New methods for the preparation of porous biomedical scaffolds have been explored for applications in tissue engineering and drug delivery. Scaffolds with controlled pore morphologies have been generated which incorporate cyclodextrin-drug inclusion complexes as the drug delivery component. Supercritical CO2 was explored as the main processing fluid in the complex formation and in the foaming of the polymer scaffold. The co-solvents, ethanol, ethyl acetate and acetone, were explored in each stage, as needed, to improve the solvent power of CO2. The first goal was to promote cyclodextrin-drug complex formation. Complex formation by traditional methods was compared with complex formation driven by processing in supercritical CO2. Complex formation was promoted by melting the drug in supercritical CO2 or in CO2 + co-solvent mixtures while in the presence of cyclodextrin. Some drugs, such as piroxicam, are prone to degradation near the drug's ambient melting temperature. However, this approach using CO2 was found to circumvent drug thermal degradation, since drug melting temperatures were depressed in the presence of CO2. The second goal was to produce porous polymeric matrices to serve as tissue engineering scaffolds. Poly(lactide-<i>co</i>-glycolide) and poly(ε-caprolactone) were investigated for foaming, since these biomedical polymers are already commonly used and FDA approved. Polymer foaming with CO2 is an alternative approach to conventional solvent-intensive methods for porosity generation. However, two major limitations of polymer foaming using CO2 as the only processing fluid have been reported, including the formation of a non-porous outer skin upon depressurization and limited pore interconnectivity. Approaches to circumvent these limitations include the use of a co-solvent and controlling depressurization rates. The effect of processing parameters, including foaming temperatures and depressurization rate, as well as co-solvent addition, were examined in polymer foaming using CO2. Drug release dynamics were compared for foams incorporated with either pure drug, cyclodextrin-drug physical mixture or cyclodextrin-drug complex. Pore morphology, polymer choice and drug release compound choice were found to alter drug release profiles. / Ph. D.

<p><strong>Apstrakt je obrađen tehnologijama za optičko prepoznavanje teksta (OCR).</strong></p><p>Ispitana je ekstrakcija timijana (<em>Thymus vulgaris L.</em>) primenom ugljendioksida u superkritičnom stanju kao ekstragensa. Razrađen je postupak tečne hromatografije pod visokim pritiskom (HPLC) za određivanje farmakolo&scaron;ki aktivnih fenolnih jedinjenja, timola i karvakrola, koji obezbeđuje visok stepen reproduktivnosti određivanja (za timol K_w = 1,29%). Za kvalitativnu i kvantitativnu analizu proizvoda na bazi timijana, etarskog ulja i ekstrakata, primenjen je metod gasne hromatografije (GC) sa masenom spektrometrijom (MS). Sadržaj etarskog ulja određen oficinalnim postupkom koji propisuje jugoslovenska farmakopeja iznosi 1,75% (V/m). Dominantna komponenta etarskog ulja timijana je timol čiji je sadržaj 50,06% (m/m), dok je karvakrol prisutan, praktično, u tragovima (1,15%). Od prisutnih parafina u etarskom ulju, največi sadržaj ima n-tetradekan (16,11%). U totalnom ekstraktu timijana dobijenom metilen- hloridom primenom ekstrakcije sa povremenim ispu&scaron;tanjem ekstrakta (Ekstrakcija po Soxhlet-u), koji je dobijen u prinosu 4,95% (m/m), dominantna komponenta je n-tetradekan (47,18%), dok je sadržaj timola 16,11%.<br />Kinetika ekstrakcije timola se može uspe&scaron;no predstaviti analogno izrazu za kinetiku reakcije prvog reda, primenom koje se dobija največa vrednost konstante brzine ekstrakcije (k) 0,2209 h^-1 za selektovani protok superkritičnog ugijendioksida 97,725 dm³/h.<br />Primenom timijana stepena usitnjenosti d₂ srednjeg prečnika 0,35 mm za ekstrakciju superkritičnim ugijendioksidom (100 bar; 40&deg;C; 2,5 sata) postiže se kvantitativna ekstrakcije prisutnog etarskog ulja. Po svom sastavu ovaj ekstrakt je najsličniji etarskom ulju timijana dobijenom destliacijom pomoću vodene pare. Produžavanje vremena ekstrakcije iznad 2,5 sata ima za posledicu povećani prinos, pre svega, parafina.<br />Primenom ugljendioksida male moći rastvaranja (80 bar; 40⁰C;&nbsp; d=0,1918 g/cm³) ne postiže se kvantitativna ekstrakcija etarskog ulja. Povećavanjem radnog pritiska od 100 do 400 bar, usled povećanja moći rastvaranja, dobijaju se ekstrakti koji su po svom sastavu sve sličniji totalnom ekstraktu dobijenom ekstrakcijom metilenhloridom.