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Chapter 1: Amphiphilic self-assembled systems as nanocarriers Nanocarriers are the nanometric size molecular assemblies that are used for the transport of small molecules into their non-solvating environments. These systems find major applications as drug delivery systems (DDS) in pharmacological research. These drug delivery systems improves solubility and stability of the drug molecules through encapsulation and also offer additional advantages like target specificity and stimuli responsive release of the drug molecules. Several types of DDS are reported in the literature, which can be prepared by a variety of processing techniques. Of these, molecular self- Chart 1: Developments in the design of amphiphilic nanocarriers assembly has attained considerable attention due to its greater tunability and control in the preparation of nanocarriers. In this chapter we discussed about the amphiphilic nanocarriers which are prepared through self-assembly of amphiphiles through hydrophobic interactions. Several developments in the area of amphiphilic nanocarriers such as di-block polymeric systems, dendritic systems and core-shell architectures are also mentioned. We also highlighted some recent developments in the design of amphiphilic nanocarriers through supramolecular interactions and advantages of such systems. Chapter 2: Bile acid derived dendrons and their application as nanocarriers Host-guest chemistry is well known for dendritic systems. To understand the influence of steric crowding, dendritic effect and importance of number of hydroxyl groups on the bile acid backbone in the host-guest chemistry of bile acid dendrons, we designed and synthesized a new series of C3 symmetric systems and studied the above-mentioned objectives through extraction of polar dyes into nonpolar media. Dye extraction experiments performed using trimeric molecules suggested that only the cholate derivatives (3 and 4) showed considerable extraction of the polar dyes into chloroform; deoxycholate derivatives did not show any extraction, thus emphasizing the importance of the number of hydroxyl groups for dye extraction in these molecular architectures. The effect of steric crowding at the core of these trimeric molecules was shown by efficient extraction of the dyes with the triethylbenzene core (4) compared to the benzene core (3). Greater influence of the aggregates in the case of triethylbenzene core on the extracted dye was also manifested in the Chart 2: Structures of the designed molecules 1-6 value of the induced circular dichroism signal. Surprisingly, a higher analogue in these molecular architectures showed lesser efficiency in dye extraction (on a per bile acid residue basis) compared to the trimers, suggesting a more compact structure for the higher analogue. This was supported by molecular modeling studies. Generality of these systems as nanocarriers for hydrophilic dyes was investigated by screening several other dyes and polar molecules, which are diverse in their structure and functionalities. All these experiments suggested a dependency of the extraction profile on the size of the dye molecule. This was also examined by dynamic light scattering studies, which showed larger size and wider distribution in the size of the aggregates in the case of larger dyes. We also demonstrated selective extraction of a single dye molecule from a blended food color (apple green) using one of the trimer (4) and demonstrated solvent dependent morphological changes in these compounds using electron microscopy. The self-assembly of these amphilic molecules at the air-water interface was studied through Langmuir monolayer studies. Chart 3: Structure of polar guest molecules (Cresol red (7). Erioglaucine (8), Eriochrome black T (9),) phenyl β-D-glucopyranoside (10) and Eosin B (11) Chapter 3: Design and synthesis of bile acid derived surfactants: Study of their aggregation and potential applications Bile acids are facially amphiphilic systems and their amphiphilicity can be improved by attaching polar groups on the bile acid back bone or by synthesizing oligomeric systems which show better self-assembly compared to their monomeric units. To study and improve the amphiphilicity of bile acids, we designed and synthesized a new tripodal surfactant system, with a phosphine oxide based central core to which the bile acids were attached through the C-3 position using click chemistry. Our molecular design also offers added advantage of studying the influence of the stereochemistry at the C-3 position on the aggregation of these molecular architectures. We synthesized trimeric systems with both cholic and deoxycholic acids attached to the central phosphine oxide core with α and β stereochemistry at the C-3 position. Aggregation of these molecules was studied by surface tension measurements, dye extraction studies and NMR. All these compounds showed aggregation at micromolar concentrations. NMR studies suggested changes in the structure of the aggregates at higher temperature and these changes were studied by DLS, which suggested thermodynamically stable monodispersed aggregates for cholic acid derivatives (13 and 15) at higher temperature. These aggregates are stable even after cooling to room temperature and with time. The aggregates of these derivatives were also characterized by atomic force microscopy. Gelation was observed in the case of α derivatives (12 and 13) in phosphate buffer (0.1 M) at pH 7.5 for both deoxy and cholic derivatives, which emphasized the influence of stereochemistry at C-3 position in these architectures. These gels were characterized by rheology experiments. Finally, the possible utility of these micellar systems as model systems to study photophysical processes was demonstrated through lanthanide sensitization experiments in these micellar solutions. Chart 4: Structure of the designed molecules Chapter 4: Synthesis of oligomeric bile acid-taurine conjugates: Study of their aggregation and efficiency in cholesterol solubilization Bile acids are bio-surfactants that are used for the emulsification of fats, vitamins etc. in our body. Bile salts also solubilize the excess cholesterol in our body through mixed micelle formation in the bile and when the bile gets saturated with cholesterol, it leads to cholesterol gallstone formation, which needs to be treated. Ursodeoxycholic acid (UDCA) is used as drug in some cases for the solubilization of (small) cholesterol gallstones, even though the efficiency to solubilize cholesterol is less for UDCA compared to the other bile acids (UDCA is less toxic than the others). So there is a need to develop new cholesterol solubilizing agents. Since oligomeric systems can aggregate better, we designed and synthesized two tetramer taurine conjugates, which differ in the spacer between the bile acid units. Since these conjugates are not soluble in water, their solubility and aggregation was studied in 10% MeOH/Water using pyrene fluorescence experiments. Aggregation studies suggested better aggregation for these molecules compared to their monomeric analogues. These aggregates were also characterized byDLS and electron microscopy. These systems were subsequently studied as nanocarriers for liphophilic dye molecules into aqueous media. Finally, the influence of oligomeric effect in cholesterol solubilization was investigated by cholesterol solubilization studied using these two tetramer taurine compounds and a control, sodium taurocholate. These studies suggested efficient solubilization of cholesterol by oligomers compared to monomeric analogues.(For structural formula pl see the abstract file)

