Contract enforcement and incentive compatibility in large economies with differential information: the role of exact feasibility

We consider exchange economies with a continuum of agents and differential information about finitely many states of nature. It was proved in Einy, Moreno and Shitovitz (2001) that if we allow for free disposal in the market clearing (feasibility) constraints then an irreducible economy has a competitive (or Walrasian expectations) equilibrium, and moreover, the set of competitive equilibrium allocations coincides with the private core. However when feasibility is defined with free disposal, competitive equilibrium allocations may not be incentive compatible and contracts may not be enforceable (see e.g. Glycopantis, Muir and Yannelis (2002)). This is the main motivation for considering equilibrium solutions with exact feasibility. We first prove that the results in Einy et al. (2001) are still valid without free-disposal. Then we define an incentive compatibility property motivated by the issue of contracts’ execution and we prove that every Pareto optimal exact feasible allocation is incentive compatible, implying that contracts of a competitive or core allocations are enforceable.

Regulação por contrato no setor de saneamento: o caso de Ribeirão Preto

A ampliação dos serviços de saneamento básico é uma questão fundamental para o desenvolvimento econômico e social. Requer, contudo, investimentos vultosos, nem sempre disponíveis, especialmente no setor público. No Brasil, o setor de saneamento é fortemente marcado pela presença de grandes companhias públicas estaduais, criadas no final da década de 1960. No entanto, em um contexto de alteração do paradigma do Estado como produtor direto de bens e serviços para o Estado regulador, alguns municípios incorporaram agentes privados ao setor, celebrando contratos de concessão de serviços de água e esgoto. Para tanto, utilizaram o próprio instrumento contratual como o arcabouço regulatório dos serviços, numa situação de regulação por contrato. Esse trabalho discute a regulação por contrato no setor de saneamento, apresentando, ao final, uma análise do caso de Ribeirão Preto, cidade do interior paulista que, em 1995, concedeu a uma empresa privada os serviços de tratamento e disposição final de esgotos. A dissertação discorre sobre a evolução histórica do setor de saneamento, os principais aspectos regulatórios e os fatores relevantes para a análise de uma iniciativa de regulação por contrato no nível local. Destaca que a regulação por contrato não pode ser resumida aos dispositivos contratuais, envolvendo também a dinâmica entre regulador e regulado, e aponta para o delicado equilíbrio entre segurança e flexibilidade da relação contratual de longo prazo.

Adaptation of the international investment contract: the hardship clause

Este trabalho acadêmico explora, em linhas gerais, a questão da adaptação do contrato de investimento internacional, e o tema ‘cláusula de hardship’ em específico. Objetiva-se efetuar uma análise detalhada da cláusula de hardship, como meio de adaptação e flexibilização de contratos internacionais de investimento sob a ótica da prática jurídica e mercantil contemporânea. A discussão se centra no contraste entre a possibilidade de adaptação do contrato por circunstâncias imprevisíveis e o imperativo de previsibilidade no investimento. Nesse sentido, o estudo busca oferecer soluções práticas para o dilema existente entre a necessidade de segurança na relação econômica (cumprimento do contato) e a prevenção da possibilidade de ruína financeira para quaisquer das partes no caso de uma mudança brusca no contexto dos negócios. O trabalho está centrado em uma investigação teórica acerca dos temas de readaptação contratual; diferenças entre sistemas jurídicos de estados-nações, e suas consequências no comércio internacional; e a cláusula de hardship em si. Como forma de contribuir para uma compreensão prática na questão da adaptação do contrato de investimento internacional devido a fatores imprevistos, este trabalho analisa casos reais e tendências atuais observadas na arbitragem internacional.

