Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Tissue Eng Part C Methods. 2021 Feb;27(2):124-138. doi: 10.1089/ten.TEC.2020.0309. Epub 2021 Feb 4.
Osteoarthritis (OA) is a painful and disabling disease that affects millions of people worldwide. Symptom-alleviating treatments exist, although none with long-term efficacy. Furthermore, there are currently no disease-modifying OA drugs (DMOADs) with demonstrated efficacy in OA patients, which is, in part, attributed to a lack of full understanding of the pathogenesis of OA. The inability to translate findings from basic research to clinical applications also highlights the deficiencies in the available OA models at simulating the clinically relevant pathologies and responses to treatments in humans. In this review, the current status in the development of DMOADs will be first presented, with special attention to those in Phase II-IV clinical trials. Next, current , and OA models are summarized and the respective advantages and disadvantages of each are highlighted. Of note, the development and application of microphysiological or tissue-on-a-chip systems for modeling OA in humans are presented and the issues that need to be addressed in the future are discussed. Microphysiological systems should be given serious consideration for their inclusion in the DMOAD development pipeline, both for their ability to predict drug safety and efficacy in human clinical trials at present, as well as for their potential to serve as a test platform for personalized medicine. Impact statement At present, no disease-modifying osteoarthritis (OA) drugs (DMOADs) have been approved for widespread clinical use by regulatory bodies. The failure of developing effective DMOADs is likely owing to multiple factors, not the least of which are the intrinsic differences between the intact human knee joint and the preclinical models. This work summarizes the current OA models for the development of DMOADs, discusses the advantages/disadvantages of each, and then proposes future model development to aid in the discovery of effective and personalized DMOADs. The review also highlights the microphysiological systems, which are emerging as a new platform for drug development.
骨关节炎（OA）是一种痛苦且使人丧失能力的疾病，影响着全球数以百万计的人。虽然有缓解症状的治疗方法，但没有一种方法具有长期疗效。此外，目前尚无具有疗效的治疗骨关节炎的疾病修饰药物（DMOAD），部分原因是对 OA 发病机制缺乏全面了解。无法将基础研究的发现转化为临床应用，也突出了现有的 OA 模型在模拟人类临床相关病理学和对治疗的反应方面的不足。在这篇综述中，首先介绍 DMOAD 开发的现状，特别关注处于 II 期-IV 期临床试验的药物。接下来，总结了现有的、正在开发的和新兴的 OA 模型，并强调了每种模型的优缺点。值得注意的是，介绍了用于模拟人类 OA 的微生理或芯片上组织系统的开发和应用，以及未来需要解决的问题。微生理系统应该被认真考虑纳入 DMOAD 开发管道，不仅因为它们目前有能力预测药物在人体临床试验中的安全性和疗效，还因为它们有可能成为个性化药物的测试平台。
影响声明
目前，还没有被监管机构批准用于广泛临床应用的治疗骨关节炎的疾病修饰药物（DMOAD）。开发有效 DMOAD 的失败可能有多种原因，其中最不明显的原因是完整的人类膝关节和临床前模型之间存在内在差异。这项工作总结了用于开发 DMOAD 的当前 OA 模型，讨论了每种模型的优缺点，然后提出了未来的模型开发，以帮助发现有效和个性化的 DMOAD。该综述还强调了微生理系统，这是一个新兴的药物开发平台。
