Integration of environmental aspects in modelling and optimisation of water supply chains.

Climate change becomes increasingly more relevant in the context of water systems planning. Tools are necessary to provide the most economic investment option considering the reliability of the infrastructure from technical and environmental perspectives. Accordingly, in this work, an optimisation approach, formulated as a spatially-explicit multi-period Mixed Integer Linear Programming (MILP) model, is proposed for the design of water supply chains at regional and national scales. The optimisation framework encompasses decisions such as installation of new purification plants, capacity expansion, and raw water trading schemes. The objective is to minimise the total cost incurring from capital and operating expenditures. Assessment of available resources for withdrawal is performed based on hydrological balances, governmental rules and sustainable limits. In the light of the increasing importance of reliability of water supply, a second objective, seeking to maximise the reliability of the supply chains, is introduced. The epsilon-constraint method is used as a solution procedure for the multi-objective formulation. Nash bargaining approach is applied to investigate the fair trade-offs between the two objectives and find the Pareto optimality. The models' capability is addressed through a case study based on Australia. The impact of variability in key input parameters is tackled through the implementation of a rigorous global sensitivity analysis (GSA). The findings suggest that variations in water demand can be more disruptive for the water supply chain than scenarios in which rainfalls are reduced. The frameworks can facilitate governmental multi-aspect decision making processes for the adequate and strategic investments of regional water supply infrastructure.

Optimizing endothelial targeting by modulating the antibody density and particle concentration of anti-ICAM coated carriers.

Targeting of drug carriers to cell adhesion molecules expressed on endothelial cells (ECs) may improve treatment of diseases involving the vascular endothelium. This is the case for carriers targeted to intercellular adhesion molecule 1 (ICAM-1), an endothelial surface protein overexpressed in many pathologies. In order to optimize our design of anti-ICAM carriers, we have explored in this study the influence of two carrier design parameters on specific and efficient endothelial targeting in vitro and in vivo: carrier dose and density of targeting molecules (antibodies-Ab) on the carrier surface. Using radioisotope tracing we assessed the role of these parameters on the biodistribution of model polymer carriers targeted to ICAM-1 ((125)I-anti-ICAM carriers) in mice. Increasing the carrier dose enhanced specific accumulation in the lung vasculature (a preferential endothelial target) and decreased non-specific hepatic and splenic uptake. Increasing the Ab density enhanced lung accumulation with minimally reduced liver and spleen uptake. These studies account for the influence of blood hydrodynamic forces on carrier binding to endothelium, relevant to arterioles, venules and larger vessels. Yet, carriers may rather bind to the extensive capillary bed where shear stress is minimal. We used fluorescence microscopy to determine binding kinetics of FITC-labeled anti-ICAM carriers in static conditions, at the threshold found in vivo and conditions mimicking low vs high ICAM-1 expression on quiescent vs activated ECs. Binding to activated ECs reached similar saturation with all tested Ab densities and carrier concentrations. In quiescent cells, carriers reached ~3-fold lower binding saturation, even at high carrier concentration and Ab density, and carriers with low Ab density did not reach saturation, reflecting avidity below threshold. Binding kinetics was positively regulated by anti-ICAM carrier concentration and Ab density. Counterintuitively, binding was faster in quiescent ECs (except for carriers with high Ab density and concentration), likely due to fast saturation of fewer binding sites on these cells. These results will guide optimization of ICAM-1-targeted carriers, e.g., in the context of targeting healthy vs diseased endothelium for prophylactic vs therapeutic interventions.

Effect of Glycocalyx on Drug Delivery Carriers Targeted to Endothelial Cells.