<br />Za modelovanje ekstrakcionog sistema timijan - superkritični ugljendioksid je primenjena jednačina Reverchon-a i Sesti Osseo-a:<br />&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;Y = 100 [1-exp(-t/t_i)]<br />gde je: Y - normalizovani ekstrakcioni prinos (%); t - vreme ekstrakcije (s) i t_i -&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; vreme unutra&scaron;nje difuzije (s)<br />odnosno njen modifikovani oblik:<br />&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; Y = 100 [1 - ehr (at + b)]<br />Izračunate vrednosti standardne gre&scaron;ke regresije (S_Y,X) ukazuju da u osnovi modifikovana jednačina bolje fituje normalizovane prinose kako totalnog ekstrakta, tako i timola, u odnosu na polaznu jednačinu.<br />Jednačine:<br />&nbsp;&nbsp; log S = a m_rel + b<br />i<br />&nbsp;&nbsp; log S = a <em>d</em>_C02 + b<br />gde je: S - rastvorljivost totalnog ekstrakta (g/dm³), odnosno timola (mg/dm ) u ugljendioksidu; m_rel - relativna masa ugljendioksida (g CO2/g timijana) i <em>d</em>_CO2 zapreminska masa ugljendioksida (g/cm³)<br />se mogu, takođe, uspe&scaron;no primeniti za modelovanje ekstrakcije ispitivanog sistema.<br />Primenom ugljendioksida u tečnom stanju (65 bar; 23&deg;C) se dobija ekstrakt timijana sličan po svom sastavu ekstraktu dobijenom ekstrakcijom superkritičnim ekstragensom na pritisku 100 bar.<br />U cilju dobijanja ekstrakta timijana koji je po svom kvalitativnom i kvantitativnom sastavu najsličniji etarskom ulju dobijenom oficinalnim postupkom destilacije pomoću vodene pare, neophodno je za ekstrakciju koristiti ugljendioksid zapreminske mase 0,6302 g/cm³( 100 bar;40&deg;C), biljni materijal stepena usitnjenosti d₂, vreme ekstrakcije 2,5 sata i protok ekstragensa 97,725 dm³/h.</p> / <p><strong>Abstract was processed by technology for Optical character recognition (OCR).</strong></p><p>The extraction of thyme (Thymus vulgaris L.) by supercritical carbon dioxide as an extragent was investigated. The developed HPLC (High Pressure Liquid Chromatography) method for determination of pharmacologically active phenolic compounds, thymol and carvacrol, showed a high reproducibility (Kw for thymol 1.29%). Qualitative and quantitative analyses of thyme products, essential oil and extracts, were carried out by gas chromatography - mass spectrometry (GC-MS). The content of essential oil determined by an official procedure given by Yugoslav pharmacopoeia was 1.75% (V/w). The predominant compound of the essential oil is thymol (50.06%; w/w), while carvacrol is present, practically, in traces (1.15%; w/w). The content of n-tetradecane in the thyme essential oil (16.11%; w/w) is higher than that of other paraffins. In the total thyme extract obtained by methylene chloride using extraction with periodical exchange of the extract (Soxhlet extraction) in a yield of 4.95%(w/w), the predominant compound was n-tetradecane (47.18%), while the content of thymol was 16.11%.</p><p>The extraction kinetic of thymol can be successfully expressed by analogy to first order reaction kinetic, and a highest value of extraction rate constant (k) of 0.2209 h-1 for the selected flow rate of supercritical carbon dioxide of 97.725 dm3/h.<br />A quantitative extraction of thyme essential oil by supercritical carbon dioxide (100 bar; 40&deg;C; 2.5hours) was obtained using thyme of the grinding degree d2 (mean particle diameter 0.35 mm). The composition of this extract is very similar to that of the essential oil obtained by steam distillation. A higher yield of extraction, primarily of paraffins, was obtained by prolonging the extraction time over 2.5 hours. The use of carbon dioxide of low solubility power (80 bar; 400C; d =0.1918 g/cm3) did not yield a quantitative extraction of thyme essential oil.<br />Ву increasing extraction pressure from 100 to 400 bar, i.e. solubility power, the extract composition was more and more similar to the composition of total extract obtained by methylene chloride.<br />То model extraction of the system thyme - supercritical carbon dioxide use was made of the Reverchon - Sesti Osseo equation:</p><p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y = 100 [1-exp(-t/ti)]</p><p>where: Y - normalized extraction yield (%); t - extraction time (s) and ti - internal diffusion time (s)<br />i.e. of its modified form:<br />&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Y = 100 [1 - ехр (at + b)]<br />The calculated values of standard error of regression (SY,X) show that the modified equation is generally a better fit for the normalized yields of total extract and thymol compared to the original equation.