Evaluating the Appropriateness of Project Delivery Systems for Different Trenchless Methods

Trenchless methods have been considered to be a viable solution for pipeline projects in urban areas. Their applicability in pipeline projects is expected to increase with the rapid advancements in technology and emerging concerns regarding social costs related to trenching methods. Selecting appropriate project delivery system (PDS) is a key to the success of trenchless projects. To ensure success of the project, the selected project delivery should be tailored to trenchless project specific characteristics and owner needs, since the effectiveness of project delivery systems differs based on different project characteristics and owners requirements. Since different trenchless methods have specific characteristics such rate of installation, lengths of installation, and accuracy, the same project delivery systems may not be equally effective for different methods. The intent of this paper is to evaluate the appropriateness of different PDS for different trenchless methods. PDS are examined through a structured decision-making process called Fuzzy Delivery System Selection Model (FDSSM). The process of incorporating the impacts of: (a) the characteristics of trenchless projects and (b) owners’ needs in the FDSSM is performed by collecting data using questionnaires deployed to professionals involved in the trenchless industry in order to determine the importance of delivery systems selection attributes for different trenchless methods, and then analyzing this data. The sensitivity of PDS rankings with respect to trenchless methods is considered in order to evaluate whether similar project delivery systems are equally effective in different trenchless methods. The effectiveness of PDS with respect to attributes is defined as follows: a project delivery system is most effective with respect to an attribute (e.g., ability to control growth in costs ) if there is no project delivery system that is more effective than that PDS. The results of this study may assist trenchless project owners to select the appropriate PDS for the trenchless method selected.

Conjugated Polymer Nanoparticles for Biological Labeling and Delivery

Cancer remains one of the world’s most devastating diseases, with more than 10 million new cases every year. However, traditional treatments have proven insufficient for successful medical management of cancer due to the chemotherapeutics’ difficulty in achieving therapeutic concentrations at the target site, non-specific cytotoxicity to normal tissues, and limited systemic circulation lifetime. Although, a concerted effort has been placed in developing and successfully employing nanoparticle(NP)-based drug delivery vehicles successfully mitigate the physiochemical and pharmacological limitations of chemotherapeutics, work towards controlling the subcellular fate of the carrier, and ultimately its payload, has been limited. Because efficient therapeutic action requires drug delivery to specific organelles, the subcellular barrier remains critical obstacle to maximize the full potential of NP-based delivery vehicles. The aim of my dissertation work is to better understand how NP-delivery vehicles’ structural, chemical, and physical properties affect the internalization method and subcellular localization of the nanocarrier. In this work we explored how side-chain and backbone modifications affect the conjugated polymer nanoparticle (CPN) toxicity and subcellular localization. We discovered how subtle chemical modifications had profound consequences on the polymer’s accumulation inside the cell and cellular retention. We also examined how complexation of CPN with polysaccharides affects uptake efficiency and subcellular localization. This work also presents how changes to CPN backbone biodegradability can significantly affect the subcellular localization of the material. A series of triphenyl phosphonium-containing CPNs were synthesized and the effect of backbone modifications have on the cellular toxicity and intracellular fate of the material. A mitochondrial-specific polymer exhibiting time-dependent release is reported. Finally, we present a novel polymerization technique which allows for the controlled incorporation of electron-accepting benzothiadiazole units onto the polymer chain. This facilitates tuning CPN emission towards red emission. The work presented here, specifically, the effect that side-chain and structure, polysaccharide formulation and CPN degradability have on material’s uptake behavior, can help maximize the full potential of NP-based delivery vehicles for improved chemotherapeutic drug delivery.

