Multi-disciplinary approaches to problem solving are needed given the increasing complexity of fundamental scientific questions. This dissertation undertakes a holistic approach to research and tackles challenges spanning the biology, chemistry, and materials interface. The central theme for most projects involves applying inorganic and main group chemistry to develop new bioconjugation strategies or polymerization methodologies to access novel materials.

Chapter One describes efforts in understanding the effects of trehalose polymers towards protein stabilization. The stabilization capability of polymers made from a set of styrenyl-based trehalose monomer regioisomers were studied. Polymers of each trehalose monomer regioisomer and one polymer which contained all three isomers combined were synthesized. All polymer regioisomers stabilized insulin to a similar degree towards agitation and heat stress.

Chapter Two details the initial discovery that icosahedral boron-rich cluster compounds of the type B12(OR12)—where “R” can be any alkyl or aryl group— could be utilized as strong one-electron photooxidants thereby initiating the polymerization of olefins. The perfunctionalized clusters are able to initiate polymerization of a range of styrene substrates under blue LED irradiation. Also demonstrated, is the visible light initiated, metal free cationic polymerization of isobutylene into poly(isobutylene).

Chapter Three introduces a new class of carborane-based chain-transfer agents (CTA’s) to be used in reversible addition-fragmentation chain-transfer (RAFT) polymerization. The carborane-based CTA’s mediate the controlled polymerization of monomers such as styrene, N-isopropylacrylamide, and methyl acrylate to produce monodisperse carborane terminated polymers. The carborane-based scaffold, appended on the polymer chain end, serves as a general 1H NMR spectroscopic handle used to elucidate polymer molecular weight. Binding of carborane into the hydrophobic cavity of β-cyclodextrin was demonstrated by isothermal titration calorimetry thereby validating its potential use as an affinity label. The carborane RAFT agents also act as Raman active probes.

Chapter Four explores the reactivity of gold(III) organometallic complexes in the context of bioconjugation chemistry. The gold(III) organometallic complexes mediated the conjugation of small molecule substrates which included heterocycles, an anti-cancer drug, biotin, and low molecular weight PEG to cysteine residues on biomolecules. The bioconjugation reactions proceeded rapidly, with high efficiency, and in a broad pH range.

Anthropogenic watershed disturbance by industry, agriculture, deforestation, roads, and urbanization alters the timing, composition, and mass of sediment loads to coral reefs, causing enhanced sediment stress on corals near the outlets of impacted watersheds (Syvitski et al., 2005; West and van Woesik, 2001). Few studies have developed an integrated understanding of sediment sources, transport processes, and deposition in small, reef-fringed embayments (Bartley et al., 2014; Draut et al., 2009; Wolanski et al., 2003) and many are outside the scope of local environmental managers in remote islands like at the study site, Tutuila, American Samoa. Ridge-to-Reef studies on sediment dynamics have three general components, which are reflected in the three chapter structure of this dissertation: watershed inputs, hydrodynamic circulation over the reef, and how they interact to govern spatiotemporal distribution of sediment accumulation on the reef. This dissertation provides an example of how a scientific, process-oriented Ridge to Reef study of sediment dynamics can answer critical scientific questions about the source, transport, and fate of sediment in the near-shore environment, and how answers to the scientific questions can support local coral management.

Data on suspended sediment yield (SSY) from small, steep, tropical watersheds is limited, and assessments of sediment mitigation projects have been hindered by interannual climatic and sediment source variability. Chapter 1 used an event-wise approach to compare SSY from disturbed and undisturbed subwatersheds from storms of the same size, estimate total SSY to Faga'alu Bay, and estimate annual SSY to compare to other watersheds. It was unknown what the dominant sediment source was in Faga'alu watershed, and what potential management solutions were available. The sediment budget developed in the first chapter of this dissertation showed the quarry was a significant source, compared to natural background, and so local managers focused on reducing sediment discharge from the quarry. Continued monitoring presented in the third dissertation chapter showed SSY to the Bay was significantly reduced following sediment mitigation at the quarry.

