A synoptic literature review of animal models for investigating the biomechanics of knee osteoarthritis.

Osteoarthritis (OA) is a common chronic disease largely driven by mechanical factors, causing significant health and economic burdens worldwide. Early detection is challenging, making animal models a key tool for studying its onset and mechanically-relevant pathogenesis. This review evaluate current use of preclinical models and progressive measurement techniques for analysing biomechanical factors in the specific context of the clinical OA phenotypes. It categorizes preclinical models into naturally occurring, genetically modified, chemically-induced, surgically-induced, and non-invasive types, linking each to clinical phenotypes like chronic pain, inflammation, and mechanical overload. Specifically, we discriminate between mechanical and biological factors, give a new explanation of the mechanical overload OA phenotype and propose that it should be further subcategorized into two subtypes, post-traumatic and chronic overloading OA. This review then summarises the representative models and tools in biomechanical studies of OA. We highlight and identify how to develop a mechanical model without inflammatory sequelae and how to induce OA without significant experimental trauma and so enable the detection of changes indicative of early-stage OA in the absence of such sequelae. We propose that the most popular post-traumatic OA biomechanical models are not representative of all types of mechanical overloading OA and, in particular, identify a deficiency of current rodent models to represent the chronic overloading OA phenotype without requiring intraarticular surgery. We therefore pinpoint well standardized and reproducible chronic overloading models that are being developed to enable the study of early OA changes in non-trauma related, slowly-progressive OA. In particular, non-invasive models (repetitive small compression loading model and exercise model) and an extra-articular surgical model (osteotomy) are attractive ways to present the chronic natural course of primary OA. Use of these models and quantitative mechanical behaviour tools such as gait analysis and non-invasive imaging techniques show great promise in understanding the mechanical aspects of the onset and progression of OA in the context of chronic knee joint overloading. Further development of these models and the advanced characterisation tools will enable better replication of the human chronic overloading OA phenotype and thus facilitate mechanically-driven clinical questions to be answered.