39 results found
Sotiriou V, Rolfe RA, Murphy P, et al., 2019, Effects of abnormal muscle forces on prenatal joint morphogenesis in mice, Journal of Orthopaedic Research, Vol: 37, Pages: 2287-2296, ISSN: 0736-0266
Fetal movements are essential for normal development of the human skeleton. When fetal movements are reduced or restricted, infants are at higher risk of developmental dysplasia of the hip and arthrogryposis (multiple joint contractures). Joint shape abnormalities have been reported in mouse models with abnormal or absent musculature, but the effects on joint shape in such models have not been quantified or characterised in detail. In this study, embryonic mouse forelimbs and hindlimbs at a single developmental stage (Theiler Stage 23) with normal, reduced or absent muscle were imaged in 3D. Skeletal rudiments were virtually segmented and rigid image registration was used to reliably align rudiments with each other, enabling repeatable assessment and measurement of joint shape differences between normal, reduced-muscle and absent muscle groups. We demonstrate qualitatively and quantitatively that joint shapes are differentially affected by a lack of, or reduction in, skeletal muscle, with the elbow joint being the most affected of the major limb joints. Surprisingly, the effects of reduced muscle were often more pronounced than those of absent skeletal muscle, indicating a complex relationship between muscle mass and joint morphogenesis. These findings have relevance for human developmental disorders of the skeleton in which abnormal fetal movements are implicated, particularly developmental dysplasia of the hip and arthrogryposis.
Lai J, Nowlan NC, Vaidyanathan R, et al., 2019, The use of actograph in the assessment of fetal well-being, Journal of Maternal-Fetal and Neonatal Medicine, Pages: 1-6, ISSN: 1476-4954
PURPOSE: Third trimester maternal perception of fetal movements is often used to assess fetal well-being. However, its true clinical value is unknown, primarily because of the variability in subjective quantification. The actograph, a technology available on most cardiotocograph machines, quantifies movements, but has never previously been investigated in relation to fetal health and existing monitoring devices. The objective of this study was to quantify actograph output in healthy third trimester pregnancies and investigate this in relation to other methods of assessing fetal well-being. METHODS: Forty-two women between 24 and 34 weeks of gestation underwent ultrasound scan followed by a computerized cardiotocograph (CTG). Post capture analysis of the actograph recording was performed and expressed as a percentage of activity over time. The actograph output results were analyzed in relation to Doppler, ultrasound and CTG findings expressed as z-score normalized for gestation. RESULTS: There was a significant association between actograph output recording and estimated fetal weight Z-score (R = 0.546, p ≤ .005). This activity was not related to estimated fetal weight. Increased actograph activity was negatively correlated with umbilical artery pulsatility index Z-score (R = -0.306, p = .049) and middle cerebral artery pulsatility index Z-score (R = -0.390, p = .011). CONCLUSION: Fetal movements assessed by the actograph are associated both with fetal size in relation to gestation and fetoplacental Doppler parameters. It is not the case that larger babies move more, however, as the relationship with actograph output related only to estimated fetal weight z-score. These findings suggest a plausible link between the frequency of fetal movements and established markers of fetal health. RATIONALE The objective of this study was to quantify actograph output in healthy third trimester pregnancies and investigate this in relation to other methods of assess
Levillain A, Rolfe RA, Huang Y, et al., 2019, Short-term foetal immobility temporally and progressively affects chick spinal curvature and anatomy and rib development., Eur Cell Mater, Vol: 37, Pages: 23-41
Congenital spine deformities may be influenced by movements in utero, but the effects of foetal immobility on spine and rib development remain unclear. The purpose of the present study was to determine (1) critical time-periods when rigid paralysis caused the most severe disruption in spine and rib development and (2) how the effects of an early, short-term immobilisation were propagated to the different features of spine and rib development. Chick embryos were immobilised once per single embryonic day (E) between E3 and E6 and harvested at E9. To assess the ontogenetic effects following single-day immobilisation, other embryos were immobilised at E4 and harvested daily between E5 and E9. Spinal curvature, vertebral shape and segmentation and rib development were analysed by optical projection tomography and histology. The results demonstrated that periods critical for movement varied for different aspects of spine and rib development. Single-day immobilisation at E3 or E4 resulted in the most pronounced spinal curvature abnormalities, multiple wedged vertebrae and segmentation defects, while single-day immobilisation at E5 led to the most severe rib abnormalities. Assessment of ontogenetic effects following single-day immobilisation at E4 revealed that vertebral segmentation defects were subsequent to earlier vertebral body shape and spinal curvature abnormalities, while rib formation (although delayed) was independent from thoracic vertebral shape or curvature changes. A day-long immobilisation in chicks severely affected spine and rib development, highlighting the importance of abnormal foetal movements at specific time-points and motivating targeted prenatal monitoring for early diagnosis of congenital scoliosis.