Sociedade em conta de participação : riscos de descaracterização do tipo societário e suas consequências

Este trabalho se dispõe a analisar as características das sociedades em conta de participação ou SCP’s, seus principais usos, os riscos de sua descaracterização e suas respectivas consequências. As SCP’s experimentaram crescimento de sua importância e uso nos últimos anos, sendo constatadas na estruturação de diversos tipos de negócios, com destaque na área imobiliária e na realização de investimentos. Como um dos tipos societários admitidos pela legislação, as SCP’s possuem grande plasticidade em sua utilização, adaptando-se às diversas necessidades de seus usuários. Algumas características específicas, no entanto, devem ser observadas pelas partes, sob risco de sua descaracterização. É o caso do papel dos sócios participantes, que não poderão se envolver na execução do objeto da SCP, nem contribuir para a formação do seu patrimônio especial com serviços que tenham relação direta com o seu objeto. E os riscos vão além daqueles previstos no Código Civil, que aponta a solidariedade, com o sócio ostensivo, do sócio participante perante terceiros afetados. Do ponto de vista fiscal, poderá haver a descaracterização da SCP para se considerar a prestação de serviços, quando ocorrerá a incidência de tributos sobre os pagamentos feitos ao sócio participante a título de dividendos. Outros riscos e consequências em modelos de negócio adotados foram explorados e apontados ao longo do trabalho, em que as SCP’s são utilizadas para dissimular uma situação jurídica, de modo a gozar de alguma vantagem. É o caso da previsão de distribuição de resultado em SCP com bens ou coisa certa e não com capital, poderia dissimular um contrato de compra e venda, e quando tal SCP for formada por um grupo de pessoas, poderia dissimular um consórcio para entrega de bens, regido pela Lei 11.795/2008. A divulgação pública de SCP, para captação de investidores, poderia caracterizar a operação como um contrato de investimento coletivo, regulado pela Lei 6.385/1976. Ao final foram listados, como sugestão, alguns cuidados a serem observados para se evitar os riscos apontados ao longo deste trabalho.

Análise dos fundamentos do modelo value-based health care delivery à luz das teorias de estratégia

O setor de saúde, globalmente, apresenta problemas relacionados aos seus custos, qualidade e acesso. Porter e Teisberg (2004, 2006) propuseram modelo de gestão específico para a administração estratégica na área, o Value-Based Health Care Delivery (VBHCD). O modelo teve relativa repercussão e vem influenciando muitos atores no setor. Contudo, o modelo vem sendo aceito sem o devido questionamento de seus fundamentos e consistência com a teoria em estratégia. O presente trabalho busca, por meio de um ensaio teórico, analisar o modelo proposto à luz de paradigmas gerais da estratégia empresarial como, por exemplo, o modelo de Porter e a Visão Baseada em Recursos (RBV). Inicialmente, o artigo sintetiza as explicações teóricas do modelo porteriano clássico e da RBV. Em seguida, o VBHCD é examinado comparado a essas explicações, buscando-se relações e, eventualmente, contradições. Conclui-se que o modelo VBHCD não se alinha integralmente a nenhum corpo teórico isoladamente. Mesmo sendo proposto por Porter, parte de seus fundamentos advém, na verdade, de outras correntes teóricas. Esta abordagem integradora de teorias concorrentes, apesar de presente na literatura, ainda apresenta dificuldades e barreiras, um aspecto que não está explícito no modelo

Functionalization of dendrimers for improved gene delivery to mesenchymal stem cell

