Complex Cell Models

Fig. 4.4. A current trend in drug transport studies is to use simplified cell models that facilitate the characterisation of selected drug transport mechanisms. However, recent research suggests that such simplified systems are not useful in cases where two or more drug transporters act in synergy. Development of cell models for such complex transport mechanisms will require the technically...

Phytochemicals have been the subject of many studies evaluating their effects in relation to common chronic human illnesses such as cancer and cardiovascular diseases. These studies encounter difficulties in using this information to influence the dietary patterns of consumers because in the past they have used models or experiments with animals. However, in the last decade, researchers have moved away from animal studies in favour of human cell models or human intervention studies. Scientists still need to determine the likely incidence of illness from exposure to known amounts of a given natural compound in the diet and specifically in relation to the complex matrices of whole foods. Therefore, it is inevitable that some animal studies have to be continued for toxicological studies. 

This permeability barrier shows selectivity in that small hydrophobic molecules can partition into and diffuse across the lipid bilayer of the cell membrane, whereas small hydrophilic molecules can only diffuse between cells (i.e., through the intercellular junctions). In addition, the presence of uptake and efflux transporters complicates our ability to predict intestinal permeability based on physicochemical properties alone because transporters may increase or decrease absorptive flux. The complexity of the permeability process makes it difficult to elucidate permeability pathways in complex biological model systems such as animals and tissues. For this reason, cultured cells in general, and Caco-2 cells in particular, have been used extensively to investigate the role of specific permeability pathways in drug absorption. 

The number of published fuel-cell-related models has increased dramatically in the past few years, as seen in Figure 2. Not only are there more models being published, but they are also increasing in complexity and scope. With the emergence of faster computers, the details of the models are no longer constrained to a lot of simplifying assumptions and analytic expressions. Full, 3-D fuel-cell models and the treatment of such complex phenomena as two-... 

In 2000 and 2001, fuel-cell models were produced by the dozens. These models were typically more complex and focused on such effects as two-phase flow ° where liquid-water transport was incorporated. The work of Wang and co-workers was at the forefront of those models treating two-phase flow comprehensively. The liquid-water flow was shown to be important in describing the overall transport in fuel cells. Other models in this time frame focused on multidimensional, transient, and more microscopic effects.The microscopic effects again focused on using an agglomerate approach in the fuel cell as well as how to model the membrane appropriately. 

Within the last five years, many fuel-cell models have come out of the Research Center in Julich, Germany. These models have different degrees of complexity and seek to identify the limiting factors in fuel-cell operation. The model of Kulikovsky et al. examined a 2-D structure of rib and channel on the cathode side of the fuel cell, and is similar to that of Springer et al. Other models by Kulikovsky included examination of depletion along long feed channels and effects in the catalyst layers.The most recent model by Kulikovsky relaxed the assumption of constant water content in the membrane and examined quasi 3-D profiles of it. Also at the research center, Eikerling et developed many... 

Due to the complexity and interconnectivity of the governing equations and constitutive relationships, most fuel-cell models are solved numerically. Al-... 

Primary cultures developed from pig and cow tissue are the best studied [29-32]. These models closely resemble the BBB, exhibiting many of the key biological properties. However isolation of blood-brain endothelial cells requires relatively complex cell isolation procedures which are labor-intensive and not ideal for screening purposes. Other cell types have been shown or proposed to induce barrier function, for example, astrocytes/pericytes. Significant improvements in barrier function was achieved in these primary culture models by including astrocyte conditioned media or co-culturing with astrocytes [33]. The complexity of primary cultures led to the use of epithelial cell lines not derived from the BBB (e.g., MDCK, MDCK-MDRl or LLC-PKl) [33]. 

In the meantime, the intense study of the simpler vesicle systems has unravelled novel, unsuspected physicochemical aspects - for example growth, fusion and fission, the matrix effect, self-reproduction, the effect of osmotic pressure, competition, encapsulation of enzymes, and complex biochemical reactions, as will be seen in the next chapter. Of course the fact that vesicles are viewed under the perspective of biological cell models renders these findings of great interest. In particular, one tends immediately to ask the question, whether and to what extent they might be relevant for the origin of life and the development of the early cells. In fact, the basic studies outlined in this chapter can be seen as the prelude to the use of vesicles as cell models, an aspect that we will considered in more detail in the next chapter. 

Ralph, J., and Helm, R. F., 1993, Lignin/hydroxycinnamic acid/ polysaccharide complexes synthetic models for regiochemical characterization, in Forage Cell Wall Structure and Digestibility, H. G. Jung, D. R. Buxton, R. D. Hatfield, and J. Ralph, eds., ASA, CSCA, SSSA, Madison, WI, pp. 201-246. 

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