<br />Equations:</p><p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; log S = a mrel + b<br />and<br />&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; log S = a dC02 + b<br />where: S - solubility of total extract (g/dm3), i.e. of thymol (mg/dm3) in carbon dioxide; mrel - relative mass of carbon dioxide (g CO2/g thyme) and dCO2 carbon dioxide density (g/cm3)</p><p>could be successfully used for modelling of the investigated extraction system.<br />The composition of thyme extract obtained by liquid carbon dioxide (65 bar; 23&deg;C ) is very similar to that obtained by supercritical extragent at a pressure of 100 bar.<br />То obtain a thyme extract whose qualitative and quantitative characteristics are most similar to those of the essential oil obtained using official procedure by steam distillation, it is necessary to use a carbon dioxide density of 0.6302 g/cm3 (100 bar; 400C), grinding degree of thyme d2, extraction time of 2.5 hours and extragent flow rate of 97.725 dm3/h.</p>

Hydrogels are three-dimension networks of water-soluble polymer chains and have attracted interest in biomedical engineering, targeted drug delivery, tissue engineering, and regenerative medicine due to their ability to retain water coupled with their highly tunable physicochemical and biological properties. In the specific context of wound care, hydrogels can both maintain high wound hydration as well as absorb and manage wound exudate, both of which are major challenges in wound care. Hydrogel wound dressings can simultaneously deliver medication directly to the wound to suppress or treat infections, including antibiotic-resistant strains such as Methicillin-resistant S. aureus (MRSA). This thesis develops two wound care products that can address challenges in the selection and delivery of drugs to treat antibiotic-resistant strain infections: (1) in situ-gelling poly(oligoethylene glycol methacrylate) (POEGMA) hydrogel wound dressings containing self-assembled nanoparticles encapsulated with fusidic acid; and (2) an in situ calcium-crosslinked alginate scaffold produced using pressurized gas expanded liquids (PGX) technology impregnated with fusidic acid or tigecycline using supercritical adsorptive precipitation (sc-AP). The POEGMA hydrogel wound dressings helped supress MRSA infection and prevent systemic infection during the course of treatment, facilitating a 1-2 fold decrease in bacterial load in the wound bed. The sc-AP technology was shown to be compatible with loading clinically-relevant doses of both antimicrobial compounds, while the resulting wound dressings were effective in treating MRSA wound infections. In case of tigecycline loaded alginate scaffolds, the infection was completely cleared. In tissue engineering applications, injectable macroporous hydrogels are particularly limited by two factors: (1) their need for invasive administration, typically implantation; and (2) their generally weak mechanics. In the first case, reports of injectable hydrogels often involve toxic compounds or by-products that result in loss of cell viability. This thesis addresses this challenge by design and development of a POEGMA-based macroporous hydrogel scaffold based on a novel, non-cytotoxic pore forming emulsion based on perfluorocarbons. Use of the pore-forming emulsion significantly improved cell viability in vitro 14 days after injection and was well tolerated in vivo with minimal to no inflammatory response. In the second case, an interpenetrating “hard-soft” nanofibrous hydrogel network was fabricated by co-electrospinning POEGMA with poly(caprolactone) (PCL). The PCL phase significantly enhanced the mechanical properties of the electrospun POEGMA hydrogel scaffold making handling and manipulating the scaffolds possible, while the presence of the POEGMA phase significantly improved the biological properties of PCL scaffolds in terms of supporting significantly enhanced cell proliferation and delayed bacterial adhesion. Collectively, the advances made in this work address key challenges in the application of hydrogels in tissue engineering and wound care, with future potential to be applied to solve practical clinical challenges. / Dissertation / Doctor of Philosophy (PhD) / Hydrogels have been studied in various applications like targeted drug