O objetivo deste estudo foi desenvolver e avaliar in vivo sistemas bioadesivos semissólidos (géis) e filmes contendo metronidazol e benzoato de metronidazol microencapsulado, liberado modificadamente intrabolsa periodontal, em pacientes submetidos a tratamento convencional para periodontite crônica (Raspagem e Alisamento Radicular - RAR) e a tratamento associado RAR ao gel ou ao filme. Foi realizado um estudo clínico controlado, randomizado e duplocego em humanos, para testar a hipótese de que o uso associado do sistema de liberação local (filme ou gel) à raspagem e alisamento radicular (RAR) é superior à terapia isolada. Participaram do estudo 45 pacientes de ambos os gêneros, da Faculdade de Odontologia de Ribeirão Preto da USP, os quais possuíam ao menos 2 dentes com periodontite crônica, totalizando para o estudo um &ldquo;n&rdquo; de 96 dentes, divididos aleatoriamente em 3 grupos: grupo 1 raspagem e alisamento radicular (RAR) controle ativo; grupo 2 - RAR + gel de metronidazol; grupo 3 RAR + filme com metronidazol. As concentrações dos fármacos e o tempo de liberação no fluido crevicular gengival foram monitorados. Os efeitos dos tratamentos foram avaliados pelo acompanhamento longitudinal de parâmetros clínicos (profundidade de sondagem, nível clínico de inserção e sangramento à sondagem) com o uso de sonda periodontal computadorizada e analisados estatisticamente por meio de ANOVA e pós-teste de Bonferroni, e microbiológicos da periodontite pela técnica de DNA-DNA Checkerboard Hibridization. Os resultados da análise das concentrações de metronidazol e benzoato de metronidazol nas bolsas periodontais dos pacientes foram considerados em avaliação paralela intragrupos e demonstraram que os fármacos foram detectados em concentração efetiva até 48 horas após a aplicação in situ, porém não foi observada diferença significante entre os grupos avaliados. Para os parâmetros microbiológicos foi detectada diferença estatística (teste de Friedmann, para valores de p<0,05) em relação aos grupos com utilização dos fármacos comparado ao grupo somente com a RAR. Conclui-se que o tratamento com os fármacos em ambas formas farmacêuticas (gel e filme), foi mais efetivo que o controle para a redução significativa dos microrganismos, tornando-se alternativa terapêutica de grande valia. / The aim of this study was to develop and evaluate in vivo bioadhesive semisolid systems (gels) and films containing metronidazole and metronidazole benzoate microencapsulated, modified release periodontal intrapocket, in patients undergoing conventional treatment for chronic periodontitis (RAR) and associated with RAR gel or film. A double - blind controlled human clinical trial was conducted to test the hypothesis that the use of the local delivery system (film or gel) to scaling and root planing (RAR) is superior to the isolated therapy. The study consisted of 45 patients from the Dental School of Ribeirão Preto - USP, both of whom had at least 2 teeth with chronic periodontitis, comprising a total of 96 teeth, randomly divided into 3 groups: group 1 - Scaling and root planing (RAR) - active control; Group 2 - RAR + gel with metronidazole Group 3 -. RAR + film with metronidazole; drug concentrations and release time in the gingival crevicular fluid were monitored. The effects of the treatments were evaluated by the longitudinal monitoring of clinical parameters (depth of probing, clinical level of insertion and bleeding to the probing) and analyzed statistically by ANOVA and Bonferroni post-test, and microbiological periodontitis by DNA-DNA Checkerboard Hibridization. The results of the analysis of metronidazole and metronidazole benzoate concentrations in patients\' periodontal pockets were considered in parallel intragroup analyzes and demonstrated that the drugs were detected in effective concentration up to 48 hours after the in situ application, but no significant difference was observed between the Groups evaluated. For the microbiological parameters a statistical difference was detected (Friedmann test, for values of p <0.05) in relation to the groups using the drugs compared to the RAR only group. It was concluded that the treatment with the drugs in both pharmaceutical forms (gel and film), was more effective than the control for the significant reduction of the microorganisms, becoming a therapeutic alternative of great value.

