We have been developed microphysiological system (MPS or tissue chip) to model joint diseases since 2014, which represents a potentially high-utility system in the development of personalized disease-modifying osteoarthritis drugs (DMOADs).The inclusion of MPS in the drug development pipeline will increase the predictive power in the discovery phase, reduce animal numbers in the preclinical stage, and predict the efficacy and toxicity of compounds prior to human clinical trials, which was highlighted in our recent review articles (2020-1, 2020-2, 2022)
Osteochondral Tissue Chip Derived From iPSCs: Modeling OA Pathologies and Testing Drugs
In this study, we aimed to develop microphysiological osteochondral (OC) tissue chips derived from human induced pluripotent stem cells (iPSCs) to model the pathologies of OA. We first induced iPSCs into mesenchymal progenitor cells (iMPCs) and optimized the chondro- and osteo-inductive conditions for iMPCs. Then iMPCs were encapsulated into photocrosslinked gelatin scaffolds and cultured within a dual-flow bioreactor, in which the top stream was chondrogenic medium and the bottom stream was osteogenic medium. After 28 days of differentiation, OC tissue chips were successfully generated and phenotypes were confirmed by real time RT-PCR and histology. To create an OA model, interleukin-1β (IL-1β) was used to challenge the cartilage component for 7 days. While under control conditions, the bone tissue promoted chondrogenesis and suppressed chondrocyte terminal differentiation of the overlying chondral tissue. Under conditions modeling OA, the bone tissue accelerated the degradation of chondral tissue which is likely via the production of catabolic and inflammatory cytokines. These findings suggest active functional crosstalk between the bone and cartilage tissue components in the OC tissue chip under both normal and pathologic conditions. Finally, a selective COX-2 inhibitor commonly prescribed drug for OA, Celecoxib, was shown to downregulate the expression of catabolic and proinflammatory cytokines in the OA model, demonstrating the utility of the OC tissue chip model for drug screening.
Stem cell-based microphysiological osteochondral system to model tissue response to interleukin-1β
Osteoarthritis (OA) is a chronic degenerative disease of the articular joint that involves both bone and cartilage degenerative changes. An engineered osteochondral tissue within physiological conditions will be of significant utility in understanding the pathogenesis of OA and testing the efficacy of potential disease-modifying OA drugs (DMOADs). In this study, a multichamber bioreactor was fabricated and fitted into a microfluidic base. When the osteochondral construct is inserted, two chambers are formed on either side of the construct (top, chondral; bottom, osseous) that is supplied by different medium streams. These medium conduits are critical to create tissue-specific microenvironments in which chondral and osseous tissues will develop and mature. Human bone marrow stem cell (hBMSCs)-derived constructs were fabricated in situ and cultured within the bioreactor and induced to undergo spatially defined chondrogenic and osteogenic differentiation for 4 weeks in tissue-specific media. We observed tissue specific gene expression and matrix production as well as a basophilic interface suggesting a developing tidemark. Introduction of interleukin-1β (IL-1β) to either the chondral or osseous medium stream induced stronger degradative responses locally as well as in the opposing tissue type. For example, IL-1β treatment of the osseous compartment resulted in a strong catabolic response in the chondral layer as indicated by increased matrix metalloproteinase (MMP) expression and activity, and tissue-specific gene expression. This induction was greater than that seen with IL-1β application to the chondral component directly, indicative of active biochemical communication between the two tissue layers and supporting the osteochondral nature of OA.
Human Mesenchymal Stem Cell-derived Knee Joint-on-a-Chip for Disease Modeling and Drug Testing
Diseases of the knee joint such as osteoarthritis affect all joint elements. A human cell-derived ex vivo model capable of simulating intraarticular tissue crosstalk is desirable for studying etiologies/pathogenesis of joint diseases and testing potential therapeutics. Herein we generated a human cell-derived microphysiological joint-on-a-chip system (microJoint), in which engineered osteochondral, synovial, and adipose tissues were integrated into a microfluidics-enabled bioreactor. This novel design facilitated different tissues communicating while still maintaining their respective phenotypes. The microJoint exhibited physiologically relevant changes when exposed to interleukin-1β mediated inflammation, which were similar to observations in joint diseases in humans. The potential of the microJoint in predicting in vivo efficacy of drug treatment was confirmed by testing the “therapeutic effect” of the nonsteroidal anti-inflammatory drug, naproxen, as well as other potential disease modifying osteoarthritis drugs. The data demonstrate that the microJoint recapitulates complex tissue interactions, thus providing a robust model for the study of joint pathology and the development of novel therapeutic interventions