References of "Geris, Liesbet"
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See detailOxygen as a critical determinant of bone fracture healing-a multiscale model.
Carlier, Aurelie; Geris, Liesbet ULg; Gastel, Nick Van et al

in Journal of theoretical biology (2015), 365

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the ... [more ▼]

A timely restoration of the ruptured blood vessel network in order to deliver oxygen and nutrients to the fracture zone is crucial for successful bone healing. Indeed, oxygen plays a key role in the aerobic metabolism of cells, in the activity of a myriad of enzymes as well as in the regulation of several (angiogenic) genes. In this paper, a previously developed model of bone fracture healing is further improved with a detailed description of the influence of oxygen on various cellular processes that occur during bone fracture healing. Oxygen ranges of the cell-specific oxygen-dependent processes were established based on the state-of-the art experimental knowledge through a rigorous literature study. The newly developed oxygen model is compared with previously published experimental and in silico results. An extensive sensitivity analysis was also performed on the newly introduced oxygen thresholds, indicating the robustness of the oxygen model. Finally, the oxygen model was applied to the challenging clinical case of a critical sized defect (3mm) where it predicted the formation of a fracture non-union. Further model analyses showed that the harsh hypoxic conditions in the central region of the callus resulted in cell death and disrupted bone healing thereby indicating the importance of a timely vascularization for the successful healing of a large bone defect. In conclusion, this work demonstrates that the oxygen model is a powerful tool to further unravel the complex spatiotemporal interplay of oxygen delivery, diffusion and consumption with the several healing steps, each occurring at distinct, optimal oxygen tensions during the bone repair process. [less ▲]

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See detailBringing computational models of bone regeneration to the clinic.
Carlier, Aurelie; Geris, Liesbet ULg; Lammens, Johan et al

in Wiley interdisciplinary reviews. Systems biology and medicine (2015), 7(4), 183-94

Although the field of bone regeneration has experienced great advancements in the last decades, integrating all the relevant, patient-specific information into a personalized diagnosis and optimal ... [more ▼]

Although the field of bone regeneration has experienced great advancements in the last decades, integrating all the relevant, patient-specific information into a personalized diagnosis and optimal treatment remains a challenging task due to the large number of variables that affect bone regeneration. Computational models have the potential to cope with this complexity and to improve the fundamental understanding of the bone regeneration processes as well as to predict and optimize the patient-specific treatment strategies. However, the current use of computational models in daily orthopedic practice is very limited or inexistent. We have identified three key hurdles that limit the translation of computational models of bone regeneration from bench to bed side. First, there exists a clear mismatch between the scope of the existing and the clinically required models. Second, most computational models are confronted with limited quantitative information of insufficient quality thereby hampering the determination of patient-specific parameter values. Third, current computational models are only corroborated with animal models, whereas a thorough (retrospective and prospective) assessment of the computational model will be crucial to convince the health care providers of the capabilities thereof. These challenges must be addressed so that computational models of bone regeneration can reach their true potential, resulting in the advancement of individualized care and reduction of the associated health care costs. WIREs Syst Biol Med 2015, 7:183-194. doi: 10.1002/wsbm.1299 For further resources related to this article, please visit the WIREs website. CONFLICT OF INTEREST: The authors have declared no conflicts of interest for this article. [less ▲]

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See detailMultifactorial Optimization of Contrast-Enhanced Nanofocus Computed Tomography for Quantitative Analysis of Neo-Tissue Formation in Tissue Engineering Constructs.
Sonnaert, Maarten; Kerckhofs, Greet; Papantoniou, Ioannis et al

in PloS one (2015), 10(6), 0130227

To progress the fields of tissue engineering (TE) and regenerative medicine, development of quantitative methods for non-invasive three dimensional characterization of engineered constructs (i.e. cells ... [more ▼]