Traffic congestion can cause late deliveries, decreased profits from vehicle fuel idling in traffic, and delayed distribution in tight delivery windows. The focus of this study was on developing strategies that business leaders could use to increase on-time deliveries. The conceptual frameworks for this case study were systems theory, traffic equilibrium theory, bathtub theory, and kinematic wave theory. Data were collected from semistructured interviews with 6 delivery service leaders from 3 delivery businesses in Southcentral Alaska. In addition, secondary data were collected from government information. Interview responses were coded to identify trends including delivery time, business activity, and amount of roadway congestion. Two major themes emerged from the interviews: time of day affecting when traffic congestion occurred, and limited alternate transportation routes causing congestion in Southcentral Alaska. The findings indicated that the best strategy to help reduce traffic congestion involved instituting toll optimization and high occupant vehicles lanes. The implications for effecting social change include how business leaders can help reduce traffic congestion using toll optimization, and how high occupant vehicle lanes could encourage Southcentral Alaskans to carpool.

Osteomyelitis is an infection of bone or bone marrow, usually caused by pyogenic bacteria. It can cultivate by hematogen way or it can cultivate by the help of local soft tissue infection. Osteomyelitis often requires prolonged antibiotic therapy and surgery. But for therapy / antibiotic must reach to effective dose in the bone. So that / for prevention and treatment of osteomyelitis controlled antibiotic release systems can be used. These systems have been developed to deliver antibiotics directly to infected tissue. As a carrier material / polymers are widely use. Polymer can be biodegradable or non biodegradable. The advantage of biodegradable polymers is / you do not need a second surgery for the removal of the carrier material from the body. In this study / vancomycin loaded PLLA/TCP composites were developed and characterized to treat implant related chronic osteomyelitis in experimental rat osteomyelitis model. Some of the composites were prepared by coating the vancomycin loaded composites with PLLA to observe the difference between the coated and uncoated composites. Also, some composites were developed free from the vancomycin to determine the biocompatibility of the composite for the bone tissue. The coating extended the release of the vancomycin up to 5 weeks and changed the surface morphology of the composites. According to the cell culture studies, vancomycin loaded PLLA/TCP composites promoted cell adhesion, cell proliferation and mineralization so / the composite was biocompatible with bone tissue. Radiological and microbiological evaluations showed that vancomycin loaded and coated vancomycin loaded PLLA/TCP composites inhibited MRSA proliferation and treat implant related chronic osteomyelitis.

The aim of this study was to develop drug delivery system based on poly(lactic acid-co-glycolic acid) (PLGA) nanoparticles (NPs) to achieve personalized treatment of selected skin disorders, like photo-aging, psoriasis and atopic dermatitis. Dead Sea Water (DSW) and Retinyl Palmitate (RP) were used as active agents and they were loaded in PLGA NPs prepared either as spheres or capsules by o/w or w/o/w methods. MgCl2 and bovine serum albumin (BSA) served as model active compounds. The diameter of the NPs was found to be in the range of 280 - 550 nm. The entrapment efficiency (E.E.) was less than 1% for RP, DSW and MgCl2, and 41% for BSA. Loading of Cl- together with BSA doubled the E.E. value of Cl- . In situ release studies showed a burst in the first day and more than 85% of the chloride content was released within a week. When the macromolecule BSA was encapsulated, a much slower and triphasic release profile was observed which continued for up to 80 days. In vitro tests were performed using L929 fibroblast cells. Results of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) test revealed that none of the NPs were cytotoxic. Additionally, all particles were hemocompatible with hemolytic activity &lt / 1.5%. L929 fibroblast and Saos 2 human osteosarcoma cells were used to study the uptake of NPs by the cells. Particles accumulate near the nucleus. The characterization and cell viability tests, and drug release behavior indicate the suitability of these NPs for further testing to develop a patient specific skin diseases treatment approach.