The fate of suspended sediment once it enters the marine environment is difficult to predict, but is strongly controlled by hydrodynamic conditions and circulation patterns. Computer models of hydrodynamic circulation require detailed forcing data, bathymetric data, and computer resources that are often unavailable to local managers. Chapter 2 of the dissertation used a simple approach combining Lagrangian GPS-logging drifters and Eulerian acoustic current profilers to determine dominant water circulation patterns under the most common conditions that characterize forcing in the Bay: calm, high onshore winds, and high waves.

Measuring sediment accumulation on the reef is a contested area of research and the most common method, using tube traps, has some weaknesses. Others argue flat surfaces should be used to show net sediment accumulation. Chapter 3 presents results from both tubular sediment traps and flat-surfaced sediment pods to show gross vs net monthly sediment accumulation over one year. While many studies deploy traps haphazardly, or just below stream outlets, here sediment traps were arranged to observe spatial patterns between the north and south sections of the reef, as a result of prevailing currents and distance from the stream outlet.

Integrating SSY and water circulation from Chapters 1 and 2 with observations of sediment accumulation in Chapter 3 showed that the predominant water circulation patterns deflect the storm-supplied terrigenous sediment from the stream over the northern reef where it caused enhanced sediment stress on corals. Temporal patterns of sedimentation were complex, and only the site nearest the stream outlet correlated with monthly SSY from the watershed, whereas nearly all sites showed increased carbonate sedimentation with increased wave energy. Sediment accumulated in traps and on sediment pods was mostly similar to surrounding benthic sediment, and correlated with wave energy, showing most sediment transport over the reef was from wind and wave-forced resuspension of carbonate sediment.

Proteins and peptides have become an important class of therapeutics due to their high specificity and general biocompatibility. However, using proteins and peptides as drugs has several intrinsic challenges. These macromolecules are generally cleared rapidly due to renal filtration and enzymatic degradation following administration. Issues of instability during storage due to their chemical composition and specific three-dimensional confirmations necessitate that most protein and peptide therapeutics be stored in the refrigerator or as a lyophilized powder. Additionally, they must be administered through injection and are not responsive to intrinsic biological signals, unlike endogenous processes. Thus, it is important to develop methods to improve characteristics of protein and peptide therapeutics to improve their stability, pharmacokinetics, and delivery in response to biological stimuli.

Chapter Two describes the investigation of the insulin stabilization properties of trehalose glycopolymer as excipient and conjugate. Addition of a styrenyl backbone trehalose polymer excipient stabilized insulin against aggregation induced by exposure of insulin to heat or mechanical agitation. Conjugation of the trehalose polymer to insulin was achieved by reductive amination and the stability assays were repeated with the conjugate, showing results like the excipient. The conjugation site was identified as GlyA1 and LysB29 by indirect characterization through acid-cleavage of the polymer. While conjugation prolonged the half-life in mice, addition of trehalose polymer excipient did not alter protein pharmacokinetics. The mechanism of insulin stabilization was investigated with a methacrylate backbone trehalose polymer excipient, showing presence of the polymer inhibits both fibrillation and deamidation.

Chapter Three continues the development of a new strategy for site-specific conjugation of a trehalose polymer to insulin for improved stability and bioactivity. Conditions for AGET ATRP under mild, aqueous conditions were optimized. A site-specific insulin macroinitiator was prepared targeting modification at LysB29 utilizing its higher nucleophilicity over the other possible amine conjugation sites and purifying to isolate the desired species. Trehalose monomer was polymerized directly from this site-specific macroinitiator resulting in a conjugate with improved heat stability. A lower dosage of the site-specific conjugate compared to the nonspecific conjugate was needed to achieve the same change in blood glucose.