To progress the fields of tissue engineering (TE) and regenerative medicine, development of quantitative methods for non-invasive three dimensional characterization of engineered constructs (i.e. cells/tissue combined with scaffolds) becomes essential. In this study, we have defined the most optimal staining conditions for contrast-enhanced nanofocus computed tomography for three dimensional visualization and quantitative analysis of in vitro engineered neo-tissue (i.e. extracellular matrix containing cells) in perfusion bioreactor-developed Ti6Al4V constructs. A fractional factorial 'design of experiments' approach was used to elucidate the influence of the staining time and concentration of two contrast agents (Hexabrix and phosphotungstic acid) and the neo-tissue volume on the image contrast and dataset quality. Additionally, the neo-tissue shrinkage that was induced by phosphotungstic acid staining was quantified to determine the operating window within which this contrast agent can be accurately applied. For Hexabrix the staining concentration was the main parameter influencing image contrast and dataset quality. Using phosphotungstic acid the staining concentration had a significant influence on the image contrast while both staining concentration and neo-tissue volume had an influence on the dataset quality. The use of high concentrations of phosphotungstic acid did however introduce significant shrinkage of the neo-tissue indicating that, despite sub-optimal image contrast, low concentrations of this staining agent should be used to enable quantitative analysis. To conclude, design of experiments allowed us to define the most optimal staining conditions for contrast-enhanced nanofocus computed tomography to be used as a routine screening tool of neo-tissue formation in Ti6Al4V constructs, transforming it into a robust three dimensional quality control methodology. [less ▲]

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See detailInvestigation of shear stress evolution during neotissue growth in a perfusion bioreactor using 3d multiphysics modeling
Guyot, Yann ULg; Papantoniou, Ioannis; Schrooten, Jan et al

Conference (2014, October)

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See detailA Multiphysics model of neotissue growth in a perfu sion bioreactor
Guyot, Yann ULg; Papantoniou, Ioannis; Schrooten, Jan et al

Conference (2014, September)

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See detailModel-guided bone tissue engineering: from bench to bedside via in silico modeling
Geris, Liesbet ULg

Conference (2014, September)

The creation of man-made living implants is the holy grail of tissue engineering (TE). As basic science advances, one of the major challenges in TE is the translation of the increasing biological ... [more ▼]

The creation of man-made living implants is the holy grail of tissue engineering (TE). As basic science advances, one of the major challenges in TE is the translation of the increasing biological knowledge on complex cell and tissue behavior into a predictive and robust engineering process. Mastering this complexity is an essential step towards clinical applications of TE. Computational modeling allows to study the biological complexity in a more integrative and quantitative way. Specifically, computational tools can help in quantifying and optimizing the TE product and process but also in assessing the influence of the in vivo environment on the behavior of the TE product after implantation. In this talk, I will use the example of bone tissue engineering to demonstrate how computational modeling can contribute in all aspects of the TE product development cycle: cells, carriers, culture conditions and clinics (figure 1 and 2). Depending on the specific question that needs to be answered the optimal model systems can vary from single scale to multiscale. Furthermore, depending on the available information, model systems can be purely data-driven or more hypothesis-driven in nature. The talk makes the case for in silico models receiving proper recognition, besides the in vitro and in vivo work in the TE field. Figure 1: overview of the 4 important components in bone tissue engineering: cells, carriers, culture and clinics. Figure 2: overview of in silico contributions to the 4 important components in bone tissue engineering: cells [1], carriers, culture [3] and clinics [4]. Acknowledgements This work presented in this talk is part of Prometheus, the KU Leuven R&D division for skeletal tissue engineering. http://www.kuleuven.be/prometheus. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreements 279100; from the Research Programme of the Research Foundation - Flanders (FWO, grant n. G.0982.11), from the Belgian National Fund for Scientific Research (FNRS) and from the special research fund of the KU Leuven (GOA/13/016) References 1. Kerkhofs J, Roberts SJ, Luyten FP, Van Oosterwyck H, Geris L. Relating the chondrocyte gene network to growth plate morphology: from genes to phenotype. PLoS One. 2012;7(4):e34729. doi: 10.1371/journal.pone.0034729 2. Guyot Y, Papantoniou I, Chai YC, Van Bael S, Schrooten J, Geris L. A computational model for cell/ECM growth on 3D surfaces using the level set method: a bone tissue engineering case study.Biomech Model Mechanobiol. 2014 3. Carlier A, Geris L, Bentley K, Carmeliet G, Carmeliet P, Van Oosterwyck H. MOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells. PLoS Comput Biol. 2012;8(10):e1002724. [less ▲]