Giorgi M, Sotiriou V, Fanchini N, et al., 2019, Prenatal growth map of the mouse knee joint by means of deformable registration technique, PLOS ONE, Vol: 14, ISSN: 1932-6203
Nowlan NC, Francis-West P, Nelson C, 2018, Mechanics of development Introduction, PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES, Vol: 373, ISSN: 0962-8436
Nowlan NC, Parisi C, Chandaria V, 2018, Blocking mechanosensitive ion channels eliminates the effects of applied mechanical loading on chick joint morphogenesis, Philosophical Transactions B: Biological Sciences, Vol: 373, ISSN: 0962-8436
Abnormalities in joint shape are increasingly considered a critical risk factor for developing osteoarthritis in life. It has been shown that mechanical forces during prenatal development, particularly those due to fetal movements, play a fundamental role in joint morphogenesis. However, how mechanical stimuli are sensed or transduced in developing joint tissues is unclear. Stretch-activated and voltage-gated calcium ion channels have been shown to be involved in the mechanoregulation of chondrocytes in vitro. In this study, we analyse, for the first time, how blocking these ion channels influences the effects of mechanical loading on chick joint morphogenesis. Using in vitro culture of embryonic chick hindlimb explants in a mechanostimulation bioreactor, we block stretch-activated and voltage-gated ion channels using, respectively, gadolinium chloride and nifedipine. We find that the administration of high doses of either drug largely removed the effects of mechanical stimulation on growth and shape development in vitro, while neither drug had any effect in static cultures. This study demonstrates that, during joint morphogenesis, mechanical cues are transduced—at least in part—through mechanosensitive calcium ion channels, advancing our understanding of cartilage development and mechanotransduction.
Verbruggen S, Kainz B, Shelmerdine SC, et al., 2018, Altered biomechanical stimulation of the developing hip joint in presence of hip dysplasia risk factors, Journal of Biomechanics, Vol: 78, Pages: 1-9, ISSN: 0021-9290
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.
Lai J, Woodward R, Alexandrov Y, et al., 2018, Performance of a wearable acoustic system for fetal movement discrimination, PLoS ONE, Vol: 13, ISSN: 1932-6203
Fetal movements (FM) are a key factor in clinical management of high-risk pregnancies such as fetal growth restriction. While maternal perception of reduced FM can trigger self-referral to obstetric services, maternal sensation is highly subjective. Objective, reliable monitoring of fetal movement patterns outside clinical environs is not currently possible. A wearable and non-transmitting system capable of sensing fetal movements over extended periods of time would be extremely valuable, not only for monitoring individual fetal health, but also for establishing normal levels of movement in the population at large. Wearable monitors based on accelerometers have previously been proposed as a means of tracking FM, but such systems have difficulty separating maternal and fetal activity and have not matured to the level of clinical use. We introduce a new wearable system based on a novel combination of accelerometers and bespoke acoustic sensors as well as an advanced signal processing architecture to identify and discriminate between types of fetal movements. We validate the system with concurrent ultrasound tests on a cohort of 44 pregnant women and demonstrate that the garment is capable of both detecting and discriminating the vigorous, whole-body ‘startle’ movements of a fetus. These results demonstrate the promise of multimodal sensing for the development of a low-cost, non-transmitting wearable monitor for fetal movements.
Parisi C, Nowlan NC, Frequency and duration of mechanical stimulation influence mineralisation of developing chick limbs cultured in vitro, WCB2018
Verbruggen S, Kainz B, Shelmerdine S, et al., 2018, Stresses and strains on the human fetal skeleton during development, Journal of the Royal Society Interface, Vol: 15, ISSN: 1742-5662
Mechanical forces generated by fetal kicks and movements result in stimulation of the fetal 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 in utero have never before been characterized. Here, we quantify the biomechanics of fetal movements during the second half of gestation by modelling fetal movements captured using novel cine-magnetic resonance imaging technology. By tracking these movements, quantifying fetal kick and muscle forces, and applying them to three-dimensional geometries of the fetal skeleton, we test the hypothesis that stress and strain change over ontogeny. We find that fetal kick force increases significantly from 20 to 30 weeks' gestation, before decreasing towards term. However, stress and strain in the fetal skeleton rises significantly over the latter half of gestation. This increasing trend with gestational age is important because changes in fetal movement patterns in late pregnancy have been linked to poor fetal outcomes and musculoskeletal malformations. This research represents the first quantification of kick force and mechanical stress and strain due to fetal movements in the human skeleton in utero, thus advancing our understanding of the biomechanical environment of the uterus. Further, by revealing a potential link between fetal biomechanics and skeletal malformations, our work will stimulate future research in tissue engineering and mechanobiology.
