Publications
59 results found
Godivier J, Lawrence EA, Wang M, et al., 2024, Compressive stress gradients direct mechanoregulation of anisotropic growth in the zebrafish jaw joint., PLoS Comput Biol, Vol: 20
Mechanical stimuli arising from fetal movements are critical factors underlying joint growth. Abnormal fetal movements negatively affect joint shape features with important implications for joint health, but the mechanisms by which mechanical forces from fetal movements influence joint growth are still unclear. In this research, we quantify zebrafish jaw joint growth in 3D in free-to-move and immobilised fish larvae between four and five days post fertilisation. We found that the main changes in size and shape in normally moving fish were in the ventrodorsal axis, while growth anisotropy was lost in the immobilised larvae. We next sought to determine the cell level activities underlying mechanoregulated growth anisotropy by tracking individual cells in the presence or absence of jaw movements, finding that the most dramatic changes in growth rates due to jaw immobility were in the ventrodorsal axis. Finally, we implemented mechanobiological simulations of joint growth with which we tested hypotheses relating specific mechanical stimuli to mechanoregulated growth anisotropy. Different types of mechanical stimulation were incorporated into the simulation to provide the mechanoregulated component of growth, in addition to the baseline (non-mechanoregulated) growth which occurs in the immobilised animals. We found that when average tissue stress over the opening and closing cycle of the joint was used as the stimulus for mechanoregulated growth, joint morphogenesis was not accurately predicted. Predictions were improved when using the stress gradients along the rudiment axes (i.e., the variation in magnitude of compression to magnitude of tension between local regions). However, the most accurate predictions were obtained when using the compressive stress gradients (i.e., the variation in compressive stress magnitude) along the rudiment axes. We conclude therefore that the dominant biophysical stimulus contributing to growth anisotropy during early joint development is
Ahmed S, Rogers AV, Nowlan NC, 2023, Mechanical loading due to muscle movement regulates establishment of the collagen network in the developing murine skeleton., R Soc Open Sci, Vol: 10, ISSN: 2054-5703
Mechanical loading is critical for collagen network maintenance and remodelling in adult skeletal tissues, but the role of loading in collagen network formation during development is poorly understood. We test the hypothesis that mechanical loading is necessary for the onset and maturation of spatial localization and structure of collagens in prenatal cartilage and bone, using in vivo and in vitro mouse models of altered loading. The majority of collagens studied was aberrant in structure or localization, or both, when skeletal muscle was absent in vivo. Using in vitro bioreactor culture system, we demonstrate that mechanical loading directly modulates the spatial localization and structure of collagens II and X. Furthermore, we show that mechanical loading in vitro rescues aspects of the development of collagens II and X from the effects of fetal immobility. In conclusion, our findings show that mechanical loading is a critical determinant of collagen network establishment during prenatal skeletal development.
Tsinman TK, Huang Y, Ahmed S, et al., 2023, Lack of skeletal muscle contraction disrupts fibrous tissue morphogenesis in the developing murine knee, JOURNAL OF ORTHOPAEDIC RESEARCH, Vol: 41, Pages: 2305-2314, ISSN: 0736-0266
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- Citations: 1
Khatib N, Monsen J, Ahmed S, et al., 2023, Mechanoregulatory role of TRPV4 in prenatal skeletal development, Science Advances, Vol: 9, Pages: 1-17, ISSN: 2375-2548
Biophysical cues are essential for guiding skeletal development, but the mechanisms underlying the mechanical regulation of cartilage and bone formation are unknown. TRPV4 is a mechanically sensitive ion channel involved in cartilage and bone cell mechanosensing, mutations of which lead to skeletal developmental pathologies. We tested the hypothesis that loading-driven prenatal skeletal development is dependent on TRPV4 activity. We first establish that mechanically stimulating mouse embryo hindlimbs cultured ex vivo stimulates knee cartilage growth, morphogenesis, and expression of TRPV4, which localizes to areas of high biophysical stimuli. We then demonstrate that loading-driven joint cartilage growth and shape are dependent on TRPV4 activity, mediated via control of cell proliferation and matrix biosynthesis, indicating a mechanism by which mechanical loading could direct growth and morphogenesis during joint formation. We conclude that mechanoregulatory pathways initiated by TRPV4 guide skeletal development; therefore, TRPV4 is a valuable target for the development of skeletal regenerative and repair strategies.
