Papers by Stefaan W Verbruggen
Elsevier eBooks, 2018
Lying at the intersection between engineering and biology, mechanobiology is a nascent field of s... more Lying at the intersection between engineering and biology, mechanobiology is a nascent field of study that investigates adaptation of the structure and behaviour of tissues in response to mechanical loading. While mechanobiology has been implicated in a range of diseases and evidence of its effects is strewn across multiple scales, it is ultimately a cell-driven process arising in response to changes in local mechanical stimulation. Therefore the field presents unique challenges to researchers, necessitating techniques to shed light on complex biophysical interactions. While bioreactors, tissue engineering and animal models are utilised at organ and tissue scales, advanced microscopy and protein analysis techniques are required to capture localised responses to mechanical stimuli at the cellular and molecular scale. Additionally, computational techniques enable calculation of these localised mechanical stimuli, and linking of these stimuli across multiple scales. This chapter describes in detail a range of techniques relevant to the study of mechanobiology. 2.2.1.2. Micropillar Arrays Micropillar arrays are another method to measure cellular traction forces. In this technique, single cells are seeded onto an array of micro-sized evenly distributed pillars/cantilevers. The tops of the cantilevers serve as the cell substrate, which results in a high density of force
Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal ske... more Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton <i>in utero</i> have never before been characterized. Here, we quantify the biomechanics of foetal movements during the second half of gestation by modelling foetal movements captured using novel cine-MRI technology. By tracking these movements, quantifying foetal kick and muscle forces, and applying them to three-dimensional geometries of the foetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that foetal kick force increases significantly from 20 to 30 weeks gestation, before decreasing towards term. However, stress and strain in the foetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in foetal movement patterns in late pregnancy have been linked to poor foetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to foetal movements in the human skeleton <i>in utero</i>, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between foetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology.
Elsevier eBooks, 2018
Abstract Bone demonstrates a remarkable ability to renew itself, adapt its architecture, and repa... more Abstract Bone demonstrates a remarkable ability to renew itself, adapt its architecture, and repair fractures to maintain strength throughout life. Mechanobiology, the study of how external mechanical loading on the bone is transferred to bone cells and transduced into a biochemical cascade that ultimately results in macroscopic changes in bone structure, is crucial to the adaptive and regenerative nature of bone. This mechanobiological process is orchestrated through a compliment of specialized cells from bone surfaces and marrow, acting in concert to maintain bone homeostasis. However, certain pathological diseases can lead to bone fractures that do not repair or cause immobility, severe pain, and deformity. Mechanical forces play a critical role in the health of the bone, and thus, the inability to sense or transduce these mechanical signals (mechanotransduction) is associated with many bone diseases, such as osteoporosis, metastatic bone disease, and osteoarthritis, thus presenting potential avenues to new mechanobiological treatments for these pathologies.
Journal of Biomechanics, Sep 1, 2018
Fetal kicking and movements generate biomechanical stimulation in the fetal skeleton, which is im... more Fetal kicking and movements generate biomechanical stimulation in the fetal skeleton, which is important for prenatal musculoskeletal development, particularly joint shape. Developmental dysplasia of the hip (DDH) is the most common joint shape abnormality at birth, with many risk factors for the condition being associated with restricted fetal movement. In this study, we investigate the biomechanics of fetal movements in such situations, namely fetal breech position, oligohydramnios and primiparity (firstborn pregnancy). We also investigate twin pregnancies, which are not at greater risk of DDH incidence, despite the more restricted intra-uterine environment. We track fetal movements for each of these situations using cine-MRI technology, quantify the kick and muscle forces, and characterise the resulting stress and strain in the hip joint, testing the hypothesis that altered biomechanical stimuli may explain the link between certain intra-uterine conditions and risk of DDH. Kick force, stress and strain were found to be significantly lower in cases of breech position and oligohydramnios. Similarly, firstborn fetuses were found to generate significantly lower kick forces than non-firstborns. Interestingly, no significant difference was observed in twins compared to singletons. This research represents the first evidence of a link between the biomechanics of fetal movements and the risk of DDH, potentially informing the development of future preventative measures and enhanced diagnosis. Our results emphasise the importance of ultrasound screening for breech position and oligohydramnios, particularly later in pregnancy, and suggest that earlier intervention to correct breech position through external cephalic version could reduce the risk of hip dysplasia.
Wiley Interdisciplinary Reviews: Systems Biology and Medicine, Sep 7, 2016
Mechanobiology, the study of the influence of mechanical loads on biological processes through si... more Mechanobiology, the study of the influence of mechanical loads on biological processes through signaling to cells, is fundamental to the inherent ability of bone tissue to adapt its structure in response to mechanical stimulation. The immense contribution of computational modeling to the nascent field of bone mechanobiology is indisputable, having aided in the interpretation of experimental findings and identified new avenues of inquiry. Indeed, advances in computational modeling have spurred the development of this field, shedding new light on problems ranging from the mechanical response to loading by individual cells to tissue differentiation during events such as fracture healing. To date, in silico bone mechanobiology has generally taken a reductive approach in attempting to answer discrete biological research questions, with research in the field broadly separated into two streams: (1) mechanoregulation algorithms for predicting mechanobiological changes to bone tissue and (2) models investigating cell mechanobiology. Future models will likely take advantage of advances in computational power and techniques, allowing multiscale and multiphysics modeling to tie the many separate but related biological responses to loading together as part of a larger systems biology approach to shed further light on bone mechanobiology. Finally, although the ever-increasing complexity of computational mechanobiology models will inevitably move the field toward patientspecific models in the clinic, the determination of the context in which they can be used safely for clinical purpose will still require an extensive combination of computational and experimental techniques applied to in vitro and in vivo applications.
