References of "Geris, Liesbet"
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See detailComputational modelling of human mesenchymal stem cell proliferation and extra cellular matrix production in 3D porous scaffolds in a perfusion bioreactor
Mehrian, Mohammad ULiege; Papantoniou, Ioannis; Lambrechts, Toon et al

Scientific conference (2018, March 26)

3D porous scaffolds are frequently used in tissue engineering (TE) applications in combination with bioreactor systems because of their ability to induce reproducible culture conditions that can control ... [more ▼]

3D porous scaffolds are frequently used in tissue engineering (TE) applications in combination with bioreactor systems because of their ability to induce reproducible culture conditions that can control specific cell behavior such as proliferation and extracellular matrix (ECM) production. A computational model describing neotissue growth inside 3D scaffolds in a perfusion bioreactor was developed, with neotissue being considered the combination of cells and their extra cellular matrix. In the model, the speed of neotissue growth depends on the flow-induced shear stress, curvature and the local concentrations of oxygen, glucose and lactate. The goal of this study is to make a distinction between the cell and the ECM fraction within the neotissue in the model to allow for a more detailed validation and optimization of the process. [less ▲]

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See detailMulti-objective optimization of cost-efficient neotissue growth inside 3D scaffolds using evolutionary algorithms
Mehrian, Mohammad ULiege; olofsson, Simon; Misener, Ruth et al

Scientific conference (2018, March 26)

Tissue engineering is a fast progressing domain where solutions are provided for organ failure or tissue damage. Computer models can facilitate the design of optimal production process conditions leading ... [more ▼]

Tissue engineering is a fast progressing domain where solutions are provided for organ failure or tissue damage. Computer models can facilitate the design of optimal production process conditions leading to robust and economically viable products. We developed a computational model describing the neotissue growth (cells + their ECM) inside 3D scaffolds in a perfusion bioreactor. Here we apply multi-objective optimization (MOO) to maximize neotissue growth whilst minimizing the cost coming from medium refreshment and associated labor. [less ▲]

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See detailMaximizing neotissue growth kinetics in a perfusion bioreactor: An in silico strategy using model reduction and Bayesian optimization
Mehrian, Mohammad ULiege; Guyot, Y.; Papantoniou, I. et al

in Biotechnology and Bioengineering (2017)

In regenerative medicine, computer models describing bioreactor processes can assist in designing optimal process conditions leading to robust and economically viable products. In this study, we started ... [more ▼]

In regenerative medicine, computer models describing bioreactor processes can assist in designing optimal process conditions leading to robust and economically viable products. In this study, we started from a (3D) mechanistic model describing the growth of neotissue, comprised of cells, and extracellular matrix, in a perfusion bioreactor set-up influenced by the scaffold geometry, flow-induced shear stress, and a number of metabolic factors. Subsequently, we applied model reduction by reformulating the problem from a set of partial differential equations into a set of ordinary differential equations. Comparing the reduced model results to the mechanistic model results and to dedicated experimental results assesses the reduction step quality. The obtained homogenized model is 105 fold faster than the 3D version, allowing the application of rigorous optimization techniques. Bayesian optimization was applied to find the medium refreshment regime in terms of frequency and percentage of medium replaced that would maximize neotissue growth kinetics during 21 days of culture. The simulation results indicated that maximum neotissue growth will occur for a high frequency and medium replacement percentage, a finding that is corroborated by reports in the literature. This study demonstrates an in silico strategy for bioprocess optimization paying particular attention to the reduction of the associated computational cost. © 2017 Wiley Periodicals, Inc. [less ▲]

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See detailBayesian Multi-Objective Optimisation of Neotissue Growth in a Perfusion Bioreactor Set-up
olofsson, Simon; Mehrian, Mohammad ULiege; Geris, Liesbet ULiege et al

Scientific conference (2017, October 01)

We consider optimising bone neotissue growth in a 3D scaffold during dynamic perfusion bioreactor culture. The goal is to choose design variables by optimising two conflicting objectives: (i) maximising ... [more ▼]

