Bart Smeets

Analysis of initial cell spreading using mechanistic contact formulations for a deformable cell model.

Adhesion governs to a large extent the mechanical interaction between a cell and its microenvironment. As initial cell spreading is purely adhesion driven, understanding this phenomenon leads to profound insight in both cell adhesion and cell-substrate interaction. It has been found that across a wide variety of cell types, initial spreading behavior universally follows the same power laws. The simplest cell type providing this scaling of the radius of the spreading area with time are modified red blood cells (RBCs), whose elastic responses are well characterized. Using a mechanistic description of the contact interaction between a cell and its substrate in combination with a deformable RBC model, we are now able to investigate in detail the mechanisms behind this universal power law. The presented model suggests that the initial slope of the spreading curve with time results from a purely geometrical effect facilitated mainly by dissipation upon contact. Later on, the spreading rate decreases due to increasing tension and dissipation in the cells cortex as the cell spreads more and more. To reproduce this observed initial spreading, no irreversible deformations are required. Since the model created in this effort is extensible to more complex cell types and can cope with arbitrarily shaped, smooth mechanical microenvironments of the cells, it can be useful for a wide range of investigations where forces at the cell boundary play a decisive role.

Emergent structures and dynamics of cell colonies by contact inhibition of locomotion

Significance The regular distribution of mesenchymal cells, the formation of epithelial monolayers, or their collapse into spheroidal tumors illustrates the broad range of possible organizations of cells in tissues. Unveiling a physical picture of their emergence and dynamics is of critical importance to understand tissue morphogenesis or cancer progression. Although the role of cell–substrate and cell–cell adhesion in the organization of cell colonies has been widely studied, the impact of the cell-type–specific contact inhibition of locomotion (CIL) remains unclear. Here, we include this interaction in simulations of active particles and find a number of structures and collective dynamics that recapitulate existing tissue phenotypes. We give analytical predictions for the epithelial–mesenchymal transition and the formation of 3D aggregates as a function of cell–cell adhesion and CIL strengths. Thus, our findings shed light on the physical mechanisms underlying multicellular organization. Cells in tissues can organize into a broad spectrum of structures according to their function. Drastic changes of organization, such as epithelial–mesenchymal transitions or the formation of spheroidal aggregates, are often associated either to tissue morphogenesis or to cancer progression. Here, we study the organization of cell colonies by means of simulations of self-propelled particles with generic cell-like interactions. The interplay between cell softness, cell–cell adhesion, and contact inhibition of locomotion (CIL) yields structures and collective dynamics observed in several existing tissue phenotypes. These include regular distributions of cells, dynamic cell clusters, gel-like networks, collectively migrating monolayers, and 3D aggregates. We give analytical predictions for transitions between noncohesive, cohesive, and 3D cell arrangements. We explicitly show how CIL yields an effective repulsion that promotes cell dispersal, thereby hindering the formation of cohesive tissues. Yet, in continuous monolayers, CIL leads to collective cell motion, ensures tensile intercellular stresses, and opposes cell extrusion. Thus, our work highlights the prominent role of CIL in determining the emergent structures and dynamics of cell colonies.

Solving microscopic flow problems using Stokes equations in SPH

Abstract Starting from the Smoothed Particle Hydrodynamics method (SPH), we propose an alternative way to solve flow problems at a very low Reynolds number. The method is based on an explicit drop out of the inertial terms in the normal SPH equations, and solves the coupled system to find the velocities of the particles using the conjugate gradient method. The method will be called NSPH which refers to the non-inertial character of the equations. Whereas the time-step in standard SPH formulations for low Reynolds numbers is linearly restricted by the inverse of the viscosity and quadratically by the particle resolution, the stability of the NSPH solution benefits from a higher viscosity and is independent of the particle resolution. Since this method allows for a much higher time-step, it solves creeping flow problems with a high resolution and a long timescale up to three orders of magnitude faster than SPH. In this paper, we compare the accuracy and capabilities of the new NSPH method to canonical SPH solutions considering a number of standard problems in fluid dynamics. In addition, we show that NSPH is capable of modeling more complex physical phenomena such as the motion of a red blood cell in plasma.