Cancers, Jan 19, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Current Osteoporosis Reports
Purpose of Review The purpose of this review is to provide a background on osteocytes and the pri... more Purpose of Review The purpose of this review is to provide a background on osteocytes and the primary cilium, discussing the role it plays in osteocyte mechanosensing. Recent Findings Osteocytes are thought to be the primary mechanosensing cells in bone tissue, regulating bone adaptation in response to exercise, with the primary cilium suggested to be a key mechanosensing mechanism in bone. More recent work has suggested that, rather than being direct mechanosensors themselves, primary cilia in bone may instead form a key chemo-signalling nexus for processing mechanoregulated signalling pathways. Recent evidence suggests that pharmacologically induced lengthening of the primary cilium in osteocytes may potentiate greater mechanotransduction, rather than greater mechanosensing. Summary While more research is required to delineate the specific osteocyte mechanobiological molecular mechanisms governed by the primary cilium, it is clear from the literature that the primary cilium has si...
Computers in Biology and Medicine
Cells Tissues Organs
The primary cilium is a solitary, sensory organelle with many roles in bone development, maintena... more The primary cilium is a solitary, sensory organelle with many roles in bone development, maintenance, and function. In the osteogenic cell lineage, including skeletal stem cells, osteoblasts, and osteocytes, the primary cilium plays a vital role in the regulation of bone formation, and this has made it a promising pharmaceutical target to maintain bone health. While the role of the primary cilium in the osteogenic cell lineage has been increasingly characterized, little is known about the potential impact of targeting the cilium in relation to osteoclasts, a hematopoietic cell responsible for bone resorption. The objective of this study was to determine whether osteoclasts have a primary cilium and to investigate whether or not the primary cilium of macrophages, osteoclast precursors, serves a functional role in osteoclast formation. Using immunocytochemistry, we showed the macrophages have a primary cilium, while osteoclasts lack this organelle. Furthermore, we increased macrophage...
Cancers
Organ-on-chip systems are capable of replicating complex tissue structures and physiological phen... more Organ-on-chip systems are capable of replicating complex tissue structures and physiological phenomena. The fine control of biochemical and biomechanical cues within these microphysiological systems provides opportunities for cancer researchers to build complex models of the tumour microenvironment. Interest in applying organ chips to investigate mechanisms such as metastatsis and to test therapeutics has grown rapidly, and this review draws together the published research using these microfluidic platforms to study cancer. We focus on both in-house systems and commercial platforms being used in the UK for fundamental discovery science and therapeutics testing. We cover the wide variety of cancers being investigated, ranging from common carcinomas to rare sarcomas, as well as secondary cancers. We also cover the broad sweep of different matrix microenvironments, physiological mechanical stimuli and immunological effects being replicated in these models. We examine microfluidic model...
Mechanobiology in Health and Disease
Lying at the intersection between engineering and biology, mechanobiology is a nascent field of s... more Lying at the intersection between engineering and biology, mechanobiology is a nascent field of study that investigates adaptation of the structure and behaviour of tissues in response to mechanical loading. While mechanobiology has been implicated in a range of diseases and evidence of its effects is strewn across multiple scales, it is ultimately a cell-driven process arising in response to changes in local mechanical stimulation. Therefore the field presents unique challenges to researchers, necessitating techniques to shed light on complex biophysical interactions. While bioreactors, tissue engineering and animal models are utilised at organ and tissue scales, advanced microscopy and protein analysis techniques are required to capture localised responses to mechanical stimuli at the cellular and molecular scale. Additionally, computational techniques enable calculation of these localised mechanical stimuli, and linking of these stimuli across multiple scales. This chapter describes in detail a range of techniques relevant to the study of mechanobiology. 2.2.1.2. Micropillar Arrays Micropillar arrays are another method to measure cellular traction forces. In this technique, single cells are seeded onto an array of micro-sized evenly distributed pillars/cantilevers. The tops of the cantilevers serve as the cell substrate, which results in a high density of force
Mechanobiology in Health and Disease, 2018
Abstract Bone demonstrates a remarkable ability to renew itself, adapt its architecture, and repa... more Abstract Bone demonstrates a remarkable ability to renew itself, adapt its architecture, and repair fractures to maintain strength throughout life. Mechanobiology, the study of how external mechanical loading on the bone is transferred to bone cells and transduced into a biochemical cascade that ultimately results in macroscopic changes in bone structure, is crucial to the adaptive and regenerative nature of bone. This mechanobiological process is orchestrated through a compliment of specialized cells from bone surfaces and marrow, acting in concert to maintain bone homeostasis. However, certain pathological diseases can lead to bone fractures that do not repair or cause immobility, severe pain, and deformity. Mechanical forces play a critical role in the health of the bone, and thus, the inability to sense or transduce these mechanical signals (mechanotransduction) is associated with many bone diseases, such as osteoporosis, metastatic bone disease, and osteoarthritis, thus presenting potential avenues to new mechanobiological treatments for these pathologies.