Neural networks have been extensively used for adaptive system identification as well as adaptive and neuroadaptive control of highly uncertain systems. The goal of adaptive and neuroadaptive control is to achieve system performance without excessive reliance on system models. To improve robustness and the speed of adaptation of adaptive and neuroadaptive controllers several controller architectures have been proposed in the literature. In this dissertation, we developed a new neuroadaptive control architecture for nonlinear uncertain dynamical systems as well as nonlinear nonnegative uncertain dynamical systems. Nonnegative systems are essential in capturing the behavior of a wide range of dynamical systems involving dynamic states whose values are nonnegative. A subclass of nonnegative dynamical systems are compartmental systems. These systems are derived from mass and energy balance considerations and are comprised of homogeneous interconnected microscopic subsystems or compartments which exchange variable quantities of material via intercompartmental flow laws. In this research, we developed a direct adaptive and neuroadaptive control framework for stabilization, disturbance rejection and noise suppression for nonnegative and compartmental dynamical systems with exogenous system disturbances. Furthermore, we developed a new neuroadaptive control architecture for nonlinear uncertain dynamical systems. Specifically, the proposed framework involves a new and novel controller architecture involving additional terms, or Q-modification terms, in the update laws that are constructed using a moving time window of the integrated system uncertainty. The Q-modification terms can be used to identify the ideal neural network system weights which can be used in the adaptive law. In addition, these terms effectively suppress system uncertainty. Finally, neuroadaptive output feedback control architecture for nonlinear nonnegative dynamical systems with input amplitude and integral constraints is developed. This architecture is used to control lung volume and minute ventilation with input pressure constraints that also accounts for spontaneous breathing by the patient. Specifically, we develop a pressure- and work-limited neuroadaptive controller for mechanical ventilation based on a nonlinear multi-compartmental lung model. The control framework does not rely on any averaged data and is designed to automatically adjust the input pressure to the patient's physiological characteristics capturing lung resistance and compliance modeling uncertainty. Moreover, the controller accounts for input pressure constraints as well as work of breathing constraints. The effect of spontaneous breathing is incorporated within the lung model and the control framework.

Commercial organic dyes are widely used for cellular staining due to their small size, high brightness, and chemical functionality. However, their blinking and photobleaching are not ideal for studying dynamics inside live cells. An improvement over organics and much larger quantum dots, silver nanodots (Ag NDs) exhibit low cytotoxicity and excellent brightness and photostability, while retaining small size. We have utilized ssDNA hairpin structures to encapsulate Ag NDs with excellent spectral purity, high concentration, and good chemical and photophysical stability in a variety of biological media. Multi-color staining of fixed and live cells has been achieved, suggesting the promise of Ag NDs as good fluorophores for intracellular imaging. The great brightness and photostability of Ag nanodots indicate that they might be outstanding imaging agents for in vivo studies when encapsulated in delivery vehicles. In addition, Ag NDs can be optically modulated, resulting in increased sensitivity within high backgrounds. These good characteristics are combined with delivery vehicles such as PLGA and nanogels. After encapsulation, Ag nanodots still retain their good photophysical properties and modulation. It might be useful for in vivo applications in the near future

The American Heart Association (AHA) estimates that at least one American will die from a coronary event every minute, costing over $150 billion in 2008 alone. Regenerating the myocardium of patients that survive the initial infarction has proven to be an elusive goal. A variety of factors - including the loss of contractile cells, inflammatory response following infarction, cardiac hypertrophy, and lack of suitable cues for progenitor cells - causes fibrosis in the heart and loss of cardiac function. This dissertation examines three drug delivery strategies aimed at improving conditions for cardiac regeneration: polyketal microspheres as non-inflammatory drug delivery vehicles; surface functionalization of microparticles with nitrilotriacetic acid-nickel (NTA-Ni) for non-covalent tethering of proteins; and using Hoechst-inspired ligands for targeting extracellular DNA in necrotic tissue.

