Bulk- and Surface-Erodable Polymers: Effects of Polymer Structure on Physico-Chemical and Biological Properties

In this dissertation, degradation and biocompatibility of biodegradable polymers were investigated with a special emphasis on structure-property relationships. The idea of using co-polymers in drug delivery was enhanced by the generation of comb-like, branched polyesters with a hydrophilic amine-modified PVA backbone and short hydrophobic PLGA side chains. A particular advantage of these branched polyesters is their versatility of structural modifications. A matrix of amine-modified PVA backbone and Amine-PVA-g-PLGA polymers was systematically characterized in vitro establishing structure-toxicity relationships. Effects of type and degree of amine substitution as well as molecular weight on cytotoxicity were evaluated in cell-based assays. A molecular weight and dose dependent cytotoxicity was found for amine-modified PVA. The type of amine functionality was of minor importance with DEAPA being slightly less cytotoxic than DEAEA and DMAPA. The cytotoxic effect is not caused by apoptosis but rather by necrotic reaction to the highly charged amine-modified PVA backbone polymers presumably by interactions of polycationic materials with cell membranes. The approach to improve the cytocompatibility of amine-modified PVA polymers using biodegradable PLGA side chains turned out to be successful. Decreased charge densities and shielding positively charged amine moieties by PLGA side chains decreased the cytotoxicity. In addition, a systematic evaluation of the influence of the polymer composition on in vitro degradation behaviour is reported. In a first set of experiments, the weight loss of solvent cast films of defined size from 19 polymers was measured as a function of incubation in phosphate buffer (pH 7.4) at 37°C over a time of 21 days. A second study was initiated focusing on three selected polymers in a similar set up, but with additional observation of pH influences (pH 2 and 9) and determination of water uptake (swelling) and molecular weights during degradation. As hypothesized, our investigations revealed the potential to influence the degradation of this polymer class by the degree of amine substitution, higher degrees leading to faster erosion. The erosion rate could further be influenced by the type of amine functionality, DEAPA-modified polyesters degrading as fast as or slightly faster than DMAPA-modified polyesters and these degrading faster than DEAEA-PVA-g-PLGA. As a third option the degradation rate could be modified by the PLGA side chain length, shorter side chains leading to faster erosion. As compared to linear PLGA, remarkably shorter degradation times could be achieved by grafting short PLGA side chains onto amine-modified PVA backbones. Erosion times from less than 5 days to more than 4 weeks could be realized by choosing the type of amine functionality, the degree of amine substitution and the PLGA side chain length at the time of synthesis. In addition, the pathway of hydrolytic degradation could be tuned to be either mainly bulk or surface erosion. The advantage of the modular conception resulting in the ability to predetermine degradation rate, degradation profile, charge density and cytocompatibility makes these amine-modified PVA-g-PLGA polymers promising materials for the controlled release of bioactive compounds and for gene delivery. While the yet investigated PLGA-based polymers were all subject to degradation upon hydrolytic cleavage of ester bonds, “biodegradation” can also occur by other mechanisms such as enzymatic or biocatalytic cleavage. Poly(ethylene carbonate) (PEC) has been shown to exhibit an in vivo surface degradation mechanism by superoxide anions produced by adhering polymorphonuclear leucocytes and macrophages. A first feasibility study exploring the utility of PEC as coating material for drug eluting stents under in vitro conditions was reported. PEC was found to be an amorphous polymer with thermoelastic properties. Tensile testing revealed a stress to strain failure of more than 600%. Due to this flexibility, we were able to prepare a PEC-coated stent that could be expanded without causing any observable damage to the polymeric coating. In vitro cytotoxicity tests showed excellent cytocompatibility of PEC. Based on these findings, a new stenting concept was suggested, pre-coating a bare-metal stent with PPX-N as non-biodegradable basis and applying a secondary PEC coating using an airbrush method. As an in vitro release model, metal plates of a defined size and area were coated under the same conditions as the stents with PEC containing radiolabelled paclitaxel. An alkaline KO2 - solution served as a superoxide source. Within 12 hours, 100% of the incorporated paclitaxel was released, while only 20% of the drug was released in non-superoxide releasing control buffer within 3 weeks. This degradation-controlled release mechanism of PEC supports our hypothesis of an “on demand” drug eluting stent coating

