No description available.

The need to tailor release-rate profiles from polymeric microspheres remains one of the leading challenges in controlled drug delivery. Microsphere size, which has a significant effect on drug release rate, can potentially be varied to design a controlled drug delivery system with desired release profile. In addition, drug release rate from polymeric microspheres is dependent on material properties such as polymer molecular weight. Mathematical modeling provides insight into the fundamental processes that govern the release, and once validated with experimental results, it can be used to tailor a desired controlled drug delivery system. To these ends, PLG microspheres were fabricated using the oil-in-water emulsion technique. A quantitative study that describes the size distribution of poly(lactide-coglycolide) (PLG) microspheres is presented. A fluid mechanics-based correlation that predicts the mean microsphere diameter is formulated based on the theory of emulsification in turbulent flow. The effects of microspheres’ mean diameter, polydispersity, and polymer molecular weight on therapeutic drug release rate from poly(lactide-co-glycolide) (PLG) microspheres were investigated experimentally. Based on the experimental results, a suitable mathematical theory has been developed that incorporates the effect of microsphere size distribution and polymer degradation on drug release. In addition, a numerical optimization technique, based on the least squares method, was developed to achieve desired therapeutic drug release profiles by combining individual microsphere populations. The fluid mechanics-based mathematical correlation that predicts microsphere mean diameter provided a close fit to the experimental results. We show from in vitro release experiments that microsphere size has a significant effect on drug release rate. The initial release rate decreased with an increase in microsphere size. In addition, the release profile changed from first order to concave-upward (sigmoidal) as the microsphere size was increased. The mathematical model gave a good fit to the experimental release data. Using the numerical optimization technique, it was possible to achieve desired release profiles, in particular zero-order and pulsatile release, by combining individual microsphere populations at the appropriate proportions. Overall, this work shows that engineering polymeric microsphere populations having predetermined characteristics is an effective means to obtain desired therapeutic drug release patterns, relevant for controlled drug delivery.

Ovarian cancer is one of the five most common causes of cancer death in women in the USA and UK. It is usually diagnosed when it is well established beyond the ovary in the peritoneum. Intravenous injection of cisplatin is a common palliative therapy for ovarian cancer patients. Intraperitoneal therapy has been shown to improve survival for patients. Poly(lactide-co-glycolide) (PLGA) is a biodegradable polyester which has been proven safe for medical implantation. PLGA microspheres or fibres have been considered in this work as depots for delivering intraperitoneal cisplatin directly to the tumour site. The aims of this work were (1) to develop microsphere depot formulations with improved drug release profiles compared to previous work; (2) Novel cisplatin containing solid and hollow fibres were to be developed and investigated as alternative structures for depot devices; (3) The drug release profiles were to be examined using mathematical models to allow rational comparison of the devices. It was found that cisplatin containing PLGA 65:35 solid and hollow fibres represent a novel, reproducible formulation for encapsulating higher amounts of cisplatin for an equivalent mass of excipient than other polymer formulations. The fibres developed in this study were able to maintain elevated concentrations of unbound cisplatin in the presence of a biological matrix for approximately 100 hours in vitro.

The synthetic chemotherapeutic agent, 5-FU, has been used for the treatment of a variety cancers, with colorectal cancer being among the most susceptible. Administration of 5-FU by continuous intravenous infusion has proven to yield greater antitumor efficacy and lower hematotoxicity compared to administration of 5-FU by intravenous bolus injections. Nevertheless, systemic application of 5-FU is often limited by its narrow therapeutic threshold, and therefore in certain situations, such as tumor resection, it may be more appropriate to provide local rather than systemic delivery of 5-FU. It was therefore proposed that 5-FU loaded PLGA millirods may be capable of providing sustained release of 5-FU at a local level which may have equivalent or greater antitumor activity and less cytotoxicity than the systemic or local delivery of soluble 5-FU. PLGA millirods loaded with 5-FU were successfully fabricated by a hot-melt extrusion technique and characterized for in vitro and in vivo release rates. It was demonstrated that percentage loading by weight of 5-FU could be adjusted to modify its release kinetics. It was also shown that millirods could be stably stored under a variety of conditions for at least 2 months. An optimal millirod formulation (PLGA 50:50 loaded with 5-FU (50% w/w)) was tested for antitumor activity and general toxicity in vivo. At the dose of 120 mg/kg 5-FU, millirods (delivered peritumorally) were efficacious (with 100% survival rates) against solid thymomas in tumor-challenged mice (causing complete regression). Whilst the soluble form of 5-FU (delivered intraperitoneally (IP) at 120 mg/kg) was also highly efficacious (90% survival rates) against thymomas it was also more hematotoxic. In addition, the millirod form provided significantly greater antitumor activity against colorectal tumors in mice compared to the soluble form of 5-FU. In terms of in vivo toxicity, surprisingly, the type of formulation did not have a significant effect on mouse weight despite both IP and subcutaneous (SC) delivery causing death of some mice. Importantly, it was found that 5-FU loaded PLGA millirods were significantly less hematotoxic than soluble 5-FU delivered by either IP or SC injection at the equivalent dose. Thus, locally implanted 5-FU loaded PLGA millirods appeared to be less toxic and possessed overall greater antitumor potency than soluble 5-FU delivered by IP or SC injection. This study further investigated whether the combination of 5-FU loaded PLGA millirods with eniluracil (in both thymoma and colorectal tumor models) or immune checkpoint inhibitors (in the colorectal tumor model) could enhance the antitumor efficacy of 5-FU millirods in mice challenged with colorectal tumors. It was found that the combination of 5-FU loaded PLGA millirods and eniluracil (millirod or solution forms) did not significantly enhance the antitumor efficacy of 5-FU millirods in either tumor models. It was also found that immune checkpoint inhibitors did not enhance the antitumor efficacy of 5-FU loaded PLGA millirods in the colorectal tumor model.