We consider optimising bone neotissue growth in a 3D scaffold during dynamic perfusion bioreactor culture. The goal is to choose design variables by optimising two conflicting objectives: (i) maximising neotissue growth and (ii) minimising operating cost. Our contribution is a novel extension of Bayesian multi-objective optimisation to the case of one black-box (neotissue growth) and one analytical (operating cost) objective function, that helps determine, within a reasonable amount of time, what design variables best manage the trade-off between neotissue growth and operating cost. Our method is tested against and outperforms the most common approach in literature, genetic algorithms, and shows its important real-world applicability to problems that combine black-box models with easy-to-quantify objectives like cost. [less ▲]

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See detailMAXIMIZING NEOTISSUE GROWTH IN A PERFUSION BIOREACTOR USING BAYESIAN OPTIMIZATION
Mehrian, Mohammad ULiege; guyot, Yann; Papantoniou, Ioannis et al

Scientific conference (2017, February 01)

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See detailModelling BMP-2 carrier device for bone tissue engineering application
Manhas, Varun ULiege; Carlier, Aurelie; Geris, Liesbet ULiege

Poster (2017, February 01)

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See detailModel-Based Optimization of the Medium Refreshment Regime During Neotissue Growth in a Perfusion Bioreactor
Mehrian, Mohammad ULiege; guyot, Yann; Papantoniou, Ioannis et al

Scientific conference (2017, January 08)

Computational models are interesting tools to facilitate the translation from the laboratory to the patient. In regenerative medicine, computer models describing bioprocesses taking place in bioreactor ... [more ▼]

Computational models are interesting tools to facilitate the translation from the laboratory to the patient. In regenerative medicine, computer models describing bioprocesses taking place in bioreactor environment can assist in designing process conditions leading to robust and economically viable products. In this study we present a low-cost computational model describing the neotissue (cells + extracellular matrix) growth in a perfusion bioreactor set-up. The neotissue growth is influenced by the geometry of the scaffold, the flow-induced shear stress and a number of metabolic factors. After initial model validation, a Genetic Algorithm optimization technique is used to find the best medium refreshment regime (frequency and percentage of medium replaced) resulting in a maximal amount of neotissue being produced in the scaffold in a 28 days of culture period. [less ▲]

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See detailImproving Perfusion Bioreactor Yields by Using Particle Swarm Optimization
Mehrian, Mohammad ULiege; guyot, Yann; Papantoniou, Ioannis et al

Scientific conference (2016, November 25)

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See detailAN IN-SILICO MODEL OF BMP-2 CARRIER DEVICE FOR BONE TISSUE ENGINEERING APPLICATION
Manhas, Varun ULiege; Carlier, Aurelie; Geris, Liesbet ULiege

Poster (2016, November 25)

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See detailMathematical modelling of ectopic bone formation in bone morphogenetic (BMP) carrier device
Manhas, Varun ULiege; Carlier, Aurelie; Geris, Liesbet ULiege

Conference (2016, September 28)

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See detailSIMULATION AND ANALYSIS OF RECEPTOR DYNAMICS IN A BMP REGULATORY NETWORK
Germain, Morgan ULiege; Bolander, Johanna; Ji, Wei et al

Poster (2016, September)

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See detailComputational modelling of local calcium ions release from calcium phosphate-based scaffolds
Manhas, Varun ULiege; Guyot, Yann; Kerckhofs, Greet et al

in Biomechanics & Modeling in Mechanobiology (2016)

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See detailMathematical modelling of the degradation behaviour of biodegradable metals
Bajger, P; Ashbourn, JMA; Manhas, Varun ULiege et al

in Biomechanics & Modeling in Mechanobiology (2016)

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See detailInvestigating in vitro calcium dissolution using a mathematical model
Manhas, Varun ULiege; Guyot, Yann; Kerckhofs, Greet et al

Scientific conference (2016, March)