Epilepsy affects up to 1% of the world's population and approximately 2.5 million people in the United States. A considerable portion (30%) of epilepsy patients are refractory to antiepileptic drugs (AEDs), and surgery can not be an effective candidate if the focus of the seizure is on the eloquent cortex. To overcome the problems with existing solutions, a notable portion of biomedical research is focused on developing an implantable or wearable system for automated seizure detection and control. Seizure detection algorithms based on signal rejection algorithms (SRA), deep neural networks (DNN), and neighborhood component analysis (NCA) have been proposed in the IoMT framework. The algorithms proposed in this work have been validated with both scalp and intracranial electroencephalography (EEG, icEEG), and demonstrate high classification accuracy, sensitivity, and specificity. The occurrence of seizure can be controlled by direct drug injection into the epileptogenic zone, which enhances the efficacy of the AEDs. Piezoelectric and electromagnetic micropumps have been explored for the use of a drug delivery unit, as they provide accurate drug flow and reduce power consumption. The reduction in power consumption as a result of minimal circuitry employed by the drug delivery system is making it suitable for practical biomedical applications. The IoMT inclusion enables remote health activity monitoring, remote data sharing, and access, which advances the current healthcare modality for epilepsy considerably.

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3]. Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports have shown the failure of conventional platinum-based chemotherapy due to various side effects and drug resistance [5]. Miriplatin, a member of platinum drug family, has been approved in Japan in 2009 for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma (HCC) [6]. Miriplatin is a lipophilic platinum drug that contains myristates (14-carbon chains) as leaving groups and diamino cyclohexane as the non-leaving carrier ligand. The application of miriplatin in clinic is limited because it has very poor solubilities both in water and in common organic solvents [7]. The structure of solid tumors and tumor microenvironment (TME) in lung cancer constitute a barrier to the deep penetration of chemotherapy agents, which limits the effectiveness of chemotherapy [8]. Nanoparticles with appropriate properties provide a promising delivery system to overcome the biological and physiochemical barriers that hinder anti-cancer activity [9]. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can delivery anti-cancer drugs to improve their anti-cancer activities. In this study, we formulated miriplatin into various micelles, liposomes, and SLNs by film-hydration and evaluated their physicochemical properties and anti-cancer activity against NSCLC cells in culture. Miriplatin-loaded formulations with different compositions were successfully prepared by the film-hydration method. Most miriplatin-loaded micelles were more homogeneous and much smaller than miriplatin-loaded liposomes and SLNs. The majority of miriplatin-loaded micelles were about 15 nm in diameter, while SLNs were around 120 nm, and liposomes were about 180 nm. Formulations with a higher molar ratio of PE-PEG2000 had smaller sizes. SLNs loaded with a higher molar ratio of miriplatin in the compositions showed smaller sizes. Inductively coupled plasma mass spectrometry (ICP-MS) and inductively coupled plasma optical emission spectrometry (ICP-OES) techniques were attempted to quantify the platinum element in the formulations. Formulations with a higher molar ratio of PE-PEG2000 had higher recovery of platinum element. Most miriplatin-loaded formulations had higher than 80% platinum recovery. The recovery of intact miriplatin was characterized by HPLC. Miriplatin-loaded micelles had much higher intact miriplatin recovery (about 100%) than SLNs (about 30%). By TEM imaging, the micelles showed the morphology of spherical dots of about 10 nm in diameter while SLNs showed both spherical and