN, 26 (60.4%) were treated with second-line NabGem; 14/117 (12.0%) patients receiving NabGem received second-line FFN (p&nbsp

This study aimed to analyze the fluoride concentrations in different dentifrices with antimicrobial and natural molecules marketed in Brazil. Thus, 12 dentifrices were selected to be analyzed for the concentration of total fluoride (TF), total soluble fluoride (TSF) and ionizable fluoride (IF). Two tubes of each brand were purchased at different locations. The samples were analyzed in duplicates using an ion-specific electrode and the concentrations were determined in μg F/g. The TF of all calcium carbonate dentifrices showed averages below 1500 ppm F. Regarding TSF, only one toothpaste had an average above 1000 ppm F−, while the IF values ​​were almost 500 ppm F. In the analysis of fluoride in dentifrices which present silica as abrasive, the TF presented averages below 1500 ppm F, while the TSF all presented averages close to 1000 ppm F−, and the IF values ​​varied from close to 500 ppm to more than 1000 ppm F. In dentifrices whose formulation contained calcium carbonate associated with silica or other formulations such as sodium bicarbonate, the TF, TSF, and IF values were all above 1000 ppm F. The evaluated dentifrices generally showed TF concentrations lower than those declared on the packaging; however, the TSF content remained close to 1000 ppm F. It can be concluded that the analyzed dentifrices with antimicrobial molecules showed values ​​close to those suggested regarding anti-caries effect.

Background: CDK4/6 inhibitors have been approved in combination with endocrine therapy for the treatment of estrogen receptor positive (ER+) metastatic breast cancer. The goal of this study was to discover mechanisms of resistance to ER antagonists alone and in combination with CDK4/6 inhibitors. Results: p21-activated kinase 1 (PAK1) is a serine/threonine kinase amplified in several human cancer types. Specifically, the survey of TCGA for copy number alterations and/or expression showed PAK1 amplification and/or overexpression in ~23% of ER+ breast cancer. To test the hypothesis that PAK1-amplification is related to CDK4/6 inhibitors resistance, we generated two ER+ breast cancer cell lines T47D (harbouring PAK1 amplification) and MCF7 (non PAK1-amplified) resistant to the combination of fulvestrant (ER downregulator) and abemaciclib (CDK4/6 inhibitor), namely T47DFAR and MCF7FAR. T47DFAR and MCF7FAR were obtained, exposing the parental cells to increasing doses of drugs. Interestingly, only the T47DFAR but not the MCF7FAR showed higher level of PAK1 expression and activation compared to the parental cell line. PAK1 pathway activation was evaluated measuring by immunoblot the levels of phosphorylation of PAK1, MEK, ERK and Beta-Catenin. Moreover, the genomic knockdown of PAK1 through RNAi causes a decrease in cell proliferation of T47DFAR, but not of MCF7FAR and parental cells, suggesting the role of PAK1 as a possible mediator of drug resistance. Conversely, overexpression of PAK1 in MCF7 and T47D parental cells was able to generate resistance to the drug combination. PAK-1 has shown to have a different role in the cytosol as pathways mediator and in the nucleus as transcriptional factor. Our data obtained by subcellular fractionation showed that after treatment with fulvestrant-abemaciclib, PAK1 protein accumulates into the cytosol in T47D-FAR compared to parental T47D, probably mediating an enhancement in cytoplasmatic cell signalling and pathway activation. To univocally demonstrate that PAK1 mediates tumor resistance to fulvestrant-abemaciclib combination, we are generating data from RNA-Seq and whole exome sequencing from T47DFAR and MCF7FAR and the relative parental cell lines. Also, we will assess the efficacy of PAK pharmacological inhibition in overcoming such resistance. Conclusions: In conclusion, our data suggest the role of PAK1 as a novel therapeutic target in ER+/PAK1-amplified breast cancer model resistant to endocrine therapy and CDK4/6 inhibitors. Citation Format: Stefania Belli, Alberto Servetto, Concetta Di Mauro, Daniela Esposito, Ada Pesapane, Fabiana Napolitano, Antonio Santaniello, Pietro De Placido, Priscilla Cascetta, Annachiara Carratù, Eleonora Mozzillo, Roberta Marciano, Roberto Bianco, Luigi Formisano. Pak1 as a novel mediator of resistance to endocrine therapy and CDK4/6 inhibitors in ER+/PAK-1amplified breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-08.

Background The facile preparation of oxygen-generating microparticles (M) consisting of Polycaprolactone (PCL), Pluronic F-127, and calcium peroxide (CPO) (PCL-F-CPO-M) fabricated through an electrospraying process is disclosed. The biological study confirmed the positive impact from the oxygen-generating microparticles on the cell growth with high viability. The presented technology could work as a prominent tool for various tissue engineering and biomedical applications. Methods The oxygen-generated microparticles fabricated through electrospraying processes were thoroughly characterization through various methods such as X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) analysis, and scanning electron microscopy (SEM)/SEM-Energy Dispersive Spectroscopy (EDS) analysis. Results The analyses confirmed the presence of the various components and the porous structure of the microparticles. Spherical shape with spongy characteristic microparticles were obtained with negative charge surface (ζ = -16.9) and a size of 17.00 ± 0.34 μm. Furthermore, the biological study performed on rat chondrocytes demonstrated good cell viability and the positive impact of increasing the amount of CPO in the PCL-F-CPO-M. Conclusion This technological platform could work as an important tool for tissue engineering due to the ability of the microparticles to release oxygen in a sustained manner for up to 7 days with high cell viability.