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See detailImmersed Boundary Models for Quantifying Flow-Induced Mechanical Stimuli on Stem Cells Seeded on 3D Scaffolds in Perfusion Bioreactors.
Guyot, Yann; Smeets, Bart; Odenthal, Tim et al

in PLoS Computational Biology (2016), 12(9), 1005108

Perfusion bioreactors regulate flow conditions in order to provide cells with oxygen, nutrients and flow-associated mechanical stimuli. Locally, these flow conditions can vary depending on the scaffold ... [more ▼]

Perfusion bioreactors regulate flow conditions in order to provide cells with oxygen, nutrients and flow-associated mechanical stimuli. Locally, these flow conditions can vary depending on the scaffold geometry, cellular confluency and amount of extra cellular matrix deposition. In this study, a novel application of the immersed boundary method was introduced in order to represent a detailed deformable cell attached to a 3D scaffold inside a perfusion bioreactor and exposed to microscopic flow. The immersed boundary model permits the prediction of mechanical effects of the local flow conditions on the cell. Incorporating stiffness values measured with atomic force microscopy and micro-flow boundary conditions obtained from computational fluid dynamics simulations on the entire scaffold, we compared cell deformation, cortical tension, normal and shear pressure between different cell shapes and locations. We observed a large effect of the precise cell location on the local shear stress and we predicted flow-induced cortical tensions in the order of 5 pN/mum, at the lower end of the range reported in literature. The proposed method provides an interesting tool to study perfusion bioreactors processes down to the level of the individual cell's micro-environment, which can further aid in the achievement of robust bioprocess control for regenerative medicine applications. [less ▲]

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See detailA Qualitative Model of the Differentiation Network in Chondrocyte Maturation: A Holistic View of Chondrocyte Hypertrophy.
Kerkhofs, Johan; Leijten, Jeroen; Bolander, Johanna et al

in PLoS ONE (2016), 11(8), 0162052

Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological ... [more ▼]

Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological processes, with osteoarthritis being a prominent example. We perform a dynamic analysis of a qualitative mathematical model of the regulatory network that directs this phenotypic switch to investigate the influence of the individual factors holistically. To estimate the stability of a SOX9 positive state (associated with resting/proliferation chondrocytes) versus a RUNX2 positive one (associated with hypertrophy) we employ two measures. The robustness of the state in canalisation (size of the attractor basin) is assessed by a Monte Carlo analysis and the sensitivity to perturbations is assessed by a perturbational analysis of the attractor. Through qualitative predictions, these measures allow for an in silico screening of the effect of the modelled factors on chondrocyte maintenance and hypertrophy. We show how discrepancies between experimental data and the model's results can be resolved by evaluating the dynamic plausibility of alternative network topologies. The findings are further supported by a literature study of proposed therapeutic targets in the case of osteoarthritis. [less ▲]

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See detailCapturing the wide variety of impaired fracture healing phenotypes in Neurofibromatosis Type 1 with eight key factors: a computational study.
carlier, aurelie; brems, h.; ashbourn, j.m.a. et al

in Scientific Reports (2016), 7

Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the ... [more ▼]

Congenital pseudarthrosis of the tibia (CPT) is a rare disease which normally presents itself during early childhood by anterolateral bowing of the tibia and spontaneous tibial fractures. Although the exact etiology of CPT is highly debated, 40-80% of CPT patients are carriers of a mutation in the Neurofibromatosis Type 1 (NF1) gene, which can potentially result in an altered phenotype of the skeletal cells and impaired bone healing. In this study we use a computational model of bone regeneration to examine the effect of the Nf1 mutation on bone fracture healing by altering the parameter values of eight key factors which describe the aberrant cellular behaviour of Nf1 haploinsufficient and Nf1 bi-allelically inactivated cells. We show that the computational model is able to predict the formation of a hamartoma as well as a wide variety of CPT phenotypes through different combinations of altered parameter values. A sensitivity analysis by "Design of Experiments" identified the impaired endochondral ossification process and increased infiltration of fibroblastic cells as key contributors to the degree of severity of CPT. Hence, the computational model results have added credibility to the experimental hypothesis of a genetic cause (i.e. Nf1 mutation) for CPT. [less ▲]