Micropartículas contendo nanopartículas de quitosana usando sulfato e genipina para liberação modificada da triancinolona: obtenção, caracterização e estudo em células tumorais

Chitosan is a polymer biocompatibility and biodegradability widely used in drug delivery systems. The co-crosslinking of chitosan with sodium sulfate and genipin, to form particulate systems is related of making them more resistant to acidic pH and to modulate the release kinetics for the oral route. Triamcinolone is a glucocorticoid with anti-inflammatory and immunosuppressive actions. The nanoparticles were prepared by co-crosslinking and characterized for particle size, PDI, zeta potential, crosslinking degree, encapsulation rate, morphology, infrared spectroscopy, thermal analysis, release kinetics and cells studies. The nanoparticles were prepared initially without genipin with sodium sulphate and the particles parameters were monitored in function of different ratio of drug / polymer, different concentrations of sodium sulfate and polysorbate 80 and the drip mode of crosslinkers on polymers. After optimizing conditions, the chosen system parameters without genipin included mean diameter of 312.20 ± 5.70 nm, PDI 0.342 ± 0.013 and zeta potential of 20.18 ± 2.28 mV. The genipin was introduced into the system analyzing different concentrations (0.5, 1.0 and 2.0 mM) and crosslinking times (3, 6, 12 and 24 h). Evaluating crosslinking time with genipin (0.5 mM) it was showed that varying the genipin reaction time the systems size ranged from 235.1 to 334.4 nm, the PDI from 0.321 to 0.392 and zeta potential 20.92 to 30.39 mV. The crosslinking degree that coud vary from 14 to 30 %. Nanoparticles without genipina, 6 h and 24 h crosslinking time were dried by spray-drying method. Analysis by scanning electron micrograph (SEM) revealed that the microparticles showed spherical morphology. The encapsulation rate was 75 ± 2.3 % using validated HPLC methodology. The infrared analysis showed chemical interactions between the components of the formulation. Thermal analysis showed that systems with a higher degree of crosslinking had a higher thermal stability. On release kinetics, increasing the degree of crosslinking was able to decrease the concentration and rate of release of triamcinolone. In studies with liver cancer cells (HepG2) and colon (HT-29), the microparticulate prepared with triamcinolone and 24 h of crosslinking with genipin showed a potential for antitumor activity in hepatic cell line HepG2. Therefore, a new delivery system for triamcinolone on polymeric nanoparticles of chitosan cocrosslinked with genipin and sodium sulfate was obtained with hepatic antitumor potential.

Dosage form preference consultation study in children and young adults:paving the way for patient-centred and patient-informed dosage form development

Objectives: The current study aims to evaluate dosage form preferences in children and young adults together with identifying the key pragmatic dosage form characteristics that would enable appropriate formulation of orally disintegrating tablets (ODTs). Methods: International, multisite, cross-sectional questionnaire of children and young adults aged from 6 to 18 years. Eligibility was based on age, ability to communicate and previous experience in taking medications. The study was carried out at three locations: the UK, Saudi Arabia and Jordan. The questionnaire instrument was designed for participant self-completion under supervision of the study team.Results 104 questionnaires were completed by the study cohort (n=120, response rate 87%). Results: showed that ODTs were the most preferred oral dosage forms (58%) followed by liquids (20%), tablets (12%) and capsules (11%). The preferred colours were pink or white while the preferred size was small (<8 mm) with a round shape. With regard to flavour, strawberry was the most preferred (30.8%), while orange was the least preferred (5.8%). The results also showed that the most important physical characteristics of ODTs were disintegration time followed by taste, size and flavour, respectively. Conclusions: The results of our study support the WHO's claim for a shift of paradigm from liquid towards ODTs dosage forms for drug administration to young children older than 6 years. Data from this study will also equip formulators to prioritise development of key physical/performance attributes within the delivery system.

Development of nanostructured hydrogel for spatial and temporal controlled release of active compounds

