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      A new sequential animal model for infection-related non-unions with segmental bone defect

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          Abstract

          Background

          The treatment of fracture-related infections (FRI) is still a challenge for orthopedic surgeons. The prevalence of FRI is particularly high in open fractures with extensive soft-tissue damage. This study aimed to develop a new two-step animal model for non-unions with segmental bone defects, which could be used to evaluate new innovative bone substitutes to improve the therapeutic options in humans with FRI and bone defects.

          Methods

          After randomization to infected or non-infected groups, 30 Sprague-Dawley rats underwent a transverse osteotomy of the mid-shaft femur with a 5 mm defect. Additionally, the periosteum at the fracture zone was cauterized at both sides. After intramedullary inoculation with 10 3 CFU Staphylococcus aureus (infected group) or PBS (non-infected group), a fracture stabilization was done by intramedullary K-wires. After 5 weeks, the bone healing process was evaluated, and revision surgery was performed in order to obtain increased bone healing. The initial K-wires were removed, and debridement of the osteotomy-gap was done followed by a more stable re-osteosynthesis with an angle-stable plate. After further 8 weeks all rats were euthanized and the bone consolidation was tested biomechanically and the callus formation quantitatively by micro-CT analysis.

          Results

          We developed and presented a new two-stage non-union animal model through a targeted S. aureus infection. After 5 weeks, all animals showed a non-union irrespective of assignment to the infected and non-infected group. Lane and Sandhu score showed a higher callus formation in the infected group. In all infected animals, the inoculated S. aureus strain was detected in the revision surgery. The second surgery did not improve bone healing, as shown by the Lane Sandhu score and in the μ-CT analysis. Similarly, biomechanical testing showed in both groups a significantly lower maximum torque as compared to the contralateral side ( p < 0.0001).

          Conclusions

          We were able to successfully develop a new two-stage non-union animal model, which reflects a genuine clinical situation of an infection-related non-union model with segmental bone defects. This model could be used to evaluate various therapeutic anti-infectious and osteoinductive strategies in FRIs.

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          Most cited references45

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          The biology of fracture healing.

          The biology of fracture healing is a complex biological process that follows specific regenerative patterns and involves changes in the expression of several thousand genes. Although there is still much to be learned to fully comprehend the pathways of bone regeneration, the over-all pathways of both the anatomical and biochemical events have been thoroughly investigated. These efforts have provided a general understanding of how fracture healing occurs. Following the initial trauma, bone heals by either direct intramembranous or indirect fracture healing, which consists of both intramembranous and endochondral bone formation. The most common pathway is indirect healing, since direct bone healing requires an anatomical reduction and rigidly stable conditions, commonly only obtained by open reduction and internal fixation. However, when such conditions are achieved, the direct healing cascade allows the bone structure to immediately regenerate anatomical lamellar bone and the Haversian systems without any remodelling steps necessary. In all other non-stable conditions, bone healing follows a specific biological pathway. It involves an acute inflammatory response including the production and release of several important molecules, and the recruitment of mesenchymal stem cells in order to generate a primary cartilaginous callus. This primary callus later undergoes revascularisation and calcification, and is finally remodelled to fully restore a normal bone structure. In this article we summarise the basic biology of fracture healing. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Bone fracture healing: cell therapy in delayed unions and nonunions.

            Bone fracture healing impairment related to mechanical problems has been largely corrected by advances in fracture management. Better protocols, more strict controls of time and function, and hardware and surgical technique evolution have contributed to better prognosis, even in complex fractures. However, atrophic nonunion persists in clinical cases where, for different reasons, the osteogenic capability is impaired. When this is the case, a better understanding of the basic mechanisms under bone repair and augmentation techniques may put in perspective the current possibilities and future opportunities. Among those, cell therapy particularly aims to correct this insufficient osteogenesis. However, the launching of safe and efficacious cell therapies still requires substantial amount of research, especially clinical trials. This review will envisage the current clinical trials on bone healing augmentation based on cell therapy, with the experience provided by the REBORNE Project, and the insight from investigator-driven clinical trials on advanced therapies towards the future. This article is part of a Special Issue entitled Stem Cells and Bone.
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              Current approaches to experimental bone grafting.

              A number of osteogenic, osteoinductive, and osteoconductive substances currently are being investigated for use in bone repair. It is conceivable that a selected combination of osteogenic cells, osteoinductive factors, and osteoconductive matrices can be combined and fabricated into an implantable material custom-suited to particular clinical demands. Consequently, it is crucial that potential graft substances be experimentally characterized in terms of their precise contribution to the bone-forming mechanisms. In this article, the authors review current areas of research in the realm of experimental grafting, including the current understanding of materials that manifest osteogenic, osteoinductive, or osteoconductive properties.
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                Author and article information

                Contributors
                lars_helbig@t-online.de
                guehring@uni-heidelberg.de
                nadine.titze@gmx.de
                dennis.nurjadi@med.uni-heidelberg.de
                robert.sonntag@med.uni-heidelberg.de
                jonas.armbruster@bgu-ludwigshafen.de
                Britt.Wildemann@med.uni-jena.de
                gerhard.schmidmaier@med.uni-heidelberg.de
                Paul.Gruetzner@bgu-ludwigshafen.de
                holger.freischmidt@bgu-ludwigshafen.de
                Journal
                BMC Musculoskelet Disord
                BMC Musculoskelet Disord
                BMC Musculoskeletal Disorders
                BioMed Central (London )
                1471-2474
                27 May 2020
                27 May 2020
                2020
                : 21
                : 329
                Affiliations
                [1 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Clinic for Orthopedics and Trauma Surgery, Center for Orthopedics, Trauma Surgery and Spinal Cord Injury, , Heidelberg University Hospital, ; Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany
                [2 ]Arcus Sportklinik Pforzheim, Rastatterstr. 17-19, 75179 Pforzheim, Germany
                [3 ]Unfallklinik Ludwigshafen, Klinik für Unfallchirurgie und Orthopädie, Ludwig-Guttmann-Strasse 13, 67071 Ludwigshafen, Germany
                [4 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Department of Infectious Diseases Medical Microbiology and Hygiene, , Heidelberg University Hospital, ; Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
                [5 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Laboratory of Biomechanics and Implant Research, Clinic for Orthopedics and Trauma Surgery, , Heidelberg University Hospital, ; Schlierbacher Landstrasse 200a, 69118 Heidelberg, Germany
                [6 ]GRID grid.275559.9, ISNI 0000 0000 8517 6224, Department of Trauma, Hand and Reconstructive Surgery, Experimental Trauma Surgery, , Universitätsklinikum Jena, ; 07747 Jena, Germany
                [7 ]Julius Wolff Institute, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
                Author information
                http://orcid.org/0000-0001-7309-478X
                Article
                3355
                10.1186/s12891-020-03355-6
                7254709
                32460740
                500970e5-9cd2-4530-972c-0e59d1c4224a
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 24 March 2020
                : 19 May 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100003417, Deutsche Gesetzliche Unfallversicherung;
                Award ID: FR252
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2020

                Orthopedics
                animal model,rat,delayed osseous union,non-union,osteitis,biomechanical testing,micro-ct,plate osteosynthesis,two stage procedure

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