Collins JM, Lang A, Parisi C, et al., 2023, YAP and TAZ couple osteoblast precursor mobilization to angiogenesis and mechanoregulated bone development., bioRxiv
Endochondral ossification requires coordinated mobilization of osteoblast precursors with blood vessels. During adult bone homeostasis, vessel adjacent osteoblast precursors respond to and are maintained by mechanical stimuli; however, the mechanisms by which these cells mobilize and respond to mechanical cues during embryonic development are unknown. Previously, we found that deletion of the mechanoresponsive transcriptional regulators, YAP and TAZ, from Osterix-expressing osteoblast precursors and their progeny caused perinatal lethality. Here, we show that embryonic YAP/TAZ signaling couples vessel-associated osteoblast precursor mobilization to angiogenesis in developing long bones. Osterix-conditional YAP/TAZ deletion impaired endochondral ossification in the primary ossification center but not intramembranous osteogenesis in the bone collar. Single-cell RNA sequencing revealed YAP/TAZ regulation of the angiogenic chemokine, Cxcl12, which was expressed uniquely in vessel-associated osteoblast precursors. YAP/TAZ signaling spatially coupled osteoblast precursors to blood vessels and regulated vascular morphogenesis and vessel barrier function. Further, YAP/TAZ signaling regulated vascular loop morphogenesis at the chondro-osseous junction to control hypertrophic growth plate remodeling. In human cells, mesenchymal stromal cell co-culture promoted 3D vascular network formation, which was impaired by stromal cell YAP/TAZ depletion, but rescued by recombinant CXCL12 treatment. Lastly, YAP and TAZ mediated mechanotransduction for load-induced osteogenesis in embryonic bone.
Sotiriou V, Huang Y, Ahmed S, et al., 2022, Prenatal murine skeletogenesis partially recovers from absent skeletal muscle as development progresses, European Cells and Materials, Vol: 44, Pages: 115-132, ISSN: 1473-2262
Skeletal muscle contractions are critical for normal skeletal growth and morphogenesis but it is unclear how the detrimental effects of absent muscle on the bones and joints change over time. Joint shape and cavitation as well as rudiment length and mineralisation were assessed in multiple rudiments at two developmental stages [Theiler stage (TS)24 and TS27] in the splotch-delayed “muscle-less limb” mouse model and littermate controls. Chondrocyte morphology was quantified in 3D in the distal humerus at the same stages. As development progressed, the effects of absent muscle on all parameters except for cavitation become less severe. All major joints in muscle-less limbs were abnormally shaped at TS24, while, by TS27, most muscle-less limb joint shapes were normal or nearly normal. In contrast, any joints that were fused at TS24 did not cavitate by TS27. At TS24, chondrocytes in the distal humerus were significantly smaller in the muscle-less limbs than in controls, while by TS27, chondrocyte volume was similar between the two groups, offering a cell-level mechanism for the partial recovery in shape of muscle-less limbs. Mineralisation showed the most pronounced changes over gestation. At TS24, all muscle-less rudiments studied had less mineralisation than the controls, while at TS27, muscle-less limb rudiments had mineralisation extents equivalent to controls. In conclusion, the effects of muscle absence on prenatal murine skeletogenesis reduced in severity over gestation. Understanding how mammalian bones and joints continue to develop in an environment with abnormal fetal movements provides insights into conditions including hip dysplasia and arthrogryposis.
