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See detailBayesian Multi-Objective Optimisation of Neotissue Growth in a Perfusion Bioreactor Set-up
olofsson, Simon; Mehrian, Mohammad ULg; Geris, Liesbet ULg 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 ULg; 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 ULg; Carlier, Aurelie; Geris, Liesbet ULg

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 ULg; 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 ULg; 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 ULg; Carlier, Aurelie; Geris, Liesbet ULg

Poster (2016, November 25)

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

Conference (2016, September 28)

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See detailSIMULATION AND ANALYSIS OF RECEPTOR DYNAMICS IN A BMP REGULATORY NETWORK
Germain, Morgan ULg; 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 ULg; 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 ULg et al

in Biomechanics & Modeling in Mechanobiology (2016)

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See detailInvestigating in vitro calcium dissolution using a mathematical model
Manhas, Varun ULg; 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 ULg 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 ULg 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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See detailCombinatorial Analysis of Growth Factors Reveals the Contribution of Bone Morphogenetic Proteins to Chondrogenic Differentiation of Human Periosteal Cells.
Mendes, Luis Filipe; Tam, Wai Long; Chai, Yoke Chin et al

in Tissue Engineering. Part C, Methods (2016), 22(5), 473-86

Successful application of cell-based strategies in cartilage and bone tissue engineering has been hampered by the lack of robust protocols to efficiently differentiate mesenchymal stem cells into the ... [more ▼]

Successful application of cell-based strategies in cartilage and bone tissue engineering has been hampered by the lack of robust protocols to efficiently differentiate mesenchymal stem cells into the chondrogenic lineage. The development of chemically defined culture media supplemented with growth factors (GFs) has been proposed as a way to overcome this limitation. In this work, we applied a fractional design of experiment (DoE) strategy to screen the effect of multiple GFs (BMP2, BMP6, GDF5, TGF-beta1, and FGF2) on chondrogenic differentiation of human periosteum-derived mesenchymal stem cells (hPDCs) in vitro. In a micromass culture (muMass) system, BMP2 had a positive effect on glycosaminoglycan deposition at day 7 (p < 0.001), which in combination with BMP6 synergistically enhanced cartilage-like tissue formation that displayed in vitro mineralization capacity at day 14 (p < 0.001). Gene expression of muMasses cultured for 7 days with a medium formulation supplemented with 100 ng/mL of BMP2 and BMP6 and a low concentration of GDF5, TGF-beta1, and FGF2 showed increased expression of Sox9 (1.7-fold) and the matrix molecules aggrecan (7-fold increase) and COL2A1 (40-fold increase) compared to nonstimulated control muMasses. The DoE analysis indicated that in GF combinations, BMP2 was the strongest effector for chondrogenic differentiation of hPDCs. When transplanted ectopically in nude mice, the in vitro-differentiated muMasses showed maintenance of the cartilaginous phenotype after 4 weeks in vivo. This study indicates the power of using the DoE approach for the creation of new medium formulations for skeletal tissue engineering approaches. [less ▲]

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See detailCoupling curvature-dependent and shear stress-stimulated neotissue growth in dynamic bioreactor cultures: a 3D computational model of a complete scaffold.
Guyot, Y.; Papantoniou, I.; Luyten, F. P. et al

in Biomechanics & Modeling in Mechanobiology (2016), 15(1), 169-80

The main challenge in tissue engineering consists in understanding and controlling the growth process of in vitro cultured neotissues toward obtaining functional tissues. Computational models can provide ... [more ▼]

The main challenge in tissue engineering consists in understanding and controlling the growth process of in vitro cultured neotissues toward obtaining functional tissues. Computational models can provide crucial information on appropriate bioreactor and scaffold design but also on the bioprocess environment and culture conditions. In this study, the development of a 3D model using the level set method to capture the growth of a microporous neotissue domain in a dynamic culture environment (perfusion bioreactor) was pursued. In our model, neotissue growth velocity was influenced by scaffold geometry as well as by flow- induced shear stresses. The neotissue was modeled as a homogenous porous medium with a given permeability, and the Brinkman equation was used to calculate the flow profile in both neotissue and void space. Neotissue growth was modeled until the scaffold void volume was filled, thus capturing already established experimental observations, in particular the differences between scaffold filling under different flow regimes. This tool is envisaged as a scaffold shape and bioprocess optimization tool with predictive capacities. It will allow controlling fluid flow during long-term culture, whereby neotissue growth alters flow patterns, in order to provide shear stress profiles and magnitudes across the whole scaffold volume influencing, in turn, the neotissue growth. [less ▲]

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See detailCombining microCT-based characterization with empirical modelling as a robust screening approach for the design of optimized CaP-containing scaffolds for progenitor cell-mediated bone formation.
Kerckhofs, G.; Chai, Y. C.; Luyten, F. P. et al

in Acta Biomaterialia (2016), 35

Biomaterials are a key ingredient to the success of bone tissue engineering (TE), which focuses on the healing of bone defects by combining scaffolds with cells and/or growth factors. Due to the widely ... [more ▼]

Biomaterials are a key ingredient to the success of bone tissue engineering (TE), which focuses on the healing of bone defects by combining scaffolds with cells and/or growth factors. Due to the widely variable material characteristics and patient-specificities, however, current bone TE strategies still suffer from low repeatability and lack of robustness, which hamper clinical translation. Hence, optimal TE construct (i.e. cells and scaffold) characteristics are still under debate. This study aimed to reduce the material-specific variability for cell-based construct design, avoiding trial-and-error, by combining microCT characterization and empirical modelling as an innovative and robust screening approach. Via microCT characterization we have built a quantitative construct library of morphological and compositional properties of six CE approved CaP-based scaffolds (CopiOs(R), BioOss, Integra Mozaik, chronOS Vivify, MBCP and ReproBone), and of their bone forming capacity and in vivo scaffold degradation when combined with human periosteal derived cells (hPDCs). The empirical model, based on the construct library, allowed identification of the construct characteristics driving optimized bone formation, i.e. (a) the percentage of beta-TCP and dibasic calcium phosphate, (b) the concavity of the CaP structure, (c) the average CaP structure thickness and (d) the seeded cell amount (taking into account the seeding efficiency). Additionally, the model allowed to quantitatively predict the bone forming response of different hPDC-CaP scaffold combinations, thus providing input for a more robust design of optimized constructs and avoiding trial-and error. This could improve and facilitate clinical translation. STATEMENT OF SIGNIFICANCE: Biomaterials that support regenerative processes are a key ingredient for successful bone tissue engineering (TE). However, the optimal scaffold structure is still under debate. In this study, we have provided a useful innovative approach for robust screening of potential biomaterials or constructs (i.e. scaffolds seeded with cells and/or growth factors) by combining microCT characterization with empirical modelling. This novel approach leads to a better insight in the scaffold parameters influencing progenitor cell-mediated bone formation. Additionally, it serves as input for more controlled and robust design of optimized CaP-containing bone TE scaffolds. Hence, this novel approach could improve and facilitate clinical translation. [less ▲]

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