Human MSC-derived Knee Joint-on-a-chip for Modeling of Disease and Drug Testing
2Orthopaedic Surgery, University of Pittsburgh, USA
3Graduate School of Biomedical Sciences, Microbiology, Immunology & Genetics, University of North Texas Health Science Center, USA
4President and Vice-Chancellor, and Institute for Tissue Engineering and Regenerative Medicine, Chinese University of Hong Kong, Hong Kong
Introduction:
Osteoarthritis (OA) is a highly prevalent condition that may severely compromise the patient’s quality of life, creating a significant socioeconomic burden. Although degeneration of articular cartilage is the hallmark of OA, this condition affects all joint elements. In vitro tissue culture platforms and animal models have increased our understanding of OA; however, a human cell-derived ex vivo model capable of simulating intraarticular tissue crosstalk among different tissue types is desirable for elucidating the etiology and pathogenesis of OA, and testing potential therapies. We have developed and characterized a three-dimensional (3D), multi-component, human cell-based, microphysiological, synovial joint-on-a-chip (microJoint) which contains osteoblasts, chondrocytes, fibroblasts and adipocytes, and mimics the biological microenvironment of synovial joints.
Methods:
The human mesenchymal stem cell-derived microJoint was engineered to contain osteochondral, synovial, and adipose tissues integrated into a 3D microfluidics-enabled bioreactor. This novel design facilitates communication of different joint tissues, while still maintaining their respective phenotypes. A hydrogel scaffold prepared with methacrylated gelatin (GelMA) was used to create 3D constructs and support hBMSC differentiation. Polarized macrophages were added to this system to further simulate inflammatory and immunomodulatory conditions.
Results:
After confirmation of their respective phenotypes, osteochondral, adipose and fibrous tissue modules were integrated into the microJoint chamber. Tissues were processed and analyzed using histological staining, RT-qPCR, and immunoassays for up to 4 weeks. The microJoint exhibited physiologically relevant changes when exposed to interleukin-1β mediated inflammation, which were similar to observations in samples of cartilage from human OA specimens. 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, and several potential disease modifying OA drugs.
Conclusion:
The microJoint recapitulates complex tissue interactions, thus providing a robust model for the study of joint pathology and the development of novel therapeutic interventions.