Infection after fracture fixation of the tibia: Analysis of healthcare utilization and related costs

INTRODUCTION One of the most challenging complications in musculoskeletal trauma surgery is the development of infection after fracture fixation (IAFF). It can delay healing, lead to permanent functional loss, or even amputation of the affected limb. The main goal of this study was to investigate the total healthcare costs and length-of-stay (LOS) related to the surgical treatment of tibia fractures and furthermore identify the subset of clinical variables driving these costs within the Belgian healthcare system. The hypothesis was that deep infection would be the most important driver for total healthcare costs. PATIENTS AND METHODS Overall, 358 patients treated operatively for AO/OTA type 41, 42, and 43 tibia fractures between January 1, 2009 and January 1, 2014 were included in this study. A total of 26 clinical and process variables were defined. Calculated costs were limited to hospital care covered by the Belgian healthcare financing system. The five main cost categories studied were: honoraria, materials, hospitalization, day care admission, and pharmaceuticals. RESULTS Multivariate analysis showed that deep infection was the most significant characteristic driving total healthcare costs and LOS related to the surgical treatment of tibia fractures. Furthermore, this complication resulted in the highest overall increase in total healthcare costs and LOS. Treatment costs were approximately 6.5-times higher compared to uninfected patients. CONCLUSION This study shows the enormous hospital-related healthcare costs associated with IAFF of the tibia. Treatment costs for patients with deep infection are higher than previously mentioned in the literature. Therefore, future research should focus more on prevention rather than treatment strategies, not only to reduce patient morbidity but also to reduce the socio-economic impact.

Quantifying the mechanical micro-environment during three-dimensional cell expansion on microbeads by means of individual cell-based modelling.

Controlled in vitro three-dimensional cell expansion requires culture conditions that optimise the biophysical micro-environment of the cells during proliferation. In this study, we propose an individual cell-based modelling platform for simulating the mechanics of cell expansion on microcarriers. The lattice-free, particle-based method considers cells as individual interacting particles that deform and move over time. The model quantifies how the mechanical micro-environment of individual cells changes during the time of confluency. A sensitivity analysis is performed, which shows that changes in the cell-specific properties of cell–cell adhesion and cell stiffness cause the strongest change in the mechanical micro-environment of the cells. Furthermore, the influence of the mechanical properties of cells and microbead is characterised. The mechanical micro-environment is strongly influenced by the adhesive properties and the size of the microbead. Simulations show that even in the absence of strong biological heterogeneity, a large heterogeneity in mechanical stresses can be expected purely due to geometric properties of the culture system. Supplemental data for this article can be accessed online.

A cell based modelling framework for skeletal tissue engineering applications

In this study, a cell based lattice free modelling framework is proposed to study cell aggregate behaviour in bone tissue engineering applications. The model encompasses cell-to-cell and cell-environment interactions such as adhesion, repulsion and drag forces. Oxygen, nutrients, waste products, growth factors and inhibitors are explicitly represented in the model influencing cellular behaviour. Furthermore, a model for cell metabolism is incorporated representing the basic enzymic reactions of glycolysis and the Krebs cycle. Various types of cell death such as necrosis, apoptosis and anoikis are implemented. Finally, an explicit model of the cell cycle controls the proliferation process, taking into account the presence or absence of various metabolites, sufficient space and mechanical stress. Several examples are presented demonstrating the potential of the modelling framework. The behaviour of a synchronised cell aggregate under ideal circumstances is simulated, clearly showing the different stages of the cell cycle and the resulting growth of the aggregate. Also the difference in aggregate development under ideal (normoxic) and hypoxic conditions is simulated, showing hypoxia induced necrosis mainly in the centre of the aggregate grown under hypoxic conditions. The next step in this research will be the application of this modelling framework to specific experimental set-ups for bone tissue engineering applications.