Molybdenum trioxide (MoO3) thin films are generally deposit on metallic surfaces to increase their tribological performance. In this manuscript, MoOx coatings were for the first time deposited on plasma nitrided surfaces. Vickers microhardness tests, X-ray diffractometry, and micro abrasive wear tests characterized the samples. It was investigated the effect of temperature in hardness and tribological properties of austenitic stainless steel surfaces. When the temperature of plasma nitriding increases, the coating thickness and the nitrogen diffusion on the treated surface also increases, favoring the hardness of the coatings. After MoOx deposition, the predominant MoO3 phase with monoclinic and orthorhombic unit cells was observed. MoOx coatings after plasma nitriding demonstrated the highest wear resistance.

Background Nanophase surface properties of titanium alloys must be obtained for a suitable biological performance, particularly to facilitate cell adhesion and bone tissue formation. Obtaining a bulk nanostructured material using severe plastic deformation is an ideal processing route to improve the mechanical performance of titanium alloys. By decreasing the grain size of a metallic material, a superior strength improvement can be obtained, while surface modification of a nanostructured surface can produce an attractive topography able to induce biological responses in osteoblastic cells. Methods Aiming to achieve such an excellent synergetic performance, a processing route, which included equal channel angular pressing (ECAP), hot and cold extrusion, and heat treatments, was used to produce a nanometric and ultrafine-grained (UFG) microstructure in the Ti-6Al-7Nb alloy (around of 200 nm). Additionally, UFG samples were surface-modified with acid etching (UFG-A) to produce a uniform micron and submicron porosity on the surface. Subsequently, alkaline treatment (UFG-AA) produced a sponge-like nanotopographic substrate able to modulate cellular interactions. Results After several kinds of biological tests for both treatment conditions (UFG-A and UFG-AA), the main results have shown that there was no cytotoxicity, expressed alkaline phosphatase activity and total protein amounts without statistical differences compared to control. However, the UFG-AA samples presented an attractive effect on the cell membranes, and cell adhesions were preferentially induced as compared with UFG-A. Both conditions demonstrated cell projections, but for UFG-AA, cells were more widely dispersed, and more quantities of filopodia formation could be observed. Conclusion Herein, the reasons for such behaviors are discussed, and further results are presented in addition to those mentioned above.

Currently, oxygen supply for in vitro cell culture is one of the major challenges in tissue engineering, especially in three-dimensional (3D) structures, such as polymeric hydrogels, because oxygen is an essential element for cells survival. In this context, oxygen levels must be maintained in articular cartilage to promote the differentiation, viability, and proliferation of chondrocytes due to the low level of oxygen presence in this region. Although some technologies employ oxygen-generating materials to add sufficient oxygen levels, the limitations and challenges of current technologies include the lack of controlled, sustained, and prolonged release of the oxygen. Moreover, the fabrication methods may leave some impurities or residues resulting in toxicity to the cells. “Click” chemistry is a facile, versatile, and compatible chemical strategy to engineer hydrogels for tissue engineering applications. Herein, we disclose the engineering of oxygen-generating microparticles in chondrocytes-laden hydrogels through a versatile catalyst-free tetrazine and norbornene inverse electron demand Diels‒Alder (iEDDA) click reaction. The hydrogels combine chondroitin sulfate (CS) and poly(ethylene glycol) (PEG) crosslinked in situ, displaying tunable rheological and mechanical properties, for sustained and prolonged oxygen-release. Gene expression analysis of the chondrocytes by real-time reverse transcription polymerase chain reaction (RT-PCR) demonstrated promising cell response within the engineered hydrogel.

Background It has been difficult to find bioactive compounds that can optimize bone repair therapy and adequate osseointegration for people with osteoporosis. The nano-hydroxyapatite (nHAp)/carbon nanotubes with graphene oxides, termed graphene nanoribbons (GNR) composites have emerged as promising materials/scaffolds for bone regeneration due to their bioactivity and osseointegration properties. Herein, we evaluated the action of nHAp/GNR composites (nHAp/GNR) to promote bone regeneration using an osteoporotic model. Materials and methods First, three different nHAp/GNR (1, 2, and 3 wt% of GNR) were produced and characterized. For in vivo analyses, 36 Wistar rats (var. albinus, weighing 250-300 g, Comissao de Etica no Uso de Animais [CEUA] n.002/17) were used. Prior to implantation, osteoporosis was induced by oophorectomy in female rats. After 45 days, a tibial fracture was inflicted using a 3.0-mm Quest trephine drill. Then, the animals were separated into six sample groups at two different time periods of 21 and 45 days. The lesions were filled with 3 mg of one of the above samples using a curette. After 21 or 45 days of implantation, the animals were euthanized for analysis. Histological, biochemical, and radiographic analyses (DIGORA method) were performed. The data were evaluated through ANOVA, Tukey test, and Kolmogorov-Smirnov test with statistical significance at P Results Both nHAp and GNR exhibited osteoconductive activity. However, the nHAp/GNR exhibited regenerative activity proportional to their concentration, following the order of 3% >2% >1% wt. Conclusion Therefore, it can be inferred that all analyzed nanoparticles promoted bone regeneration in osteoporotic rats independent of analyzed time.

A method for the direct electrodeposition of globular nano-hydroxyapatite (nHAp) onto reduced graphene oxide (RGO) is presented and a model for the specific growth preference is discussed. Results show that the carboxyl (carboxylic acid)/carboxylate functional groups attached directly to the RGO after oxygen plasma treatment were essential to accelerate the OH– formation and the deposition of globular nHAp crystals. High resolution scanning electron microscopy, energy dispersive X-ray and X-ray diffraction showed that homogeneous, highly crystalline, stoichiometric nHAp crystals, with preferential growth in the (002) plane direction, were formed without any thermal treatment. The nHAp/RGO composites were shown to be an appropriate surface for mesenchymal stem cell adhesion with active formation of membrane projections.

