The feasibility of the injection moulding (IM) was explored for the development of novel drug delivery systems. Controlled release formulations were developed using a substituted cellulose derivative, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and a graft co-polymer (Soluplus®). BCS class II drugs ibuprofen and the felodipine were selected based on their physicochemical properties. In the present work, a homogenous dispersion of drugs in the polymer matrices was achieved using Hot Melt Extrusion (HME) and extruded pellets obtained were used for the development of the injection moulded systems. Four systems were developed using the IM consisting of ibuprofen-HPMCAS, ibuprofen-Soluplus®, felodipine-PEO-HPMCAS and felodipine-Soluplus®. The ibuprofen acts as a good plasticiser compared to felodipine therefore, felodipine containing IM systems required a plasticiser (PEO) when processed with HPMCAS. The analysis of extruded pellets and injection moulded systems using modulated DSC (MDSC) and Raman spectroscopy confirmed the formation of an amorphous molecular dispersion (i.e solid solution) in the case of all four systems. The phase separation behaviour and the amorphous stability of the systems was studied at various stress conditions. This revealed the “surface crystallisation” behaviour of the ibuprofen-HPMCAS systems. Temperature-composition phase diagram constructed based on the melting point depression and the Flory-Huggins lattice solution theory provided the explanation for the phase separation and crystallisation behaviour of ibuprofen-HPMCAS systems. The advanced characterisation techniques like DMA, 2D XRD and 3D laser microscopy provided the detailed understanding of crystal habits, phase seperation and surface crystallisation. The significant effect of the stress conditions on the rate of shrinkage was observed where, higher shrinkage tendency of a HPMCAS IM system was observed compared to Soluplus® IM systems. The extruded pellets provided the faster drug release compared to the moulded tablets suggests the effect of particle size as well as the densification during IM on the dissolution rate of the dosage form. The nature of the polymer and processing history were the contributing factors for the dissolution of the dosage forms. / The thesis is hardbound in two volumes. Volume II starts at Chapter 5, page 135.

Repeated partial cutting in the Appalachian hardwood region has often favored the development of tolerant species like American beech (Fagus grandifolia Ehrh.) and stands with a high proportion of cull trees. Crop tree release is a widely recommended practice to improve species composition and growth rates in these unevenaged structured stands. Chemical control offers some distinct advantages from the standpoint of safety and residual stand damage, over mechanical methods. Control of American beech was the primary focus of this study. Beech is a low value timber tree, normally considered difficult to control. It is a major competitor to more valuable trees, especially on better sites in the Appalachians. Research plots were established in hardwood stands at three sites in central West Virginia to evaluate the effectiveness of glyphosate (Accord), imazapyr (Arsenal AC and Chopper), and triclopyr (Garlon 3A and Garlon 4) using the hack-and-squirt application method and low volume basal spray treatments. In the injection treatments .051 fl oz (1.5 ml) of solution was used per inch of diameter (dbh). The basal spray treatments used 0.101 fl oz (3 ml) of solution per inch of diameter. The following concentrations were used: Accord (65.2%), Arsenal AC (7.5%), Garlon 3A (50%), Garlon 4 (26.25%), and Chopper (6.25% ). These concentrations were determined by using the highest costing injection and basal treatment at the lowest recommended labeled rate as standards, Garlon 3A and Chopper respectively. Eighteen 0.1 acre plots were systematically located at each study site where crop trees were present and to maximize the number of American beech on each plot. Crop trees, mostly black cherry (Prunus serotina Ehrh.) were chosen on a 0.025 acre subplot established at each plot center. All beech two inches and larger on the 0.1 acre plots and competing trees touching crop trees were treated in June 1998. The treatments were evaluated in September of 1998 and again in June of 1999. A numerical rating system ranging from 1-7, (0-100% crown affected), which utilized visual symptoms, was used to evaluate the efficacy of each treatment. Trees receiving a rating of 5 (75 % crown control) or greater were considered controlled. The relationship between the kinds of herbicide, application method, and numerical rating were analyzed by means of one-way analysis of variance with an incomplete random factorial design. The most effective treatments for the three month evaluations were the Accord and Garlon 3A injection treatments. Average beech crown control ranged from 95-99% for Accord to 96-99% for Garlon 3A across all study sites. The basal spray treatments were not effective. Average crown control ranged from 1-22%, across all study sites. Accord, Garlon 3A, and Arsenal AC were the most effective treatments for the 