Project Details
Projekt
Influence of age and alcohol intoxication on fracture healing and the regenerative potential after trauma-hemorrhage in a murine model
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
from 2014 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 250170148
Multiple trauma is frequently associated with (trauma-)hemorrhage and fractures of the extremities. These patients show in the clinicalsetting a higher rate of impaired fracture healing (delayed healing and non-union) compared to those patients sustaining isolated fractures. In the previous project we analyzed the effect of trauma-hemorrhage on fracture healing. In detail the fracture healing was investigated over a period of 7, 14, 21, 28 and 42 days in vivo in a murine model consisting of a femur osteotomy with or without trauma-hemorrhage. In this study we were able to show that the impact of trauma-hemorrhage on fracture healing was massive compared with an isolated fracture healing. In detail we observed in the combined trauma group after 2 weeks: 1) a delayed fracturehealing analyzed by macroscopic analyses and X-ray, 2) a significant lower density of bone including callus as well as a significant higher share of callus/ volume of bone mass analyzed by μCT, 3) significantly reduced maximum bending moment in the three-point-bending test, 4) significant less bone and cartilage, but more soft tissue and bone marrow analyzed by histology, 5) and an activation of the IL6 and OPG/RANKL signaling pathways. These results demonstrate that a hemorrhagic shock had a negative effect on fracture healing after surgery in a murine model. However, in this project young, healthy male mice were analyzed, which does not mimic the clinical scenario with regard to age; but neither to important other healing-influencing factors such as alcohol use. The relevance of acute alcohol intoxication, as frequently observed in traumatized patients, on regenerative potential of fractures remains unknown. The aim of the present study is to answer the following hypotheses in a combination of trauma-hemorrhage and osteotomy of the femur compared to isolated osteotomy of the femur: 1. Hypothesis: With increasing age the local capacity for fracture healing (histology), and therefore the biomechanical stability (μCT analysis, three-point-bending test), or the general capacity for regeneration is decreased. 2. Hypothesis: With increasing age a loss of immune competence of the monocytes and neutrophil granulocytes, as a marker for the systemic immunological status quo, can be determined, which has negative effects on fracture healing. 3. Hypothesis: Acute intoxication with alcohol impairs the age-dependent loss of the local regenerative capacity and fracture healing after trauma via inhibition of Nf-kappaB and the subsequent inhibition of the inflammatory response. 4. Hypothesis: Acute intoxication with alcohol impairs the first line of immune defense consisting of monocytes and neutrophil granulocytes, as markers for systemic immunological status quo leading to an alcohol-induced healing disorder synergistically with increasing age.
DFG Programme
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