We present a simple, low cost, and fast method to produce free-standing nanohydroxyapatite/carbon-based scaffolds. We electrodeposited nanohydroxyapatite onto vertically aligned carbon nanotube flakes and reticulated vitreous carbon bars. We prepared a highly crystalline and homogeneous thin film without any post-thermal treatment, and our results evidence that we can control the nanohydroxyapatite crystal formation according to the substrate employed. Immersion tests using simulated body fluid showed that these new nanobiomaterials had in vitro bioactivity. The free-standing nanohydroxyapatite/carbon-based scaffolds have been shown to be a suitable surface for mesenchymal stem cell adhesion with active formation of membrane projections and cell monolayer formation.

Though they reduce microorganism growth, current hospital disinfectants also damage many of today’s modern electronic devices such as tablets and smartphones. Herein, the efficacy of a new chlorhexidine digluconate gel (CDG) was tested as a disinfectant for mobile and electronic devices in a clinical environment. Specifically, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus were used to infect the screen of eight smartphones. The CDG was prepared at concentrations of 2%, 4% and 6%, and tested on paper disks infected with these bacteria before being tested on the smartphones. The devices were disinfected with the CDG gel (4%) at two times: immediately and after 5 min of the bacterial contamination. In all cases, the CDG gel eliminated 100% of gram-positive and gram-negative microorganisms compared to the control (without any agent). In addition, the gel did not damage the smartphones. Therefore, our study suggests that the CDG gel may be applied to disinfect a wide range of electronic devices for health care professionals in the hospital environment.

Herein, we evaluated the influence of different experimental parameters to obtain high anti-corrosive anatase TiO2 thin films on stainless steel using a simple and low cost cathodic cage plasma deposition technique at low pressure and temperature. The thin TiO2 films were deposited on duplex stainless-steel (dimension). Different mixtures of O2, H2 and Ar were used and further correlated with resulting structural properties and corrosion resistance. The temperature was kept at 450 °C with a deposition time from 1 to 4 h. Raman spectroscopy, grazing incidence X-ray diffraction and a corrosion test were used to evaluate the TiO2 films. A thin TiO2 adherent, crystalline, protective film was obtained when 60% H2/40% Ar was used. Our proposed method to obtain TiO2 films shows promise for use in different industrial applications.

Super duplex stainless steels are widely used in harsh environments due to their high corrosion resistance. However, the improvement of their tribological properties can contribute to a better performance of these materials in service. In this regard, this study aimed to evaluate the application influence of duplex treatment on the tribological properties of the UNS S32760 super duplex stainless steel. Two treatment times, 2 h and 4 h, were studied for both the nitriding step and the cathodic cage plasma deposition step. The results showed that the combination of the nitrided layer and the TiN film, confirmed with the application of Rietveld refinement on the XRD data, contributes to the wear volume decrease by up to 9.41 times. This behaviour was associated with the increase in surface microhardness and the excellent adhesion conditions (HF1) presented by the film deposited over the nitrided layer. The film provided a change in the wear mechanism, evidenced by the reduction in the tendency to wear by scratches. Additionally, was observed the presence of lower oxygen content in the wear region of the treated samples, that can be associated a lower heating of the samples during the test. Thus, the duplex treatment has a great application potential for improving the wear resistance of UNS S32760 steel.

To date is emergent the development of novel coatings to protect erosion, especially to preventive dentistry and restorative dentistry. Here, for the first time we report the effectiveness of multi-walled carbon nanotube/graphene oxide hybrid carbon-base material (MWCNTO-GO) combined with nanohydroxyapatite (nHAp) as a protective coating for dentin erosion. Fourier transform Raman spectroscopy (FT-Raman), scanning electron (SEM), and transmission electron (TEM) microscopy were used to investigated the coatings and the effect of acidulated phosphate fluoride gel (APF) treatment on bovine teeth root dentin before and after erosion. The electrochemical corrosion performance of the coating was evaluated. Raman spectra identified that: (i) the phosphate (ν1PO43-) content of dentin was not significantly affected by the treatments and (ii) the carbonate (ν1CO32-) content in dentin increased when nHAp was used. However, the nHAp/MWCNTO-GO composite exposited lower levels of organic matrix (CH bonds) after erosion compared to other treatments. Interesting, SEM micrographs identified that the nHAp/MWCNTO-GO formed layers after erosive cycling when associate with APF treatment, indicating a possible chemical bond among them. Treatments of root dentin with nHAp, MWCNTO-GO, APF_MWCNTO-GO, and APF_nHAp/MWCNTO-GO increased the carbonate content, carbonate/phosphate ratio, and organic matrix band area after erosion. The potentiodynamic polarization curves and Nyquist plot showed that nHAp, MWCNT-GO and nHAp/MWCNT-GO composites acted as protective agents against corrosion process. Clearly, the nHAp/MWCNTO-GO composite was stable after erosive cycling and a thin and acid-resistant film was formed when associated to APF treatment.

Graphene oxide nanoribbons (O-GNR) surges as an interesting nanomaterial for biomedical applications due to feasibility to incorporate functional groups and possible bactericidal properties. Herein, high concentrations of O-GNR were biologically evaluated using human osteoblast cells and gram positive and negative bacteria. Briefly, our goal were to evaluate: (1) synthetic pathway, (2) characterization and (3) effects of O-GNR composition and structural factors as a new approach for biomedical applications. For this, O-GNR were produced combining chemical vapor deposition and oxygen plasma treatment of multiwalled carbon nanotubes. Then, we analyzed the bioactivity, cell viability, osteogenic differentiation, matrix mineralization, mRNA levels of the five genes related direct to bone repair and bactericidal effect of high concentrations of O-GNR (10μgmL-1, 100μgmL-1, 200μgmL-1 and 300μgmL-1). Impressively, O-GNR showed no cytotoxic effects up to a concentration of 100μgmL-1 and no gene expression alteration when used in its dose. We also observed that S. aureus and E. coli bacteria are susceptible to damage when incubated with 100μgmL-1 of O-GNR, showing approximately 50% of bacterial death. We consider that O-GNR displays attractive properties when used at a suitable dose, displaying bactericidal effect and apparently lacking to cause damages in the bone repair process.

