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      Refining animal models in fracture research: seeking consensus in optimising both animal welfare and scientific validity for appropriate biomedical use

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          Abstract

          Background

          In an attempt to establish some consensus on the proper use and design of experimental animal models in musculoskeletal research, AOVET (the veterinary specialty group of the AO Foundation) in concert with the AO Research Institute (ARI), and the European Academy for the Study of Scientific and Technological Advance, convened a group of musculoskeletal researchers, veterinarians, legal experts, and ethicists to discuss, in a frank and open forum, the use of animals in musculoskeletal research.

          Methods

          The group narrowed the field to fracture research. The consensus opinion resulting from this workshop can be summarized as follows:

          Results & Conclusion

          Anaesthesia and pain management protocols for research animals should follow standard protocols applied in clinical work for the species involved. This will improve morbidity and mortality outcomes. A database should be established to facilitate selection of anaesthesia and pain management protocols for specific experimental surgical procedures and adopted as an International Standard (IS) according to animal species selected. A list of 10 golden rules and requirements for conduction of animal experiments in musculoskeletal research was drawn up comprising 1) Intelligent study designs to receive appropriate answers; 2) Minimal complication rates (5 to max. 10%); 3) Defined end-points for both welfare and scientific outputs analogous to quality assessment (QA) audit of protocols in GLP studies; 4) Sufficient details for materials and methods applied; 5) Potentially confounding variables (genetic background, seasonal, hormonal, size, histological, and biomechanical differences); 6) Post-operative management with emphasis on analgesia and follow-up examinations; 7) Study protocols to satisfy criteria established for a "justified animal study"; 8) Surgical expertise to conduct surgery on animals; 9) Pilot studies as a critical part of model validation and powering of the definitive study design; 10) Criteria for funding agencies to include requirements related to animal experiments as part of the overall scientific proposal review protocols. Such agencies are also encouraged to seriously consider and adopt the recommendations described here when awarding funds for specific projects. Specific new requirements and mandates related both to improving the welfare and scientific rigour of animal-based research models are urgently needed as part of international harmonization of standards.

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          Most cited references62

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          The critical size defect as an experimental model for craniomandibulofacial nonunions.

          Little consistency has been manifest among investigators in choosing an appropriate experimental model for maxillofacial bone research. In an effort to develop a protocol for the experimental analysis of maxillofacial nonunions, previous studies using calvarial and mandibular defects as models were reviewed. The creation of nonunions in animals within the calvaria and mandible was size dependent. Defects of a size that will not heal during the lifetime of the animal may be termed critical size defects (CSDs). A rationale was postulated for testing bone repair materials (BRMs) using CSDs in a hierarchy of animal models. This rationale suggests that testing should be initiated in the calvaria of the rat and rabbit, followed by testing in the mandibles of dogs and monkeys. While calvarial CSDs have been established in the rat, rabbit, and dog, further research is necessary to determine the CSD in the calvaria of the monkey, as well as the mandibles of dogs and monkeys.
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            Production of a standard closed fracture in laboratory animal bone.

            To develop a technique for the production of a standard closed experimental fracture, a new apparatus was designed and tested on 40 male Sprague-Dawley rats. First, the femur was treated with an intramedullary Steinmann pin. The femoral diaphysis was then fractured by means of a blunt guillotine driven by a dropped weight. Radiographically, this technique resulted in a highly reproducible transverse fracture. There was minimal comminution and minimal angulation of the intramedullary pin. Histologically, there was minimal soft tissue damage. Mechanical testing showed that all fractures healed. Pin removal was accomplished with ease and without disturbance of the healed fracture site. The apparatus is simple to use and inexpensive to build. Through its use, a highly reproducible closed fracture model is established.
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              Influence of size and stability of the osteotomy gap on the success of fracture healing.

              Flexible fixation of fractures with minimally invasive surgical techniques has become increasingly popular. Such techniques can lead to relatively large fracture gaps (larger than 5 mm) and considerable interfragmentary movements (0.2-5 mm). We investigated the influence of the size of the fracture gap, interfragmentary movement, and interfragmentary strain on the quality of fracture healing. A simple diaphyseal long-bone fracture was modeled by means of a transverse osteotomy of the right metatarsus in sheep. In 42 sheep, the metatarsus was stabilized with a custom-made external ring fixator that was adjustable for gap size and axial interfragmentary movement. The sheep were randomly divided into six groups with three different gap sizes (1, 2, or 6 mm) and small or large interfragmentary strain (approximately 7 or 31%). The movement of the fracture gap was monitored telemetrically by a displacement transducer attached to the fixator. After 9 weeks of healing, the explanted metatarsus was evaluated mechanically in a three-point bending test to determine bending stiffness and was radiographed to measure the amount of periosteal callus formation. Increased size of the gap (from 1 to 6 mm) resulted in a significant reduction in the bending stiffness of the healed bones. Larger interfragmentary movements and strains (31 compared with 7%) stimulated larger callus formation for small gaps (1-2 mm) but not for larger gaps (approximately 6 mm). The treatment of simple diaphyseal fractures with flexible fixation can be improved by careful reduction of the fracture; this prevents large interfragmentary gaps. The experimental fracture model for the metatarsus showed that the healing process was inferior when the gap was larger than 2 mm.
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                Author and article information

                Journal
                BMC Musculoskelet Disord
                BMC Musculoskeletal Disorders
                BioMed Central (London )
                1471-2474
                2007
                1 August 2007
                : 8
                : 72
                Affiliations
                [1 ]Equine Hospital, Vetsuisse Faculty University of Zurich, Winterthurerstrasse 260, CH-8057 Zurich, Switzerland
                [2 ]Royal Veterinary College and Institute of Orthopaedics and Musculoskeletal Science, University College, London, UK
                [3 ]College of Veterinary Medicine, Michigan State University, East Lansing, MI, 48824, USA
                [4 ]AO Research Institute, AO Foundation, Clavadelerstrasse 8, CH-7270 Davos, Switzerland
                [5 ]Institut für Unfallchirurgische Forschung und Biomechanik, Universitätsklinikum Ulm, Germany
                [6 ]MatSearch, Ch. Jean Pavillard 14, CH-1009 Pully, Switzerland
                [7 ]Institut für Öffentliches Recht, Universität Bonn, Germany
                [8 ]European Academy for the Study of Scientific and Technological Advance, Bad Neuenahr-Ahrweiler, Germany
                [9 ]Ethik im Diskurs, University of Zurich, Zurich, Switzerland
                [10 ]Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA
                Article
                1471-2474-8-72
                10.1186/1471-2474-8-72
                1952063
                17678534
                d2bbffb8-5fe0-4793-ae5d-9fb6e3c61390
                Copyright © 2007 Auer et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 November 2006
                : 1 August 2007
                Categories
                Correspondence

                Orthopedics
                Orthopedics

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