Godivier J, Lawrence EA, Wang M, et al., 2022, Growth orientations, rather than heterogeneous growth rates, dominate jaw joint morphogenesis in the larval zebrafish, JOURNAL OF ANATOMY, Vol: 241, Pages: 358-371, ISSN: 0021-8782
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- Citations: 1
Nowlan N, Ahmed S, Kaimaki DM, et al., 2021, Prenatal muscle forces are necessary for vertebral segmentation and disc structure, but not for notochord involution in mice, European Cells and Materials, Vol: 41, Pages: 558-575, ISSN: 1473-2262
Embryonic muscle forces are necessary for normal vertebral development and spinal curvature, but their involvement in intervertebral disc (IVD) development remains unclear. The aim of the current study was to determine how muscle contractions affect (1) notochord involution and vertebral segmentation, and (2) IVD development including the mechanical properties and morphology, as well as collagen fibre alignment in the annulus fibrosus. Muscular dysgenesis (mdg) mice were harvested at three prenatal stages: at Theiler Stage (TS)22 when notochord involution starts, at TS24 when involution is complete, and at TS27 when the IVD is formed. Vertebral and IVD development were characterised using histology, immunofluorescence, and indentation testing. Our results revealed that notochord involution and vertebral segmentation occurred independently of muscle contractions between TS22 and TS24. However, in the absence of muscle contractions, we found vertebral fusion in the cervical region at TS27, along with (i) a displacement of the nucleus pulposus towards the dorsal side, (ii) a disruption of the structural arrangement of collagen in the annulus fibrosus, and (iii) an increase in viscous behaviour of the annulus fibrosus. These findings emphasise the important role of mechanical forces during IVD development, and demonstrate a critical role of muscle loading during development to enable proper annulus fibrosus formation. Our findings further suggest a need for mechanical loading in the creation of fibre-reinforced tissue engineering replacement IVDs as a therapy for IVD degeneration.
Khatib N, Parisi C, Nowlan N, 2021, Differential effect of frequency and duration of mechanical loading on fetal chick cartilage and bone development, European Cells and Materials, Vol: 41, Pages: 531-545, ISSN: 1473-2262
Developmental engineering strategies aim to recapitulate aspects of development in vitro as a means to form functional engineered tissues, including cartilage and bone for tissue repair and regeneration. Biophysical stimuli arising from fetal movements are critical for guiding skeletogenesis, but there have been few investigations of the biomechanical parameters which optimally promote cartilage and bone development events in in vitro explants. In this study, we quantitatively and qualitatively assessed the effect of applied flexion-extension movement frequencies (0.33 and 0.67 Hz) and durations (2 h periods, once, twice or three times per day) on knee (stifle) joint cartilage shape, chondrogenesis and diaphyseal mineralisation of fetal chick hindlimbs cultured in a mechanostimulation bioreactor. It was hypothesised that increasing frequency and duration of movements would synergistically promote cartilage and bone formation in a dose-dependent manner. Increasing loading duration promoted cartilage growth, shape development and mineralisation of the femoral condyles and tibiotarsus. While increasing frequency had a significant positive effect on mineralisation, hyaline cartilage growth and joint shape were unaffected by frequency change within the ranges assessed, and there were limited statistical interactions between the effects of movement frequency and duration on cartilage or bone formation. Increased glycosaminoglycan deposition and cell proliferation may have contributed to the accelerated cartilage growth and shape change under increasing loading duration. The results demonstrate that frequencies and durations of applied biomechanical stimulation differentially promoted cartilage and bone formation, with implications for developmentally inspired tissue engineering strategies aiming to modulate tissue construct properties.
Pierantoni M, Le Cann S, Sotiriou V, et al., 2021, Muscular loading affects the 3D structure of both the mineralized rudiment and growth plate at early stages of bone formation, BONE, Vol: 145, ISSN: 8756-3282
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- Citations: 5
Bridglal DL, Boyle CJ, Rolfe RA, et al., 2021, Quantifying the tolerance of chick hip joint development to temporary paralysis and the potential for recovery, DEVELOPMENTAL DYNAMICS, Vol: 250, Pages: 450-464, ISSN: 1058-8388
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- Citations: 6
Lawrence EA, Aggleton J, van Loon J, et al., 2021, Exposure to hypergravity during zebrafish development alters cartilage material properties and strain distribution, BONE & JOINT RESEARCH, Vol: 10, Pages: 137-148, ISSN: 2046-3758
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- Citations: 6
Ghosh AK, Balasubramanian S, Devasahayam S, et al., 2020, Detection and Analysis of Fetal Movements Using an Acoustic Sensor-based Wearable Monitor, Pages: 512-516
Monitoring of fetal movements (FM) is considered an important part of fetal well-being assessment due to its association with several fetal health conditions, e.g. fetal distress, fetal growth restriction, hypoxia, etc. However, the current standard methods of FM quantification, e.g. ultrasonography, MRI, and cardiotocography, are limited to their use in clinical environments. In this paper, we evaluate the performance of an acoustic sensor-based, cheap, wearable FM monitor that can be used by pregnant women at home. For data analysis, we develop a thresholding-based signal processing algorithm that fuses outputs from all the sensors to detect FM automatically. Obtained results demonstrate the promising performance of the system with a sensitivity, specificity, and accuracy of 83.3%, 87.8%, and 87.1%, respectively, relative to the maternal sensation of FM. Finally, a spike-like morphology of acoustic signals corresponding to true detected movements is found in the time-frequency domain through spectrogram analysis, which is expected to be useful for developing a more advanced signal processing algorithm to further improve the accuracy of detection.