Animation showing fetal kicks at various ages over the latter half of gestation
Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal ske... more Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton <i>in utero</i> have never before been characterized. Here, we quantify the biomechanics of foetal movements during the second half of gestation by modelling foetal movements captured using novel cine-MRI technology. By tracking these movements, quantifying foetal kick and muscle forces, and applying them to three-dimensional geometries of the foetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that foetal kick force increases significantly from 20 to 30 weeks gestation, before decreasing towards term. However, stress and strain in the foe...
Animation of the computational pipeline, demonstrating how fetal movements are tracked and modele... more Animation of the computational pipeline, demonstrating how fetal movements are tracked and modeled using musculoskeletal modelling and finite element analysis techniques.
The osteocyte is believed to act as the primary sensor of mechanical stimulus in bone, controllin... more The osteocyte is believed to act as the primary sensor of mechanical stimulus in bone, controlling signalling for bone growth and resorption in response to changes in the mechanical demands placed on bones throughout life. Alterations in local bone tissue composition and structure arising during osteoporosis likely disrupt the local mechanical environment of these mechanosensitive bone cells, and may thereby initiate a mechanobiological response. However, due to the difficulties in directly characterising the mechanical environment of bone cells in vivo, the mechanical stimuli experienced by osteoporotic bone cells are not known. The global aim of this
Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal ske... more Mechanical forces generated by foetal kicks and movements result in stimulation of the foetal skeleton in the form of stress and strain. This stimulation is known to be critical for prenatal musculoskeletal development; indeed, abnormal or absent movements have been implicated in multiple congenital disorders. However, the mechanical stress and strain experienced by the developing human skeleton <i>in utero</i> have never before been characterized. Here, we quantify the biomechanics of foetal movements during the second half of gestation by modelling foetal movements captured using novel cine-MRI technology. By tracking these movements, quantifying foetal kick and muscle forces, and applying them to three-dimensional geometries of the foetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that foetal kick force increases significantly from 20 to 30 weeks gestation, before decreasing towards term. However, stress and strain in the foetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in foetal movement patterns in late pregnancy have been linked to poor foetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to foetal movements in the human skeleton <i>in utero</i>, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between foetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology.
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Papers by Stefaan W Verbruggen
The first study of this thesis involved the development of 3D finite element models of osteocytes, including their cell body and the surrounding pericellular matrix (PCM) and extracellular matrix (ECM), using confocal images of the lacunar-canalicular network. These anatomically representative models demonstrated the significance of geometry for strain amplification within the osteocyte mechanical environment. A second study employed fluid-structure interaction (FSI) modelling to investigate the complex multi-physics environment of osteocytes in vivo. These models built upon the anatomically representative models developed in the first study, and FSI methods were used to simulate loading-induced interstitial fluid flow through the lacunar-canalicular network. Interestingly, the in vivo mechanical stimuli (strain and shear stress) predicted using these computational approaches were above thresholds known to elicit osteogenic responses from osteoblastic cells in vitro, and thereby provide a novel insight into the complex multi-physics mechanical environment of osteocytes in vivo.
The third study of this thesis sought to experimentally characterise the strain environment of osteoblasts and osteocytes under physiological loading conditions in healthy and osteoporotic bone, using a rat model of osteoporosis. A custom-designed loading device compatible with a confocal microscope was constructed to apply strains to fluorescently stained femur samples from normal and ovariectomised rats. Confocal imaging was performed simultaneously during loading and digital image
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correlation techniques were used to characterise cellular strains from the images acquired. These results suggested that the mechanical environment of osteoblasts and osteocytes is altered during early-stage osteoporosis, and it is proposed that a mechanobiological response restores the homeostatic mechanical environment by late-stage osteoporosis. A final study applied these results as inputs for the developed computational models to investigate whether changes in tissue properties, lacunar-canalicular architecture or amplification mechanisms during osteoporosis could explain the altered mechanical stimulation of osteocytes observed. The findings of this study shed new light on the osteocyte mechanical environment in both healthy and osteoporotic bone, elucidating a possible mechanobiological relationship between increases in strain stimulation of the osteocyte and subsequent increases in mineralisation of bone tissue as key events in the progression of osteoporosis.
Together, the studies in this thesis provide a novel insight into the closed mechanical environment of the osteocyte. Using both computational and experimental methods, the mechanical stimuli that osteocytes experience under physiological loading in vivo, in both healthy and osteoporotic bone, were elucidated. In particular, the research in this thesis provides a missing mechanobiological link in the temporal development of post-menopausal osteoporosis, and the information gained from this body of work may inform future treatments for osteoporosis.