Local remodelling and mechanoregulation of bone fracture healing in healthy, aged, and osteoporotic humans

• Applicants: Professorin Dr. Anita Ignatius; Dr.-Ing. Ulrich Simon
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323231527

The current knowledge of fracture healing is mainly based on experimental animal studies of diaphyseal bone healing, even though many age and osteoporosis associated fractures occur in the bone metaphysis. Little is known about the mechanoregulation of trabecular bone healing and the existing knowledge is based on histological evaluations on the macroscopic tissue-level. We therefore need to better understand the healing process and its mechanoregulation in healthy, aged, and osteoporotic human bone. This is, however, challenging as bone resorption and formation needs to be quantified in vivo and non-invasively during fracture healing in patients. Investigating the mechanoregulation requires furthermore the calculation of local tissue loading, which in turn requires the definition of global loading - that are forces acting upon the bone on the organ-level - which usually cannot be measured in patients and its influence on the healing is not well understood. In the proposed study, we aim at (1) investigating local remodelling and (2) the effect of global loading conditions on the fracture healing process as well as (3) local mechanoregulation of metaphyseal bone fracture healing in healthy, aged, and osteoporotic humans. To achieve the first aim, we propose a clinical trial using high-resolution peripheral quantitative computed tomography (HR-pQCT) to assess bone microstructure at the distal forearm in patients, and to develop image analysis methods to quantify microstructural differences between time-lapse images. To achieve the second aim, global loading effects on fracture healing will be studied in humans where additional loading will be induced with hand grip exercises. A computational muscle model will be developed to calculate the forces at the distal radius from the measured hand grip strength as well as a computational model of fracture healing to determine the sensitivity of global loading on this process. Results will be validated with data from animal trials where global loading was controlled experimentally. To achieve the third aim, micro-finite element (micro-FE) methods will be developed to calculate local tissue loading in HR-pQCT images of fractures with global loading as quantified with the muscle model of aim 2. Correlating local tissue loading and remodelling sites as determined in aim 1 will finally allow to investigate the mechanoregulation of healing in aged and osteoporotic human bone. Overall, this project requires an extremely broad range of expertise that will be provided in a German-Austrian-Swiss (DACH) collaboration. Innsbruck University and Inselspital Bern with their experience in performing longitudinal clinical studies will be responsible for aim 1, Ulm University with its expertise in histological and computational studies for aim 2, and ETH Zurich with its expertise in bone imaging and micro-FE analysis for aim 3.

• DFG Programme: Research Grants
• International Connection: Austria, Switzerland
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Cooperation Partners: Professor Dr. Michael Blauth; Professor Dr. Kurt Lippuner; Professor Dr. Ralph Müller