The aim of this project was to create a novel biodegradable, synthetic scaffold that will provide the correct topographical cues for myoblast alignment and efficient differentiation into myotubes. Skeletal muscle repair after major surgery or serious burns is often overlooked leading to poor healing and consequent loss of power in movements of affected limbs. In order to overcome this problem a tissue engineered construct could be utilised as a grafting patch to encourage further regeneration and enhance possible power to the limb. Using a biodegradable polymer can provide structural support until the tissue is established, and will be excreted by the body's natural processes as it degrades. A synthetic polymer is desirable as it can reduce the risk of immunogenic responses thus reduce risk of graft rejection. For successful in vitro growth of skeletal muscle, the cells must be encouraged to arrange themselves into parallel arrays in order for efficient fusion and consequent contraction. By incorporating the correct topographical cues into the scaffold to promote contact guidance for cellular alignment this can be achieved. Electrospinning is a reliable technique which yields highly reproducible aligned fibres from the micro- to the nanoscale. This project focuses upon creating and characterising the electrospun scaffold, checking biocompatibility with myoblasts by monitoring the topography, residual solvent within the scaffold, the mechanical properties of the scaffold, and a brief investigation into the degradation profile of the electrospun fibres. The immunogenicity of the scaffold was investigated by monitoring cytokine release from macrophages. Myoblast morphology was monitored, as was the efficiency of the cells to differentiate and their potential to become contractile myofibres. Cellular adhesion to the scaffold was also looked into by measuring the expression of integrins during early and late adhesion and on substrates with different topographies. It was found that the electrospun scaffold did not contain a significant amount of residual solvent, and macrophages were not activated any more than on tissue culture plastic. Myoblasts responded to the topography of the aligned fibres by aligning along the length of the fibres, showing elongation and bi-axial cytoskeletal arrangement after just 30 minutes culture on the aligned fibres. This elongation prompted fusion and differentiation of the myoblasts to occur faster than cells which were not exposed to the aligned topography, and this global alignment was maintained in long term culture.

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.

Residual value is defined as the price for which a used piece of equipment can be sold in the market at a particular time. It is an important element of the owning costs of equipment and needs to be estimated by equipment managers for making investment decisions. The purpose of this study is to gain insights into the residual value of selected groups of heavy construction equipment and to develop a mathematical model for its prediction. Auction sales data were collected from two online databases. Manufacturer publications and an online source provided size parameters and manufacturers suggested retail prices matching the auction records. Macroeconomic indicator values were collected from a variety of sources, including government agencies. The data were brought into the same electronic format and were matched by model name and calendar date, respectively. Data from auctions in the U.S. and in Canada were considered for this study. Equipment from four principal manufacturers of up to 15 years of age at the time of sale was included. A total of 35,542 entries were grouped into 11 different equipment types and 28 categories by size as measured by horse power, standard operating weight, or bucket volume. Equipment types considered were track and wheel excavators, wheel and track loaders, backhoe loaders, integrated toolcarriers, rigid frame and articulated trucks, track dozers, motor graders, and wheel tractor scrapers. Multiple linear regression analyses of the 28 datasets were carried out after outliers had been deleted. Explanatory variables for the regression model were age in years, the indicator variables manufacturer, condition rating, and geographic region, and selected macroeconomic indicators. The response variable was residual value percent, defined as auction price divided by manufacturers suggested retail price. Different first, second, and third-order polynomial models and exponential and logarithmic models of age were examined. A second-order polynomial was selected from these functional forms based on the adjusted coefficient of determination. Coefficients for the 28 models and related statistics were tabulated. A spreadsheet tool incorporating the final regression model and its coefficients was developed. It allows performing the residual value prediction in an interactive and intuitive manner. / Ph. D.