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See detail3D MODELING OF SHEAR STRESS DEVELOPMENT DURING NEOTISSUE GROWTH IN A PERFUSION BIOREACTOR
Guyot, Yann ULg; Papantoniou, Ioannis; Schrooten, Jan et al

Conference (2014, July)

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See detailA Multiphycics approach to calculate shear stresses during neotissue growth in perfusion bioreactor
Guyot, Yann ULg; Papantoniou, Ioannis; Schrooten, Jan et al

Conference (2014, July)

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See detailSpatial optimization in perfusion bioreactors improves bone tissue-engineered construct quality attributes
Papantoniou, Ioannis; Guyot, Yann ULg; Sonnaert, Maarten et al

in Biotechnology and Bioengineering (2014)

Perfusion bioreactors have shown great promise for tissue engineering applications providing a homogeneous and consistent distribution of nutrients and flow-induced shear stresses throughout tissue ... [more ▼]

Perfusion bioreactors have shown great promise for tissue engineering applications providing a homogeneous and consistent distribution of nutrients and flow-induced shear stresses throughout tissue-engineered constructs. However, non uniform fluid-flow profiles found in the perfusion chamber entrance region have been shown to affect tissue-engineered construct quality characteristics during culture. In this study a whole perfusion and construct, three dimensional (3D) computational fluid dynamics approach was used in order to optimize a critical design parameter such as the location of the regular pore scaffolds within the perfusion bioreactor chamber. Computational studies were coupled to bioreactor experiments for a case-study flow rate. Two cases were compared in the first instance seeded scaffolds were positioned immediately after the perfusion chamber inlet while a second group was positioned at the computationally determined optimum distance were a steady state flow profile had been reached. Experimental data showed that scaffold location affected significantly cell content and neo-tissue distribution, as determined and quantified by contrast enhanced nanoCT, within the constructs both at 14 and 21 days of culture. However gene expression level of osteopontin and osteocalcin was not affected by the scaffold location. This study demonstrates that the bioreactor chamber environment, incorporating a scaffold and its location within it, affects the flow patterns within the pores throughout the scaffold requiring therefore dedicated optimization that can lead to bone tissue engineered constructs with improved quality attributes [less ▲]

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See detailA computational model for cell/ECM growth on 3D surfaces using the level set method: a bone tissue engineering case study
Guyot, Yann ULg; papantoniou, Ioannis; Chai, Yoke Chin et al

in Biomechanics and Modeling in Mechanobiology (2014)

Three dimensional (3D) open porous scaffolds are commonly used in tissue engineering (TE) applications to provide an initial template for cell attachment and subsequent cell growth and construct ... [more ▼]

Three dimensional (3D) open porous scaffolds are commonly used in tissue engineering (TE) applications to provide an initial template for cell attachment and subsequent cell growth and construct development. The macroscopic geometry of the scaffold is key in determining the kinetics of cell growth and thus in vitro ‘tissue’ formation. In this study we developed a computational framework based on the level set methodology to predict curvature-dependent growth of the cell/extracellular matrix domain within TE constructs. Scaffolds with various geometries (hexagonal, square, triangular) and pore sizes (500 and 1000 µm) were produced in house by additive manufacturing, seeded with human periosteum-derived cells and cultured under static conditions for 14 days. Using the projected tissue area as an output measure, the comparison between the experimental and the numerical results demonstrated a good qualitative and quantitative behavior of the framework. The model in its current form is able to provide important spatio-temporal information on final shape and speed of pore-filling of tissue engineered constructs by cells and extracellular matrix during static culture. [less ▲]

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See detailBringing regenerating tissues to life: the importance of angiogenesis in tissue engineering
Carlier, Aurélie ULg; Van Gastel, Nick; Geris, Liesbet ULg et al