delivery, tissue engineering, regenerative medicine, and medical devices due to their tunable nature and their capacity to retain water. In many of these applications the pore size and porosity are the key to the performance of a hydrogel in a given application. In particular, the rate at which nutrients or wastes can move through a hydrogel, the stiffness of a hydrogel, and the interactions of a hydrogel with cells are all strongly dependent on the porosity of a hydrogel. Therefore, many techniques have been developed to produce hydrogels with well-defined pore sizes, in particular “macroporous” hydrogels that have larger pores at or above the size of a cell. However, the typical techniques used to make such hydrogels often require additives or manufacturing steps that make them challenging to implement in different applications. This thesis addresses challenges in the fabrication of controllable porosity of hydrogels for applications in wound care (including the treatment of antibiotic-resistant infected wounds) and regenerative medicine, in the latter case enabling minimally invasive injection of a macroporous hydrogel as well as enhancing its mechanics to better mimic native tissues. Each of these solutions aims to bring effective novel treatments to patients, offering alternative therapies for existing challenges in healthcare.

The power generation industry is facing new challenging issues regarding accelerating growth of electricity demand, fuel cost and environmental pollution. These challenges accompanied by concerns of energy resources becoming scarce necessitate searching for sustainable and economically competitive solutions to supply the future electricity demand. To this end, supercritical carbon dioxide (S-CO2) Brayton cycles present great promise particularly in high temperature concentrated solar power (CSP) and waste heat recovery (WHR) applications. With this regard, this dissertation is intended to perform thorough thermodynamic analyses and optimization of S-CO2 Brayton cycles for both of these applications. A modeling tool has been developed, which enables one to predict and analyze the thermodynamic performance of the S-CO2 Brayton cycles in various configurations employing recuperation, recompression, intercooling and reheating. The modeling tool is fully flexible in terms of encompassing the entire feasible design domain and rectifying possible infeasible solutions. Moreover, it is computationally efficient in order to handle time consuming optimization problems. A robust optimization tool has also been developed by employing the principles of genetic algorithm. The developed genetic algorithm code is capable of optimizing non-linear systems with several decision variables simultaneously, and without being trapped in local optimum points. Two optimization schemes, i.e. single-objective and multi-objective, are considered in optimizing the S-CO2 cycles for high temperature solar tower applications. In order to reduce the size and cost of solar block, the global maximum efficiency of the power block should be realized. Therefore, the single-objective optimization scheme is considered to find the optimum design points that correspond to the global maximum efficiency of S-CO2 cycles. Four configurations of S-CO2 Brayton cycles are investigated, and the optimum design point for each configuration is determined. Ultimately, the effects of recompression, reheating, and intercooling on the thermodynamic performance of the recuperated S-CO2 Brayton cycle are analyzed. The results reveal that the main limiting factors in the optimization process are maximum cycle temperature, minimum heat rejection temperature, and pinch point temperature difference. The maximum cycle pressure is also a limiting factor in all studied cases except the simple recuperated cycle. The optimized cycle efficiency varies from 55.77% to 62.02% with consideration of reasonable component performances as we add recompression, reheat and intercooling to the simple recuperated cycle (RC). Although addition of reheating and intercooling to the recuperated recompression cycle (RRC) increases the cycle efficiency by about 3.45 percent points, the simplicity of RC and RRC configurations makes them more promising options at this early development stage of S-CO2 cycles, and are used for further studies in this dissertation. The results of efficiency maximization show that achieving the highest efficiency does not necessarily coincide with the highest cycle