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See detailThe combined mechanism of bone morphogenetic protein- and calcium phosphate-induced skeletal tissue formation by human periosteum derived cells.
Bolander, J.; Ji, W.; Geris, Liesbet ULiege et al

in European Cells and Materials (2016), 31

When combining osteogenic progenitor cells such as human periosteum derived cells (hPDCs) with osteoconductive biomaterials like calcium phosphate (CaP)-scaffolds, in vivo bone formation can be achieved ... [more ▼]

When combining osteogenic progenitor cells such as human periosteum derived cells (hPDCs) with osteoconductive biomaterials like calcium phosphate (CaP)-scaffolds, in vivo bone formation can be achieved. This process is dependent on the early activation of Bone morphogenetic protein (BMP)-signalling. However, the bone forming process is slow and routinely only a limited amount of bone and bone marrow is formed. Therefore, we hypothesised that a robust clinically relevant outcome could be achieved by adding more physiological levels of potent BMP-ligands to these cell- and CaP-based constructs. For this, hPDCs were characterised for their responsiveness to BMP-ligands upon in vitro 2D stimulation. BMP-2, -4, -6 and -9 robustly induced osteochondrogenic differentiation. Subsequently, these ligands were coated onto clinically approved CaP-scaffolds, BioOss(R) and CopiOs(R), followed by hPDC-seeding. Protein lysates and conditioned media were investigated for activation of BMP signalling pathways. Upon in vivo implantation, the most abundant bone formation was found in BMP-2 and BMP-6-coated scaffolds. Implanted cells actively contributed to the newly formed bone. Remnants of cartilage could be observed in BMP-coated CopiOs(R)-constructs. Computational analysis displayed that the type of BMP-ligand as well as the CaP-scaffold affects skeletal tissue formation, observed in a qualitative as well as quantitative manner. Furthermore, the in vitro mechanism appears to predict the in vivo outcome. This study presents further evidence for the potential of BMP-technology in the development of clinically relevant cell-based constructs for bone regenerative strategies. [less ▲]

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See detailEarly BMP, Wnt and Ca(2+)/PKC pathway activation predicts the bone forming capacity of periosteal cells in combination with calcium phosphates.
Bolander, Johanna; Chai, Yoke Chin; Geris, Liesbet ULiege et al

in Biomaterials (2016), 86

The development of osteoinductive calcium phosphate- (CaP) based biomaterials has, and continues to be, a major focus in the field of bone tissue engineering. However, limited insight into the ... [more ▼]

The development of osteoinductive calcium phosphate- (CaP) based biomaterials has, and continues to be, a major focus in the field of bone tissue engineering. However, limited insight into the spatiotemporal activation of signalling pathways has hampered the optimisation of in vivo bone formation and subsequent clinical translation. To gain further knowledge regarding the early molecular events governing bone tissue formation, we combined human periosteum derived progenitor cells with three types of clinically used CaP-scaffolds, to obtain constructs with a distinct range of bone forming capacity in vivo. Protein phosphorylation together with gene expression for key ligands and target genes were investigated 24 hours after cell seeding in vitro, and 3 and 12 days post ectopic implantation in nude mice. A computational modelling approach was used to deduce critical factors for bone formation 8 weeks post implantation. The combined Ca(2+)-mediated activation of BMP-, Wnt- and PKC signalling pathways 3 days post implantation were able to discriminate the bone forming from the non-bone forming constructs. Subsequently, a mathematical model able to predict in vivo bone formation with 96% accuracy was developed. This study illustrates the importance of defining and understanding CaP-activated signalling pathways that are required and sufficient for in vivo bone formation. Furthermore, we demonstrate the reliability of mathematical modelling as a tool to analyse and deduce key factors within an empirical data set and highlight its relevance to the translation of regenerative medicine strategies. [less ▲]

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