Biology subjects

Davies, N. H.

Publications and source records attributed to Davies, N. H..

10 recordsLinked to original sources

bioRxiv2025

A Mathematical Model for Chemo-mechanically Induced Collective Cell Motility on Planar Elastic Substrates

Cells interact with mechanical and chemical environmental cues, such as mechanical cues from other cells and chemical signals from growth factors. The current study aims to develop a mathematical model for combined chemically and mechanically induced collective cell motility on planar substrates. The mechanically induced cell motility is simulated using strain energy density gradients generated in an elastic substrate by cellular traction forces. For chemotaxis, Greens function and Duhamels principle are used to solve the diffusion equation that describes the distribution of a growth factor and to represent chemo-mechanically induced deterministic collective cell motility on planar elastic substrates. Chemically induced motility of cells towards a growth factor source is predicted for different growth factor production and diffusion rates. Chemo-mechanical cues with varying growth factor production and diffusion rates are explored for the motility of four cells and one motile cell in the presence of one stationary cell. The developed model describes the chemo-mechanically induced motility of individual cells on planar substrates. The model provides valuable information for in vivo or in vitro studies due to its suitability for extension to other chemical source shapes, mobilised sources, many sources, and soluble concentration gradients.

biophysics↗

bioRxiv2023

In silico mechanics and TGF-β expression of stem cells intramyocardially transplanted with a biomaterial injectate for treatment of myocardial infarction

PurposeBiomaterial and stem cell delivery are promising approaches to treating myocardial infarction. However, the mechanical and biochemical mechanisms underlying the therapeutic benefits require further clarification. This study aimed to assess the deformation of stem cells injected with the biomaterial into the infarcted heart. MethodsA microstructural finite element model of a mid-wall infarcted myocardial region was developed from ex vivo microcomputed tomography data of a rat heart with left ventricular infarct and intramyocardial biomaterial injectate. Nine cells were numerically seeded in the injectate of the microstructural model. The microstructural and a previously developed biventricular finite element model of the same rat heart were used to quantify the deformation of the cells during a cardiac cycle for a biomaterial elastic modulus (Einj) ranging between 4.1 and 405,900 kPa. ResultsThe transplanted cells deformation was largest for Einj = 7.4 kPa, matching that of the cells, and decreased for an increase and decrease in Einj. The cell deformation was more sensitive to Einj changes for softer (Einj [≤] 738 kPa) than stiffer biomaterials. ConclusionsCombining the microstructural and biventricular finite element models enables quantifying micromechanics and signalling of transplanted cells in the heart. The approach offers a broader scope for in silico investigations of biomaterial and cell therapies for myocardial infarction and other cardiac pathologies.

bioengineering↗

bioRxiv2022

Mathematical Model of Mechanosensing and Mechanically Induced Collective Motility of Cells on Planar Elastic Substrates

Cells mechanically interact with their environment to sense, for example, topography, elasticity and mechanical cues from other cells. Mechano-sensing has profound effects on cellular behaviour, including motility. The current study aims to develop a mathematical model of cellular mechano-sensing on planar elastic substrates and demonstrate the models predictive capabilities for the motility of individual cells in a colony. In the model, a cell is assumed to transmit an adhesion force, derived from a dynamic focal adhesion integrin density, that locally deforms a substrate, and to sense substrate deformation originating from neighbouring cells. The substrate deformation from multiple cells is expressed as total strain energy density with a spatially varying gradient. The magnitude and direction of the gradient at the cell location define the cell motion. Cell-substrate friction, partial motion randomness, and cell death and division are included. The substrate deformation by a single cell and the motility of two cells are presented for several substrate elasticities and thicknesses. The collective motility of 25 cells on a uniform substrate mimicking the closure of a circular wound of 200 m is predicted for deterministic and random motion. Cell motility on substrates with varying elasticity and thickness is explored for four cells and 15 cells, the latter again mimicking wound closure. Wound closure by 45 cells is used to demonstrate the simulation of cell death and division during migration. The mathematical model can adequately simulate the mechanically-induced collective cell motility on planar elastic substrates. The model is suitable for extension to other cell and substrates shapes and the inclusion of chemotactic cues, offering the potential to complement in vitro and in vivo studies.