Silva Barreto I, Le Cann S, Ahmed S, et al., 2020, Multiscale characterization of embryonic long bone mineralization in mice, Advanced Science, Vol: 7, Pages: 1-13, ISSN: 2198-3844
Long bone mineralization occurs through endochondral ossification, where a cartilage template mineralizes into bone‐like tissue with a hierarchical organization from the whole bone‐scale down to sub‐nano scale. Whereas this process has been extensively studied at the larger length scales, it remains unexplored at some of the smaller length scales. In this study, the changes in morphology, composition, and structure during embryonic mineralization of murine humeri are investigated using a range of high‐resolution synchrotron‐based imaging techniques at several length scales. With micro‐ and nanometer spatial resolution, the deposition of elements and the shaping of mineral platelets are followed. Rapid mineralization of the humeri occurs over approximately four days, where mineral to matrix ratio and calcium content in the most mineralized zone reach adult values shortly before birth. Interestingly, zinc is consistently found to be localized at the sites of ongoing new mineralization. The mineral platelets in the most recently mineralized regions are thicker, longer, narrower, and less aligned compared to those further into the mineralized region. In summary, this study demonstrates a specific spatial distribution of zinc, with highest concentration where new mineral is being deposited and that the newly formed mineral platelets undergo slight reshaping and reorganization during embryonic development.
Ghosh AK, Burniston SF, Krentzel D, et al., 2020, A novel fetal movement simulator for the performance evaluation of vibration Sensors for wearable fetal movement monitors, Sensors, Vol: 20, ISSN: 1424-8220
Fetal movements (FM) are an important factor in the assessment of fetal health. However, there is currently no reliable way to monitor FM outside clinical environs. While extensive research has been carried out using accelerometer-based systems to monitor FM, the desired accuracy of detection is yet to be achieved. A major challenge has been the difficulty of testing and calibrating sensors at the pre-clinical stage. Little is known about fetal movement features, and clinical trials involving pregnant women can be expensive and ethically stringent. To address these issues, we introduce a novel FM simulator, which can be used to test responses of sensor arrays in a laboratory environment. The design uses a silicon-based membrane with material properties similar to that of a gravid abdomen to mimic the vibrations due to fetal kicks. The simulator incorporates mechanisms to pre-stretch the membrane and to produce kicks similar to that of a fetus. As a case study, we present results from a comparative study of an acoustic sensor, an accelerometer, and a piezoelectric diaphragm as candidate vibration sensors for a wearable FM monitor. We find that the acoustic sensor and the piezoelectric diaphragm are better equipped than the accelerometer to determine durations, intensities, and locations of kicks, as they have a significantly greater response to changes in these conditions than the accelerometer. Additionally, we demonstrate that the acoustic sensor and the piezoelectric diaphragm can detect weaker fetal movements (threshold wall displacements are less than 0.5 mm) compared to the accelerometer (threshold wall displacement is 1.5 mm) with a trade-off of higher power signal artefacts. Finally, we find that the piezoelectric diaphragm produces better signal-to-noise ratios compared to the other two sensors in most of the cases, making it a promising new candidate sensor for wearable FM monitors. We believe that the FM simulator represents a key development towards enabl
Lai J, Nowlan NC, Vaidyanathan R, et al., 2020, The use of actograph in the assessment of fetal well-being, Journal of Maternal-Fetal and Neonatal Medicine, Vol: 33, Pages: 2116-2121, 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
Nowlan N, Ahmed S, 2020, Initiation and emerging complexity of the collagen network during prenatal skeletal development, European Cells and Materials, Vol: 39, Pages: 136-155, ISSN: 1473-2262
The establishment of a complex collagen network is critical for the architecture and mechanical properties of cartilage and bone. However, when and how the key collagens in cartilage and bone develop has not been characterised in detail. The study provides a detailed qualitative characterisation of the spatial localisations of collagens I-III, V-VI and IX-XI in the mouse and their regional architecture variation over three developmentally significant time points: when the rudiment starts to form at E13.5 [Theiler stage (TS) 22], when mineralisation is present at E16.5 (TS25) and during the latest prenatal stage at E18.5 (TS27). Dynamic changes in collagen distribution between stages with the progression of the growth plate and mineralisation (particularly collagens I, II, V, X and XI) and dramatic changes in collagen structural organisation and complexity with maturation, especially for collagens II and XI, were observed. The future articular cartilage region was demarcated by pronounced collagens II and VI expression at TS27 and the emergence of collagens I, III, V, IX and XI in the tendon and its insertion site was observed. The present study revealed, for the first time, the emergence and maturation of key cartilage and bone collagens, in high resolution, at multiple locations across the entire rudiment, including the joint regions, at three of the most developmentally significant stages of skeletogenesis, furthering the understanding of disease and regeneration of skeletal tissues.