Disease, injury, and age problems compromise human quality of life and continuously motivate the search for new and more efficacious therapeutic approaches. The field of Tissue Regeneration and Engineering has greatly evolved over the last years, mainly due to the combination of the important advances verified in Biomaterials Science and Engineering with those of Cell and Molecular Biology. In particular, a new and promising area arose – Nanomedicine – that takes advantage of the extremely small size and especial chemical and physical properties of Nanomaterials, offering powerful tools for health improvement. Research on Stem Cells, the self-renewing progenitors of body tissues, is also challenging to the medical and scientific communities, being expectable the appearance of new and exciting stem cell-based therapies in the next years. The control of cell behavior (namely, of cell proliferation and differentiation) is of key importance in devising strategies for Tissue Regeneration and Engineering. Cytokines, growth factors, transcription factors and other signaling molecules, most of them proteins, have been identified and found to regulate and support tissue development and regeneration. However, the application of these molecules in long-term regenerative processes requires their continuous presence at high concentrations as they usually present short half-lives at physiological conditions and may be rapidly cleared from the body. Alternatively, genes encoding such proteins can be introduced inside cells and be expressed using cell’s machinery, allowing an extended and more sustained production of the protein of interest (gene therapy). Genetic engineering of stem cells is particularly attractive because of their self-renewal capability and differentiation potential. For Tissue Regeneration and Engineering purposes, the patient’s own stem cells can be genetically engineered in vitro and, after, introduced in the body (with or without a scaffold) where they will not only modulate the behavior of native cells (stem cell-mediated gene therapy), but also directly participate in tissue repair. Cells can be genetically engineered using viral and non-viral systems. Viruses, as a result of millions of years of evolution, are very effective for the delivery of genes in several types of cells, including cells from primary sources. However, the risks associated with their use (like infection and immunogenic reactions) are driving the search for non-viral systems that will efficiently deliver genetic material into cells. Among them, chemical methods that are promising and being investigated use cationic molecules as carriers for DNA. In this case, gene delivery and gene expression level remain relatively low when primary cells are used. The main goal of this thesis was to develop and assess the in vitro potential of polyamidoamine (PAMAM) dendrimers based carriers to deliver genes to mesenchymal stem cells (MSCs). PAMAM dendrimers are monodispersive, hyperbranched and nanospherical molecules presenting unique characteristics that make them very attractive vehicles for both drug and gene delivery. Although they have been explored for gene delivery in a wide range of cell lines, the interaction and the usefulness of these molecules in the delivery of genes to MSCs remains a field to be explored. Adult MSCs were chosen for the studies due to their potential biomedical applications (they are considered multipotent cells) and because they present several advantages over embryonic stem cells, such as easy accessibility and the inexistence of ethical restrictions to their use. This thesis is divided in 5 interconnected chapters. Chapter I provides an overview of the current literature concerning the various non-viral systems investigated for gene delivery in MSCs. Attention is devoted to physical methods, as well as to chemical methods that make use of polymers (natural and synthetic), liposomes, and inorganic nanoparticles as gene delivery vectors. Also, it summarizes the current applications of genetically engineered mesenchymal stem cells using non-viral systems in regenerative medicine, with special focus on bone tissue regeneration. In Chapter II, the potential of native PAMAM dendrimers with amine termini to transfect MSCs is evaluated. The level of transfection achieved with the dendrimers is, in a first step, studied using a plasmid DNA (pDNA) encoding for the β-galactosidase reporter gene. The effect of dendrimer’s generation, cell passage number, and N:P ratio (where N= number of primary amines in the dendrimer; P= number of phosphate groups in the pDNA backbone) on the level of transfection is evaluated, being the values always very low. In a second step, a pDNA encoding for bone morphogenetic protein-2, a protein that is known for its role in MSCs proliferation and differentiation, is used. The BMP-2 content produced by transfected cells is evaluated by an ELISA assay and its effect on the osteogenic markers is analyzed through several classical assays including alkaline phosphatase activity (an early marker of osteogenesis), osteocalcin production, calcium deposition and mineralized nodules formation (late osteogenesis markers). Results show that a low transfection level is enough to induce in vitro osteogenic differentiation in MSCs. Next, from Chapter III to Chapter V, studies are shown where several strategies are adopted to change the interaction of PAMAM dendrimers with MSCs cell membrane and, as a consequence, to enhance the levels of gene delivery. In Chapter III, generations 5 and 6 of PAMAM dendrimers are surface functionalized with arginine-glycine-aspartic acid (RGD) containing peptides – experiments with dendrimers conjugated to 4, 8 and 16 RGD units were performed. The underlying concept is that by including the RGD integrin-binding motif in the design of the vectors and by forming RGD clusters, the level of transfection will increase as MSCs highly express integrins at their surface. Results show that cellular uptake of functionalized dendrimers and gene expression is enhanced in comparison with the native dendrimers. Furthermore, gene expression is dependent on both the electrostatic interaction established between the dendrimer moiety and the cell surface and the nanocluster RGD density. In Chapter IV, a new family of gene delivery vectors is synthesized consisting of a PAMAM dendrimer (generation 5) core randomly linked at the periphery to alkyl hydrophobic chains that vary in length and number. Herein, the idea is to take advantage of both the cationic nature of the dendrimer and the capacity of lipids to interact with biological membranes. These new vectors show a remarkable capacity for internalizing pDNA, being this effect positively correlated with the –CH2– content present in the hydrophobic corona. Gene expression is also greatly enhanced using the new vectors but, in this case, the higher efficiency is shown by the vectors containing the smallest hydrophobic chains. Finally, chapter V reports the synthesis, characterization and evaluation of novel gene delivery vectors based on PAMAM dendrimers (generation 5) conjugated to peptides with high affinity for MSCs membrane binding - for comparison, experiments are also done with a peptide with low affinity binding properties. These systems present low cytotoxicity and transfection efficiencies superior to those of native dendrimers and partially degraded dendrimers (Superfect®, a commercial product). Furthermore, with this biomimetic approach, the process of gene delivery is shown to be cell surface receptor-mediated. Overall, results show the potential of PAMAM dendrimers to be used, as such or modified, in Tissue Regeneration and Engineering. To our knowledge, this is the first time that PAMAM dendrimers are studied as gene delivery vehicles in this context and using, as target, a cell type with clinical relevancy. It is shown that the cationic nature of PAMAM dendrimers with amine termini can be synergistically combined with surface engineering approaches, which will ultimately result in suitable interactions with the cytoplasmic membrane and enhanced pDNA cellular entry and gene expression. Nevertheless, the quantity of pDNA detected inside cell nucleus is always very small when compared with the bigger amount reaching cytoplasm (accumulation of pDNA is evident in the perinuclear region), suggesting that the main barrier to transfection is the nuclear membrane. Future work can then be envisaged based on the versatility of these systems as biomedical molecular materials, such as the conjugation of PAMAM dendrimers to molecules able to bind nuclear membrane receptors and to promote nuclear translocation.