Chapter Four details the synthesis of blood triggered self-immolative linkers designed for use as spacers for rapid-acting insulin-trehalose glycopolymer conjugates. Linkers triggered by serum albumin through base-catalyzed β-elimination were first prepared and triggering was characterized. During conjugation, the first linker underwent premature triggering from the primary amines of insulin and the exposed amine catalyzed further triggering. The second linker design underwent base-catalyzed self-immolation over the course of 20 h. Linkers that could be triggered by the thiol concentration in the blood were then synthesized and evaluated. Both aliphatic and aromatic linkers underwent rapid self-immolation with small molecules across the disulfide under relevant glutathione concentrations. Conjugation with trehalose glycopolymer slowed the kinetics of the self-immolation, likely because of the increase in steric bulk.

Chapter Five describes optimization of the background release of insulin from a trehalose glycopolymer hydrogel for improved stability and glucose-responsive delivery of the protein. Several strategies were used to decrease the background release. Two methods to increase the binding affinity of the boronic acid to polyols was used to strengthen the hydrogel network. The influence of pore size/crosslink density was also explored. Finally, incorporation of comonomers for electrostatic attraction to insulin resulted in the lowest background release of insulin without glucose after optimization of gelation procedure.

Chapter Six introduces glucose-responsive materials for regulation of glucagon delivery. Glucose-responsive nanogels are prepared by precipitation polymerization and post-polymerization modification with phenylboronic acid as glucose-sensing unit. Nanogels were thermo- and glucose-responsive through incorporation of thermoresponsive pNIPAM or pPEGMA with glucose acting as an additive that alters the hydration of the polymers. Native glucagon was found to degrade during the loading of the nanogels, so a more stable soluble analog was used that improved to loading.

Eccrine squamous syringometaplasia (ESS) is a rare finding defined as metaplastic change of the cuboidal epithelial cells of eccrine glands into two or more layers of squamous epithelial cells. We present a patient who developed ESS after induction of CLAG chemotherapy [2-Chlorodeoxyadenosine (2-CdA) with cytarabine (Ara-C) and (granulocyte-colony stimulating factor) G-CSF] for management of the blast crisis of his chronic myelogenous leukemia (CML). Our patient’s ESS eruption presented with a variety of morphologies, thus multiple skin biopsies were taken to determine the possible diagnosis(es). All skin biopsies showed ESS and the eruption resolved with topical corticosteroids after CLAG therapy was finished.

Millimeter-scale components produced by metal additive manufacturing (AM) expand the design possibilities in myriad applications from aerospace engines to biomedical bone implants. A major obstacle to commercialization of this versatile technology is the inconsistent failure behavior of such parts, attributable primarily to surface defects, geometric irregularities, and microstructural heterogeneities. There is a gap in process-structure-property knowledge for millimeter-scale metal AM because at small scales, additive melt pool sizes approach to part dimensions, and this limits control of effective mechanical properties. The in-situ scan strategy and post-process machining options employed to produce desirable properties in larger parts become unfeasible at small length scales, often leaving mm-scale parts with as-printed microstructures and surface roughness.

In this work, experimental and computational approaches are used to explore the implications of mm-scale component geometry for the mechanical performance of high and low hardening structural alloys. Two types of approaches are taken: bottom-up and top-down. In the bottom-up studies, (a) surface roughness and microstructure are determined to have a statistical influence on the mechanical performance variation in mm-scale AM Ti-6Al-4V struts; and (b) defect-driven mechanical property debits are quantified by finite element analysis (FEA) for a thin strut intersection topology with two deformation modes, as a function of defect location, spacing, and depth, as well as material hardening rate. The material scope of the latter investigation is intentionally broad and dimensionless so that the results may be generalized to multiple structural alloys such as Ti-64, steels, and Inconel alloys. In the top-down studies, (a) FEA is used to solve the inverse problem and determine the effective properties of AM Inconel 625 thin strut T-intersections to reveal the influence of critical part dimension on the properties of high hardening materials; (b) the value of the proxy geometry method for predicting the mechanical performance of AM parts with complex geometries is investigated, and the possibility of locally varying and anisotropic properties from printing-induced microstructure variation is examined by FEA; and (c) assuming limited property optimization can be employed in mm-scale parts, an extensive FEA parameter study over the reported property range for AM IN718 bounds the impact of AM-induced material property variations on the mechanical response of a bend-dominated thin strut intersection.