Biology subjects

Dunne, N.

Publications and source records attributed to Dunne, N..

3 recordsLinked to original sources

bioRxiv2024

Embryo movement is required for limb tendon maturation

Following early cell specification and tenocyte differentiation at the sites of future tendons, very little is known about how tendon maturation into robust load-bearing tissue is regulated. Between embryonic day (E)16 and E18 in the chick, there is a rapid change in mechanical properties which is dependent on normal embryo movement. However, the tissue, cellular and molecular changes that contribute to this transition are not well defined. Here we profiled aspects of late tendon development (collagen fibre alignment, cell organisation and Yap pathway activity), describing changes that coincide with tissue maturation. We compared effects of rigid (constant static loading) and flaccid (no loading) immobilisation to gain insight into developmental steps influenced by mechanical cues. We show that YAP signalling is active and responsive to movement in late tendon. Collagen fibre alignment increased over time and under static loading. Cells organise into end-to-end stacked columns with increased distance between adjacent columns, where collagen fibres are deposited; this organisation was lost following both types of immobilisation. We conclude that specific aspects of tendon maturation requires controlled levels of dynamic muscle-generated stimulation. Such a developmental approach to understanding how tendons are constructed will inform future work to engineer improved tensile load-bearing tissues.

developmental biology↗

bioRxiv2023

Structural Determinants of Tendon Function During Development and Their Sensitivity to Mechanical Stimulation

The load-bearing capabilities of tendon are acquired during neonatal stages of development, characterized by an abrupt increase in multiscale mechanical properties. While prior work has identified numerous changes within the collagenous structure during these developmental periods, the primary structural elements that give rise to this abrupt mechanical functionality, and their mechanobiological sensitivity, remains unclear. To address this gap in knowledge, we leveraged a combination of ultrastructural imaging, biochemical/thermodynamic assays, multiscale mechanical testing, and shear lag modeling to probe the dynamic structure-function relationships and establish their sensitivity to mechanical stimulation during tenogenesis. Mechanical testing and modeling suggested that the rapid increase in multiscale mechanics can be explained by a increasing fibril length and intrafibrillar crosslinking. To test this, we inhibited collagen crosslinking during development and observed a drastic reduction in multiscale mechanical capabilities that was explained by a reduction in both fibril modulus and length. Using muscle paralysis to investigate mechanosensitivity, we observed a significantly impaired multiscale mechanical response despite small changes in fibril diameter and fibril area fraction. While there was no change in crosslinking density, there was a decrease in thermal stability with flaccid paralysis, and our shear-lag model suggested that flaccid paralysis produces a reduction in fibril length and intrafibrillar crosslinking. Together, these data suggest that both intrafibrillar crosslink formation and fibril elongation are critical to the formation of load-bearing capabilities in tenogenesis and are sensitive to musculoskeletal activity. These findings provide critical insights into the biological mechanisms that give rise to load-bearing soft tissue.

bioengineering↗

bioRxiv2019

Multi-objective optimisation of material properties and strut geometry for poly(L-lactic acid) coronary stents using response surface methodology

Coronary stents for treating atherosclerosis are traditionally manufactured from metallic alloys. However, metal stents permanently reside in the body and may trigger undesirable immunological responses. Bioresorbable polymer stents can provide a temporary scaffold that resorbs once the artery heals but are mechanically inferior, requiring thicker struts for equivalent radial support, which may increase thrombosis risk. This study addresses the challenge of designing mechanically effective but sufficiently thin poly(L-lactic acid) stents through a computational approach that optimises material properties and stent geometry. Forty parametric stent designs were generated: cross-sectional area (post-dilation), foreshortening, stent-to-artery ratio and radial collapse pressure were evaluated computationally using finite element analysis. Response surface methodology was used to identify performance trade-offs by formulating relationships between design parameters and response variables. Multi-objective optimisation was used to identify suitable stent designs from approximated Pareto fronts and an optimal design is proposed that offers comparable performance to designs in clinical practice. In summary, a computational framework has been developed that has potential application in the design of high stiffness, thin strut polymeric stents that contend with the performance of their metallic counterparts.

bioengineering↗