Animal models have shown that coupling ligands, targeted to endothelium surface receptors, with drug delivery carriers (DDC) can optimize the treatment of diseases by specific vascular delivery. The endothelium is exposed to hydrodynamic forces that modulate the expression of these cellular adhesion molecules (CAMs) and affect the structural and biological activity of endothelial cells (ECs). In order to investigate how delivery of targeted DDC can be optimized, we investigated carriers binding to flow adapted ECs under flow conditions. Comparison of live ECs to fixed cells from our previous experiments give insight into the effect of receptor motility on the cell surface as well as the effect of other factors such as glycocalyx (a protective layer of carbohydrates on the surface of cells) and actin remodeling. A flow chamber model is used to investigate how DDC size variation alters binding under flow conditions. Binding experiments were done with and without glycocalyx in order to elucidate its protective effect. Using fluorescence microscopy we determined the real time binding and rolling speeds of DDC under flow conditions. We also demonstrate the presence of glycocalyx and image actin filament remodeling. The binding of 1 µm carriers to ECs decreased after flow adaptation, in both non-activated and TNF-α activated ECs compared to non-flow adapted live cells. After removal of the glycocalyx by degrading enzymes binding increased in quiescent ECs, but only increased in activated cells after 2 hr of perfusion with particles. The binding with 100 nm carriers also decreased after flow adaptation but to a lesser extent and partially increased after enzyme degradation. These experiments give insight as to how tunable affinity parameters can be optimized to enhance therapeutic capabilities.

A boundary element model of the transport of a semi-infinite bubble through a microvessel bifurcation.

Motivated by a developmental gas embolotherapy technique for selective occlusion of blood flow to tumors, we examined the transport of a pressure-driven semi-infinite bubble through a liquid-filled bifurcating channel. Homogeneity of bubble splitting as the bubble passes through a vessel bifurcation affects the degree to which the vascular network near the tumor can be uniformly occluded. The homogeneity of bubble splitting was found to increase with bubble driving pressure and to decrease with increased bifurcation angle. Viscous losses at the bifurcation were observed to affect the bubble speed significantly. The potential for oscillating bubble interfaces to induce flow recirculation and impart high stresses on the vessel endothelium was also observed.

Flow dynamics, binding and detachment of spherical carriers targeted to ICAM-1 on endothelial cells.

Vascular drug delivery by administration of carriers targeted to endothelial surface determinants, such as intercellular adhesion molecule (ICAM-1), holds considerable promise to improve disease treatment. As a model to define elusive factors controlling the interplay between carrier motion in the bloodstream and its interactions with molecular targets in the endothelial wall, we used 1 mum beads coated with ICAM-1 monoclonal antibody (Ab) at 370, 1100 or 4100 Ab/microm2. Carriers were perfused at two shear rates over resting or activated endothelial cells, expressing minimum vs. maximum ICAM-1 levels, to determine carrier rolling, binding and detachment. Even at 0.1 Pa and 4100 Ab/microm2, carriers attached only to activated cells (21 fold increase over resting cells), ideal for specific drug targeting to sites of pathology. Binding was increased by raising the Ab surface density on the carrier, e.g., 59.4+/-11.1% increase for carriers having 4100 vs. 1100 Ab/microm2, as a consequence of decreased rolling velocity. Carrier binding was stable even under a high shear stress: carriers with 1100 and 4100 Ab/microm2 withstand shear stress over 3 Pa without detaching from the cells. This is further supported by theoretical modeling. These results will guide vascular targeting of drug carriers via rational design of experimentally tunable parameters.

Bubble splitting in bifurcating tubes: a model study of cardiovascular gas emboli transport.

The transport of long gas bubbles, suspended in liquid, through symmetric bifurcations, is investigated experimentally and theoretically as a model of cardiovascular gas bubble transport in air embolism and gas embolotherapy. The relevant dimensionless parameters in the models match the corresponding values for arteries and arterioles. The effects of roll angle (the angle the plane of the bifurcation makes with the horizontal), capillary number (a dimensionless indicator of flow), and bubble volume (or length) on the splitting of bubbles as they pass through the bifurcation are examined. Splitting is observed to be more homogenous at higher capillary numbers and lower roll angles. It is shown that, at nonzero roll angles, there is a critical value of the capillary number below which the bubbles do not split and are transported entirely into the upper branch. The value of the critical capillary number increases with roll angle and parent tube diameter. A unique bubble motion is observed at the critical capillary number and for slightly slower flows: the bubble begins to split, the meniscus in the lower branch then moves backward, and finally the entire bubble enters the upper branch. These findings suggest that, in large vessels, emboli tend to be transported upward unless flow is unusually strong but that a more homogeneous distribution of emboli occurs in smaller vessels. This corresponds to previous observations that air emboli tend to lodge in the upper regions of the lungs and suggests that relatively uniform infarction of tumors by gas embolotherapy may be possible.