L’utilisation de nanovecteurs pour la livraison contrôlée de principes actifs est un concept commun de nous jours. Les systèmes de livraison actuels présentent encore cependant des limites au niveau du taux de relargage des principes actifs ainsi que de la stabilité des transporteurs. Les systèmes composés à la fois de nanovecteurs (liposomes, microgels et nanogels) et d’hydrogels peuvent cependant permettre de résoudre ces problèmes. Dans cette étude, nous avons développé un système de livraison contrôlé se basant sur l’incorporation d’un nanovecteur dans une matrice hydrogel dans le but de combler les lacunes des systèmes se basant sur un vecteur uniquement. Une telle combinaison pourrait permettre un contrôle accru du relargage par stabilisation réciproque. Plus spécifiquement, nous avons développé un hydrogel structuré intégrant des liposomes, microgels et nanogels séparément chargés en principes actifs modèles potentiellement relargués de manière contrôlé. Ce contrôle a été obtenu par la modification de différents paramètres tels que la température ainsi que la composition et la concentration en nanovecteurs. Nous avons comparé la capacité de chargement et la cinétique de relargage de la sulforhodamine B et de la rhodamine 6G en utilisant des liposomes de DOPC et DPPC à différents ratios, des nanogels de chitosan/acide hyaluronique et des microgels de N-isopropylacrylamide (NIPAM) à différents ratios d’acide méthacrylique, incorporés dans un hydrogel modèle d’acrylamide. Les liposomes présentaient des capacités de chargement modérés avec un relargage prolongé sur plus de dix jours alors que les nanogels présentaient des capacités de chargement plus élevées mais une cinétique de relargage plus rapide avec un épuisement de la cargaison en deux jours. Comparativement, les microgels relarguaient complétement leur contenu en un jour. Malgré une cinétique de relargage plus rapide, les microgels ont démontré la possibilité de contrôler finement le chargement en principe actif. Ce contrôle peut être atteint par la modification des propriétés structurelles ou en changeant le milieu d’incubation, comme l’a montré la corrélation avec les isothermes de Langmuir. Chaque système développé a démontré un potentiel contrôle du taux de relargage, ce qui en fait des candidats pour des investigations futures.

Cationic Bovine Serum Albumin (CBA) conjugated Poly Lactic-co-Glycolic Acid (PLGA) nanoparticles for extended delivery of methotrexate into brain tumor

Current treatment strategies for the treatment of brain tumor have been hindered primarily by the presence of highly lipophilic insurmountable blood-brain barrier (BBB). The purpose of current research was to investigate the efficiency of engineered biocompatible polymeric nanoparticles (NPs) as drug delivery vehicle to bypass the BBB and enhance biopharmaceutical attributes of anti-metabolite methotrexate (MTX) encapsulated NPs. The NPs were prepared by solvent diffusion method using cationic bovine serum albumin (CBA), and characterized for physicochemical parameters such as particle size, polydispersity index, and zeta-potential; while the surface modification was confirmed by FTIR, and NMR spectroscopy. Developed NPs exhibited zestful relocation of FITC tagged NPs across BBB in albino rats. Further, hemolytic studies confirmed them to be non-toxic and biocompatible as compared to free MTX. In vitro cytotoxicity assay of our engineered NPs on HNGC1 tumor cells proved superior uptake in tumor cells; and elicited potent cytotoxic effect as compared to plain NPs and free MTX solution. The outcomes of the study evidently indicate the prospective of CBA conjugated poly (D,L-lactide-co-glycolide) (PLGA) NPs loaded with MTX in brain cancer bomber with amplified capability to circumvent BBB.

Daunorubicin and gambogic acid co-loaded cysteamine-CdTe quantum dots minimizing the multidrug resistance of lymphoma in vitro and in vivo

To minimize the side effects and the multidrug resistance (MDR) arising from daunorubicin (DNR) treatment of malignant lymphoma, a chemotherapy formulation of cysteamine-modified cadmium tellurium (Cys-CdTe) quantum dots coloaded with DNR and gambogic acid (GA) nanoparticles (DNR-GA-Cys-CdTe NPs) was developed. The physical property, drug-loading efficiency and drug release behavior of these DNR-GA-Cys-CdTe NPs were evaluated, and their cytotoxicity was explored by 3-[4,5-dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide assay. These DNR-GA-Cys-CdTe NPs possessed a pH-responsive behavior, and displayed a dose-dependent antiproliferative activity on multidrug-resistant lymphoma Raji/DNR cells. The accumulation of DNR inside the cells, revealed by flow cytometry assay, and the down-regulated expression of P-glycoprotein inside the Raji/DNR cells measured by Western blotting assay indicated that these DNR-GA-Cys-CdTe NPs could minimize the MDR of Raji/DNR cells. This multidrug delivery system would be a promising strategy for minimizing MDR against the lymphoma.

