Microvessel Chaste: An Open Library for Spatial Modeling of Vascularized Tissues

Grogan, James A.; Connor, Anthony J.; Markelc, Boštjan; Muschel, Ruth J.; Maini, Philip K.; Byrne, Helen M.; Pitt-Francis, Joe

doi:10.1016/j.bpj.2017.03.036

Cited by 29 publications

(41 citation statements)

References 26 publications

(58 reference statements)

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“…The importance of the microenvironment is widely recognized, and several researchers have tackled the problem of its description and understanding from the computational point of view, e.g. [24,28,15,37,30,40,41] , and the reviews [21,10].…”

Section: Introductionmentioning

confidence: 99%

Fine-grained simulations of the microenvironment of vascularized tumours

Fredrich

Rieger

Chignola

et al. 2019

Preprint

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8One of many important features of the tumour microenvironment is that it is a place of active Darwinian selection where different tumour clones become adapted to the variety of ecological niches that make up the microenvironment. These evolutionary processes turn the microenvironment into a powerful source of tumour heterogeneity and contribute to the development of drug resistance in cancer. Here, we describe a computational tool to study the ecology of the microenvironment and report results about the ecology of the tumour microenvironment and its evolutionary dynamics. 9 Introduction 10The tumour microenvironment is characterized by large chemical gradients and contains a mixture of normal and tumour cells. 11The presence of high gradients favours the formation of different ecological niches which can become an important source of 12 tumour heterogeneity 1-6 . 13The actual size of the niches is quite small, as it is mostly determined by the structure of the scaffold of capillary vessels 14 that envelope and feed the tumour mass. This structure is highly irregular, with a chaotic blood vessel network, a missing 15 lymphatic network, elevated acidity, poor oxygenation, and high interstitial fluid pressure. The distance between blood vessels 16 may be as large as a few hundred µm, and the regions in between them can become highly hypoxic 4 . 17The fine-graininess and the large spatial variability are essential features in the formation of the ecological niches and they 18 must belong to any mathematical model that aims to explain tumour heterogeneity as the result of Darwinian selection driven 19 by the local environment. The importance of the microenvironment is widely recognized, and several researchers have tackled 20 the problem of its description and understanding from the computational point of view, e.g. 7-13 , and the reviews 14, 15 . 21The studies, however, mainly focus on the biochemical, cellular and biophysical properties of the tumour microenvironment 22 and not on its active role in providing varied evolutionary paths to genetic variants of the tumour cells. As it has already been 23 pointed out 16, 17 , the adaptive evolution of tumour clones (central concept of Darwinian dynamics) is driven by the formation of 24 new environmental niches. Many practical difficulties limit the experimental study of the adaptation process, while computer 25 simulations can shed light -albeit in a limited way -on the dynamics of many steps like the convergent evolution of different 26 genotypes to the same phenotype, and the selective loss of specific cell functions. 27Simulations of avascular solid tumours show that the microenvironment of these small cell aggregates is formed by rather 28 homogeneous niches with smooth gradients of oxygen, of other nutrients, waste molecules and cell viability 18 . After the 29 angiogenic transition, however, the microenvironment differentiates in unpredictable ways. To identify underlying processes and 30 provide reasoning, we have developed a computational model that is a tool t...

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Section: Introductionmentioning

confidence: 99%

Fine-grained simulations of the microenvironment of vascularized tumours

Fredrich

Rieger

Chignola

et al. 2019

Preprint

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“…Simulations are built using the Microvessel Chaste library, which is a collection of 89 C++ classes providing models and numerical tools for creating angiogenesis simulations. 90 The library motivation and high-level design are described in a dedicated 91 publication [21]. Users of the library build their own simulations from the available 92 C++ classes, as has been done in the present study for the particular problem at hand, 93 rather than use it as a monolithic solver.…”

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confidence: 99%

“…3D) cultures and mathematical models, a selection of which are shown in Figs 1D and E. 18 As reviewed in Jackson and Zheng [6], many mathematical models of neovascularization have 19 been motivated by the micropocket assay, providing valuable insights into the process [5,[7][8][9][10][11][12][13][14]. 20 To date, these models have adopted either one-dimensional (1D) or 2D representations of the 21 cornea-pellet system, with the former allowing efficient, continuum modeling of the developing 22 vessel network by the solution of systems of partial differential equations (PDEs) [5,10,11]. 23 However, the in vivo configuration of a cylindrical pellet placed 'off-center' in a hemispherical 24 volume is most naturally described using a 3D representation.…”