Poster (2014, March 11)

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See detailSize does matter: an integrative in vivo-in silico approach for the treatment of critical size bone defects.
Carlier, Aurelie; van Gastel, Nick; Geris, Liesbet ULg et al

in PLoS computational biology (2014), 10(11), 1003888

Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non ... [more ▼]

Although bone has a unique restorative capacity, i.e., it has the potential to heal scarlessly, the conditions for spontaneous bone healing are not always present, leading to a delayed union or a non-union. In this work, we use an integrative in vivo-in silico approach to investigate the occurrence of non-unions, as well as to design possible treatment strategies thereof. The gap size of the domain geometry of a previously published mathematical model was enlarged in order to study the complex interplay of blood vessel formation, oxygen supply, growth factors and cell proliferation on the final healing outcome in large bone defects. The multiscale oxygen model was not only able to capture the essential aspects of in vivo non-unions, it also assisted in understanding the underlying mechanisms of action, i.e., the delayed vascularization of the central callus region resulted in harsh hypoxic conditions, cell death and finally disrupted bone healing. Inspired by the importance of a timely vascularization, as well as by the limited biological potential of the fracture hematoma, the influence of the host environment on the bone healing process in critical size defects was explored further. Moreover, dependent on the host environment, several treatment strategies were designed and tested for effectiveness. A qualitative correspondence between the predicted outcomes of certain treatment strategies and experimental observations was obtained, clearly illustrating the model's potential. In conclusion, the results of this study demonstrate that due to the complex non-linear dynamics of blood vessel formation, oxygen supply, growth factor production and cell proliferation and the interactions thereof with the host environment, an integrative in silico-in vivo approach is a crucial tool to further unravel the occurrence and treatments of challenging critical sized bone defects. [less ▲]

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See detailStaphylococcal biofilm growth on smooth and porous titanium coatings for biomedical applications.
Braem, Annabel; Van Mellaert, Lieve; Mattheys, Tina et al

in Journal of biomedical materials research. Part A (2014), 102(1), 215-24

Implant-related infections are a serious complication in prosthetic surgery, substantially jeopardizing implant fixation. As porous coatings for improved osseointegration typically present an increased ... [more ▼]

Implant-related infections are a serious complication in prosthetic surgery, substantially jeopardizing implant fixation. As porous coatings for improved osseointegration typically present an increased surface roughness, their resulting large surface area (sometimes increasing with over 700% compared to an ideal plane) renders the implant extremely susceptible to bacterial colonization and subsequent biofilm formation. Therefore, there is particular interest in orthopaedic implantology to engineer surfaces that combine both the ability to improve osseointegration and at the same time reduce the infection risk. As part of this orthopaedic coating development, the interest of in vitro studies on the interaction between implant surfaces and bacteria/biofilms is growing. In this study, the in vitro staphylococcal adhesion and biofilm formation on newly developed porous pure Ti coatings with 50% porosity and pore sizes up to 50 mum is compared to various dense and porous Ti or Ti-6Al-4V reference surfaces. Multiple linear regression analysis indicates that surface roughness and hydrophobicity are the main determinants for bacterial adherence. Accordingly, the novel coatings display a significant reduction of up to five times less bacterial surface colonization when compared to a commercial state-of-the-art vacuum plasma sprayed coating. However, the results also show that a further expansion of the porosity with over 15% and/or the pore size up to 150 mum is correlated to a significant increase in the roughness parameters resulting in an ascent of bacterial attachment. Chemically modifying the Ti surface in order to improve its hydrophilicity, while preserving the average roughness, is found to strongly decrease bacteria quantities, indicating the importance of surface functionalization to reduce the infection risk of porous coatings. [less ▲]

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See detailIn vivo ectopic bone formation by devitalized mineralized stem cell carriers produced under mineralizing culture condition.
Chai, Yoke Chin; Geris, Liesbet ULg; Bolander, Johanna et al

in BioResearch open access (2014), 3(6), 265-77

Functionalization of tissue engineering scaffolds with in vitro-generated bone-like extracellular matrix (ECM) represents an effective biomimetic approach to promote osteogenic differentiation of stem ... [more ▼]

