Variations in fracture healing due to age-dependent changes in the adaptation of immune cells towards the hypoxic environment of the fracture gap

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Today about 20% of the people in Germany are of age 65 or higher with a tendency towards an increasing frequency for the next decades. In 2060 every third will be aged 65 or older. This demographic development will lead to a higher incidence of surgical interventions (such as fracture treatment and arthroplasty) as a result of an impaired or delayed bone healing, a degenerative joint disease, osteoarthrosis or osteoporosis. Therefore, we have an unconditional need to better recognize and understand the cause of an impaired or delayed bone healing in order to develop early diagnosis and an efficient therapy. The initial inflammatory phase of fracture healing is of great importance for clinical outcome while setting the course for the follow-up phases the initial phase is inducing angiogenesis and osteogenesis. Compromising the initial inflammatory phase due to immunosuppression or due to aging-dependent immune senescence results in an impaired or delayed bone healing. Our data and studies from other research groups support the hypothesis that efficacy and quality of fracture healing strongly depends on the bioenergetic adaptation of participating immune cells to the pathophysiological hypoxic environment (<2%O2) in the fracture gap. To address this hypothesis, we will examine cellular and humoral composition of the early fracture hematoma (6h-72h) and its impact on the functionality on immune cells with regard to the age of the patients. Moreover, we will analyze and quantify the age-dependent changes of monocytes and T cells in cellular bioenergetic adaptation towards a hypoxic microenvironment focusing on hypoxia-mediated hypoxia-inducible factor (HIF) pathways. We hypothesize that an increase of age leads to a decrease of cellular adaptation towards hypoxia which results in (i) an augmented innate and/or adaptive effector immune response (in eg. monocytes, neutrophils and CTL, Th17, Th1, respectively) while (ii) control of effector response by regulatory immune cells (eg. Treg) is compromised. Therefore, we further assume that promotion of cellular adaptation towards pathophysiological hypoxia could normalize an aging-dependent excessive and/or deregulated immune response. In a proof-of-principle approach, we aim to force the cellular adaptation towards hypoxia in immune cells of aged donors by using chemical stabilization of HIFs.