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confidence: 99%

“…The 34 primary strengths of the study are: i) the simulation of neovascularization in large, 3D tissue 35 domains and ii) the ability to compare predictions across several different geometries and with 36 different biophysical processes activated and de-activated. These attributes are facilitated by 37 the use of the open source Microvessel Chaste simulation library [20], recently developed by the 38 authors. 39 As part of this comparison we also identify metrics of neovascularization with high and low 40 sensitivity to the choice of tissue domain.…”

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confidence: 99%

“…For our pellet volume of 0.0075 mm 3 and 189 VEGF molecular weight of 45 kDa, this corresponds to a pellet concentration of approximately 190 c p = 1330 µM, which is adopted for the dynamic VEGF model. [20], which is a plug-in for the Chaste library for soft tissue modeling [31]. This allows 198 efficient modeling of neovascularization in a range of different geometrical configurations and, 199 thanks to its modular construction, allows different biophysical features of the sprouting 200 angiogenesis model to be activated and de-activated.…”

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confidence: 99%

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The importance of geometry in the corneal micropocket angiogenesis assay

Grogan

Connor

Pitt-Francis

et al. 2017

Preprint

Self Cite

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The corneal micropocket assay is an experimental protocol for studying vessel network formation, or neovascularization, in vivo. The assay is attractive due to the ease with which the developing vessel network can be observed in the same animal over time. However, it is difficult to relate observations of neovascularization in the hemispherical geometry of the cornea to predictions from mathematical (in silico) models and observations from in vitro models, which mostly adopt planar geometries. Here, we develop a three-dimensional, off-lattice mathematical model of neovascularization in the cornea, with a new repulsion model for the interaction of vessels with tissue boundaries. The model allows us to: i) investigate how the hemispherical geometry of the cornea influences vessel network formation and ii) identify the metrics of neovascularization that are most robust to geometrical differences between typical in silico, in vitro and in vivo tissue domains. We predict that two-dimensional geometries lead to increased vessel 'merging', or anastomosis, relative to three-dimensional versions, with differences being most pronounced when circular geometries are adopted. Cuboidal geometries lead to patterns of neovascularization that most closely mimic the in vivo case. The 'distance of the vascular front to the limbus' is found to be a robust metric of neovascularization across the studied tissue domains, while densities of tip cells and vessels and 'vascularized fraction' are more sensitive to domain choice. Given the widespread adoption and attractive simplicity of planar tissue domains, the differences identified in the present study should prove useful in relating the results of previous and future in silico and in vitro studies of neovascularization to in vivo observations in the cornea. Author summaryNeovascularization, or the formation of new blood vessels, is an important process in development, wound healing and cancer. The corneal micropocket assay is used to better understand the process and, in the case of cancer, how it can be controlled with drug therapies for improved patient outcomes. In the assay, the hemispherical shape of the cornea can influence the way the vessel network forms. This makes it difficult to directly compare results from experiments with the predictions of mathematical models or cell culture experiments, which are

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Seven challenges in the multiscale modeling of multicellular tissues

Fletcher

Osborne

2021

WIREs Mechanisms of Disease

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The growth and dynamics of multicellular tissues involve tightly regulated and coordinated morphogenetic cell behaviors, such as shape changes, movement, and division, which are governed by subcellular machinery and involve coupling through short-and long-range signals. A key challenge in the fields of developmental biology, tissue engineering and regenerative medicine is to understand how relationships between scales produce emergent tissue-scale behaviors. Recent advances in molecular biology, live-imaging and ex vivo techniques have revolutionized our ability to study these processes experimentally. To fully leverage these techniques and obtain a more comprehensive understanding of the causal relationships underlying tissue dynamics, computational modeling approaches are increasingly spanning multiple spatial and temporal scales, and are coupling cell shape, growth, mechanics, and signaling. Yet such models remain challenging: modeling at each scale requires different areas of technical skills, while integration across scales necessitates the solution to novel mathematical and computational problems. This review aims to summarize recent progress in multiscale modeling of multicellular tissues and to highlight ongoing challenges associated with the construction, implementation, interrogation, and validation of such models.

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Microvessel Chaste: An Open Library for Spatial Modeling of Vascularized Tissues

Cited by 29 publications

References 26 publications

Fine-grained simulations of the microenvironment of vascularized tumours

Fine-grained simulations of the microenvironment of vascularized tumours

The importance of geometry in the corneal micropocket angiogenesis assay

Seven challenges in the multiscale modeling of multicellular tissues

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