MCMC Sampling of Directed Flag Complexes with Fixed Undirected Graphs

Constructing null models to test the significance of extracted information is a crucial step in data analysis. In this work, we provide a uniformly sampleable null model of directed graphs with the same (or similar) number of simplices in the flag complex, with the restriction of retaining the underlying undirected graph. We describe an MCMC-based algorithm to sample from this null model and statistically investigate the mixing behaviour. This is paired with a high-performance, Rust-based, publicly available implementation. The motivation comes from topological data analysis of connectomes in neuroscience. In particular, we answer the fundamental question: are the high Betti numbers observed in the investigated graphs evidence of an interesting topology, or are they merely a byproduct of the high numbers of simplices? Indeed, by applying our new tool on the connectome of C. Elegans and parts of the statistical reconstructions of the Blue Brain Project, we find that the Betti numbers observed are considerable statistical outliers with respect to this new null model. We thus, for the first time, statistically confirm that topological data analysis in microscale connectome research is extracting statistically meaningful information

Capital Market Imperfections and Trade Liberalization in General Equilibrium

This paper develops a new international trade model with capital market imperfections and endogenous borrowing costs in general equilibrium. Our theoretical model is motivated by new empirical patterns from enterprise survey data of the World Bank. Observing that a substantial fraction of the variation in financial constraints is across firms within industries, we allow for firm-specific exposure to financial constraints. This leads to credit rationing and divides producers into financially constrained and unconstrained ones. We show that endogenous adjustments of capital costs represent a new channel that reduces common gains from globalization. Trade liberalization increases the demand for capital and thus the borrowing rate. This leads to a reallocation of market shares towards financially unconstrained producers and a larger fraction of credit-rationed firms. Both effects increase the within-industry variance of firm outcomes and reduce welfare gains as consumers dislike heterogeneity in prices

Effective tax rates, endogenous mark-ups and heterogeneous firms

We provide a new explanation why effective tax rates are smaller for larger firms even in the absence of common channels like profit shifting and lobbying. This result emerges in a heterogeneous firms model with endogenous mark-ups. Our framework features imperfect tax pass-through into prices and partial deductibility of production costs. Corporate taxes reduce mark-ups and hence pre-tax profits, especially for high cost firms. As production costs are only partially deductible, high cost producers are affected most by taxes. We further show that shocks which affect mark-ups through competition, like globalization, reinforce the heterogeneity in effective tax rates across firms

Credit constraints, endogenous innovations, and price setting in international trade

We introduce credit frictions motivated by moral hazard in a general equilibrium model of international trade with two dimensions of heterogeneity and endogenous investments. Firms’ competitiveness consists of capabilities to conduct process and quality innovations at low costs, whereas investment outlays have to be financed by external capital. We show that the scope for vertical product differentiation in a sector determines how credit tightening affects investment and price setting. Consistent with recent empirical evidence, our model rationalizes positive as well as negative correlations of firm-level FOB prices with financial frictions and variable trade costs. Faced with an increase in the borrowing rate, producers reduce both types of innovation resulting in opposing effects on marginal production costs and prices. In general equilibrium, financial frictions intensify quality-based (cost-based) sorting of firms if the scope for vertical product differentiation is high (low). Consequently, credit tightening leads to firm exit, increased innovation activity among existing suppliers, and welfare losses that are larger in sectors with low investment intensity

Credit constraints, endogenous innovations, and price setting in international trade

We introduce credit frictions motivated by moral hazard in a general equilibrium model of international trade with two dimensions of heterogeneity and endogenous investments. Firms’ competitiveness consists of capabilities to conduct process and quality innovations at low costs, whereas investment outlays have to be financed by external capital. We show that the scope for vertical product differentiation in a sector determines how credit tightening affects investment and price setting. Consistent with recent empirical evidence, our model rationalizes positive as well as negative correlations of firm-level FOB prices with financial frictions and variable trade costs. Faced with an increase in the borrowing rate, producers reduce both types of innovation resulting in opposing effects on marginal production costs and prices. In general equilibrium, financial frictions intensify quality-based (cost-based) sorting of firms if the scope for vertical product differentiation is high (low). Consequently, credit tightening leads to firm exit, increased innovation activity among existing suppliers, and welfare losses that are larger in sectors with low investment intensity

Nanoproteomic analysis of ischemia-dependent changes in signaling protein phosphorylation in colorectal normal and cancer tissue

Additional file 1: Table S1. Clinical data for the 20 patients analyzed in the study. Presents patient clinical data including tumor stage and grade