Cell-responsive nanogels for anticancer drug delivery

One of the main goals in Nanomedicine is to create innovative drug delivery systems (DDS) capable of delivering drugs into a specific location with high efficiency. In the development of DDS, some essential properties are desired, such as biocompatibility and biodegradability. Furthermore, an ideal DDS should be able to deliver a drug in a controlled manner and minimize its side effects. These two objectives are still a challenge for researchers all around the world. Nanogels are an excellent vehicle to use in drug delivery and several other applications due to their biocompatibility. They are polymer-based networks, chemically or physically crosslinked, with at least 80-90% water in their composition. Their properties can be tuned, like the nanogel size, multifunctionality and degradability. Nanogels are capable of carrying in their interior bioactive molecules and deliver them into cells. The main objective of this project was to produce nanogels for the delivery of anticancer drugs with the ability of responding to existent stimuli inside cells (cellresponsiveness nanogels) and/or of controlled drug delivery. The nanogels were mainly based on alginate (AG), a natural biopolymer, and prepared using emulsion approaches. After their synthesis, they were used to encapsulate doxorubicin (Dox) which was chosen as a model drug. In the first part of the experimental work, disulfide-linked AG nanogels were prepared and, as expected, were redox-sensitive to a reducing environment like the intracellular medium. In the second part, AG nanogels crosslinked with both calcium ions and cationic poly(amidoamine) dendrimers were developed with improved sustained drug delivery. The prepared nanogels were characterized in terms of size, chemical composition, morphology, and drug delivery behavior (under redox/pH stimuli). The in vitro cytotoxicity of the nanogels was also tested against CAL-72 cells (an osteosarcoma cell line).

