The cytokines and micro-environment of fracture haematoma: Current evidence

Fracture haematoma formation is the first and foremost important stage of fracture healing. It orchestrates the inflammatory and cellular processes leading to the formation of callus and the restoration of the continuity of the bone. Evidence suggests that blocking this initial stage could lead to an impairment of the overall bone healing process. This review aims to analyse the existing evidence of molecular contributions to bone healing within fracture haematoma and to determine the potential to modify the molecular response to fracture in the haematoma with the aim of improving union times. A comprehensive search of literature documenting fracture haematoma cytokine content was performed. Suitable papers according to prespecified criteria were identified and analysed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. A total of 89 manuscripts formed the basis of this analysis. Low oxygen tension, high acidity, and high calcium characterised initially the fracture haematoma micro-environment. In addition, a number of cytokines have been measured with concentrations significantly higher than those found in peripheral circulation. Growth factors have also been isolated, with an observed increase in bone morphogenetic proteins, platelet-derived growth factor, and transforming growth factor. Although molecular modification of fracture haematoma has been attempted, more research is required to determine a suitable biological response modifier leading to therapeutic effects. The cytokine content of fracture haematoma gives insight into processes occurring in the initial stages of fracture healing. Manipulation of signalling molecules represents a promising pathway to target future therapies aiming to upregulate the osteogenesis.