Biofidelic simulations of embryonic joint growth and morphogenesis

Abstract

During skeletal development, the opposing surfaces in the joint mould into interlocking and reciprocal shapes in a process called morphogenesis. Morphogenesis is critical to the health and function of the joint, and yet, little is known about the process of joint morphogenesis. For example, how do different joints acquire their specific shapes? Which cellular processes underlie joint shaping and how are they regulated? However, it is known that fetal movements are critical to joint development, with alterations or absences of movement being implicated in multiple pre- and post-natal musculoskeletal conditions. This doctorate explored the cell-level dynamics governing joint growth and the implication of movements in regulating them, using novel biofidelic and mechanobiological models of joint growth. Cell-level data from wild type zebrafish larvae were tracked and synthesised in a biofidelic simulation of zebrafish jaw joint growth. Growth characteristics were quantified revealing a strong anisotropy (Chapter 3). Next, zebrafish larvae were immobilised using drug treatment. The material properties of the zebrafish jaw cartilage were measured using nano-indentation in the presence or absence of movement showing a delay in cartilage stiffening in immobilised larvae (Chapter 4). Then, I developed a novel mechanobiological model of zebrafish jaw joint growth, which identified a correlation between growth characteristics and the dynamic patterns of mechanical stimuli experienced by joint elements over jaw motion (Chapter 5). Finally, local growth rates were characterised in the mouse elbow in the presence or absence of skeletal muscles. Spatial heterogeneity in the growth rates correlated with the emergence of specific shape features at the level of the condyles. Immobilisation led to disruption of the local growth rates correlated with failed shape differentiation of the condyles. The relative contribution of key cell activities to growth such as cell volume expansion, cell number increases and extracellular matrix expansion, were shown to vary over time in both wild types and muscleless-limbs and to be altered in the absence of skeletal muscles (Chapter 6). This research offers avenues for improvement in simulations of joint development and potentially other organs. It provides fundamental advance in our understanding of mechanoregulation in the developing joint and increases our understanding of the origins of musculoskeletal abnormalities.