International 3Rs Prize now open for applications. £30k prize (£2k personal award) for outstanding science with demonstrable 3Rs impacts.

NC3Rs | 20 Years: Pioneering Better Science
PhD Studentship

Creating an in vitro model of pathogenic ossification to explore methods for dispersion

""

At a glance

Completed
Award date
July 2014 - July 2017
Grant amount
£90,000
Principal investigator
Professor Liam Grover

Co-investigator(s)

Institute
University of Birmingham

R

  • Replacement
Read the abstract
View the grant profile on GtR

Contents

Application abstract

Pathological ossification can occur as a symptom of disease (ankylosing spondylitis) or following trauma due to surgery or following exposure to an explosion. The ossification that occurs is frequently very painful and requires resection of the affected tissue or in the case of less severe mineralisation, temporary immobilisation. In some cases, such as the mineralised ligament and tendon in AS, there is no real adequate treatment and the patient permanently loses mobility. The aetiology of many of these ossifications is unclear and this partly due to our inability to probe factors that may influence hard tissue formation in the existing animal models. Currently, in vivo models of mineralisation rely on the production of a modified mouse strain that overexpresses bone morphogenic protein and is prone to pathological mineralisation. These animals can require physical injury in order to induce the formation of the ossification and clearly this, in addition to the chronic debilitating effects of the ossification, mean that the animals endure significant suffering during their lifetime. Furthermore, the animal models that are used provide a poor approximation of the mineralisation that can occur in a human patient. Mice, for example, have a considerably higher rate of metabolism than humans and can be more refractory. In addition, the absolute volume of bone formation is typically significantly lower. This means that the nature of the newly formed mineral in the mouse differs from the mature bone that can be found in cases of heterotopic ossification. The proposed project would develop an in vitro model of pathological mineralisation, so that we can improve on existing animal models, eventually eliminating the need for them. The model will also enable us to systematically investigate the factors that might influence hard tissue formation. It will also help us to evaluate how existing drugs and other treatments may be used to disperse the ossification.

Impacts

Publications

  1. Iordachescu A et al. (2019). Organotypic Culture of Bone‐Like Structures Using Composite Ceramic‐Fibrin Scaffolds. Current Protocols in Stem Cell Biology 48(1): e79. doi:10.1002/cpsc.79
  2. Iordachescu A et al. (2018). A novel method for the collection of nanoscopic vesicles from an organotypic culture model. RSC advances 8(14):7622-7632. doi: 10.1039/C7RA12511A
  3. Iordachescu A et al. (2017). An In Vitro Model for the Development of Mature Bone Containing an Osteocyte Network. Advanced Biosystems 1(12):1700156. doi: 10.1002/adbi.201700156
  4. Eisenstein NM et al. (2016). Bedside, Benchtop, and Bioengineering: Physicochemical Imaging Techniques in Biomineralization. Advanced Healthcare Materials 5(5):507-28. doi: 10.1002/adhm.201500617
  5. Hulley PA et al. (2015). Hypoxia-inducible factor 1-alpha does not regulate osteoclastogenesis but enhances bone resorption activity via prolyl-4-hydroxylase 2. The Journal of Pathology 242(3):322-333. doi: 10.1002/path.4906
  6. Wudebwe UN et al. (2015). Exploiting cell-mediated contraction and adhesion to structure tissues in vitro. Phil. Trans. R. Soc. B. 370(1661):20140200. doi: 10.1098/rstb.2014.0200