Functionalization of tissue engineering scaffolds with in vitro-generated bone-like extracellular matrix (ECM) represents an effective biomimetic approach to promote osteogenic differentiation of stem cells in vitro. However, the bone-forming capacity of these constructs (seeded with or without cells) is so far not apparent. In this study, we aimed at developing a mineralizing culture condition to biofunctionalize three-dimensional (3D) porous scaffolds with highly mineralized ECM in order to produce devitalized, osteoinductive mineralized carriers for human periosteal-derived progenitors (hPDCs). For this, three medium formulations [i.e., growth medium only (BM1), with ascorbic acid (BM2), and with ascorbic acid and dexamethasone (BM3)] supplemented with calcium (Ca(2+)) and phosphate (PO4 (3-)) ions simultaneously as mineralizing source were investigated. The results showed that, besides the significant impacts on enhancing cell proliferation (the highest in BM3 condition), the formulated mineralizing media differentially regulated the osteochondro-related gene markers in a medium-dependent manner (e.g., significant upregulation of BMP2, bone sialoprotein, osteocalcin, and Wnt5a in BM2 condition). This has resulted in distinguished cell populations that were identifiable by specific gene signatures as demonstrated by the principle component analysis. Through devitalization, mineralized carriers with apatite crystal structures unique to each medium condition (by X-ray diffraction and SEM analysis) were obtained. Quantitatively, BM3 condition produced carriers with the highest mineral and collagen contents as well as human-specific VEGF proteins, followed by BM2 and BM1 conditions. Encouragingly, all mineralized carriers (after reseeded with hPDCs) induced bone formation after 8 weeks of subcutaneous implantation in nude mice models, with BM2-carriers inducing the highest bone volume, and the lowest in the BM3 condition (as quantitated by nano-computed tomography [nano-CT]). Histological analysis revealed different bone formation patterns, either bone ossicles containing bone marrow surrounding the scaffold struts (in BM2) or bone apposition directly on the struts' surface (in BM1 and BM3). In conclusion, we have presented experimental data on the feasibility to produce devitalized osteoinductive mineralized carriers by functionalizing 3D porous scaffolds with an in vitro cell-made mineralized matrix under the mineralizing culture conditions. [less ▲]

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See detailRegenerative orthopaedics: in vitro, in vivo ... in silico.
Geris, Liesbet ULg

in International orthopaedics (2014), 38(9), 1771-8

In silico, defined in analogy to in vitro and in vivo as those studies that are performed on a computer, is an essential step in problem-solving and product development in classical engineering fields ... [more ▼]

In silico, defined in analogy to in vitro and in vivo as those studies that are performed on a computer, is an essential step in problem-solving and product development in classical engineering fields. The use of in silico models is now slowly easing its way into medicine. In silico models are already used in orthopaedics for the planning of complicated surgeries, personalised implant design and the analysis of gait measurements. However, these in silico models often lack the simulation of the response of the biological system over time. In silico models focusing on the response of the biological systems are in full development. This review starts with an introduction into in silico models of orthopaedic processes. Special attention is paid to the classification of models according to their spatiotemporal scale (gene/protein to population) and the information they were built on (data vs hypotheses). Subsequently, the review focuses on the in silico models used in regenerative orthopaedics research. Contributions of in silico models to an enhanced understanding and optimisation of four key elements-cells, carriers, culture and clinics-are illustrated. Finally, a number of challenges are identified, related to the computational aspects but also to the integration of in silico tools into clinical practice. [less ▲]

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See detailIn silico biology of bone regeneration inside calcium phosphate scaffolds
Carlier, Aurélie ULg; Van Oosterwyck, Hans; Geris, Liesbet ULg

in Tissue Engineering: Computer Modeling, Biofabrication and Cell Behavior (2014)

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See detailOxygen: a critical component of critically sized defects
Carlier, Aurélie ULg; Van Gastel, Nick; Geris, Liesbet ULg et al

Poster (2013, December 19)

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