12 month evaluations, with average beech crown control ranging from 99-100% across all study sites. The imazapyr treatments (Arsenal Ac and Chopper) had adverse effects on the crop trees and are not recommended for hardwood crop tree release. The cost effectiveness based on treatment costs and the amount of basal area (BA) controlled were averaged for all study sites. The average treatment costs based on the 12 month evaluations expressed in dollars/ft2 BA controlled were as follows: Accord ($0.91), Garlon 3A ($1.04), Arsenal AC ($0.84), Garlon 4 ($15.09), and Chopper ($7.74). NE-TWIGS was used to predict future composition and value of the projected stands. The stem injection treatments decreased the amount of beech and increased the amount of black cherry sawtimber thereby dramatically increasing the future value of the stands. Real rates of return were calculated for the stem injection (8.81%) and low-volume basal spray (-0.81%). / Master of Science

The response of loblolly pine (Pinus taeda L.) to fertilization and weed control at stand establishment, using various formulations of conventional and controlled release N fertilizers was evaluated in a greenhouse study and at two field trials in the Virginia Piedmont, in 2002 and 2003. The greenhouse study evaluated five fertilizer treatments; 1) check with no fertilizer; 2) granular ammonium nitrate (10-10-10 + micro-nutrients) applied to the soil surface; 3) granular methylene urea (40-0-0) applied to the soil surface; 4) methylene urea (20-10-5) in tablet form applied in the planting hole; and 5) isobutylidenediurea (IBDU) (9-9-4) in tablet form applied in the planting hole. Equal amounts of N and P were applied. Fertilization significantly increased seedling root collar diameter and volume at the end of the first growing season in the greenhouse study. Differences in diameter and volume were still significantly different late in the second growing season, however at the last measurement the differences were no longer significant. An analysis of transformed growth curves for 2003 indicated that the ammonium nitrate treated seedlings had a significantly steeper slope than all other treatments. In field trials, at an old-field site and a cut-over site, the same fertilizer products were tested, except granular diammonium phosphate (18-46-0) was used substituted for the ammonium nitrate. Higher rates of N and P were used in the field trials. Complete weed control increased seedling volume by over 700 % after two growing seasons at the reforested old-field site, however fertilizer effects were not significant. At the reforested cut-over site an interaction between weed control and fertilizer treatments was observed. The MU and DAP granular, and the IBDU tablet treatments each had significantly greater seedling volume than the check and the other tablet controlled release fertilizer. IBDU tablets appear to have high fertilizer efficiency, due to the slow release nature and are safe to place in close proximity to the seedling root system. / Master of Science

Cancer is one of the leading causes of death in the world. For women in the U.S. and the European countries, breast cancer is the most common type and it continuously threatens the lives of the patients and causes huge economic losses. Chemotherapy and endocrine therapy are the common treatments for recurrence prevention and metastatic cancer symptom palliation. However, the uses of these therapies are meanwhile largely limited because their toxic side effects and non-specificity usually lead to low quality lives of the patients. Low aqueous solubility, multi-drug resistance, degradation of drug, limited intra-tumor diffusion and etc. are other limitations of conventional chemotherapies and endocrine therapies. Nanoparticle based drug carriers were extensively studied for therapeutic drug delivery. Many carriers could be loaded with high dose of hydrophobic and hydrophilic drugs, protect the drug from the surrounding in vivo environment during the transportation, specifically target and enter the tumor cells and slowly release the drug thereafter. Advanced nanoparticle drug carriers are studied driven by the need of a more efficient drug delivery. The 3rd generation of nanoparticle based drug carriers are recently developed. They usually consist of more than one type of nanoparticles. Different part of the particle has more specialized functions. Therefore, by carefully selecting from the conventional nanoparticle carriers, a 3rd generation particle could have the properties such as high loading capacity of multiple drugs, prolonged half-life in circulation, higher tendency of accumulating at the tumor site, improved specificity to the tumor cells, higher cell uptake rate and accurately triggered controlled release, and combination of the above-mentioned properties. In our study, a paclitaxel loaded nanoparticle supported immunoliposome was assembled for metastatic breast cancer drug delivery. Functionalized single walled carbon nanohorn or poly(lactic-co-glycolic acid) was encapsulated in the polyethylene glycol (PEG) coated liposome for high drug loading and controlled release. Anti-Her2 antibody or Herceptin® was