Listen to Niamh discuss her path to research and how it was influenced by her own orthopaedic conditions, and her career so far from 🇮🇪 to 🇺🇸 to 🇪🇸 to 🇬🇧 to 🇮🇪 . Part of the UCD Conway Institute‘s CLASS Acts podcast series. Thanks to Dr Eoin Cummins for being an expert interviewer!
The Developmental Biomechanics Group finally met in person again in November 2021, when the London contingent travelled to Dublin for three days. The retreat kicked off with a beautiful hike around Howth Head on a windy but lovely and sunny day. James kept Niamh distracted from the steep cliff edges and Kinder Buenos kept the blood sugar levels up. The walk was nicely rounded off by some traditional fish and chips at the harbour. The next two days were filled with in-depth updates from the seasoned group members. It was so great to be together again and discuss all the exciting data everyone has been gathering over the pandemic.
In the paper we investigated how frequency and duration of loading affect cartilage and bone development. We used an in vitro explant culture system to culture embryonic chick limb explants under a range of loading regimes in which the amount of loading and the frequency were systematically varied. We found that increasing the duration (amount) of loading promoted cartilage growth, shape development and mineralisation of the femur and tibiotarsus. However, varying frequency only had significant effects on mineralisation, and not on cartilage growth or shape. Increased glycosaminoglycan deposition and cell proliferation may have contributed to the accelerated cartilage growth and shape change under increasing loading duration. The results demonstrated 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.
The work described in this paper was funded by an ERC Starting Grant. Congratulations Nidal and Cristian!
Aurélie‘s paper, together with Saima, Stephanie and Seb, and our lovely collaborators from the Evolutionary Biomechanics group at Imperial College and Prof James Iatridis from the Icahn School of Medicine at Mount Sinai, has been published in European Cells & Materials (eCM).
In previous papers by Aurélie, Rebecca and others, we demonstrated that muscle loading is needed for normal development of the spine, including spinal curvature, vertebral shape and vertebral segmentation in the chick embryo. However, the chick embryo does not have the same type of discs as humans (or mammals in general) as it lacks a nucleus pulposus. Therefore, we needed to switch to the mouse to look at the influence of muscles on development of the discs. Our usual mouse line of choice (splotch delayed) wasn’t suitable due to the fact that spine development and vertebral segmentation is known to be abnormal in this line. Therefore we used the “mdg” or muscular dysgenesis line (with grateful thanks to Prof Eli Zelzer, Weizmann Institute) in which skeletal muscles form but do not contract.
In this paper, we investigated how muscle forces affect (1) notochord involution and vertebral segmentation, and (2) intravertebral disc (IVD) development including the mechanical properties and morphology, as well as collagen fibre alignment in the annulus fibrosus. We looked at three different stages of development; 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. We found 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. Therefore, mechanical loading due to muscle contractions are important for the later stages of disc development, particularly for annulus fibrosus formation. We believe our results suggest a need for mechanical loading in the creation of fibre-reinforced tissue engineering replacement IVDs as a therapy for IVD degeneration.
The research described in this paper was funded by the Leverhulme Trust and by an ERC Starting Grant.
Dr Nowlan has accepted a Professorship position in the School of Mechanical and Materials Engineering at University College Dublin (UCD), Ireland, with effect from January 2021. Her web profile at UCD can be found here. For the next few years, the Developmental Biomechanics group will be split between London and Ireland, with plenty of travel between (once feasible). Niamh is excited about this new opportunity and for what the future holds for the research group and programme!
Congratulations to Devi (together with collaborators Rebecca and Colin Boyle) on publication of her paper entitled “Quantifying the tolerance of chick hip joint development to temporary paralysis and the potential for recovery” in Developmental Dynamics.
In this paper, we wanted to discover when- and for how long- fetal movements are most important for development of the hip joint, in order to better understand conditions affecting the skeletons of babies who may have had restricted or reduced movements in utero, including developmental dysplasia of the hip (where the hip joint is unstable) and arthrogryposis (multiple joint contractures). We also wanted to know if joint development can be “rescued” by external manipulation even when immobilised.
We varied the initiation and duration of drug-induced paralysis in the chick embryo, and found that a three day period between 4 and 7 embryonic days was most important for hip joint shape. In terms of hip joint development, this timeline is equivalent to roughly 10 to 12 gestational weeks in humans, and means that the end of the first trimester would be a useful time for targeted screening for arthrogryposis and hip dysplasia. We found that cavitation was more dependent on duration of paralysis, rather than timing.
When we externally manipulated the immobilised chick limbs, the hip joints had more normal shapes, and more normal progression of cavitation, compared to the contralateral limbs of the same chicks. This implies that the developing limb has the potential to recover from periods of immobility, and external manipulation provides an innovative avenue for prevention and treatment of developmental joint pathologies.
The full paper is available open-access here. The research was funded by ERC Starting Grant #336306.
Huge congratulations to Vivien (soon to be Dr Sotiriou) for passing her PhD viva in September 2020! Thank-you to the examiners Prof Malcolm Logan from King’s College London and Dr Neal Bangerter for a thoughtful and in-depth virtual viva. Thanks also to the group and alumni who joined the virtual celebrations afterwards!
Saima is leaving our group and we will miss her so much! We are excited however to continue working on all the lovely data and papers in preparation. Saima will start studying medicine in the Autumn, and we wish her the very best in her studies.
Saima‘s paper funded by the ERC characterising the collagens in the developing skeletal rudiment was published in eCM. We used immuno-fluorescence to look at the major and minor collagens in sections of the humerus at TS22 (e13.5, before formation of the primary ossification centre), TS25 (e15.5) and TS27 (e17.5).
Several collagens change substantially with the progression of the ossification centre, like for example Col V.
Some develop amazingly complex structures over the period of development studied, like Col II (green) and XI (grey).
Congratulations Saima on this beautiful work!
Big congratulations to Devi, who passed her PhD viva. Her thesis is entitled “The role of movement in early embryonic joint development”. Many thanks to the examiners, Prof Neil Vargesson and Dr Angela Kedgley. Devi is now studying graduate entry medicine at King’s College London so will be a double-doctor in a few years time! Well done Devi!