Application deadline: 3rd March
Interviews to be held: 31 March 2021
The first semester of this project will be based at the University of Manchester and the remaining duration will be based at the University Sheffield as this CDT is a partnership between the two universities.
Globally, musculoskeletal (MSK) conditions are the leading contributor to disability and are commonly linked with depression and negative impacts on quality of life. MSK conditions have a significant economic impact worldwide and their prevalence is predicted to rise with an increasingly ageing global population.
Currently drug treatments for MSK conditions are screened using monocultures or, at best, co-cultures of cells growing in monolayers in vitro. However, the cell-cell and cell-matrix interactions within the tissues together with the differing mechanical and structural properties of these tissues at the interface between muscle, bone and cartilage mean that monolayer models fail to capture these interactions. MSK ageing also induces extracellular matrix changes but simple 2D monocultures are incapable of recapitulating these changes in any meaningful way. As a consequence, researchers often turn to animal models. However, important differences in size, anatomy and biomechanics limit their relevance and hinder successful outcomes in the MSK drug development.
Attempts to develop 3D models have been described in the literature, but success in this area is limited with many versions incorporating the cells from only one tissue type and therefore omitting the interactions between cell types. There is therefore an unmet need for a reliable, biologically relevant in vitro model of the MSK interface that can reduce and replace animal models, reflect the ageing process and thereby accelerate the development of MSK treatments.
Main questions to be answered
The project will build an in vitro MSK model containing three tissue types: bone, cartilage and muscle. Cells will be grown on 3D microporous polyHIPE (polymerised high internal phase emulsions) scaffolds, with graded mechanical properties to mimic those of the tissues. Electrospun, cell impermeable barriers will be used between regions of polyHIPE to limit cell infiltration while still allowing cell signalling to occur to ensure spatially controlled growth of cells. This will allow us to answer the following:-
1. Can a model be constructed which recapitulates the basic physiology of bone, muscle and cartilage? This will be assessed through (i) cell metabolic activity and proliferation, (ii) expression of relevant chondrogenic, osteogenic and muscle gene expression, appropriate extracellular matrix (ECM) production and mineralisation (for bone model), (iii) histological evaluation, (iv) cell imaging
2. Can ageing by induced through exposure to compounds known to promote the process of ageing? Advanced glycation endproducts (AGEs) and reactive oxygen species (ROS) are produced spontaneously during metabolism. They play important roles in MSK ageing in vivo and in vitro.
3. Can the healthy and aged models be used to asses cell response to compounds used in MSK treatments e.g. ibuprofen, known to reduce bone healing and cartilage synthesis; and vitamin D, which may affect bone and cartilage regeneration?
EPSRC Centre for Doctoral Training in Advanced Biomedical Materials
This project is part of the EPSRC Centre for Doctoral Training in Advanced Biomedical Materials. All available projects are listed here.
Find out how to apply, with full details on eligibility and funding here.
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