Hybrid materials for biomedical applications

The increased longevity of humans and the demand for a better quality of life have led to a continuous search for new implant materials. Scientific development coupled with a growing multidisciplinarity between materials science and life sciences has given rise to new approaches such as regenerative medicine and tissue engineering. The search for a material with mechanical properties close to those of human bone produced a new family of hybrid materials that take advantage of the synergy between inorganic silica (SiO4) domains, based on sol-gel bioactive glass compositions, and organic polydimethylsiloxane, PDMS ((CH3)2.SiO2)n, domains. Several studies have shown that hybrid materials based on the system PDMS-SiO2 constitute a promising group of biomaterials with several potential applications from bone tissue regeneration to brain tissue recovery, passing by bioactive coatings and drug delivery systems. The objective of the present work was to prepare hybrid materials for biomedical applications based on the PDMS-SiO2 system and to achieve a better understanding of the relationship among the sol-gel processing conditions, the chemical structures, the microstructure and the macroscopic properties. For that, different characterization techniques were used: Fourier transform infrared spectrometry, liquid and solid state nuclear magnetic resonance techniques, X-ray diffraction, small-angle X-ray scattering, smallangle neutron scattering, surface area analysis by Brunauer–Emmett–Teller method, scanning electron microscopy and transmission electron microscopy. Surface roughness and wettability were analyzed by 3D optical profilometry and by contact angle measurements respectively. Bioactivity was evaluated in vitro by immersion of the materials in Kokubos’s simulated body fluid and posterior surface analysis by different techniques as well as supernatant liquid analysis by inductively coupled plasma spectroscopy. Biocompatibility was assessed using MG63 osteoblastic cells. PDMS-SiO2-CaO materials were first prepared using nitrate as a calcium source. To avoid the presence of nitrate residues in the final product due to its potential toxicity, a heat-treatment step (above 400 °C) is required. In order to enhance the thermal stability of the materials subjected to high temperatures titanium was added to the hybrid system, and a material containing calcium, with no traces of nitrate and the preservation of a significant amount of methyl groups was successfully obtained. The difficulty in eliminating all nitrates from bulk PDMS-SiO2-CaO samples obtained by sol-gel synthesis and subsequent heat-treatment created a new goal which was the search for alternative sources of calcium. New calcium sources were evaluated in order to substitute the nitrate and calcium acetate was chosen due to its good solubility in water. Preparation solgel protocols were tested and homogeneous monolithic samples were obtained. Besides their ability to improve the bioactivity, titanium and zirconium influence the structural and microstructural features of the SiO2-TiO2 and SiO2-ZrO2 binary systems, and also of the PDMS-TiO2 and PDMS-ZrO2 systems. Detailed studies with different sol-gel conditions allowed the understanding of the roles of titanium and zirconium as additives in the PDMS-SiO2 system. It was concluded that titanium and zirconium influence the kinetics of the sol-gel process due to their different alkoxide reactivity leading to hybrid xerogels with dissimilar characteristics and morphologies. Titanium isopropoxide, less reactive than zirconium propoxide, was chosen as source of titanium, used as an additive to the system PDMS-SiO2-CaO. Two different sol-gel preparation routes were followed, using the same base composition and calcium acetate as calcium source. Different microstructures with high hydrophobicit were obtained and both proved to be biocompatible after tested with MG63 osteoblastic cells. Finally, the role of strontium (typically known in bioglasses to promote bone formation and reduce bone resorption) was studied in the PDMS-SiO2-CaOTiO2 hybrid system. A biocompatible material, tested with MG63 osteoblastic cells, was obtained with the ability to release strontium within the values reported as suitable for bone tissue regeneration.

Transdermal delivery of cyclosporin A by electrically enhanced permeation techniques