biophysics↗

bioRxiv2022

Effect of biomaterial stiffness on cardiac mechanics in a biventricular infarcted rat heart model with microstructural representation of in situ intramyocardial injectate

Intramyocardial delivery of biomaterials is a promising concept for treating myocardial infarction. The delivered biomaterial provides mechanical support and attenuates wall thinning and elevated wall stress in the infarct region. This study aimed at developing a biventricular finite element model of an infarcted rat heart with a microstructural representation of an in situ biomaterial injectate, and a parametric investigation of the effect of the injectate stiffness on the cardiac mechanics. A three-dimensional subject-specific biventricular finite element model of a rat heart with left ventricular infarct and microstructurally dispersed biomaterial delivered one week after infarct induction was developed from ex vivo microcomputed tomography data. The volumetric mesh density varied between 303 mm-3 in the myocardium and 3,852 mm-3 in the injectate region due to the microstructural intramyocardial dispersion. Parametric simulations were conducted with the injectates elastic modulus varying from 4.1 to 405,900 kPa, and myocardial and injectate strains were recorded. With increasing injectate stiffness, the end-diastolic median myocardial fibre and cross-fibre strain decreased in magnitude from 3.6% to 1.1% and from -6.0% to -2.9%, respectively. At end-systole, the myocardial fibre and cross-fibre strain decreased in magnitude from -20.4% to -11.8% and from 6.5% to 4.6%, respectively. In the injectate, the maximum and minimum principal strains decreased in magnitude from 5.4% to 0.001% and from -5.4% to -0.001%, respectively, at end-diastole and from 38.5% to 0.06% and from -39.0% to -0.06%, respectively, at end-systole. With the microstructural injectate geometry, the developed subject-specific cardiac finite element model offers potential for extension to cellular injectates and in silico studies of mechanotransduction and therapeutic signalling in the infarcted heart with an infarct animal model extensively used in preclinical research.

biophysics↗

bioRxiv2022

Effect of paclitaxel treatment on cellular mechanics and morphology of human oesophageal squamous cell carcinoma of South African origin in 2D and 3D environments

During chemotherapy, structural and mechanical changes in malignant cells have been observed in several cancers, including leukaemia and pancreatic and prostate cancer. Such cellular changes may act as physical biomarkers for chemoresistance and cancer recurrence. This study aimed to determine how exposure to paclitaxel affects the intracellular stiffness of human oesophageal cancer of South African origin in vitro. A human oesophageal squamous cell carcinoma cell line WHCO1 was cultured on glass substrates (2D) and in collagen gels (3D) and exposed to paclitaxel for up to 48 hours. Cellular morphology and stiffness were assessed with confocal microscopy, visually aided morpho-phenotyping image recognition, and mitochondrial particle tracking microrheology at 24 and 48 hours. In the 2D environment, the intracellular stiffness was higher for the paclitaxel-treated than for untreated cells at 24 and 48 hours. In the 3D environment, the paclitaxel-treated cells were stiffer than the untreated cells at 24 hours, but no statistically significant differences in stiffness were observed at 48 hours. In 2D, paclitaxel-treated cells were significantly larger at 24 and 48 hours and more circular at 24 but not at 48 hours than the untreated controls. In 3D, there were no significant morphological differences between treated and untreated cells. The distribution of cell shapes was not statistically significant different across the different treatment conditions in 2D and 3D environments. Future studies with patient-derived primary cancer cells and prolonged drug exposure will help identify physical cellular biomarkers to detect chemoresistance onset and assess therapy effectiveness in oesophageal cancer patients. InsightMechanical changes in cancer cells by chemotherapeutic drugs exposure offer possible physical biomarkers for chemoresistance and cancer recurrence. This study on human oesophageal squamous cell carcinoma indicated that in vitro paclitaxel treatment induced stiffening and enlarging of malignant cells in two-dimensional environments at 24 and 48 hours. In physiologically more relevant three-dimensional collagen matrices the paclitaxel treatment led to cellular stiffening at 24 hours but softening thereafter, without significant changes in cellular size at any time. The outcomes need to be confirmed in future studies with prolonged drug exposure and patient-derived primary cancer cells.

