Comparative study of aseptic and septic non-unions: lnfluence of systemic and local factors on bone metabolism and fracture healing.

Status:

completed 03/2021

Aims:

Both aseptic and septic non-unions represent a severe complication for the patient and the treating surgeon. There are no comparable studies to determine the similarities in the development of aseptic and septic non-unions. It is unclear whether this is due to a local or systemic deficiency of growth factors or if cells at the fracture site are impaired in their function. The aim of this study is to compare aseptic and septic non-unions using clinical, cellular, and animal experimental approaches to find new therapeutic strategies for the treatment of non-unions.

Activities/Methods:

Cancellous bone from the non-unions and from iliac crest was collected from 82 patients for comparative clinical and cellular studies. In addition, microbiological specimens were collected. Patients were classified as aseptic, or septic based on microbiology results. The harvested tissue was analyzed by gene expression to investigate pathomechanisms in osteoblastogenesis. As a basis for evaluating different bone substitutes and growth factors in the therapy of impaired fracture healing the first sequential non-union animal model was developed in thirty Sprague-Dawley rats. In addition to the bone substitutes Cerament® G (gentamicin-added calcium hydroxyapatite from Boneupport) and Bonealive® putty (S53P4, Bioglass from Bonealive), the systemic use of Forsteo® (parathyroid hormone from Lilly) was investigated in another ninety rats. The different therapies were compared using microbiological, histological and biomechanical examinations as well as μ-CT.

Results:

The clinical study is not completed. The intermediate results do not allow to exclude a systemic regulation of osteoblastogenesis. First prognostic markers for the development of aseptic or septic non-unions, such as interleukin 6, Wnt5a, Runx2 or Osterix become obvious. In the future, this could be the key to different therapeutic approaches. We were able to establish the first sequential non-union model (aseptic and septic). This allowed the investigation of different bone substitutes and growth factors mentioned above. Both, Bonealive® putty and Cerament® G, were unable to heal infected non-unions. While Bonealive® putty only showed osteoinductive properties in the aseptic model, Cerament® G was able to convince by osteoconduction and osteoinduction. Additive systemic administration of Forsteo® in aseptic non-unions treated with Cerament® G resulted in significantly increased vascularization of the bone substitute. However, 8 weeks after surgery, both bone substitutes failed to demonstrate sufficient stability in biomechanical analysis. In clinical routine, these results are already used with success of reduced revision surgeries. So far, the additive systemic administration of Forsteo® in the treatment of aseptic non-unions has not been tested in humans due to the fact, that it is only possible as an "off label use".

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