Made available in DSpace on 2018-11-26T17:34:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-07-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Brazilian Innovation Agency (FINEP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Combining polyester scaffolds with synthetic nanohydroxyapatite (nHAp), which is bioactive and osteoconductive, is a plausible strategy to improve bone regeneration. Here, we propose the combination of PBAT [poly(butylene-adipate-co-terephthalate)] and synthetic nHAp (at 3 and 5 wt%). PBAT is a relatively a new polymer with low crystallinity and attractive biodegradability and mechanical properties for orthopedic applications, however, with a still underexplored potential for in vivo applications. Then, we performed a careful biological in vitro and in vivo set of experiments to evaluate the influence of PBAT containing two different nHAp loads. For in vitro assays, osteoblast-like MG63 cells were used and the bioactivity and gene expression related to osteogenesis were evaluated by qRT-PCR. For in vivo experiments, twenty-four male rats were used and a tibial defect model was applied to insert the scaffolds. Micro-computed tomography (Micro-CT) and histological analysis were used to assess e bone neoformation after 6 weeks of implantation. Three point flexural tests measured the mechanical properties of the neoformed bone. All scaffolds showed promising in vitro properties, since they were not cytotoxic against MG-63 cells and promoted high cell proliferation and formation of mineralized nodules. From a mechanistic point-of-view, nHAp loading increased hydrophilicity, which in turn allowed for a better adsorption of proteins and consequent changes in the phenotypic expression of osteoblasts. nHAp induced better cellular responses on/in the scaffolds, which was mainly attributed to its osteoconductive and osteoinductive properties. Micro-CT images showed that nHAp at 3% and 5 wt% led to more effective bone formation, presenting the highest bone volume after 6 weeks of implantation. Considering the three point flexural tests, 5 wt% of nHAp positively influenced the flexural mode of the neoformed bone, but the stiffness was similar between the 3% and 5 wt% groups. In summary, this investigation demonstrated great potential for the application of these novel scaffolds towards bone regeneration and, thus, should be further studied. (C) 2017 Elsevier B.V. All rights reserved, Sao Paulo State Univ, Inst Sci & Technol, Dept Biosci & Oral Diag, Sao Jose Dos Campos, SP, Brazil Univ Brasil, Lab Biomed Nanotechnol, Itaquera, SP, Brazil Univ Vale Paraiba, Inst Res & Dev IP&D, Lab Biomed Nanotechnol, Sao Jose Dos Campos, SP, Brazil Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Biomat Innovat Res Ctr, Cambridge, MA USA Northeastern Univ, Dept Chem Engn, Nanomed Lab, Boston, MA 02115 USA Sao Paulo State Univ, Inst Sci & Technol, Dept Biosci & Oral Diag, Sao Jose Dos Campos, SP, Brazil FAPESP: 2011/17877-7 FAPESP: 2011/20345-7 FAPESP: 2015/09697-0 FAPESP: 2016/00575-1 CNPq: 474090/2013-2 Brazilian Innovation Agency (FINEP): 0113042800 CAPES: 88887.095044/2015-00 FAPESP: 2015/08523-8

Researchers have been looking for modifying surfaces of polymeric biomaterials approved by FDA to obtain nanofeatures and bactericidal properties. If modified, it would be very interesting because the antibiotic administration could be reduced and, therefore, the bacterial resistance. Here, we report the electrospinning of poly (lactic acid) (PLA) with high loadings of titanium dioxide nanoparticles (TiO 2 , 1–5 wt%) and their bactericidal properties. TiO 2 nanoparticles have been recognized for a long time for their antibacterial, low cost and self-cleaning properties. However, their ability to reduce bacteria functions when used in polymers has not been well studied to date. In this context, we aimed here to generate nanostructured PLA electrospun fiber-TiO 2 nanoparticle composites for further evaluation of their bactericidal activity and cell viability. TEM and SEM micrographs revealed the successful electrospinning of PLA/TiO 2 and the generation of polymer-TiO 2 nanostructures. When increasing the TiO 2 concentration, we observed a proportional increase in the nanoparticle density along the fiber and surface. The nanostructured PLA/TiO 2 nanofibers showed no mammalian cell toxicity and, most importantly, possessed bactericidal activity with higher TiO 2 loads. Such results suggest that the present PLA electrospun fiber-TiO 2 nanoparticle composites should be further studied for a wide range of biomedical applications.

