A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy, Department of Pharmacy and Pharmacology, University of the Witwatersrand, Johannesburg, 2017. / Numerous pharmaceutical solid dosage form manufacturing techniques have emerged over the years and among them, 3D-Printing (3DP) has emerged as a highly attractive and versatile approach. 3DP is a cutting edge technology set to expand and revolutionize tablet manufacturing among various other applications in industry. The study reported in this thesis focuses on developing a humic acid-polyquaternium-10 (HA-PQ10) 3D-Printable ink for the delivery of three anti-HIV bioactives, efavirenz (EFV), tenofovir (TDF) and emtricitabine (FTC). HA was strategically employed based on its capability of entrapping both hydrophilic and hydrophobic drugs. PQ10 contributed towards the system’s swellability in aqueous media. The HA-PQ10 PEC was responsible for retarding drug release therefore it behaved as a drug reservoir. Validation of HA-PQ10 complexation was carried out by synthesizing the HA-PQ10 polyelectrolyte complex (PEC) in aqueous media at pH 6, 7 and 8. The complexation yielded fibrilla and porous PECs. The PEC formation was attributed to ionic interactions between the quaternary ammonium centres (PQ10) and carboxylic groups (HA). The PECs were determined to be amorphous in nature and exhibited good biocompatibility when tested for cytotoxicity in human adenocarcinoma cell line (Caco2). The model drug, efavirenz (EFV) was loaded into HA-PQ10 using the complexation-precipitation (C-P) technique. The resultant EFV-loaded HA-PQ10 was compared to benchtop extrudates manufactured using the extrusion-spheronization (E-S) process. Assessment of the EFV saturation solubility and intestinal permeability showed EFV solubility and permeability enhancement of 14.14±2.81% and 61.24±6.92% respectively. The properties were compared to those of a marketed comparator product. Loading RTV into the optimized HA-PQ10 further validated the solubility and permeability enhancing properties in the BCS class IV drug as well. The extrudates performed superiorly compared to the formulation synthesized by C-P. The E-S technique was utilized to optimize HA-PQ10 based on drug release and intestinal permeation enhancement. The optimal HA-PQ10 was employed for 3DP of EFV-loaded HA-PQ10 into an oral tablet formulation. It was imperative to add cellulose acetate phthalate (CAP) to enhance the 3D-Printability of the HA-PQ10. CAP made the synthesized delivery system pH responsive and drug release results showed that most of the release occurred under intestinal conditions. The EFV-loaded 3DP tablet was compared to a tablet synthesized by direct compression. 3DP was more porous, less dense and more swellable than the direct compression tablet. These remarkable differences were attributed to the tableting method. 3DP leads to the formation of solid bridges between particles as the sludge (ink) undergoes extrusion and drying process. The direct compression technique involves axial powder compaction at high pressures which force particles to interact through Van der Waals forces or hydrogen bond formation. High drug loading of EFV was achieved and the tablet was further optimized to manufacture the ‘controlled release tritherapeutic tablet’, CRTT, a fixed dose combination (FDC) consisting of EFV, TDF and FTC. In vivo studies were conducted in large white pigs and CRTT absorption was compared to a marketed FDC, Atripla®. There was sustained release of EFV, TDF and FTC from CRTT and this was validated by the long residence times determined from pharmacokinetic analysis. EFV was maintained within the therapeutic index of the drug during the 24 hour study. Through this study, 3DP proved to be a technology with potential for manufacturing novel formulations. As more research is underway in the 3DP field, it can only be appreciated that its scope of use will continue to grow and restructure pharmaceutical manufacturing processes. / LG2018