grafted onto the surface of the liposome for a higher affinity to the Her2 overexpressing breast cancer cells. Firstly, the conjugation of protein to the surface of liposome and PEGylated liposomes were investigated. Proteins with or without membrane binding domain were conjugated to liposome and PEGylated liposomes through covalent and non-covalent binding for comparison. A modified enzyme-linked immune sorbent assay was developed for surface grafted protein quantification. Secondly, the encapsulation of solid nanoparticle into PEGylated immunoliposome was investigated. Results showed a new structure of solid nanoparticle in PEGylated immunoliposome at a 1:1 ratio was formed during the repeated freeze-thawing process. Supported immunoliposomes with high homogeneity in size and structure were purified by sucrose density gradient centrifugation. Thirdly, the drug loading, triggered release, cell binding, cell uptake and cell toxicities of the supported immunoliposome were studied. Release results showed a minimum drug leakage in serum at body temperature from the particle. The release was initiated with a minor burst trigged by low pH inside the tumor cell and followed with a long term linear pattern. Cell assay results showed the highest binding affinity of the antibody or Herceptin® grafted nanoparticles to Her2 overexpressing cell lines and a lysosomal intracellular distribution of the endocytosised particles. In the final study, a fabrication process for polymeric material nanoparticles was established. The process was capable of providing accurate control of the particle size with significant high output rates, thus largely extends the scope of materials for supporting the immunoliposome. / Ph. D.

The adaptation of trees to temperate and boreal climates depends on their ability to respond to environmental signals that are markers of seasonal changes in order to survive winter and maximize growth. The genus Populus (poplars) is a model system for identifying the genes and molecular mechanisms that regulate growth and dormancy transitions. Photoperiod and temperature regulate both vegetative and floral phenology. FLOWERING LOCUS T (FT) and FLOWERING LOCUS D (FD) are key regulators of flowering time in Arabidopsis and other plants. The distinct functions of three poplar FD-LIKE (FDL) genes and two FTs were explored through gain-of-function, dominant repression, and CRISPR/CAS9-mediated gene editing. We studied trees in controlled environments, including manipulation of daylength and temperature to mimic an annual seasonal growth and dormancy cycle. Our studies showed that the FDL proteins share less than complete functional equivalency. Among the three paralogs, only FDL2.2 promoted precocious flowering, whereas FDL1 and FDL3 appear to have distinct roles in vegetative growth and phenology. Whereas overexpression of any FDL gene delays short day-induced growth cessation and bud set, only FDL3 coordinately altered leaf development and the transition to secondary growth in a photoperiod-dependent manner. For the first time, we demonstrate distinct functions of the two FT paralogs in vegetative phenology. Study of ft1ft2 double mutants and ft1-specific mutants showed that FT1 promotes dormancy release, whereas FT2 is necessary to sustain growth. Collectively, our results reveal that poplar FTs and FDLs have distinct roles in controlling different aspects of vegetative phenology and woody shoot development. / PHD / The adaptation of trees to temperate and boreal climates depends on their ability to respond to environmental signals that are markers of seasonal changes in order to survive winter and maximize growth. The genus Populus (poplars) is a model system for identifying the genes and molecular mechanisms that regulate growth and dormancy transitions. Photoperiod and temperature regulate both vegetative and floral phenology. FLOWERING LOCUS T (FT) and FLOWERING LOCUS D (FD) are key regulators of flowering time in Arabidopsis and other plants. The distinct functions of three poplar FD-LIKE (FDL) genes and two FTs were explored through gain-of-function, dominant repression, and CRISPR/CAS9-mediated gene editing. We studied trees in controlled environments, including manipulation of daylength and temperature to mimic an annual seasonal growth and dormancy cycle. Our studies showed that the FDL proteins share less than complete functional equivalency. Among the three paralogs, only FDL2.2 promoted precocious flowering, whereas FDL1 and FDL3 appear to have distinct roles in vegetative growth and phenology. Whereas overexpression of any FDL gene delays short day-induced growth cessation and bud set, only FDL3 coordinately altered leaf development and the transition to secondary growth in a photoperiod-dependent manner. For the first time, we demonstrate distinct functions of the two FT paralogs in vegetative phenology. Study of ft1ft2 double mutants and ft1-specific mutants showed that FT1 promotes dormancy release, whereas FT2 is necessary to sustain growth. Collectively, our results reveal that poplar FTs and FDLs have distinct roles in controlling different aspects of vegetative phenology and woody shoot development.