Immersed Boundary Models for Quantifying Flow-Induced Mechanical Stimuli on Stem Cells Seeded on 3D Scaffolds in Perfusion Bioreactors.

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/μm, 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.

A discrete element approach for modelling the compression of crop stems

Virtual crop stems were created in the DEMeter++ software.Realistic data-based contact models were developed for stem interactions.The effect of plastic deformation and damage was incorporated in the models.The models were successfully validated by comparing simulations and measurements. The discrete element method (DEM) offers a powerful tool for simulating the interactions of large numbers of particles. Recently, DEM was used to simulate the interactions of tubular particles. While the existing linear elastic and Hertzian contact models can approximate the reversible compression for small deformations, they are inadequate for larger deformations. Here, the force-deformation behaviour is highly non-linear and plastic. In this study, data based contact models were developed for crop stems. These models combine realistic deformation behaviour with a minimal number of model parameters. Furthermore, the effect of plastic deformation and damage was incorporated in the model. The contact models were successfully used to validate, through comparison of simulations and measurements, individual stem and bulk compression. A good agreement was found between both. These validated DEM contact models for compression of crop stems allow to simulate the processing of large numbers of crop stems.

Functional outcome and general health status after treatment of AO type 43 distal tibial fractures

INTRODUCTION Distal tibial fractures are uncommon, but they result in poor overall outcome. The objective of this study was to assess functional outcome and general health status after the treatment of distal tibial fractures and identify factors that affect these outcome measures. PATIENTS AND METHODS A retrospective cohort study including 118 AO type 43 distal tibial fractures in 116 patients was conducted. With regard to articular involvement, fractures were classified as either simple (A1-B2, n=70) or complex (B3-C3, n=48). Twenty relevant demographic and operative variables were studied. Functional outcome, quality of life and pain were assessed using the Foot Function Index (FFI) and AOFAS ankle score, physical and mental SF-36, and Visual Analog Scale (VAS) questionnaires, respectively. RESULTS Over 75% of patients experienced noteworthy loss of ankle function. The general health status assessment showed markedly affected quality of life with more than two-third of all responding patients suffering from pain every day. In fact, complex fractures and increased complication rate were associated with worse functional outcome, whereas prolonged time to definite surgery affected both functional outcome and general health status significantly. CONCLUSIONS Complex distal tibial fractures were associated with poor functional outcome scores and delayed (-staged) surgery has been shown to prevent postoperative soft tissue problems. However, soft tissue injury associated with distal tibial fractures itself affected both the postoperative functional outcome and general health status as well. This should contribute to the understanding of treatment and outcome of distal tibial fractures. LEVEL OF EVIDENCE 3.

A discrete element approach for modelling bendable crop stems

Realistic data-based bending models were developed for virtual DEM crop stems.The effect of plastic deformation and damage was incorporated in the models.The bending model was validated through comparison of simulations and measurements.The effect of stem length and support distance were also taken into account.Pendulum experiments showed that the deformation rate has no significant effect. A requirement for optimising crop processing machinery using DEM simulations is the application of virtual stems that behave realistically during deformation. In this study, data based bending models were developed for virtual segmented crop stems. These models combine realistic bending behaviour with a minimal number of model parameters. Also the effects of plastic deformation and damage were incorporated in the model. The bending model was successfully used to validate the bending behaviour of individual stems through comparison of simulations and validation measurements. It was also shown that the model is suitable for virtual stems with different numbers of segments. Moreover, based on a stem measurement it could be predicted what would happen to the same stem if it would have other dimensions or if it would be supported at different locations. Additional stem measurements were used to validate this. No significant difference ( α = 0.05 ) was observed between measurements and simulations. Finally, pendulum experiments showed that the deformation rate has no significant effect ( α = 0.05 ) on the deformation behaviour of individual crop stems.