The enormous growing problem with antibiotic resistance in pathogenic microbes is one of the greatest threats we are facing today. In the context of orthopedic applications, infections also lead to the limited healing ability of infected and defected bone. Generally, these problems are treated with a load of antibiotics or surgical intervention. Therefore, having antibacterial properties integrated with a biomaterial would reduce the time of healing and treatment, amount of antibiotic needed, and total cost. Currently, there exists several strategies and materials with the potential of tackling these challenges. Some materials with antibacterial properties currently employed are silver nanoparticles (AgNPs), cerium oxide nanoparticles (CeO2NPs), selenium nanoparticles (SeNPs), copper nanoparticles (CuNPs), antimicrobial peptides (AMPs), biopolymers (such as chitosan), and carbon nanostructures. On the other hand, osteoinductive and osteoconductive materials are important to promote bone healing and regeneration. Within this framework, materials which have been employed widely are bioactive glasses (BG), calcium phosphates (CaPs) (e.g., hydroxyapatite (HA), tricalcium β-phosphate (β-TCP), and biphasic calcium phosphate (BCP)), peptides, growth factors, and other elements (e.g., magnesium (Mg), zinc (Zn), strontium (Sr), silicon (Si), selenium (Se), and Cu, to name a few). Some of the current technological solutions that have been employed are, for instance, the use of a co-delivery system, where both the antibacterial and the osteoinducing agents are delivered from the same delivery system. However, this approach requires overcoming challenges with local delivery in a sustained and prolonged way, thus avoiding tissue toxicity. To address these challenges and promote novel biomaterials with dual action, sophisticated thinking and approaches have to be employed. For this, it is of the utmost importance to have a solid fundamental understanding of current technologies, bacteria behavior and response to treatments, and also a correlation between the material of use, the host tissue and bacteria. We hope by highlighting these aspects, we will promote the invention of the next generation of smart biomaterials with dual action ability to both inhibit infection and promote tissue growth.

Neste trabalho, filmes finos de carbono tipo diamante DLC (Diamond-like carbon) foram depositados em substratos de aco ferramenta AISI D6 por meio da tecnica de deposicao a plasma com gaiola catodica de grafite, com o objetivo de avaliar a influencia dos parâmetros de tratamento, tais como a duracao do tratamento e a polarizacao das amostras. As amostras tratadas foram avaliadas em termos de morfologia e estrutura por Difracao de Raios X (DRX), Espectroscopia Raman e Microscopia Eletronica de Varredura (MEV). Os resultados dos difratogramas indicaram a presenca das estruturas de ferrita, grafite e diamante para as amostras tratadas com alumina e a formacao de grafite com estrutura hexagonal para amostras tratadas sem alumina. Os espectros Raman identificaram a banda D e G caracteristicos de materiais grafiticos e os melhores resultados foram obtidos para as amostras que nao utilizaram alumina. As micrografias dos filmes utilizando alumina indicaram estruturas na forma de minusculas particulas, com contornos mais claros e definidos. Ja para as amostras sem alumina, os filmes DLC apresentaram um aspecto mais uniforme e de coalescencia dos graos. As camadas das amostras tratadas com alumina apresentaram as maiores espessuras de camadas, principalmente para a amostra tratada durante 6 horas. Em relacao aos tratamentos sem alumina, as amostras tratadas por 5 e 6 horas apresentaram em media a maior espessura de camada. Assim, foi possivel afirmar que a alumina e, tambem, o tempo de tratamento influenciam de forma significativa nas caracteristicas de microestrutura e espessura final do filme. Palavras-chave: Deposicao por Plasma, Filmes DLC e Gaiola Catodica

A hybrid hydrogel combining collagen and chitosan (Ch) and human amniotic membranes (AM) were produced. To produce hybrid hydrogels, a fixed concentration of chitosan (2%) was used, adding AM as a ...

Made available in DSpace on 2020-12-10T20:06:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-07-27 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Polycaprolactone (PCL) is a biocompatible, biodegradable synthetic polymer which in combination with nanohydroxyapatite (nHAp) can give rise to a low cost, nontoxic bioactive product with excellent mechanical properties and slow degradation. Here we produced, characterized and evaluated in vivo the bone formation of PCL/nHAp scaffolds produced by the rotary jet spinning technique. The scaffolds produced were firstly soaked into simulated body fluid for 21 days to also obtain nHAp onto PCL/nHAp scaffolds. Afterwards, the scaffolds were characterized by scanning electron microscopy (SEM), energy dispersive spectroscopy and Raman spectroscopy. For in vivo experiments, 20 male Wistar rats were used and randomly divided in 4 experimental groups (n = 5). A critical defect of 3 mm in diameter was made in the tibia of the animals, which were filled with G1 control (clot); G2-PCL scaffold; G3-PCL/nHAp (5%) scaffold; G4-PCL/nHAp (20%) scaffold. All animals were euthanized 60 days after surgery, and the bone repair in the right tibiae were evaluated by radiographic analysis, histological analysis and histomorphometric analysis. While in the left tibias, the areas of bone repair were submitted to the flexural strength test. Radiographic and histomorphometric analyses no showed statistical difference in new bone formation between the groups, but in the three-point flexural tests, the PCL/nHAp (20%) scaffold positively influenced the flexural mode of the neoformed bone. These findings indicate that PCL/nHAp (20%) scaffold improve biomechanical properties of neoformed bone and could be used for bone medicine regenerative. Sao Paulo State Univ, Inst Sci & Technol, Dept Biosci & Oral Diag, BR-12245000 Sao Jose Dos Campos, SP, Brazil Univ Brasil, Inst Cient & Tecnol, BR-08230030 Sao Paulo, Brazil Uninassau Univ, BR-64017775 Teresina, Piaui, Brazil UFPI Fed Univ Piaui, Dept Phys, BR-64017775 Teresina, Piaui, Brazil UFPI Fed Univ Piaui, Dept Mat Engn, LIMAV Interdisciplinary Lab Adv Mat, BioMatLab, BR-64049550 Teresina, Piaui, Brazil Sao Paulo State Univ, Inst Sci & Technol, Dept Biosci & Oral Diag, BR-12245000 Sao Jose Dos Campos, SP, Brazil CNPq: 303752/2017-3 CNPq: 404683/2018-5 CNPq: 304133/2017-5 CNPq: 424163/2016-0 FAPESP: 2016/20820-0