Seven stories: location based story-delivery system

Location aware content-based experiences have a substantial tradition in HCI, several projects over the last two decades have explored the association of digital media to specific locations or objects. However, a large portion of the literature has little focus on the creative side of designing of the experience and on the iterative process of user evaluations. In this thesis we present two iterations in the design and evaluation of a location based story delivery system (LBSDS), inspired by local folklore and oral storytelling in Madeira. We started by testing an already existing location based story platform, PlaceWear, with short multimedia clips that recounted local traditions and folktales, to this experience we called iLand. An initial evaluation of iLand, was conducted; we shadowed users during the experience and then they responded to a questionnaire. By analyzing the evaluation results we uncovered several issues that informed the redesign of the system itself as well as part of the story content. The outcome of this re design was the 7Stories experience. In the new experience we performed the integration of visual markers in the interface and the framing of the fragmented story content through the literary technique of the narrator. This was done aiming to improving the connection of the audience to the physical context where the experience is delivered. The 7Stories experience was evaluated following a similar methodology to the iLand evaluation but the user’s experience resulted considerably different; because of the same setting for the experience in both versions and the constancy of the most of the content across the two versions we were able to assess the specific effect of the new design and discuss its strengths and shortcomings. Although we did not run a formal and strict comparative test between the two evaluations, it is evident from the collected data how the specific design changes to our LBSDS influenced the user experience.

PEGylated polyethyleneimine-entrapped gold nanoparticles for enhanced and targeted gene delivery applications

Gene therapy, which involves the transfer of nucleic acid into target cells in patients, has become one of the most important and widely explored strategies to treat a variety of diseases, such as cancer, infectious diseases and genetic disorders. Relative to viral vectors that have high immunogenicity, toxicity and oncogenicity, non-viral vectors have gained a lot of interest in recent years. This is largely due to their ability to mimic viral vector features including the capacity to overcome extra- and intra-cellular barriers and to enhance transfection efficiency. Polyethyleneimine (PEI) has been extensively investigated as a non-viral vector. This cationic polymer, which is able to compact nucleic acid through electrostatic interactions and to transport it across the negatively charged cell membranes, has been shown to effectively transfect nucleic acid into different cell lines. Moreover, entrapment of gold nanoparticles (Au NPs) into such an amine-terminated polymer template has been shown to significantly enhance gene transfection efficiency. In this work, a novel non-viral nucleic acid vector system for enhanced and targeted nucleic acid delivery applications was developed. The system was based on the functionalization of PEI with folic acid (FA; for targeted delivery to cancer cells overexpressing FA receptors on their surface) using polyethylene glycol (PEG) as a linker molecule. This was followed by the preparation of PEI-entrapped Au NPs (Au PENPs; for enhancement of transfection efficiency). In the synthesis process, the primary amines of PEI were first partially modified with fluorescein isothiocyanate (FI) using a molar ratio of 1:7. The formed PEI-FI conjugate was then further modified with either PEG or PEGylated FA using a molar ratio of 1:1. This process was finally followed by entrapment of Au NPs into the modified polymers. The resulting conjugates and Au PENPs were characterized by several techniques, namely Nuclear Magnetic Resonance, Dynamic Light Scattering and Ultraviolet-Visible Spectroscopy, to assess their physicochemical properties. In the cell biology studies, the synthesized conjugates and their respective Au PENPs were shown to be non-toxic towards A2780 human ovarian carcinoma cells. The role of these materials as gene delivery agents was lastly evaluated. In the gene delivery studies, the A2780 cells were successfully transfected with plasmid DNA using the different vector systems. However, FA-modification and Au NPs entrapment were not determinant factors for improved transfection efficiency. In the gene silencing studies, on the other hand, the Au PENPs were shown to effectively deliver small interfering RNA, thereby reducing the expression of the B-cell lymphoma 2 protein. Based on these results, we can say that the systems synthesized in this work show potential for enhanced and targeted gene therapy applications.