Parisi C, Chandaria VC, Nowlan NC, The Role of Mechanosensitive Ion Channels in Mechanoregulation of Prenatal Joint Morphogenesis, ORS2018
Verbruggen SVW, Oyen M, Phillips A, et al., 2017, Function and failure of the fetal membrane: Modelling the mechanics of the chorion and amnion, PLOS One, Vol: 12, ISSN: 1932-6203
The fetal membrane surrounds the fetus during pregnancy and is a thin tissue composed of two layers, the chorion and the amnion. While rupture of this membrane normallyoccurs at term, preterm rupture can resultin increased risk of fetal mortality and morbidity, as well as danger of infection in the mother. Although structural changes have been observed in the membrane in such cases, the mechanical behaviour of the human fetal membrane in vivoremains poorly understoodand is challenging to investigate experimentally.Therefore,the objectiveof this study wasto developsimplifiedfinite element models toinvestigatethe mechanical behaviourand ruptureof the fetal membrane, particularlyits constituent layers,under variousphysiological conditions.It was found that modelling the chorion and amnion as a single layer predicts remarkably different behaviourcompared with a more anatomically-accurate bilayer, significantly underestimating stress in the amnion and under-predicting the risk ofmembrane rupture. Additionally,reductions in chorion-amnion interface lubrication and chorion thickness (reported in cases of preterm rupture)both resultedin increasedmembrane stress. Interestingly, the inclusion of a weak zone in the fetal membrane that has been observed to develop overlying the cervix would likelycause it to fail atterm,during labour. Finally, these findings support the theory that the amnion is the dominant structural component of the fetal membrane and is required to maintain its integrity. The results provide a novel insight into the mechanical effect of structural changes in the chorion and amnion, in cases of bothnormal andpreterm rupture.
Verbruggen SW, Nowlan NC, 2017, Ontogeny of the Human Pelvis., Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, Vol: 300, Pages: 643-652, ISSN: 1932-8486
The human pelvis has evolved over time into a remarkable structure, optimised into an intricate architecture that transfers the entire load of the upper body into the lower limbs, while also facilitating bipedal movement. The pelvic girdle is composed of two hip bones, os coxae, themselves each formed from the gradual fusion of the ischium, ilium and pubis bones. Unlike the development of the classical long bones, a complex timeline of events must occur in order for the pelvis to arise from the embryonic limb buds. An initial blastemal structure forms from the mesenchyme, with chondrification of this mass leading to the first recognisable elements of the pelvis. Primary ossification centres initiate in utero, followed post-natally by secondary ossification at a range of locations, with these processes not complete until adulthood. This cascade of events can vary between individuals, with recent evidence suggesting that fetal activity can affect the normal development of the pelvis. This review surveys the current literature on the ontogeny of the human pelvis.
Nowlan NC, Rolfe RA, Iatridis JC, et al., 2017, Abnormal fetal muscle forces result in defects in spinal curvature and alterations in vertebral segmentation and shape, Journal of Orthopaedic Research, Vol: 35, Pages: 2135-2144, ISSN: 1554-527X
The incidence of congenital spine deformities, including congenital scoliosis, kyphosis and lordosis, may be influenced by the in utero mechanical environment, and particularly by fetal movements at critical time-points. There is a limited understanding of the influence of fetal movements on spinal development, despite the fact that mechanical forces have been shown to play an essential role in skeletal development of the limb. This study investigates the effects of muscle forces on spinal curvature, vertebral segmentation and vertebral shape by inducing rigid or flaccid paralysis in the embryonic chick. The critical time-points for the influence of fetal movements on spinal development were identified by varying the time of onset of paralysis. Prolonged rigid paralysis induced severe defects in the spine, including curvature abnormalities, posterior and anterior vertebral fusions and altered vertebral shape, while flaccid paralysis did not affect spinal curvature or vertebral segmentation. Early rigid paralysis resulted in more severe abnormalities in the spine than later rigid paralysis. The findings of this study support the hypothesis that the timing and nature of fetal muscle activity are critical influences on the normal development of the spine, with implications for the understanding of congenital spine deformities.