One of the important components in tissue engineering is material structure, providing a model for fixing and the development of cells and tissues, which allows for the transport of nutrients and regulatory molecules to and from cells. The community claims the need for new materials with better properties for use in the clinic. Poly (e-caprolactone) (PCL) is a biodegradable polymer, semi crystalline, with superior mechanical properties and has attracted an increasing interest due to its usefulness in various biomedical applications. Herein, two different methods (electrospinning versus rotary jet spinning) with different concentrations of PCL produced ultra thin-fibers each with particular characteristics, verified and analyzed by morphology, wettability, thermal and cytotoxicity features and for bacteria colonization. Different PCL scaffold morphologies were found to be dependent on the fabrication method used. All PCL scaffolds showed greater mammalian cell interactions. Most impressively, rotary-jet spun fibers showed that a special rough surface decreased bacteria colonization, emphasizing that no nanoparticle or antibiotic was used; maybe this effect is related with physical (scaffold) and/or biological mechanisms. Thus, this study showed that rotary jet spun fibers possess a special topography compared to electrospun fibers to reduce bacteria colonization and present no cytotoxicity when in contact with mammalian cells.

Raman spectroscopy and scanning electron microscopy (SEM) were used to investigate the effect of coating materials and acidulated phosphate fluoride gel (APF) treatment on dentin before and after erosion-abrasion cycles. A multi-walled carbon nanotube/graphene oxide hybrid carbon-based material (MWCNTO-GO), nanohydroxyapatite (nHAp), or a combined composite (nHAp/MWCNTO-GO) were used as a coating. Seventy root dentin fragments obtained from 40 bovine teeth were prepared and divided into groups (n = 10): negative control, artificial saliva - C, positive control – APF; nHAp; MWCNTO-GO; APF_nHAp; APF_MWCNTO-GO and APF_nHAp/MWCNTO-GO. All samples were subjected to cycles of demineralization (orange juice, pH ~3.7, room temperature, 1 min) followed by remineralization (saliva, 37 °C, 1 h). The remineralization procedures were followed by tooth brushing (150 strokes). The above cycle was repeated 3×/day for 5 days. The previous APF treatment of dentin allowed a better affinity of nHAp and MWCNTO-GO with the inorganic and organic portion of dentin, respectively. This interaction indicates the formation of a protective layer for the dentin surface and for the collagen giving possible protection against erosion. SEM micrographs illustrated the formation of a protective layer after application of the biomaterials and that it was partially or totally removed after the erosion and abrasion. Raman spectroscopy combined with multivariate analysis could distinguish samples with respect to treatment efficacy. The APF_nHAP/MWCNT-GO composite has shown to be a promising material since it has binding characteristics both to the inorganic and organic portion of the dentin and reduced solubility. Mineral-to-matrix ratio (MMR) parameter analysis confirmed the binding capability of MWCNTO-GO-based materials to dentin.

Here, butylene adipate-co-terephthalate/polypyrrole with nanohydroxyapatite (PBAT/PPy/nHAp) scaffolds were fabricated and characterized. The electrospinning process was carried out using 12 kV, a needle of 23 G, an infusion pump set at 0.3 mL/h, and 10 cm of distance. Afterwards, nHAp was directly electrodeposited onto PBAT/PPy scaffolds using a classical three-electrode apparatus. For in vivo assays (comet assay, acute and chronic micronucleus), 60 male albino Wistar rats with 4 groups were used in each test (n = 5): PBAT/PPy, PBAT/PPy/nHAp, positive control (cyclophosphamide), and the negative control (distilled water). Peripheral blood samples were collected from the animals to perform the comet test after 4 h (for damage) and 24 h (for repair). In the comet test, it was shown that the scaffolds did not induce damage to the % DNA tail and neither for tail length. After the end of 48 h (for acute micronucleus) and 72 h (for chronic micronucleus), bone marrow was collected from each rat to perform the micronucleus test. All of the produced scaffolds did not present genotoxic effects, providing strong evidence for the biological application of PBAT/PPy/nHAp scaffolds.

Made available in DSpace on 2019-10-04T11:56:43Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) National Council for Scientific and Technological Development The polyester for bone tissue engineering is produced using different concentrations of hydroxyapatite. Poly(butylene adipate-co-terephthalate) (PBAT) solutions containing different concentrations of nano-hydroxyapatite (nHAp) (1, 2, 3, 4, 5 and 6% wt) were evaluated to assess their potential to produce scaffolds via electrospinning. The characteristics of these solutions were evaluated using surface tension analysis. Different solutions were electrospun and characterized using scanning electron microscopy, X-ray diffractometry (XRD), infrared spectroscopy (FTIR), and differential scanning calorimetry analysis. In vitro and in vivo experiments were performed using MG-63 osteoblast cells and male Wistar rats. The MTT assay was used to evaluate the cytotoxicity of scaffolds. Microtomography and a three-point bend test were used to analyze parameters of bone neoformation 4 weeks after implantation. We observed a requirement for solutions containing nHAp to reach chemical stability to produce ultrathin fibers. FTIR and XRD data demonstrated the presence of carbonate and phosphate groups, and thermal analysis showed a reduction in crystallinity of the nanocomposites when the concentration of nHAp was increased. None of the scaffolds analyzed demonstrated cytotoxicity when compared to controls. All of the PBAT/nHAp scaffolds analyzed promoted bone repair; however, a solution of PBAT with 3% nHAp improved bone volume, force, and stiffness when compared to controls. Univ Porto, Fac Engn FEUP, P-4200465 Porto, Portugal Univ Brasil, Inst Cient & Tecnol, BR-08230030 Sao Paulo, SP, Brazil Ctr Univ UNINOVAFAPI, BR-64073505 Teresina, Piaui, Brazil Univ Estadual Paulista, Inst Ciencia & Tecnol, BR-12245000 Sao Jose Dos Campos, SP, Brazil Univ Fed Piaui, Lab Interdisciplinhar Mat Avancados, Programa Posgrad Ciencia & Engn Mat, Campus Univ Ministro Petronio Portella Bairro, BR-64049550 Teresina, Piaui, Brazil Univ Estadual Paulista, Inst Ciencia & Tecnol, BR-12245000 Sao Jose Dos Campos, SP, Brazil FAPESP: 2011/17877-7 FAPESP: 2015/01259-3 FAPESP: 2011/20345-7 FAPESP: 2016/04618-7 National Council for Scientific and Technological Development: 303752/2017-3 National Council for Scientific and Technological Development: 304133/2017-5