rodlike structures of about 120 nm in diameter. The TEM results were consistent with the size and PDI results by the Zetasizer. Three-dimensional multicellular spheroids (3D MCS) of A549 and A549-iRFP cell lines were successfully established as cell culture models to evaluate activity against non-small cell lung cancer. The viability of 3D MCS after 7-days treatment with miriplatin-loaded micelles was about 0%, which was similar to cisplatin. Miriplatin-loaded formulations with a higher molar ratio of PE-PEG2000 in the compositions had higher anti-cancer activity against 3D MCS. The anticancer activity of miriplatin-loaded formulations against 3D MCS was positively associated with the recovery of intact miriplatin from the formulations. The IC50 value of miriplatin-loaded micelles against A549-iRFP 3D MCS was around 25 µM, while that of cisplatin was 84.78 µM. In summary, the reported lipid-based nano-formulations represent a promising delivery system of miriplatin against NSCLC.

This thesis deals with the study of preparation and characterization of hyaluronan-micelle aggregates. The theoretical part deals with drug delivery systems, characterization of used materials and methods especially fluorescence spectroscopy, dynamic light scattering and turbidimetry. Methods of determination of measured data are summarized in the experimental section. The result section is divided into two subsections dedicated to different preparation methods of hyaluronan-surfactant complexes. Induced aggregates of hyaluronan with Septonex are characterized in terms of their origin and stability, and the results are compared with previously studied surfactants CTAB. In the second part are discussed so-called decorated micelles, their formation, properties and stability.

Tissue engineering (TE) uses a combination of biomaterial scaffolds, cells, and drug delivery systems (DDS) to create tissues that resemble the human physiology. Such engineered tissues could be used to treat, repair, replace, and augment damaged tissues or organs, for disease modeling, and drug screening purposes. This work describes the development and use of novel strategies for engineering neural tissue using a combination of drug delivery systems (DDS), human induced pluripotent stem cells (hiPSCs), and bioprinting technologies for the generation of a drug screening tool to be used in the process of drug discovery and development. The DDS consisted of purmorphamine (puro) loaded microspheres that were fabricated using an oil-in-water single emulsion with 84% encapsulation efficiency and showed the slow release of puro for up to 46 days in vitro. Puro and retinoic acid (RA)-loaded microspheres were combined with hiPSCs-derived neural aggregates (NAs) that differentiated into neural tissues expressing βT-III and showed increased neural extension. hiPCS-derived neural progenitor cells (NPCs) were bioprinted on a layer-by-layer using a fibrin based-bioink and extrusion based- bioprinting. The bioprinted structures showed >81% cellular viability after 7 days of culture in vitro and the expression of the mature motor neuron (MN) markers HB9 and CHAT. Lastly, hiPCS-derived NPCs were bioprinted in combination with puro and RA-loaded microspheres and cultured for 45 days in vitro. The microspheres slowly released the drug and after 30 and 45 days the tissues contained mature neurons, astrocytes and oligodendrocytes expressing CHAT, GFAP, and O4, respectively. Changes in membrane potential indicated tissue responsiveness to different types of treatments such as acetylcholine and gamma-aminobutyric acid (GABA). In the future the bioprinted tissues could contain localized regions of varied drug releasing microspheres using a concentration gradient to promote differentiation into specific cell types in order to create more complex tissues. Moreover, these tissues will benefit from the presence of a neurovascular unit (NVU). Upon validation, the engineered tissues could be used as preclinical tools to test potential drugs and be used for personalized medicine by using patient specific hiPSCs. / Graduate / 2020-11-19