specific power. In addition to the efficiency, the specific power is also an important parameter when it comes to investment and decision making since it directly affects the power generation capacity, the size of components and the cost of power blocks. Consequently, the multi-objective optimization scheme is devised to simultaneously maximize both the cycle efficiency and specific power in the simple recuperated and recuperated recompression configurations. The optimization results are presented in the form of two optimum trade-off curves, also known as Pareto fronts, which enable decision makers to choose their desired compromise between the objectives, and to avoid naive solution points obtained from a single-objective optimization approach. Moreover, the comparison of the Pareto optimal fronts associated with the studied configurations reveals the optimum operational region of the recompression configuration where it presents superior performance over the simple recuperated cycle. Considering the extensive potential of waste heat recovery from energy intensive industries and stand-alone gas turbines, this dissertation also investigates the optimum design point of S-CO2 Brayton cycles for a wide range of waste heat source temperatures (500 K to 1100 K). Once again, the simple recuperated and recuperated recompression configurations are selected for this application. The utilization of heat in WHR applications is fundamentally different from that in closed loop heat source applications. The temperature pinching issues are recognized in the waste recovery heat exchangers, which brings about a trade-off between the cycle efficiency and amount of recovered heat. Therefore, maximization of net power output for a given waste heat source is of paramount practical interest rather than the maximization of cycle efficiency. The results demonstrate that by changing the heat source temperature from one application to another, the variation of optimum pressure ratio is insignificant. However, the optimum CO2 to waste gas mass flow ratio and turbine inlet temperature should properly be adjusted. The RRC configuration provides minor increase in power output as compared to RC configuration. Although cycle efficiencies as high as 34.8% and 39.7% can be achieved in RC and RRC configurations respectively, the overall conversion efficiency is less than 26% in RRC and 24.5% in RC.

Concerns about the environmental impact of the textile industry are increasing, and there is an urgent need to develop and implement sustainable technologies. In particular, the environmental impact of dyeing, which emits a large amount of wastewater and chemicals, is one production process that needs to be resolved. Dyeing using supercritical carbon dioxide is attracting attention as a technology that uses carbon dioxide as a solvent instead of water and eliminates liquid waste from the process. It is a development that allows dyeing to be carried out with less energy and a lower environmental impact. In this study, the experiment was done on the application of this supercritical carbon dioxide technology to the dyeing of natural indigo cotton. The aim of study is contribution to the development of dyeing methods with less environmental impact. Natural indigo has the hydrophobicity and non polar which might be compatible scCO2 dyeing, a sustainable and biodegradable dye, offers eco-friendly advantages and poses no harm to humans. In contrast, synthetic indigo raises concerns about waste generation and environmental persistence. It is suggested that the possibility of natural indigo in renewable raw materials could be used to create eco-experiences not only in the textile industry but also in new areas, such as in coatings, design and biodegradable products. The experimental results showed that dyed cotton fabric using supercritical carbon dioxide as a solvent but small coloration and polyethylene glycol as a swelling agent improved dyeability, but mathematical describing was still small. Swelling agent can support the dye penetration into cotton fabric for better coloration. Changes in dyeability were also observed by increasing the process parameters. In the future, it is hoped that the technology can be scaled up to the industrial level and contribute to reducing the environmental impact of the dyeing of denim, a product that has a significant impact on the market, and to reducing the environmental impact and water scarcity of the textile industry as a whole.