Here, we report the electrospinning and further biological evaluation of poly (lactic acid) (PLA) scaffolds containing low loads of diamond nanoparticles (ND, 0.1–1 wt%). ND particles have been long recognized for their low cost, chemical stability, biocompatibility and ability to work as a cellular growth support. In this context, we aimed to produce electrospun PLA/ND scaffolds to assess their final wettability, bioactivity and cytotoxicity effects. The successful electrospinning of PLA/ND scaffolds was confirmed via Field Emission Scanning Electron Microscopy and Transmission Electron Microscopy. Contact angle measurements showed that all scaffolds ND-loaded presented lower advanced contact angles than neat PLA, pointing their decreased hydrophobicity. The biological assays showed that our PLA/ND scaffolds were not cytotoxic using L929 cells, presented bioactive properties and favoured cell adhesion, especially at low ND loads. These findings indicate the surface improvement and the potential range of applicability of electrospun polyesters ND-loaded for tissue engineering purposes.

Bioresorbable electrospun fibres have highly functional features that can preserve drug efficacy, avoiding premature degradation, and control drug release rates over long periods. In parallel, it is known that Alzheimer's disease (AD) has been linked to impaired insulin signalling in the brain. Glucagon-like peptide 1 (GLP-1) analogues have beneficial effects on insulin release and possess exceptional neuroprotective properties. Herein, we describe for the first time the incorporation of a GLP-1 analogue, liraglutide, into electrospun poly (lactic acid) (PLA) fibres with in situ gelatin capsules, in order to provide the controlled release of liraglutide, improving neuroprotective properties. In this study, PLA, a bioresorbable polymer in which degradation products have neurogenesis characteristics, was electrospun and loaded with liraglutide. Moreover, PLA/liraglutide fibres were encapsulated with gelatin and were shown to have better properties than the non-encapsulated fibres in terms of the controlled release of liraglutide, which was accomplished in the present study for up to 60 days. We observed that this biodevice was completely encapsulated with gelatin, which made the material more hydrophilic than PLA fibres alone and the biodevice was able to enhance fibroblast interaction and reduce mitochondrial stress in a neuroblastoma cell line. In this manner, this study introduces a new material which can improve neuroprotective properties from AD oxidative stress via the sustained long-lasting release of liraglutide. Graphical Abstract ᅟ.

We have prepared a novel 3D porous biomaterial combining poly ( dl -lactic acid) (PDLLA) and graphene and multi-walled carbon nanotubes oxides (MWCNTO-GO) composite. PDLLA as control and a high loading of PDLLA/MWCNTO-GO (50/50 w/w) bioscaffolds were prepared and functionalized. MWCNTs were exfoliated to form MWCNTO-GO by oxygen plasma etching. The later was also applied to enhance the scaffolds wettability, attaching oxygen-containing groups on their surfaces. This approach produced a porous architecture observed by scanning electron microscopy and semi-quantified by electrochemical analysis. The later also indicated a notable increase on the conductivity of PDLLA/MWCNTO-GO scaffold compared to MWCNTO-GO free PDLLA (about 5 orders of magnitudes at low frequencies). Thermogravimetric analysis showed that the MWCNTO-GO acted protecting the PDLLA matrix, enhancing its thermal stability. The PDLLA/MWCNTO-GO scaffolds had significant cellular adhesion, did not present cytotoxicity effect, besides reduced bactericidal proliferation and produced mineralized tissues in SBF media. The metallic MWCNTO-GO powder held together by PDLLA polymer opens a whole new branch of applications, including bioelectroanalyses, drug delivery systems and tissue engineering.

Made available in DSpace on 2018-12-11T16:59:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-02-01 The use of poly (butylene adipate-co-terephthalate) (PBAT) in tissue engineering, more specifically in bone regeneration, has been underexplored to date due to its poor mechanical resistance. In order to overcome this drawback, this investigation presents an approach into the preparation of electrospun nanocomposite fibers from PBAT and low contents of superhydrophilic multi-walled carbon nanotubes (sMWCNT) (0.1-0.5 wt.%) as reinforcing agent. We employed a wide range of characterization techniques to evaluate the properties of the resulting electrospun nanocomposites, including Field Emission Scanning Electronic Microscopy (FE-SEM), Transmission Electronic Microscopy (TEM), tensile tests, contact angle measurements (CA) and biological assays. FE-SEM micrographs showed that while the addition of sMWCNT increased the presence of beads on the electrospun fibers' surfaces, the increase of the neat charge density due to their presence reduced the fibers' average diameter. The tensile test results pointed that sMWCNT acted as reinforcement in the PBAT electrospun matrix, enhancing its tensile strength (from 1.3 to 3.6 MPa with addition of 0.5 wt.% of sMWCNT) and leading to stiffer materials (lower elongation at break). An evaluation using MG63 cells revealed cell attachment into the biomaterials and that all samples were viable for biomedical applications, once no cytotoxic effect was observed. MG-63 cells osteogenic differentiation, measured by ALP activity, showed that mineralized nodules formation was increased in PBAT/0.5%CNTs when compared to control group (cells). This investigation demonstrated a feasible novel approach for producing electrospun nanocomposites from PBAT and sMWCNT with enhanced mechanical properties and adequate cell viability levels, which allows for a wide range of biomedical applications for these materials. Laboratory of Biomedical Nanotechnology, Institute of Research and Development (IPandD), University of Vale Do Paraiba (UNIVAP), Sao Jose Dos Campos, Av. Shishima Hifumi 2911 Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, Sao Paulo State University (UNESP), Sao Jose Dos Campos, Av. Engenheiro Francisco Jose Longo 777 Department of Bioscience and Oral Diagnosis, Institute of Science and Technology, Sao Paulo State University (UNESP), Sao Jose Dos Campos, Av. Engenheiro Francisco Jose Longo 777

