Human Mesenchymal Stem Cell‐Derived Miniature Joint System for Disease Modeling and Drug Testing

Abstract

Diseases of the knee joint such as osteoarthritis (OA) affect all joint elements. An in vitro human cell-derived microphysiological system capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein, a human mesenchymal stem cell-derived miniature joint system (miniJoint) is generated, in which engineered osteochondral complex, synovial-like fibrous tissue, and adipose tissue are integrated into a microfluidics-enabled bioreactor. This novel design facilitates different tissues communicating while still maintaining their respective phenotypes. The miniJoint exhibits physiologically relevant changes when exposed to interleukin-1𝜷 mediated inflammation, which are similar to observations in joint diseases in humans. The potential of the miniJoint in predicting in vivo efficacy of drug treatment is confirmed by testing the "therapeutic effect" of the nonsteroidal anti-inflammatory drug, naproxen, as well as four other potential disease-modifying OA drugs. The data demonstrate that the miniJoint recapitulates complex tissue interactions, thus providing a robust organ chip model for the study of joint pathology and the development of novel therapeutic interventions.

Modeling early changes associated with cartilage trauma using human-cell-laden hydrogel cartilage models

“…Perhaps more prolonged, altered intracellular signaling or intra-tissue paracrine signaling is required to increase MMP13 gene expression in our system. Future evaluation of these hypotheses using the recently reported micro-Joint system will help elucidate these points [47][48][49][50].…”

The Emerging Use of ASC/Scaffold Composites for the Regeneration of Osteochondral Defects

“…To better understand the intra-articular tissue cross-talk and the etiology of OC defects, Li et al (2022) have developed an MSC-derived miniature joint system containing OC tissue, fibrous tissue, and adipose tissue. Such systems will not only enhance the understanding of the OC unit but can potentially be adapted to engineer patient-specific OC units for transplantation in the future.…”

Towards establishing human body-on-a-chip systems

“…systemic administration, in their BoC [ 1 ]. Future applications of BoCs should also examine other routes of drug administration, such as topical application of drugs on the skin component and intraarticular injection of therapeutics for the treatment of degenerative joint disorders [ 3 ].…”

“…It should be pointed out that for many organs, the phenotypic characteristics of tissues depend on the presence of and the interactions with other tissues, e.g. the relationship between articular cartilage and subchondral bone [ 3 ], highlighting an additional, unique advantage of multi-tissue BoC platforms. In addition, blood and personal health data as well as information derived from patient-derived biopsies and tissue explants should be taken into consideration to strengthen the patient-specificity of BoC platforms.…”

“…A modular, "plugand-play" design is highly desirable to allow convenient integration of different organ modules depending on the specific applications (Fig. 1B) [1][2][3]. A key consideration not fully addressed in previously developed BoC platforms is the need to accurately downscale the human body components.…”