Chandaria VV, McGinty J, Nowlan NC, 2016, Characterising the effects of in vitro mechanical stimulation on morphogenesis of developing limb explants, Journal of Biomechanics, Vol: 49, Pages: 3635-3642, ISSN: 1873-2380
Mechanical forces due to fetal movements play an important role in joint shape morphogenesis, and abnormalities of the joints relating to abnormal fetal movements can have long-term health implications. While mechanical stimulation during development has been shown to be important for joint shape, the relationship between the quantity of mechanical stimulation and the growth and shape change of developing cartilage has not been quantified. In this study, we culture embryonic chick limb explants in vitro in order to reveal how the magnitude of applied movement affects key aspects of the developing joint shape. We hypothesise that joint shape is affected by movement magnitude in a dose-dependent manner, and that a movement regime most representative of physiological fetal movements will promote characteristics of normal shape development. Chick hindlimbs harvested at seven days of incubation were cultured for six days, under either static conditions or one of three different dynamic movement regimes, then assessed for joint shape, cell survival and proliferation. We demonstrate that a physiological magnitude of movement in vitro promotes the most normal progression of joint morphogenesis, and that either under-stimulation or over-stimulation has detrimental effects. Providing insight into the optimal level of mechanical stimulation for cartilage growth and morphogenesis is pertinent to gaining a greater understanding of the etiology of conditions such as developmental dysplasia of the hip, and is also valuable for cartilage tissue engineering.
Ford CA, Nowlan NC, Thomopoulos S, et al., 2016, Effects of imbalanced muscle loading on hip joint development and maturation, Journal of Orthopaedic Research, Vol: 35, Pages: 1128-1136, ISSN: 1554-527X
The mechanical loading environment influences the development and maturation of joints. In this study, the influence of imbalanced muscular loading on joint development was studied using localized chemical denervation of hip stabilizing muscle groups in neonatal mice. It was hypothesized that imbalanced muscle loading, targeting either Gluteal muscles or Quadriceps muscles, would lead to bilateral hip joint asymmetry, as measured by acetabular coverage, femoral head volume and bone morphometry, and femoral-acetabular shape. The contralateral hip joints as well as age-matched, uninjected mice were used as controls. Altered bone development was analyzed using micro-computed tomography, histology, and image registration techniques at post-natal days (P) 28, 56, and 120. This study found that unilateral muscle unloading led to reduced acetabular coverage of the femoral head, lower total volume, lower bone volume ratio, and lower mineral density, at all three time points. Histologically, the femoral head was smaller in unloaded hips, with thinner triradiate cartilage at P28 and thinner cortical bone at P120 compared to contralateral hips. Morphological shape changes were evident in unloaded hips at P56. Unloaded hips had lower trabecular thickness and increased trabecular spacing of the femoral head compared to contralateral hips. The present study suggests that decreased muscle loading of the hip leads to altered bone and joint shape and growth during post-natal maturation. Statement of Clinical Significance: Adaptations from altered muscle loading during postnatal growth investigated in this study have implications on developmental hip disorders that result from asymmetric loading, such as patients with limb-length inequality or dysplasia. This article is protected by copyright. All rights reserved.
The key determinant to a fetus maintaining its health is through adequate perfusion and oxygen transfer mediated by the functioning placenta. When this equilibrium is distorted, a number of physiological changes including reduced fetal growth occur to favour survival. Technologies have been developed to monitor these changes with a view to prolong intrauterine maturity whilst reducing the risks of stillbirth. Many of these strategies involve complex interpretation, for example Doppler ultrasound for fetal blood flow and computerisedcomputerized analysis of fetal heart rate changes. However, even with these modalities of fetal assessment to determine the optimal timing of delivery, fetal movements remain integral to clinical decision making. In high risk cohorts with fetal growth restriction, the manifestation of a reduction in perceived movements may warrant an expedited delivery. Despite this, there remains has been little evolution in the development of technologies to objectively define evaluate normal fetal movement behavior for behavior, and where there has, there has been no linkage to clinical useapplication. In tThis review we is an attempt to understand synthesize currently available literature on the value of fetal movement analysis as a method of assessing fetal wellbeing, and show how interdisciplinary developments in this area may aid in improvements to clinical outcomes.
Fetal movements in the uterus are a natural part of development, and are known to play an important role in normal musculoskeletal development. However, very little is known about the biomechanical stimuli that arise during movements in utero, despite these stimuli being crucial to normal bone and joint formation. Therefore the objective of this study is to create a series of computational steps by which the forces generated during a kick in utero could be predicted from clinically observed fetal movements using novel cine-MRI data of three fetuses, aged 20-22 weeks. A custom tracking software was designed to characterise the movements of joints in utero, and average uterus deflection of 6.95 ± 0.41 mm due to kicking was calculated. These observed displacements provided boundary conditions for a finite element model of the uterine environment, predicting an average reaction force of 0.52 ± 0.15 N generated by a kick against the uterine wall. Finally, these data were applied as inputs for a musculoskeletal model of a fetal kick, resulting in predicted maximum forces in the muscles surrounding the hip joint of approximately 8 N, while higher maximum forces of approximately 21 N were predicted for the muscles surrounding the knee joint. This study provides a novel insight into the closed mechanical environment of the uterus, with an innovative method allowing elucidation of the biomechanical interaction of the developing fetus with its surroundings.