This thesis investigates the feasibility of utilizing biodegradable polymeric microspheres loaded with the anticancer drug 5-fluorouracil (5FU) and superparamagnetic iron oxide nanoparticles (SPIONs) to magnetically deliver the cancer therapeutic 5FU to a target tumor in the human body. The primary method of material loading consisted of a w/o/w double emulsion mechanism which 1) loads and protects 5FU in the inner water phase consisting of distilled water and polyvinyl alcohol (PVA), 2) dispersed SPIONs in the biodegradable polymeric organic phase consisting of methylene chloride (MeCl2) for eventual magnetic transport, and 3) suspended these w/o emulsion droplets in an outer aqueous phase comprised of water and PVA and then evaporating the solvent by convection. This procedure produced dried double emulsion microspheres below 2 µm in diameter. They were characterized using scanning electron microscopy (SEM), and magnetometry, which demonstrated their size and superparamagnetic properties. The encapsulation efficiency of 5FU into these polymeric microspheres was above 95%. Drug release of 5FU from dried double emulsion microspheres was significant over 63 days in water and phosphate buffered saline (PBS). Drug release was faster at 37 °C compared to room temperature (21 °C). The medium of PBS at pH 7.4 and 5.4 promoted faster release than distilled water at pH 7.0. Release was faster from PLGA than from PLA. Antibiotic potency of 5FU remained effective after drug release and degradation of carrier. Application of these microspheres in future clinical trials may present a noninvasive, low-risk method to treating malign tumors in nonresectable regions while demonstrating more effective results than systemic administration of chemotherapy. This research presents a significant innovation in therapeutic drug delivery technology for nonresectable cancerous tumors, particularly in the head and neck regions.

In the effort to reduce emission and fuel consumption in industrial gas turbines, lean premixed combustion is utilized but is susceptible to thermoacoustic instabilities. These instabilities occur due to an in-phase relationship between acoustic pressure and unsteady heat release in a combustor. Thermoacoustic instabilities have been shown to cause structural damage and limit operability of combustors. To mitigate these instabilities, a variety of active and passive methods can be employed. The addition of porous inert media (PIM) is a passive mitigation technique that has been shown to be effective at mitigating an instability. Practical industrial application of a mitigation strategy requires early-stage design considerations such as reduced order modeling, which is often used to study a systems' stability response to geometric changes and mitigation approaches. These reduced order models rely on flame transfer functions (FTF) which numerically represent the relationship between heat release and acoustic perturbations. The accurate quantification of heat release is critical in the study of these instabilities and is a necessary component to improve the reduced order model's predictive capability. Heat release quantification presents numerous challenges. Previous work resolving heat release has used optical diagnostics. For perfectly premixed, laminar flames, it has been shown there are proportional relationships between OH* or CH* chemiluminescence to heat release. This is an ideal case; in reality, practical burners produce turbulent and partially premixed flames. Due to the additional straining of the flame caused by turbulence, the heat release is no longer proportional to chemiluminescence quantities. Also, partially premixed systems have spatially varying equivalence ratios and heat release rates, meaning analysis reliant on perfectly premixed assumptions cannot be used and techniques that can handle spatial variations is needed. The objective of this thesis is to incorporate PIM effects into a reduced order model and resolve quantities vital to understand how PIM is mitigating thermoacoustic instabilities in a partially premixed, turbulent combustion environment. The initial work presented in this thesis is the development of a reduced order model for predicting mode shapes and system stability with and without PIM. This was the first time that a reduced order model was developed to study PIM effects on the thermoacoustic response. Model development used a linear FTF and can predict the system frequency and stability response. Through the frequency response, mode shapes can be constructed which show the axial variation in acoustic values, along with node and anti-node locations. Stability trends can be predicted, such as the independent effects of system parameter variation, to determine its stability response. The model was compared to canonical case studies as well as experimental data with reasonable agreement. With PIM addition, it was shown that a combustor would be under stable operation at more flow conditions than without PIM. The work also