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.
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., European Cells and Materials, Vol: 37, Pages: 23-41, ISSN: 1473-2262
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, Pages: 1-11, ISSN: 1932-6203
Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63μm) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions computed from repeated images were found for both epiphyses (between 1.3μm and 1.4μm for the proximal tibia and between 0.7μm and 1.0μm for the femur, along all directions). The protocol was found to be reproducible with maximum Modified Housdorff Distance (MHD) differences equal to 1.9 μm and 1.5 μm for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps with MHD of 21.7 μm and 21.9 μm for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors.
Ahmed S, Nowlan NC, 2018, Dynamic expression of matrix components during skeletal development, Matrix Biology Europe Meeting, Publisher: WILEY, Pages: A19-A19, ISSN: 0959-9673
Ahmed S, Nowlan NC, 2018, Mechanical forces determine the spatial and temporal organisation of essential collagens in the developing skeleton, Matrix Biology Europe Meeting, Publisher: WILEY, Pages: A65-A65, ISSN: 0959-9673
Nowlan NC, Francis-West P, Nelson C, 2018, Mechanics of development Introduction, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol: 373, Pages: 1-3, 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.
Giorgi M, Sotiriou V, Fanchini N, et al., 2018, Prenatal growth map of the mouse knee joint by mean of deformable registration technique
<jats:title>Abstract</jats:title><jats:p>Joint morphogenesis is the process during which distinct and functional joint shapes emerge during pre- and post-natal joint development. In this study, a repeatable semi-automatic protocol capable of providing a 3D realistic developmental map of the prenatal mouse knee joint was designed by combining Optical Projection Tomography imaging (OPT) and a deformable registration algorithm (Sheffield Image Registration toolkit, ShIRT). Eleven left limbs of healthy murine embryos were scanned with OPT (voxel size: 14.63¼m) at two different stages of development: Theiler stage (TS) 23 (approximately 14.5 embryonic days) and 24 (approximately 15.5 embryonic days). One TS23 limb was used to evaluate the precision of the displacement predictions for this specific case. The remaining limbs were then used to estimate Developmental Tibia and Femur Maps. Acceptable uncertainties of the displacement predictions were found for both epiphyses (between 0.7 and 1.4 μm, along all directions and anatomical sites) for nodal spacing of 1 voxel. The protocol was found to be reproducible with maximum Modified Housdorff Distance differences equal to 1.9 μm and 1.5 μm for the tibial and femoral epiphyses respectively. The effect of the initial shape of the rudiment affected the developmental maps by 21.7 μm and 21.9 μm for the tibial and femoral epiphyses respectively, which correspond to 1.4 and 1.5 times the voxel size. To conclude, this study proposes a repeatable semi-automatic protocol capable of providing mean 3D realistic developmental map of a developing rudiment allowing researchers to study how growth and adaptation are directed by biological and mechanobiological factors.</jats:p>
Lai J, Woodward R, Alexandrov Y, et al., 2018, Performance of a wearable acoustic system for fetal movement discrimination, PLoS One, Vol: 13, Pages: 1-14, 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, 2018, 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, Pages: 1-11, 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, 2017, The Role of Mechanosensitive Ion Channels in Mechanoregulation of Prenatal Joint Morphogenesis, ORS2018
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