The role of topology and mechanics in uniaxially growing cell networks

In biological systems, the growth of cells, tissues, and organs is influenced by mechanical cues. Locally, cell growth leads to a mechanically heterogeneous environment as cells pull and push their neighbors in a cell network. Despite this local heterogeneity, at the tissue level, the cell network is remarkably robust, as it is not easily perturbed by changes in the mechanical environment or the network connectivity. Through a network model, we relate global tissue structure (i.e. the cell network topology) and local growth mechanisms (growth laws) to the overall tissue response. Within this framework, we investigate the two main mechanical growth laws that have been proposed: stress-driven or strain-driven growth. We show that in order to create a robust and stable tissue environment, networks with predominantly series connections are naturally driven by stress-driven growth, whereas networks with predominantly parallel connections are associated with strain-driven growth

Growth regulation in Hydra. Relationship between epithelial cell cycle length and growth rate

The relationship between epithelial cell production and growth rate was investigated in Hydra attenuata under different feeding regimes. The increase of epithelial cell number was compared to the duration of the epithelial cell cycle using standard methods of cell cycle analysis. The results indicate that cell cycle changes accompanying changes in feeding regime are not sufficient to explain the altered growth rate. Under heavy feeding regimes, epithelial cell production equals tissue growth rate. At low feeding level or under starvation conditions the epithelial cell cycle lengthens and growth rate of epithelial cell population is slowed. However, the cell cycle changes are insufficient to account for the reduction in tissue growth and thus there is an effective overproduction of epithelial cells amounting to 10% per day. Evidence suggests that these excess cells are phagocytized by neighboring cells in the tissue. Thus phagocytosis is directly or indirectly involved in regulating the growth of hydra tissue

A multiple scale model for tumor growth

We present a physiologically structured lattice model for vascular tumor growth which accounts for blood flow and structural adaptation of the vasculature, transport of oxygen, interaction between cancerous and normal tissue, cell division, apoptosis, vascular endothelial growth factor release, and the coupling between these processes. Simulations of the model are used to investigate the effects of nutrient heterogeneity, growth and invasion of cancerous tissue, and emergent growth laws

A level-set method for the evolution of cells and tissue during curvature-controlled growth

Most biological tissues grow by the synthesis of new material close to the tissue's interface, where spatial interactions can exert strong geometric influences on the local rate of growth. These geometric influences may be mechanistic, or cell behavioural in nature. The control of geometry on tissue growth has been evidenced in many in-vivo and in-vitro experiments, including bone remodelling, wound healing, and tissue engineering scaffolds. In this paper, we propose a generalisation of a mathematical model that captures the mechanistic influence of curvature on the joint evolution of cell density and tissue shape during tissue growth. This generalisation allows us to simulate abrupt topological changes such as tissue fragmentation and tissue fusion, as well as three dimensional cases, through a level-set-based method. The level-set method developed introduces another Eulerian field than the level-set function. This additional field represents the surface density of tissue synthesising cells, anticipated at future locations of the interface. Numerical tests performed with this level-set-based method show that numerical conservation of cells is a good indicator of simulation accuracy, particularly when cusps develop in the tissue's interface. We apply this new model to several situations of curvature-controlled tissue evolutions that include fragmentation and fusion.Comment: 15 pages, 10 figures, 3 supplementary figure

Critical Point in Self-Organized Tissue Growth

We present a theory of pattern formation in growing domains inspired by biological examples of tissue development. Gradients of signaling molecules regulate growth, while growth changes these graded chemical patterns by dilution and advection. We identify a critical point of this feedback dynamics, which is characterized by spatially homogeneous growth and proportional scaling of patterns with tissue length. We apply this theory to the biological model system of the developing wing of the fruit fly \textit{Drosophila melanogaster} and quantitatively identify signatures of the critical point.Comment: 5 pages, 3 figure

The interplay between tissue growth and scaffold degradation in engineered tissue constructs

In vitro tissue engineering is emerging as a potential tool to meet the high demand for replacement tissue, caused by the increased incidence of tissue degeneration and damage. A key challenge in this field is ensuring that the mechanical properties of the engineered tissue are appropriate for the in vivo environment. Achieving this goal will require detailed understanding of the interplay between cell proliferation, extracellular matrix (ECM) deposition and scaffold degradation.\ud \ud In this paper, we use a mathematical model (based upon a multiphase continuum framework) to investigate the interplay between tissue growth and scaffold degradation during tissue construct evolution in vitro. Our model accommodates a cell population and culture medium, modelled as viscous fluids, together with a porous scaffold and ECM deposited by the cells, represented as rigid porous materials. We focus on tissue growth within a perfusion bioreactor system, and investigate how the predicted tissue composition is altered under the influence of (i) differential interactions between cells and the supporting scaffold and their associated ECM, (ii) scaffold degradation, and (iii) mechanotransduction-regulated cell proliferation and ECM deposition.\ud \ud Numerical simulation of the model equations reveals that scaffold heterogeneity typical of that obtained from μCT scans of tissue engineering scaffolds can lead to significant variation in the flow-induced mechanical stimuli experienced by cells seeded in the scaffold. This leads to strong heterogeneity in the deposition of ECM. Furthermore, preferential adherence of cells to the ECM in favour of the artificial scaffold appears to have no significant influence on the eventual construct composition; adherence of cells to these supporting structures does, however, lead to cell and ECM distributions which mimic and exaggerate the heterogeneity of the underlying scaffold. Such phenomena have important ramifications for the mechanical integrity of engineered tissue constructs and their suitability for implantation in vivo

Growth factor releasing scaffolds for cartilage tissue engineering

Over the last century, life expectancy has increased at a rapid pace resulting in an increase of articular cartilage disorders. To solve this problem, extensive research is currently performed using tissue engineering approaches. Cartilage tissue engineering aims to reconstruct this tissue both structurally and functionally by combining cells and biomaterials mimicking extracellular matrix (scaffolds). Although significant progress has been achieved over the last decade, the complete regeneration of cartilage is not yet at hand. The opportunity to release growth factors from porous scaffolds in a controlled way might allow to further enhance cartilage tissue engineering. However, from the literature reviewed in Chapter 2, it can be concluded that many hurdles still have to be overcome to allow the safe incorporation of labile proteins such as growth factors to scaffolds. As a result, the attempts to release growth factors from scaffolds are often restricted to surface adsorption, which only\ud allows a limited control on the release rates. In addition, important knowledge is still lacking regarding the most effective rate at which relevant growth factors should be delivered. Therefore, the aim of this thesis was to design polymeric scaffolds containing and releasing\ud growth factors in a safe and controlled way to further study the relations between release rate and cartilage formation

Role of growth factors in the pathogenesis of tissue fibrosis in systemic sclerosis.

The most severe clinical and pathologic manifestations of systemic sclerosis (SSc) are the result of a fibrotic process characterized by the excessive and often progressive deposition of collagen and other connective tissue macromolecules in skin and numerous internal organs. The mechanisms involved in the initiation and progression of the remarkable fibrotic process in SSc remain largely unknown. Extensive recent studies have indicated that a variety of polypeptide growth factors play a crucial role in this process. The most commonly implicated growth factors include transforming growth factor beta (TGF-β), connective tissue growth factor (CTGF), platelet derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Here, the experimental evidence supporting the participation of various growth factors in the pathogenesis of the fibrotic process in SSc and the molecular mechanisms involved will be reviewed