MaNGA – Methods against Non-Union: from Grassroots to clinical Application, subproject "Determination of local vascularization for diagnosis of (low-grade) infected non-union"

Status:

ongoing

Aims:

Aseptic and septic non-union require different therapeutic approaches and, sometimes, diametrically opposed surgical procedures. Therefore, early and ideally preoperative identification of the underlying cause of the non-union is an important step in optimizing treatment. Currently, however, it is not possible to definitively determine preoperatively whether a non-union is due to infection or not. This can only be determined postoperatively after analyzing intraoperative tissue samples from the non-union zone. However, even the current intraoperative methods for differential diagnosis do not provide satisfactory diagnostic performance. This is particularly problematic given the high proportion of so-called low-grade infected non-union, which are septic non-union without clinical indication of an underlying infection.

Therefore, this research project aims to develop and refine (pre-)operative diagnostic criteria to differentiate between aseptic and septic non-union, including low-grade infection, in patients with post-traumatic non-union. The focus of these diagnostics will be the preoperative use of non-invasive contrast-enhanced ultrasound (CEUS) to determine perfusion patterns in the non-union zone, as well as analyzing concentrations of angiogenesis and vascularization markers in peripheral blood samples. Additionally, immunohistochemical analyses will be performed on tissue obtained intraoperatively with regard to vascularization. Established microbiological diagnostics – including the membrane filtration of sonication fluid – will serve as the gold standard.

Activities/Methods:

In a multicenter clinical study, patients with tibial non-union, with and without suspected underlying infection, and planned surgical revision of the non-union will be included. Preoperatively, vascularization will be assessed by determining the perfusion rate in the non-union zone using CEUS. Additionally, a peripheral blood sample will be collected preoperatively for an ELISA-based analysis of systemic angiogenesis and vascularization markers. In addition to routine diagnostics, tissue samples will be taken during the surgical revision of the non-union for immunohistochemical analysis of vascularization markers in the non-union tissue. Sonication with membrane filtration of sonication fluid will be performed with the osteosynthesis material removed during revision surgery as an adjunctive diagnostic method to clinical microbiology. The healing process of the included patients will be followed up for 12 months to account for the aforementioned postoperative diagnostic uncertainty. The definitive diagnosis of septic or aseptic non-union will then be made according to the consensus definition for fracture-related infections. Thus, at the end of the follow-up period, there will be three study groups: non-union with expected and confirmed underlying infection, low-grade infected non-union without preoperative suspicion of infection, and aseptic non-union.

Between these groups, the determined parameters will be statistically analyzed for their ability to discriminate between (low-grade) infected non-union and aseptic non-union, as well as their diagnostic performance compared to currently established methods.

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