The invasive nature of glioblastoma (GBM) represents a significant challenge to the standard of care and contributes to poor clinical outcomes. Invasion of tumors into healthy brain restricts chemotherapeutic access and complicates surgical resection. The central hypothesis of the thesis is that an effective anti-invasive agent can enhance the standard chemotherapeutic response in invasive brain tumors. Through a screen of novel compounds, a new anti-invasive small molecule, Imipramine Blue (IB), was identified. This triphenylmethane compound inhibits invasion of highly invasive glioma in vitro and in vivo. To elicit a response in vivo, Imipramine Blue was liposomally encapsulated to yield better delivery to tumor. Using this formulation, it is shown that IB attenuates invasion of glioma in vivo leading to a more compact tumor in an aggressively invasive rodent glioma model. Further, it is shown that this novel compound binds NADPH oxidases and alters expression of actin regulatory elements to elicit this anti-invasive activity. To test our hypothesis that anti-invasive therapy coupled with chemotherapy will enhance efficacy, nano-IB therapy was followed by liposomally encapsulated doxorubicin (DXR) chemotherapy. Additionally, a co-encapsulated formulation of IB and DXR was developed and tested in vivo. This combination therapy significantly enhanced survival compared to IB or DXR alone, resulting in long-term survival in the syngeneic invasive rat astrocytoma model RT2. It was seen that sequential treatment was more effective than the co-encapsulated treatment indicating a benefit of pre-treating the tumor with the anti-invasive. This thesis demonstrates that novel anti-invasive IB mediated 'containment' of diffuse glioma significantly enhances the efficacy of DXR chemotherapy compared to chemotherapy or anti-invasive therapy alone.

Hydrogel micro- and nanoparticles (microgels and nanogels) are a promising class of drug delivery vehicles. Composed of hydrophilic polymers arranged into a cross-linked network structure, nanogels show several attractive features for the delivery of macromolecule therapeutics. For instance, the hydrated, porous internal cavity of the nanogel may serve as a high capacity compartment for loading macromolecules, whereas the periphery of the nanogel may be used as a scaffold for conjugating cell-specific targeting moieties. This dissertation presents recent investigations of nanogels as targeted delivery vehicles for oligonucleotides to cancer cells, while exploring new nanogel chemistries that enable future in vivo applications. For instance, synthetic efforts have produced particles capable of erosion into low molar mass constituents, providing a possible mechanism of particle clearance after repeated administration in vivo. In another example, the microgel network chemistry was tuned to promote the encapsulation of charged proteins. In parallel with those synthetic efforts, new light scattering methodologies were developed to accurately quantify the particle behaviors (e.g. loading, erosion). Using multiangle light scattering (MALS), changes in particle molar mass and radius were measured, providing a quantitative and direct approach for monitoring nanogel erosion and macromolecule encapsulation. The new particle chemistries demonstrated, together with enabling light scattering methods, will catalyze the development of improved delivery vehicles in the near future.

Histone deacetylase (HDAC) inhibitors (HDACi) have demonstrated a wealth of biological effects, including anti-proliferative, anti-inflammatory, anti-parasitic, and cognition-enhancing activities. The recent FDA approvals of the inhibitors SAHA and FK-228 have validated HDACi clinical use in cutaneous T cell lymphoma, while numerous clinical trials are currently ongoing using HDACi against a variety of disease states. While the future of the HDAC field looks increasingly promising, there are lingering issues hindering broader use. Recent data point to dysregulation of specific HDAC isoforms in many disease states. However, most current HDACi are pan-inhibitors, lacking the specificity to target individual isoforms. Adding to this, there are currently 18 identified HDAC isoforms, and most lack a defined crystal structure, further complicating the task of designing isoform-specific inhibitors. Most importantly, HDACi have demonstrated a lack of efficacy against solid tumors in the clinic, a major obstacle to broader use in cancer therapy. Several of these issues could more fully be addressed through specific targeting of HDACi, and could bring HDACi into wider and more efficacious pharmaceutical use. Targeting the specific tissue or organelle where HDAC dysregulation occurs could confer greater efficacy in vivo. To this end, we have created four classes of compounds: (1) aryltriazolyl HDACi that potently inhibit HDAC activity and prostate cancer cell growth, (2) dual-targeted inhibitors of Topoisomerase II and HDAC and (3) dual-targeted inhibitors of Topoisomerase I and HDAC, both of which have potent inhibition against both target enzymes as well as cancer cell lines, and finally (4) macrocyclic HDACi that potently inhibit the growth of lung cancer cell lines and preferentially target lung tissue in vivo.