cancer biology↗

bioRxiv2020

Micromechanical homogenisation of a hydrogel-filled electrospun scaffold for tissue-engineered epicardial patching of the infarcted heart

This study aimed at developing a formulation to link microscopic structure and macroscopic mechanics of a fibrous scaffold filled with a hydrogel for use as a tissue-engineered patch for local epicardial support of the infarcted heart. Mori-Tanaka mean field homogenisation, closed-cell foam mechanics and finite element (FE) methods were used to represent the macroscopic elastic modulus of the filled fibrous scaffold. The homogenised constitutive description of the scaffold was implemented for an epicardial patch in a FE model of a human cardiac left ventricle (LV) to assess effects of patching on myocardial mechanics and ventricular function in presences of an infarct. The macroscopic elastic modulus of the scaffold was predicted to be 0.287 MPa with the FE method and 0.290 MPa with the closed-cell model for the realistic fibre structure of the scaffold, and 0.108 and 0.540 MPa with mean field homogenization for randomly oriented and completely aligned fibres. Epicardial patching was predicted to reduce maximum myocardial stress in the infarcted LV from 19 kPa (no patch) to 9.5 kPa (patch), and to increase the ventricular ejection fraction from 40% (no patch) to 43% (patch). The predictions of the macroscopic elastic modulus of the realistic scaffold with the FE and the closed-cell model agreed well, and were bound by the mean field homogenisation prediction for random and fully aligned fibre orientation of the scaffold. This study demonstrates the feasibility of homogenization techniques to represent complex multiscale structural features in an simplified but meaningful manner.

bioengineering↗

bioRxiv2019

Electrospun polyester-urethane scaffold preserves mechanical properties and exhibits strain stiffening during in situ tissue ingrowth and degradation

Consistent mechanical performance from implantation through healing and scaffold degradation is highly desired for tissue-regenerative scaffolds, e.g. when used for vascular grafts. The aim of this study was the paired in vivo mechanical assessment of biostable and fast degrading electrospun polyester-urethane scaffolds to isolate the effects of material degradation and tissue formation after implantation. Biostable and degradable polyester-urethane scaffolds with substantial fibre alignment were manufactured by electrospinning. Scaffold samples were implanted paired in subcutaneous position in rats for 7, 14 and 28 days. Morphology, mechanical properties and tissue ingrowth of the scaffolds were assessed before implantation and after retrieval. Tissue ingrowth after 28 days was 83 {+/-} 10% in the biostable scaffold and 77 {+/-} 4% in the degradable scaffold. For the biostable scaffold, the elastic modulus at 12% strain increased significantly between 7 and 14 days and decreased significantly thereafter in fibre but not in cross-fibre direction. The degradable scaffold exhibited a significant increase in the elastic modulus at 12% strain from 7 to 14 days after which it did not decrease but remained at the same magnitude, both in fibre and in cross-fibre direction. Considering that the degradable scaffold loses its material strength predominantly during the first 14 days of hydrolytic degradation (as observed in our previous in vitro study), the consistency of the elastic modulus of the degradable scaffold after 14 days is an indication that the regenerated tissue construct retains it mechanical properties.

bioengineering↗

bioRxiv2019

Tissue ingrowth markedly reduces mechanical anisotropy and stiffness in fibre direction of highly aligned electrospun polyurethane scaffolds