shows the stability sensitivity to different porous parameters and PIM locations within the combustor. The model has been used to aid in the design of other combustion systems developed at Virginia Tech's Advanced Propulsion and Power Laboratory. To better understand how PIM is affecting the system stability and demonstrate measurements for the improvement of a numerical FTF, experimental work to resolve the spatially varying equivalence ratio fluctuations was conducted in an atmospheric, swirl-stabilized combustor. The experimental studies worked to improve the fundamental understanding of PIM and its mitigation effects through spatially and temporally resolved equivalence ratios during a self-excited instability. The experimental combustor has an optically accessible flame region which allowed for high speed chemiluminescence to be captured during the instability. Equivalence ratio values were calculated from a relation involving OH*/CH* chemiluminescence ratio. The acoustic perturbations were studied to show how the equivalence ratio fluctuations were being generated and coupling with the acoustic waves. The fluctuation in equivalence ratio showed about 65% variation around its mean value during the period of an instability cycle. When porous media was added to the system, the fluctuation in equivalence ratio was mitigated and a reduction in peak frequency (sound pressure level) SPL of 38 dB was observed. Changes in the spatial distribution of equivalence ratio with PIM addition were shown to produce a more stable operation. Effects such as locally richer burning and changes to recirculation zones promoted more stable operation with PIM addition. Testing with forced acoustic input was also conducted to quantify the flame response. The results demonstrated that a flame in a system with PIM responds differently than without PIM, highlighting the need to develop FTF for systems with PIM. This experimental study was the first to study equivalence ratio in a turbulent, partially premixed combustor using PIM as a mitigation technique. A final experimental investigation was conducted to resolve the spatially defined heat release and its fluctuation during a thermoacoustic instability period. This was the first time that heat release had been investigated in a partially premixed, thermoacoustically unstable system, using PIM as a migration method. Heat release was quantified using equivalence ratio, strain rate, OH* intensity, and a correction factor determined from a chemical kinetic solver. The heat release analysis built upon the equivalence ratio study with additional flow field analysis using PIV. The velocity vectors showed prominent corner and central recirculation zones in the no PIM case which have been shown to be feedback mechanisms that support instability formation. With PIM addition, these flow features were reduced and decoupled from the combustor inlet reactants. The velocity results were decomposed using a spectral proper orthogonal decomposition (SPOD) method. The energy breakdown showed how PIM reduced and distributed the energy in the flow structures, creating a more stable flow field. Heat release results with velocity information demonstrated the significant coupling mechanisms in the flow field that were mitigated with the PIM addition. The no PIM case showed high heat release areas being directly influenced by the incoming flow fluctuations. The feedback mechanisms, both mean flow and acoustic, have a direct path to the incoming flow to the combustor. In the PIM case, there is significant mixing and burning taking place in locations where it is less likely that feedback can reach the incoming flow to couple to form an instability. The methodology to quantify heat release provides a framework for quantifying a non-linear FTF with PIM. The development and testing to determine a non-linear FTF with PIM are reserved for future work and discussed in the final chapter. The methodologies and modeling conducted here provided insight and understanding to answer why PIM is effective at mitigating a thermoacoustic instability and how it can be studied using a reduced order numerical tool. / Doctor of Philosophy / In the effort to reduce emission and fuel consumption in industrial gas turbines, lean premixed combustion is utilized but is susceptible to thermoacoustic instabilities. These instabilities occur due to a relationship between acoustic pressure and unsteady heat release in a combustor. Thermoacoustic instabilities have been shown to cause structural damage and limit operability of combustors. To mitigate these instabilities, a variety of active and passive methods can be employed. The addition of porous inert media (PIM) is a passive mitigation technique that has been shown to be effective at mitigating an instability. Implementation of these mitigation strategies require early-stage design considerations such as reduced order modeling, which is often used to study a systems' stability response to geometric changes and mitigation approaches. These