11,750 research outputs found
The role of Computer Aided Process Engineering in physiology and clinical medicine
This paper discusses the potential role for Computer Aided Process Engineering (CAPE) in developing engineering analysis and design approaches to biological systems across multiple levels—cell signalling networks, gene, protein and metabolic networks, cellular systems, through to physiological systems. The 21st Century challenge in the Life Sciences is to bring together widely dispersed models and knowledge in order to enable a system-wide understanding of these complex systems. This systems level understanding should have broad clinical benefits. Computer Aided Process Engineering can bring systems approaches to (i) improving understanding of these complex chemical and physical (particularly molecular transport in complex flow regimes) interactions at multiple scales in living systems, (ii) analysis of these models to help to identify critical missing information and to explore the consequences on major output variables resulting from disturbances to the system, and (iii) ‘design’ potential interventions in in vivo systems which can have significant beneficial, or potentially harmful, effects which need to be understood. This paper develops these three themes drawing on recent projects at UCL. The first project has modeled the effects of blood flow on endothelial cells lining arteries, taking into account cell shape change resulting in changes in the cell skeleton which cause consequent chemical changes. A second is a project which is building an in silico model of the human liver, tieing together models from the molecular level to the liver. The composite model models glucose regulation in the liver and associated organs. Both projects involve molecular transport, chemical reactions, and complex multiscale systems, tackled by approaches from CAPE.
Chemical Engineers solve multiple scale problems in manufacturing processes – from molecular scale through unit operations scale to plant-wide and enterprise wide systems – so have an appropriate skill set for tackling problems in physiology and clinical medicine, in collaboration with life and clinical scientists
The in silico macrophage: toward a better understanding of inflammatory disease
Macrophages function as sentinel, cell-regulatory hubs capable of initiating,
perpetuating and contributing to the resolution of an inflammatory response,
following their activation from a resting state. Highly complex and varied gene
expression programs within the macrophage enable such functional diversity. To
investigate how programs of gene expression relate to the phenotypic attributes
of the macrophage, the development of in silico modeling methods is needed.
Such models need to cover multiple scales, from molecular pathways in
cell-autonomous immunity and intercellular communication pathways in tissue
inflammation to whole organism response pathways in systemic disease. Here, we
highlight the potential of in silico macrophage modeling as an amenable and
important yet under-exploited tool in aiding in our understanding of the immune
inflammatory response. We also discuss how in silico macrophage modeling can
help in future therapeutic strategies for modulating both the acute protective
effects of inflammation (such as host defense and tissue repair) and the
harmful chronic effects (such as autoimmune diseases).Comment: 7 pages plus 1 figur
A Mathematical Model for Lymphangiogenesis in Normal and Diabetic Wounds
Several studies suggest that one possible cause of impaired wound healing is
failed or insufficient lymphangiogenesis, that is the formation of new
lymphatic capillaries. Although many mathematical models have been developed to
describe the formation of blood capillaries (angiogenesis) very few have been
proposed for the regeneration of the lymphatic network. Moreover,
lymphangiogenesis is markedly distinct from angiogenesis, occurring at
different times and in a different manner. Here a model of five ordinary
differential equations is presented to describe the formation of lymphatic
capillaries following a skin wound. The variables represent different cell
densities and growth factor concentrations, and where possible the parameters
are estimated from experimental and clinical data. The system is then solved
numerically and the results are compared with the available biological
literature. Finally, a parameter sensitivity analysis of the model is taken as
a starting point for suggesting new therapeutic approaches targeting the
enhancement of lymphangiogenesis in diabetic wounds. The work provides a deeper
understanding of the phenomenon in question, clarifying the main factors
involved. In particular, the balance between TGF- and VEGF levels,
rather than their absolute values, is identified as crucial to effective
lymphangiogenesis. In addition, the results indicate lowering the
macrophage-mediated activation of TGF- and increasing the basal
lymphatic endothelial cell growth rate, \emph{inter alia}, as potential
treatments. It is hoped the findings of this paper may be considered in the
development of future experiments investigating novel lymphangiogenic
therapies
A multiscale model for collagen alignment in wound healing
It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring
Cancer modelling: Getting to the heart of the problem
Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols
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