PurposeThe lack of long-term patency of synthetic vascular grafts currently available on the market has directed research towards improving the performance of small diameter grafts. Improved radial compliance matching and tissue ingrowth into the graft scaffold are amongst the main goals for an ideal vascular graft. MethodsBiostable polyurethane scaffolds were manufactured by electrospinning and implanted in subcutaneous and circulatory positions in the rat for 7, 14 and 28 days. Scaffold morphology, tissue ingrowth, and mechanical properties of the scaffolds were assessed before implantation and after retrieval. ResultsTissue ingrowth after 24 days was 96.5 {+/-} 2.3% in the subcutaneous implants and 77.8 {+/-} 5.4% in the circulatory implants. Over the 24 days implantation, the elastic modulus at 12% strain decreased by 59% in direction of the fibre alignment whereas it increased by 1379% transverse to the fibre alignment of the highly aligned scaffold of the subcutaneous implants. The lesser aligned scaffold of the circulatory graft implants exhibited an increase of the elastic modulus at 12% strain by 77% in circumferential direction. ConclusionBased on the observations, it is proposed that the mechanism underlying the softening of the highly aligned scaffold in the predominant fibre direction is associated with scaffold compaction and local displacement of fibres by the newly formed tissue. The stiffening of the scaffold, observed transverse to highly aligned fibres and for more a random fibre distribution, represents the actual mechanical contribution of the tissue that developed in the scaffold.

bioengineering↗

bioRxiv2019

In silico stress fibre content affects peak strain in cytoplasm and nucleus but not in membrane for uniaxial substrate stretch

Existing in silico models for single cell mechanics feature limited representations of cytoskeletal structures that contribute substantially to the mechanics of a cell. We propose a micromechanical hierarchical approach to capture the mechanical contribution of actin stress fibres. For a cell-specific fibroblast geometry with membrane, cytoplasm and nucleus, the Mori-Tanaka homogenization method was employed to describe cytoplasmic inhomogeneities and constitutive contribution of actin stress fibres. The homogenization was implemented in a finite element model of the fibroblast attached to a substrate through focal adhesions. Strain in cell membrane, cytoplasm and nucleus due to uniaxial substrate stretch was assessed for different stress fibre volume fractions and different elastic modulus of the substrate. A considerable decrease of the peak strain with increasing stress fibre content was observed in cytoplasm and nucleus but not the membrane, whereas the peak strain in cytoplasm, nucleus and membrane increased for increasing elastic modulus of the substrate.

biophysics↗

bioRxiv2019

Identification of orthotropic material parameters for acute, necrotic, fibrotic and remodelling myocardial infarcts in the rat

Finite element (FE) models have been effectively utilized in studying biomechanical aspects of myocardial infarction (MI). Although the rat is a widely used animal model for MI, there is a lack of material parameters based on anisotropic constitutive models for rat myocardial infarcts in literature. This study aimed at employing inverse methods to identify the parameters of an orthotropic constitutive model for myocardial infarcts in the acute, necrotic, fibrotic and remodelling phases utilizing the biaxial mechanical data developed in a previous study. FE model was developed mimicking the setup of the biaxial tensile experiment. The orthotropic case of the generalized Fung constitutive model was utilized to model the material properties of the infarct. The parameters of Fung model were optimized so that the FE solution best fitted the biaxial experimental stress-strain data. A genetic algorithm was used to minimize the objective function. Fung orthotropic material parameters for different infarct stages were identified. The FE model predictions best approximated the experimental data of the 28 days infarct stage with 3.0% mean absolute percentage error. The worst approximation was for the 7 days stage with 3.6% error. This study demonstrated that the experimental biaxial stress-strain data of healing rat infarcts could be successfully approximated using inverse FE methods and genetic algorithms. The material parameters identified in this study will provide an essential platform for FE investigations of biomechanical aspects of MI and the development of therapies.

bioengineering↗