Indiana University-Purdue University Indianapolis (IUPUI) / Introduction: In order to successfully treat an infected root canal system (RCS), it is required to locate all root canals and have an access path to the apex of each canal. This can be challenging in teeth with pulp canal obliteration (PCO), often leading to increased chair time and increased risk of iatrogenic errors. Guided endodontic access (GEA) combines information from a cone-beam computed tomography (CBCT) scan with an intra-oral scan to create a stent. GEA stents with or without fixation pins have been shown to be successful in accurately negotiating a RCS with PCO. Objective: Compare the degree of deviation and difference in 3D offset at the base to apical tip of the drill from the designed access path when a GEA stent with and without pin fixation is used to access tooth #8 with PCO. Materials and Methods: A 3-D printed maxillary model of an anonymous patient had a GEA stent designed using coDiagnonstiX software. The stent extended from tooth #3 to tooth #14 with the guide sleeve over tooth #8. Tooth #8 with no calcification, calcification to the cervical third, and calcification to the middle third of the RCS were designed in the coDiagnostiX software. Tooth #8 will be accessed using a 1.3 mm drill that fits a 1.3 mm sleeve used for both access and pin fixation. 15 of the 30 GEA samples will utilized pin fixation, while the other 15 samples did not utilize pin fixation. Following GEA in all 30 samples a CBCT was taken of each sample. Each post-operative CBCT was aligned with the pre-operative CBCT in the coDiagnostiX software. The coDiagnostiX software was able to calculate the degree of deviation and difference in 3D offset between the base and apical tip of the drill during GEA. Paired t-tests were used to test each group for significant differences in 3D offset between base and tip. Two-way ANOVA was used to evaluate the effects of pin fixation and calcification on the degree of deviation and the deviation of 3D offset of the entry point and tip. Results: There was a significant interaction between use of pin fixation and calcification level on the degree of deviation of GEA. GEA with pin fixation had a significantly larger degree of deviation than GEA without pin fixation with calcification extending to the middle third of the RCS. GEA with and without pin fixation did not have a significant difference when calcification extended to the cervical third of the RCS or no calcification was present. There was a significant interaction between use of pin fixation and calcification level on 3D offset difference. GEA with pin fixation had a significantly larger 3D offset difference than GEA with no pin fixation for calcification in the middle third of the RCS. For GEA with and without pin fixation there was no significant difference when calcification extended to the cervical third of the RCS or no calcification was present. Conclusion: The use of pin fixation did not result in a decrease of degree of deviation or difference in 3D offset during GEA access. It can be concluded that the use of pin fixation is not necessary for GEA of teeth with PCO when a full dentition is present to provide stability and retention of the stent. / 2022-06-21

Orientador: Lidia Parsekian Martins / Resumo: OBJETIVO: Identificar e quantificar diferenças nas propriedades mecânicas de quatro resinas para impressão por estereolitografia em função do tempo de exposição à luz ultravioleta pós impressão e quantificar diferenças dimensionais em modelos odontológicos produzidos por estereolitografia em relação à inserção de barra estabilizadora transversal na região posterior, à orientação de impressão, vertical ou horizontal, tipo de modelo, oco ou maciço, e pós cura com luz ultravioleta ou não, por meio de medições lineares. MÉTODOS: 140 espécimes foram impressos em impressoras 3D do tipo SLA (estereolitografia a laser) e DLP (estereolitografia por processamento digital de luz) para cada teste mecânico realizado e foram divididos em 28 grupos, de acordo com a resina (4 tipos: Blue, Gray, Surgical Guide, Standard) e o tempo de pós cura com luz ultravioleta (7 tempos: 0, 5, 10, 15, 30, 60 e 120 minutos). Foram realizados os testes de microdureza Vickers, tração diametral e flexão três pontos. Os dados obtidos foram submetidos a uma ANOVA de dois níveis e ao pós teste de Tukey. Para a avaliação das alterações dimensionais de modelos odontológicos foram realizados dois experimentos distintos. No primeiro, 56 modelos odontológicos do arco maxilar em formato de ferradura foram impressos na impressora MoonRay S100 (SprintRay) com a resina Gray (SprintRay), variando a orientação de impressão, a presença de barra e o processo de pós cura. Depois de impressos foram escaneados em escâner de mesa... