A review of the biomarkers and in vivo models for the diagnosis and treatment of heterotopic ossification following blast and trauma-induced injuries.

Heterotopic ossification (HO) is the process of de novo bone formation in non-osseous tissues. HO can occur following trauma and burns and over 60% of military personnel with blast-associated amputations develop HO. This rate is far higher than in other trauma-induced HO development. This suggests that the blast effect itself is a major contributing factor, but the pathway triggering HO following blast injury specifically is not yet fully identified. Also, because of the difficulty of studying the disease using clinical data, the only sources remain the relevant in vivo models. The aim of this paper is first to review the key biomarkers and signalling pathways identified in trauma and blast induced HO in order to summarize the molecular mechanisms underlying HO development, and second to review the blast injury in vivo models developed. The literature derived from trauma-induced HO suggests that inflammatory cytokines play a key role directing different progenitor cells to transform into an osteogenic class contributing to the development of the disease. This highlights the importance of identifying the downstream biomarkers under specific signalling pathways which might trigger similar stimuli in blast to those of trauma induced formation of ectopic bone in the tissues surrounding the site of the injury. The lack of information in the literature regarding the exact biomarkers leading to blast associated HO is hampering the design of specific therapeutics. The majority of existing blast injury in vivo models do not fully replicate the combat scenario in terms of blast, fracture and amputation; these three usually happen in one insult. Hence, this paper highlights the need to replicate the full effect of the blast in preclinical models to better understand the mechanism of blast induced HO development and to enable the design of a specific therapeutic to supress the formation of ectopic bone.