cells Review In Vitro Human Joint Models Combining Advanced 3D Cell Culture and Cutting-Edge 3D Bioprinting Technologies Christian Jorgensen 1, * ,† and Matthieu Simon 2,†   Citation: Jorgensen, C.; Simon, M. In Vitro Human Joint Models Combining Advanced 3D Cell Culture and Cutting-Edge 3D Bioprinting Technologies. Cells 2021, 10, 596. https://doi.org/10.3390/ cells10030596 Academic Editor: Alexander V. Ljubimov Received: 29 January 2021 Accepted: 26 February 2021 Published: 8 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 UFR de Médecine, Université MONTPELLIER 1, 34000 Montpellier, France 2 IRMB, CARTIGEN, CHU de Montpellier, 34090 Montpellier, France; matthieusimon.work@gmail.com * Correspondence: christian.jorgensen@inserm.fr; Tel./Fax: +33-(0)-4-99-63-60-26 † These authors contributed equally to this work. Abstract: Joint-on-a-chip is a new technology able to replicate the joint functions into microscale systems close to pathophysiological conditions. Recent advances in 3D printing techniques allow the precise control of the architecture of the cellular compartments (including chondrocytes, stromal cells, osteocytes and synoviocytes). These tools integrate fluid circulation, the delivery of growth factors, physical stimulation including oxygen level, external pressure, and mobility. All of these structures must be able to mimic the specific functions of the diarthrodial joint: mobility, biomechanical aspects and cellular interactions. All the elements must be grouped together in space and reorganized in a manner close to the joint organ. This will allow the study of rheumatic disease physiopathology, the development of biomarkers and the screening of new drugs. Keywords: musculoskeletal progenitor/stromal cells; organoids; microspheres 1. Introduction Osteoarthrosis (OA) is a chronic degenerative disease of diarthrodial joints affecting people over forty resulting in chronic joint pain and progressive loss of mobility. In 2019 OA affected about 7% of the world’s population [1]. So far, there is no therapy available that effectively stops the structural degradation of cartilage and bone or is able to successfully reverse this joint deterioration [2]. OA leads to chronic pain, and severe restriction in mobility inducing loss in quality of life. This statement emphasizes the need to develop new therapeutics in order to improve the current treatment which consists only of killing the patient’s pain. Nowadays two different models are commonly used to better understand OA physiopathology, to develop biomarkers and assay new drugs. These models are animals and in vitro models [3]. Both models have advantages and disadvantages (Table 1). In vitro models and cell cultures are easy to set up, as a large number of cells can be produced allowing high throughput drug screening applications. However, due to their simplicity these models cannot properly replicate the complexity of an organ like a diarthrodial joint, such as intracellular signaling, fluid forces or the influence of tissue interconnexion. On the other hand, animal models like the DMM model (disease induced by menisectomy) or CIOA (collagenase-induced osteoarthritis) bring this missing organ complexity and have largely contributed to a better understanding of the function of the joint. Unfortunately, the use of animals and more particularly large ones which better mimic human articulation is limited because of ethical concerns and the obvious practicality [4]. In a recent review Cope et al. discussed all the advantages and disadvantages of in vivo and ex vivo models to study OA [5]. They finally concluded that at this time no suitable model accurately reflected the natural human OA particularly at the early stages of the disease when a preventive treatment could be initiated to slow or even reverse the progression of the disease. Cells 2021, 10, 596. https://doi.org/10.3390/cells10030596 https://www.mdpi.com/journal/cells