Yes / We report a technique for the fabrication of micropockets within electrospun membranes in which to study cell behavior. Specifically, we describe a combination of microstereolithography and electrospinning for the production of PLGA (Poly(lactide-co-glycolide)) corneal biomaterial devices equipped with microfeatures.

No description available.

<p>Degradable polymers have gained an increased attention in the field of biomedical applications over the past decades, for example in tissue engineering. One way of improving the biocompatibility of these polymers is by chemical surface modification, however the risk of degradation during the modification procedure is a limiting factor. In some biomedical applications, for example in nerve guides, a patterned surface is desired to improve the cell attachment and proliferation.</p><p>In this thesis a new non-destructive, single-step, and solvent free method for surface modification of degradable polymers is described. Poly(L-lactide) (PLLA) substrates have been functionalized with one of the following vinyl monomers; N-vinylpyrrolidone (VP), acrylamide (AAm), or maleic anhydride (MAH) grafts. The substrates were subjected to a vapor phase atmosphere constituted of a mixture of a vinyl monomer and a photoinitiator (benzophenone) in a closed chamber at very low pressure and under UV irradiation. Poly(ε-caprolactone) (PCL), poly(lactide-co-glycolide) (PLGA), and poly(trimethylene carbonate) (PTMC) have been surface modified with VP using the same procedure to show the versatility of the method. The wettability of all of the four substrates increased after grafting. The surface compositions were confirmed by ATR-FTIR and XPS. The VP grafted PLLA, PTMC and PLGA substrates have been shown to be good substrates for the normal human cells i.e. keratinocytes and fibroblasts, to adhere and proliferate on. The topography of substrates with well defined nano patterns was preserved during grafting, since the grafted layer is very thin. We have also shown that the method is useful for a simultaneous chemical and topographical modification of substrates by masked vapor phase grafting. The surface topography was determined with SEM and AFM.</p> / <p>Intresset för användningen av nedbrytbara polymerer till biomedicinska applikationer som till exempel vävnads rekonstruktion har ökat avsevärt de senaste decennierna. Ett sätt att öka biokompatibiliteten hos dessa polymerer är genom kemisk ytmodifiering, men risken för nedbrytning under själva modifieringen är en begränsande faktor. I vissa biomedicinska applikationer, till exempel nervguider, är det önskvärt att ha en väldefinierad ytstruktur för att öka vidhäftningen och tillväxten av celler.</p><p>I den här avhandlingen presenteras en ny ickeförstörande, lösningsmedelsfri enstegsprocess för ytmodifiering av nedbrytbara polymerer. Substrat av poly(L-laktid) (PLLA) har ytfunktionaliserats med var och en av följande vinylmonomerer, N-vinylpyrrolidon (VP), akrylamid (AAm) eller maleinsyraanhydrid (MAH). Substraten har exponerats för en gasfasatmosfär av en blandning av en vinylmonomer och en fotoinitiator (bensofenon) i en tillsluten reaktor vid mycket lågt tryck och under UV-strålning. Metodens mångsidighet har även påvisats genom att ytmodifiera substrat av poly(ε-kaprolakton) (PCL), poly(laktid-co-glykolid) (PLGA) och poly(trimetylen karbonat) (PTMC) med VP. Vätbarheten ökade för alla fyra materialen efter ympning med en vinylmonomer. Ytsammansättningen fastställdes med ATR-FTIR och XPS. De VP ympade filmerna av PLLA, PLGA och PTMC visade sig vara bra substrat för mänskliga celler, i detta fall keratinocyter och fibroblaster, att vidhäfta och växa på. Yttopografin hos filmer med väldefinierade nanomönstrade ytor kunde bevaras efter ympning, tack vare att det ympade lagret är så tunt. Gasfas metoden har också visat sig användbar för att simultant ytmodifiera både kemiskt och topografiskt genom maskad gasfasympning. Yttopografin bestämdes med SEM och AFM.</p>