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: OBJECTIVE: To identify and quantify differences in the mechanical properties of four resins for stereolithography printing varying time of exposure to ultraviolet light and to quantify dimensional differences in dental models produced by stereolithography regarding the insertion of a transverse stabilizer bar in the posterior region, the printing orientation, vertical or horizontal, model type, hollow or solid, and post-cure with ultraviolet light or not, by means of linear measurements. METHODS: 140 specimens were printed by SLA (laser stereolithography) and DLP (digital light processing stereolithography) printers for each mechanical test performed and were divided into 28 groups, according to the resin (4 types: Blue, Gray, Surgical Guide, Standard) and the post-cure time with ultraviolet light (7 times: 0, 5, 10, 15, 30, 60 and 120 minutes). Vickers microhardness tests, diametrical traction and three point flexion were performed. The data obtained were submitted to a two-way ANOVA and the Tukey post-test. To evaluate the dimensional changes of dental models, two different experiments were carried out. In the first, 56 horseshoe-shaped dental models of a maxillary arch were printed on the MoonRay S100 (SprintRay) with Gray resin (SprintRay), varying the printing orientation, the presence of a bar and the post-curing process. After printing, they were scanned on a R700 table scanner (3Shape) and then measurements between canines, first and second premolars and molars and ar... (Complete abstract click electronic access below) / Doutor

Orientador: Osmir Batista de Oliveira Junior / Abstract: A regeneração óssea caracteriza-se por ser um processo fisiológico complexo que envolve a participação coordenada entre angiogênese e osteogênese. Envolve um processo de múltiplas etapas que inclui migração, proliferação e diferenciação de vários tipos de células, como células endoteliais, fibroblastos, osteoblastos e osteoclastos. Sabe-se que os biomateriais sintéticos têm demonstrado ser uma excelente alternativa ao reparo ósseo. Assim, o objetivo deste estudo foi avaliar o efeito do Biosilicato de sódio (BS) e dos compósitos 3D de 30% de hidroxiapatita e ácido poliláctico (3D 30% HA / PLA) e 30% hidroxiapatita e ácido poli (ácido láctico-co-glicólico) (30% HA / PLGA), e em defeitos críticos na calvária de ratos. Cento e vinte ratos machos de 90 dias com 350g de massa corporal em média foram aleatoriamente divididos em grupos de acordo com materiais de enxerto e tempo de análise, apresentando 6 animais em cada um. Os defeitos de tamanho crítico foram criados empregando-se uma trefina de 8 mm de diâmetro interno e preenchidos com os materiais mencionados ou apenas o coágulo sanguíneo como controle. Após 14 (T1), 30 (T2), 60 (T3), 90 (T4) e 120 dias (T5) dias do procedimento cirúrgico, a regeneração óssea foi avaliada por radiografia, microtomografia computadorizada (μ-CT) e histologia. A avaliação macroscópica mostrou biocompatibilidade em torno da área de interesse entre os biomateriais e ossos adjacentes. As imagens de μ-CT e de raios-x revelaram uma considerável formação ... (Complete abstract click electronic access below) / Resumo: The process of bone regeneration requires a coordinated coupling between osteogenesis and angiogenesis involveing a multistep process that includes migration, proliferation, and differentiation of several types of cells such as endothelial, fibroblasts, osteoblasts and osteoclasts. It is known that synthetic biomaterials have been proven to be an excellent alternative to bone repair. Thus, the aim of this study is to evaluate the effect of calcium and sodium Biosilicate (BS), a 3D scaffold of hydroxyapatite and polylactic acid (30% HA / PLA) and a hydroxyapatite and poly (lactic-co-glycolic acid) (30% HA / PLGA) composites in critical-sized calvarial defects. One hundred and twenty 90 days old male rats with 350g of body mass on average were randomly divided into groups (n = 6) according to graft materials and analysis time. Critical-size defects were created by means of a 8 mm inner diameter trephine bur and were filled with a 3D 30% HA/PLGA scaffold, 30% HA/PLA, BS or blood clot as control. After 15 (T1), 30 (T2), 60 (T3), 90 (T4) and 120 (T5) days of the cirurgical procedure, bone regeneration was evaluated by histology, x-ray and micro-computed tomography (µ-CT). Macroscopic evaluation showed no significant inflamation around the interest area. µ-CT results indicates that 30% HA/PLA and 3D 30% HA/PLGA composites were not fully degraded and images revealed considerable bone formation in 90 days and 120 days in relation to these materials. On the other hand, BS presented a ... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor