Development and evaluation of enzymatically-degradable hydrogel microparticles for pulmonary delivery of nanoparticles and biologics

textThe emerging class of biologic drugs, including proteins, peptides, and gene therapies, are widely administered by injection, despite potential systemic side effects. Rational design of targeted carriers that can be delivered non-invasively, with reduced side effects, is essential for the success of these therapies, as well as for the improvement of patient compliance and quality of life. One potential approach is to take advantage of specific physiological cues, such as enzymes, which would trigger drug release from a drug carrier. Enzymatic cleavage is highly specific and could be tailored for certain diseased tissues where specific enzymes are up regulated. Enzymatically-degradable hydrogels, which incorporate an enzyme- cleavable peptide into the network structure, have been extensively reported for releasing drugs for tissue engineering applications. These studies showed that a rapid response and corresponding drug release occurs upon enzyme exposure, whereas minimal degradation occurs without enzyme. Recently, Michael addition reactions have been developed for the synthesis of such enzymatically-degradable hydrogels. Michael addition reactions occur under mild physiological conditions, making them ideally suited for polymerizing hydrogels with encapsulated biologic drugs without affecting its bioactivity, as in traditional polymerization and particle synthesis. The focus of my research was to create enzymatically-degradable hydrogel microparticles, using Michael addition chemistry, to evaluate for use as an inhalable, disease-responsive delivery system for biologic drugs and nanoparticles. In this dissertation, I utilize bioconjugation and Michael addition chemistries in the design and development of enzymatically-degradable hydrogels, which may be tailored to a multitude of disease applications. I then introduce a new method of hydrogel microparticle, or microgel, synthesis known as the Michael Addition During Emulsion (MADE) method. These microgel carriers were evaluated in vitro, and found to exhibit triggered release of encapsulated biologic drugs in response to enzyme, no significant cytotoxic effects, and the ability the avoid rapid clearance by macrophages. Lastly, in vivo studies in mice were conducted, and microgels were found to exhibit successful delivery to the deep lung, as well as prolonged pulmonary retention after intratracheal aerosol delivery. In conclusion, a new class of enzymatically-degradable microgels were successfully developed and characterized as a versatile and promising new system for pulmonary, disease-responsive delivery of biologic drugs.Biomedical Engineerin

Thermodynamic Properties of Block Copolymer Electrolytes Containing Imidazolium and Lithium Salts

We report on the thermal properties, phase behavior, and thermodynamics of a series of polystyrene-block-poly(ethylene oxide) copolymers (SEO) mixed with the ionic species Li[N(SO_(2)CF_3)_2] (LiTFSI), imidazolium TFSI (ImTFSI), and an equimolar mixture of LiTFSI and ImTFSI (Mix). Differential scanning calorimetric scans reveal similar thermal behavior of SEO/LiTFSI and SEO/ImTFSI at the same salt concentrations. Phase behavior and thermodynamics were determined using a combination of small-angle X-ray scattering and birefringence. The thermodynamics of our mixtures can be mapped on to the theory of neat block copolymer phase behavior provided the Flory−Huggins interaction parameter, χ, between the blocks is replaced by an effective χ (χ_(eff)) that increases linearly with salt concentration. The phase behavior and the value of m, the slope of the χ_(eff) versus salt concentration data, were similar for SEO/LiTFSI, SEO/ImTFSI, and SEO/Mix blends. The theory developed by Wang [ J. Phys. Chem. B. 2008, 41, 16205] provides a basis for understanding the fundamental underpinnings of the measured value of m. We compare our experimental results with the predictions of this theory with no adjustable parameters

Evaluation of impacts of future climate change and water use scenarios on regional hydrology

General circulation models (GCMs) have been widely used to simulate current and future climate at the global scale. However, the development of frameworks to apply GCMs to assess potential climate change impacts on regional hydrologic systems, ability to meet future water demand, and compliance with water resource regulations is more recent. In this study eight GCMs were bias-corrected and downscaled using the bias correction and stochastic analog (BCSA) downscaling method and then used, together with three ET0 methods and eight different water use scenarios, to drive an integrated hydrologic model previously developed for the Tampa Bay region in western central Florida. Variance-based sensitivity analysis showed that changes in projected streamflow were very sensitive to GCM selection, but relatively insensitive to ET0 method or water use scenario. Changes in projections of groundwater level were sensitive to both GCM and water use scenario, but relatively insensitive to ET0 method. Five of eight GCMs projected a decrease in streamflow and groundwater availability in the future regardless of water use scenario or ET method. For the business as usual water use scenario all eight GCMs indicated that, even with active water conservation programs, increases in public water demand projected for 2045 could not be met from ground and surface water supplies while achieving current groundwater level and surface water flow regulations. With adoption of 40&thinsp;% wastewater reuse for public supply and active conservation four of the eight GCMs indicate that 2045 public water demand could be met while achieving current environmental regulations; however, drier climates would require a switch from groundwater to surface water use. These results indicate a high probability of a reduction in future freshwater supply in the Tampa Bay region if environmental regulations intended to protect current aquatic ecosystems do not adapt to the changing climate. Broad interpretation of the results of this study may be limited by the fact that all future water use scenarios assumed that increases in water demand would be the result of intensification of water use on existing agricultural, industrial, and urban lands. Future work should evaluate the impacts of a range of potential land use change scenarios, with associated water use change projections, over a larger number of GCMs.</p