reduced order models rely on flame transfer functions (FTF) which numerically model the flame response. The accurate quantification of heat release is critical in the study of these instabilities and is a necessary component to improve the reduced order model's predicative capability. Heat release quantification presents numerous challenges. Previous work resolving heat release has used optical diagnostics with varying levels of success. For perfectly premixed, laminar flames, it has been shown there are proportional relationships between flame light emission and heat release. This is an ideal case; in reality, practical burners produce complex turbulent flames. Due to complex turbulent flame, the heat release is no longer proportional to the flame light emission quantities. Also, partially premixed systems have spatially variant flame quantities, meaning analyses reliant on perfectly premixed assumptions cannot be used and techniques that can handle spatial variations are required. The objective of this thesis is to incorporate PIM effects into a reduced order model and resolve quantities vital to understand how PIM is mitigating thermoacoustic instabilities in a partially premixed, turbulent combustion environment. The initial work presented in this thesis is the development of a reduced order model for predicting mode shapes and system stability with and without PIM. The model uses a simple relationship to model the flame response in an acoustic framework. To improve the model and understanding of PIM mitigation, experimental data such as the local heat release rates and equivalence ratios need to be quantified. An experimental technique was utilized on an optically accessible atmospheric, swirl-stabilized combustor, to resolve the spatially variant equivalence ratio and heat release rates. From these results, better understanding of how PIM is improving the stability in a combustion environment is shown. Quantities such as velocity, acoustic pressure, equivalence ratio, and heat release are all studied and used to explain the improved stability with PIM addition. The methodologies and modeling conducted here provided insight and understanding to answer why PIM is effective at mitigating a thermoacoustic instability and how it can be studied using a reduced order numerical tool. Furthermore, the present work provides a framework for quantifying spatially varying heat release measurements, which can be used to develop FTF for use with thermoacoustic modeling approaches.

Yes / We outline the valuation process for a No-Negative Equity Guarantee in an Equity Release Mortgage loan and for an Equity Release Mortgage that has such a guarantee. Illustrative valuations are provided based on the Black ’76 put pricing formula and mortality projections based on the M5, M6 and M7 mortality versions of the Cairns–Blake–Dowd (CBD) family of mortality models. Results indicate that the valuations of No-Negative Equity Guarantees are high relative to loan amounts and subject to considerable model risk but that the valuations of Equity Release Mortgage loans are robust to the choice of mortality model. Results have significant ramifications for industry practice and prudential regulation.

No / This study compares the performance of neurofuzzy logic and neural networks using two software packages (INForm and FormRules) in generating predictive models for a published database for an immediate release tablet formulation. Both approaches were successful in developing good predictive models for tablet tensile strength and drug dissolution profiles. While neural networks demonstrated a slightly superior capability in predicting unseen data, neurofuzzy logic had the added advantage of generating rule sets representing the cause-effect relationships contained in the experimental data.

Yes / Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed “polypill” capsules with bespoke release patterns for multiple drugs. Complex structures are devised using combined fused deposition modeling 3D printing aligned with hot-filling syringes. Two unibody highly modular capsule skeletons with four separate compartments are devised: i) concentric format: two external compartments for early release while two inner compartments for delayed release, or ii) parallel format: where nondissolving capsule shells with free-pass corridors and dissolution rate-limiting pores are used to achieve immediate and extended drug releases, respectively. Controlling drug release is achieved through digital manipulation of shell thickness in the concentric format or the size of the rate limiting pores in the parallel format. Target drug release profiles are achieved with variable orders and configurations, hence confirming the modular nature with capacity to accommodate therapeutics of different properties. Projection of the pharmacokinetic profile of this digital system capsules reveal how the developed approach can be applied in dose individualization and achieving multiple desired pharmacokinetic profiles.