Gene delivery using dendrimer/pDNA complexes immobilized in electrospun fibers using the layer-by-layer technique

Tissue engineering is an important branch of regenerative medicine that uses cells, materials (scaffolds), and suitable biochemical and physicochemical factors to improve or replace specific biological functions. In particular, the control of cell behavior (namely, of cell adhesion, proliferation and differentiation) is a key aspect for the design of successful therapeutical approaches. In this study, poly(lactic-co-glycolic acid) (PLGA) fiber mats were prepared using the electrospinning technology (the fiber diameters were in the micrometer range). Furthermore, the electrospun fiber mats thus formed were functionalized using the layer-by- layer (LbL) technique with chitosan and alginate (natural and biodegradable polyelectrolytes having opposite charges) as a mean for the immobilization of pDNA/dendrimer complexes. The polyelectrolyte multilayer deposition was confirmed by fluorescence spectroscopy using fluorescent-labeled polyelectrolytes. The electrospun fiber mats coated with chitosan and alginate were successfully loaded with complexes of pDNA and poly(amidoamine) (PAMAM) dendrimers (generation 5) and were able of releasing them in a controlled manner along time. In addition, these mats supported the adhesion and proliferation of NIH 3T3 cells and of human mesenchymal stem cells (hMSCs) in their surface. Transfection experiments using a pDNA encoding for luciferase showed the ability of the electrospun fiber mats to efficiently serve as gene delivery systems. When a pDNA encoding for bone morphogenetic protein-2 (BMP-2) was used, the osteoblastic differentiation of hMSCs cultured on the surface of the mats was promoted. Taken together, the results revealed that merging the electrospinning technique with the LbL technique, can be a suitable methodology for the creation of biological active matrices for bone tissue engineering.

Nanotechnological delivery systems for the oral administration of active molecules: Polymeric microparticles and microemulsions applied to anti-inflammatory and anti-infectious drugs

This thesis was devoted to the development of innovative oral delivery systems for two different molecules. In the first part, microparticles (MPs) based on xylan and Eudragit® S- 100 were produced and used to encapsulate 5-aminosalicylic acid for colon delivery. Xylan was extracted from corn cobs and characterized in terms of its physicochemical, rheological and toxicological properties. The polymeric MPs were prepared by interfacial cross-linking polymerization and spray-drying and characterized for their morphology, mean size and distribution, thermal stability, crystallinity, entrapment efficiency and in vitro drug release. MPs with suitable physical characteristics and satisfactory yields were prepared by both methods, although the spray-dried systems showed higher thermal stability. In general, spraydried MPs would be preferable systems due to their thermal stability and absence of toxic agents used in their preparation. However, drug loading and release need to be optimized. In the second part of this thesis, oil-in-water microemulsions (O/W MEs) based on mediumchain triglycerides were formulated as drug carriers and solubility enhancers for amphotericin B (AmB). Phase diagrams were constructed using surfactant blends with hydrophiliclipophilic balance values between 9.7 and 14.4. The drug-free and drug-loaded MEs presented spherical non-aggregated droplets around 80 and 120 nm, respectively, and a low polydispersity index. The incorporation of AmB was high and depended on the volume fraction of the disperse phase. These MEs did not reduce the viability of J774.A1 macrophage-like cells for concentrations up to 25 μg/mL of AmB. Therefore, O/W MEs based on propylene glycol esters of caprylic acid may be considered as suitable delivery systems for AmB

Drug delivery systems: Past, present, and future

Drug delivery systems are essential components of drugs controlled release. In the last decades, several drug delivery technologies have emerged including capsules, liposomes. microparticles, nanoparticles, and polymers. These components must be biocompatible, biodegradable, and display a desired biodistribution providing a long-term availability of the therapeutic at specific target over time.