Transdermal drug delivery has recently received increasing attention in the face of growing challenges to deliver peptide and protein drugs. Controlled transdermal delivery is an important route for the delivery of peptides and proteins that can maintain the therapeutic effectiveness of the drug by minimizing enzymatic degradation which is a major concern in other noninvasive routes of delivery such as the oral route. Although the advantages of transdermal delivery are very desirable, the natural obstacle to drug entry imposed by the skin's barrier function makes it one of the most difficult route of administration. Iontophoresis and electroporation have been reported to be useful as permeation enhancing techniques in the transdermal delivery of protein and peptide drugs. The objective of present study is to use the above enhancement techniques to deliver cyclosporin A (CSA) to treat psoriasis. The in vitro experiments were performed using hairless rat skin as the model with Franz diffusion cells for iontophoresis and custom made diffusion cells for electroporation. The donor drug solution of CSA consisted of an aqueous solution of CSA - polymer solid dispersion, coevaporate, and/or a hydroethanolic solution of CSA PBS was used as the receiver solution. ³H labelled CSA and ¹⁴C labelled ethanol were used to facilitate analysis using a liquid scintillation counter. The control experiment consisted of passive diffusion study. Silver/silver chloride electrodes were used in all studies. In the iontophoresis experiments a constant DC current (0.5 mA/cm²) was used. In the electroporation experiments different delivery parameters were studied: (1) applied electrode voltage (Uelectrode), (2) decay time constant (τ), (3) the number of pulses delivered - single or multiple, and { 4) the time of diffusive contact with drug after electroporation ('contact duration'). Compared to the passive diffusion, iontophoresis did not result in a significant increase in the amount of CSA delivered transdermally with both the CSA-polymer donor and hydroethanolic drug solutions. With the use of electroporation there was a significant increase in the transdermal delivery, compared to passive transport. With the CSA-polymer coevaporate donor solution the increase in delivery was only about 6 fold higher whereas with the hydroethanolic solution the increase was about 60 times higher compared to passive diffusion. The 'contact duration• was an important fader and a 4-hour 'contact duration' was found to be the optimum time period required for effective transdermal delivery. Use of single pulse (τ=5.6 ms) electroporation resulted in a significant increase {p<0.05) in the delivery of CSA in skin {CSA.n) and EtOH in receiver (EtOHreceiver). With multiple pulse (τ=10 ms. 25 pulses) the increase in CSAskin was more pronounced with a 60 fold increase than compared to the passive delivery. However there was no significant increase in the other two quantities viz. CSAreceiver, and EtCHreceiver.

Lipid-Based Liquid Crystals As Carriers for Antimicrobial Peptides: Phase Behavior and Antimicrobial Effect

International audience

Lipid-based nanoformulations for peptide delivery

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Joint Optimization for Social Content Delivery in Wireless Networks

Over the last decade, success of social networks has significantly reshaped how people consume information. Recommendation of contents based on user profiles is well-received. However, as users become dominantly mobile, little is done to consider the impacts of the wireless environment, especially the capacity constraints and changing channel. In this dissertation, we investigate a centralized wireless content delivery system, aiming to optimize overall user experience given the capacity constraints of the wireless networks, by deciding what contents to deliver, when and how. We propose a scheduling framework that incorporates content-based reward and deliverability. Our approach utilizes the broadcast nature of wireless communication and social nature of content, by multicasting and precaching. Results indicate this novel joint optimization approach outperforms existing layered systems that separate recommendation and delivery, especially when the wireless network is operating at maximum capacity. Utilizing limited number of transmission modes, we significantly reduce the complexity of the optimization. We also introduce the design of a hybrid system to handle transmissions for both system recommended contents ('push') and active user requests ('pull'). Further, we extend the joint optimization framework to the wireless infrastructure with multiple base stations. The problem becomes much harder in that there are many more system configurations, including but not limited to power allocation and how resources are shared among the base stations ('out-of-band' in which base stations transmit with dedicated spectrum resources, thus no interference; and 'in-band' in which they share the spectrum and need to mitigate interference). We propose a scalable two-phase scheduling framework: 1) each base station obtains delivery decisions and resource allocation individually; 2) the system consolidates the decisions and allocations, reducing redundant transmissions. Additionally, if the social network applications could provide the predictions of how the social contents disseminate, the wireless networks could schedule the transmissions accordingly and significantly improve the dissemination performance by reducing the delivery delay. We propose a novel method utilizing: 1) hybrid systems to handle active disseminating requests; and 2) predictions of dissemination dynamics from the social network applications. This method could mitigate the performance degradation for content dissemination due to wireless delivery delay. Results indicate that our proposed system design is both efficient and easy to implement.

Iron metabolism: a double-edged sword in the resistance of glioblastoma to therapies

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Targeting and treatment of glioblastomas with human mesenchymal stem cells carrying ferrociphenol lipid nanocapsules

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