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En los últimos años la gestión de las obras ha tenido un desarrollo importante en el Perú a partir de la incorporación de prácticas jurídicas y técnicas propias del mundo anglosajón, como es el caso de los formatos contractuales internacionales (NEC y FIDIC), y tecnologías como el building information modelling. Así, con el pasar del tiempo presenciamos un acercamiento de las figuras del construction law a nuestro sistema jurídico. En ese contexto, la presente investigación analiza una de las figuras medulares del construction law: el project delivery system, con el objetivo de demostrar, en primer término, su compatibilidad con nuestro sistema jurídico, y, en segundo término, que a través de dicha figura los agentes intervinientes de la obra pueden gestionar con eficacia y eficiencia uno de los conflictos más recurrentes en la industria: los derivados de los errores y/o indefiniciones del alcance. / In recent years, the management of works has had an important development in Peru from the incorporation of legal and technical practices typical of the Anglo-Saxon world, as is the case of international contractual formats (NEC and FIDIC), and technologies such as building information modeling. Thus, with the passing of time we witness an approach of the figures of construction law to our legal system. In this context, the present research analyzes one of the core figures of construction law: the project delivery system, with the aim of demonstrating, firstly, its compatibility with our legal system, and, secondly, that through said figure the agents involved in the work can effectively and efficiently manage one of the most recurrent conflicts in the industry: those derived from errors and / or indefinite scope. / Tesis

Background: Electronic nicotine delivery systems (ENDS) use among adolescents in the United States (U.S.) has surpassed conventional tobacco products (CTPs), including cigarettes. Increasingly, ENDS are used concurrently with CTPs and substances such as cannabis. However, few studies involve Central Appalachia, a region with historically high rates of tobacco and other substance use. Objective: To examine prevalence of concurrent use of ENDS and cannabis among school-going adolescents in Appalachian Tennessee and delineate associations between ENDS use and substance-related risk behavior (cannabis use), social relations (peer use), and school-related risk behavior (academic performance). Methods: Data were obtained from a survey conducted with youth aged 13-17 years in 2018 in a county in Appalachian Tennessee (n = 280). A multivariable logistic regression model was fit to evaluate associations between ENDS and cannabis use, and other factors. Results: Overall, lifetime ENDS and cannabis prevalence estimates were 31.1% and 18.6%, respectively. Lifetime ENDS users had increased odds of also being lifetime cannabis users [OR = 9.22, 95% confidence interval (CI): 3.44-24.75]. Lifetime ENDS users had increased odds of reporting ENDS use among peers [OR = 12.11; 95% CI: 5.40-27.12] and lower academic performance (OR associated with mostly C or D vs. A grades was 4.28, 95% CI: 1.68-10.90). Conclusion: This study found an association between ENDS and cannabis use among adolescents in Appalachian Tennessee exists. Additionally, peer use and academic performance were associated with ENDS use. The findings have implications for public health intervention planning to address not only ENDS but also substance use among Appalachian youth.

Cooperative Construction in Schools in California John M. Donley The construction industry has lost efficiency since 1964, while becoming increasingly more litigious. Schools in California can ill afford the time to allow the construction industry time to fully evolve. It may take years or decades to fully improve the efficiency of, and reduce the conflict within the construction industry. At the same time, the construction industry has developed new processes to improve efficiency and reduce conflict. These processes are beginning to be broadly embraced by the industry. They all contain cooperative elements. Taken together they represent a new organizing principle for the construction industry, cooperative construction. Also concurrently, a previously little-used provision of the California Education Code allows schools freedom to contract for school construction in nearly any reasonable contractual arrangement they see fit for their project and district needs. As a result, school districts in California have developed a new system of project delivery. They are borrowing from here and there and inventing new tools to make projects work for them. Again, cooperative elements at the hearts of the processes.