Porous metal oxide materials, particularly those comprised of silica or titania, find use in many applications such as low-k dielectric materials for microelectronics as well as chemical sensors, micro/nanofluidic devices, and catalyst substrates. For this dissertation, the focus will be on the processing of porous metal oxide materials covering two subjects: hierarchical porosity exhibited over two discrete length scales and incorporation of functional nanomaterials. To generate the porous silica materials, the technique of supercritical carbon dioxide infusion (scCO2) processing was heavily relied upon. Briefly, the scCO2 infusion processing utilizes phase selective chemistries within a pre-organized amphiphilic block copolymer template using scCO2 as the reaction medium to selectively hydrolyze and condense silica precursors to yield mesoporous materials. To further develop the scCO2 infusion processing technique, hierarchically porous silica materials were generated on unique substrates. Hierarchically structured silica nanochannels were created using a combination of scCO2 infusion processing and nanoimprint lithography (NIL) patterned sacrificial polymer templates to yield mesopores and airgap structures respectively. Hierarchically porous silica materials were also generated on alternative substrates, in the form of cellulose filter paper, which were used to host the amphiphilic block copolymer template to yield tri-modal porosity silica materials. To extend the applicability of mesoporous silica generated from scCO2 infusion processing, functional nanomaterials, in the form of pre-synthesized gold nanoparticles, fullerene derivatives, and polyhedral oligomeric silsequioxanes (POSS) were embedded within the mesoporous silica to produce unique composite materials. The functional nanomaterials were able to impart specific properties, typically only affored to the functional nanomaterials, upon the mesoporous silica thin film with an example being enhanced thermal and hydrothermal properties of mesoporous silica doped with POSS molecules. To continue research with functional nanomaterials, nanoparticle composite materials, comprised of crystalline metal oxide nanoparticles and binder/filler materials, either organic or inorganic, were also evaluated as novel NIL resist materials. Patterning of the nanoparticle composite materials, specifically, but not limited to, titanium dioxide based materials, into two dimensional, arbitrarily shaped, sub-micron features was readily achieved on either rigid or flexible substrates. True three-dimensional structures, based on nanoparticle composite materials, were fabricated by utilizing release layers and pre-patterned substrates.

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This work is concerned with the production of high performance polymer foams via a benign foaming process. The first goal of this project was to develop a process and the conditions necessary to produce a low density (>80% density reduction) foam from poly(arylene ether sulfone) (PAES). Water and supercritical carbon dioxide (scCO2) were used as the blowing agents in a one-step batch foaming process. Both water and scCO2 plasticize the PAES, allowing for precise control on both the foam morphology and the foam density. To optimize the foaming conditions, both thermogravimetric analysis and differential scanning calorimetery (DSC) were used to determine the solubility and the reduced glass transition temperature (Tg) due to plasticization of the polymer. It was determined that 2 hours was sufficient time to saturate the PAES with water and scCO2 when subjected to a temperature of 220 oC and 10.3 MPa of pressure. Under these conditions, a combination of 7.5% of water and scCO2 were able to diffuse into the PAES specimen, correlating to ~60 oC reduction in the Tg of the PAES. The combination of water and scCO2 produced foam with up to an 80% reduction in density. The compressive properties, tensile modulus, and impact strength of the foam were measured. The relative compressive properties were slightly lower than the commercially available structural foam made of poly(methacrylimide). The second objective of the dissertation was to enhance the compressive properties of the PAES foam, without concern for the foam density. Foam was produced over a range of density, by controlling the cell size, in order to optimize the compressive properties. Carbon nanofibers (CNFs) were also added to the PAES matrix prior to foaming to both induce heterogeneous nucleation, which leads to smaller cell size, and to reinforce the cell walls. Dynamic mechanical thermal analysis (DMTA), on saturated CNF-PAES, was used to determine the reduced Tg due to plasticization and establish the temperature for pressure release during foaming. DMTA proved to be more effective than DSC in establishing quantitative results on the reduction in the Tg. The CNF-PAES foam produced had compressive properties up to 1.5 times the compressive properties of the PAES foam. / Ph. D.