A biomineralization processes is disclosed for engineering nanomaterials that support bone repair. The material was fabricated through a hot press process using electrospun poly(lactic acid) (PLA) matrix covered with hybrid composites of carbon nanotubes/graphene nanoribbons (GNR) and nanohydroxyapatite (nHA). Various scaffolds were devised [nHA/PLA, PLA/GNR, and PLA/nHA/GNR (1 and 3%)] and their structure and morphology characterized through Scanning electron microscopy (SEM), Energy dispersive X-ray spectroscopy (EDS), and Atomic force microscope (AFM). Moreover, thorough biocompatibility and toxicity studies were performed. Here, in vivo studies on toxicity and cytotoxicity were conducted in aqueous dispersions of the biomaterials at concentrations of 30, 60, and 120 μg/mL using the Allium cepa test. Further toxicity studies were performed through hemolysis toxicity tests and genotoxicity tests evaluating the damage index and damage frequencies of DNAs through comet assays with samples of the animals' peripheral blood, marrow, and liver. Additionally, the regenerative activity of the scaffolds was analyzed by measuring the cortical tibiae of rats oophorectomized implanted with the biomaterials. Biochemical analyzes [glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), urea, calcium, phosphorus, and alkaline phosphatase (ALP)] were also performed on blood samples. The results suggested a toxicity and cytotoxicity level for the GNR biomaterials at a concentration of 60 and 120 μg/mL, but non-toxicity and cytotoxicity for the 30 μg/mL concentration. The scaffolds obtained at a concentration of 0.3 mg/cm2 were not toxic in the hemolysis test and demonstrated no cytotoxicity, genotoxicity, and mutagenicity in the blood, marrow, and liver analyzes of the animals, corroborating data from the biochemical markers of GPT, GOT, and urea. Tissue regeneration was performed in all groups and was more pronounced in the group containing the combination of nHA/GNR (3%), which is consistent with the data obtained for the calcium, serum phosphorus, and ALP concentrations. Consequently, the study indicates that the engineered nanobiomaterial is a promising candidate for bone tissue repair and regenerative applications. Statement of significance The scientific contribution of this study is the engineering of a synthetic hybrid biomaterial, in nanoscale by a pressing and heating process. A biodegradable polymeric matrix was covered on both sides with a carbonated hybrid bioceramic/graphene nanoribbons (GNR), which has hydrophilic characteristics, with chemical elements stoichiometrically similar to bone mineral composition. The nanomaterial displayed promising bone regeneration ability, which is the first example to be used in an osteoporotic animal model. Moreover, detailed biocompatibility and toxicity studies were performed on the nanomaterials and their compositions, which is of great interest for the scientific community.

Cartilage is one of our body's tissues which are not repaired automatically by itself. Problems associated with cartilage are very common worldwide and are considered the leading cause of pain and disability. Smart biomaterial or "Four dimensional" (4D) biomaterials has started emerging as a suitable candidate, which are principally three dimensional (3D) materials that change their morphology or generate a response measured at space and time to physiologic stimuli. In this context, the release of oxygen through hydrogels in contact with water is considered as 4D biomaterials. The objective of this study is to develop strategies to release oxygen in a sustainable and prolonged manner through hydrogels systems to promote chondrocytes survival in oxygen-free environment. The 4D biomaterials are engineered from gelatin methacryloyl (GelMA) loaded with calcium peroxide (CPO), which have the ability to generate oxygen in a controlled and sustained manner for up to 6 days. The incorporation of CPO into the hydrogel system provided materials with enhanced mechanical and porosity properties. Furthermore, the hydrogels promoted chondrocyte survival and reduced cell death under oxygen-free conditions.

Titanium dioxide (TiO2) and aluminum oxide (Al2O3) thin films, with thicknesses around 100 nm, were grown on commercial pure- and resin-coated Al substrates using the atomic layer deposition (ALD). A comprehensive and comparative study of corrosion protection was carried out by linear sweep voltammetry (LSV) and electrochemical impedance spectroscopy (EIS) measurements for a set of six samples: two reference samples (Al-bare and Al-resin), and four ALD coated samples ( Al-TiO2, Al-Al2O3, Al-resin-TiO2, and Al-resin-Al2O3). The LSV and EIS results display good mutual agreement, indicating a higher protection efficiency of all ALD-coated samples after immersion in NaCl. When compared to Al-bare, all ALD coated samples (TiO2 or Al2O3) showed a corrosion inhibition enhancement factor of 99%. Besides, our results demonstrated that Al-resin+Al2O3 has 24.95% and 33.40% more corrosion inhibition than Al-Al2O3 and Al-resin, respectively. EIS data were fitted by an equivalent electric circuit (EEC). The Nyquist and Bode plots from the experiments showed that ALD films are a potential candidate for altering/improving commercial resin-coated Al cans.