Nowlan NC, Giorgi M, Shefelbine SJ, et al., 2015, Effects of normal and abnormal loading conditions on morphogenesis of the prenatal hip joint: application to hip dysplasia, Journal of Biomechanics, Vol: 48, Pages: 3390-3397, ISSN: 1873-2380
Joint morphogenesis is an important phase of prenatal joint development during which the opposing cartilaginous rudiments acquire their reciprocal and interlocking shapes. At an early stage of development, the prenatal hip joint is formed of a deep acetabular cavity that almost totally encloses the head. By the time of birth, the acetabulum has become shallower and the femoral head has lost substantial sphericity, reducing joint coverage and stability. In this study, we use a dynamic mechanobiological simulation to explore the effects of normal (symmetric), reduced and abnormal (asymmetric) prenatal movements on hip joint shape, to understand their importance for postnatal skeletal malformations such as developmental dysplasia of the hip (DDH). We successfully predict the physiological trends of decreasing sphericity and acetabular coverage of the femoral head during fetal development. We show that a full range of symmetric movements helps to maintain some of the acetabular depth and femoral head sphericity, while reduced or absent movements can lead to decreased sphericity and acetabular coverage of the femoral head. When an abnormal movement pattern was applied, a deformed joint shape was predicted, with an opened asymmetric acetabulum and the onset of a malformed femoral head. This study provides evidence for the importance of fetal movements in the prevention and manifestation of congenital musculoskeletal disorders such as DDH.
Bowles C, Nowlan NC, Hayat TTA, et al., 2015, Machine learning for the automatic localisation of foetal body parts in cine-MRI scans, Medical Imaging 2015: Image Processing, Publisher: Society of Photo-optical Instrumentation Engineers (SPIE), ISSN: 0277-786X
Nowlan NC, 2015, BIOMECHANICS OF FOETAL MOVEMENT, EUROPEAN CELLS & MATERIALS, Vol: 29, Pages: 1-21, ISSN: 1473-2262
Nowlan NC, Chandaria V, Sharpe J, 2014, Immobilized Chicks as a Model System for Early-Onset Developmental Dysplasia of the Hip, JOURNAL OF ORTHOPAEDIC RESEARCH, Vol: 32, Pages: 777-785, ISSN: 0736-0266
Nowlan NC, Sharpe J, 2014, Joint shape morphogenesis precedes cavitation of the developing hip joint, JOURNAL OF ANATOMY, Vol: 224, Pages: 482-489, ISSN: 0021-8782
Giorgi M, Carriero A, Shefelbine SJ, et al., 2014, Mechanobiological simulations of prenatal joint morphogenesis, JOURNAL OF BIOMECHANICS, Vol: 47, Pages: 989-995, ISSN: 0021-9290
Rolfe RA, Nowlan NC, Kenny EM, et al., 2014, Identification of mechanosensitive genes during skeletal development: alteration of genes associated with cytoskeletal rearrangement and cell signalling pathways, BMC GENOMICS, Vol: 15, ISSN: 1471-2164
Nowlan NC, Jepsen KJ, Morgan EF, 2011, Smaller, weaker, and less stiff bones evolve from changes in subsistence strategy, Publisher: SPRINGER LONDON LTD, Pages: 1967-1980, ISSN: 0937-941X
Nowlan NC, Dumas G, Tajbaksh S, et al., 2011, Biophysical stimuli generated by passive movements contribute to the mechanoregulation of skeletogenesis, Biomechanics and Modeling in Mechanobiology
Nowlan NC, Jepsen KJ, Morgan EF, 2011, Smaller, Weaker and Less Stiff Bones Evolve from Changes in Lifestyle, Osteoporosis International, Vol: 22, Pages: 1967-1980
Nowlan NC, Sharpe J, Roddy KA, et al., 2010, Mechanobiology of Embryonic Skeletal Development: Insights from Animal Models, Birth Defects Research Part C: Embryo Today Reviews, Vol: 90, Pages: 203-213
Nowlan NC, Bourdon C, Dumas G, et al., 2010, Developing Bones are Differentially Affected by Compromised Skeletal Muscle Formation, Bone, Vol: 46, Pages: 1275-1285
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