Assistant Professor Cornell University Ithaca, New York, United States
Introduction: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that afflicts the synovial lining of joints and manifests in reduced range of motion, pain, swelling, and numerous other complications. No effective cure has been identified, and palliative biological drugs such as disease-modifying antirheumatic drugs (DMARDs) only alleviate inflammation and are becoming ineffective for a rising portion of the population. In recent years, attention has shifted to eradicating the source of synovial autoimmunity and inflammation, with a key area being the synovial-draining lymphatics, given new insights into the role of lymphatics in disease pathogenesis. However, very few in vitro models to date have been made for the synovium microenvironment, and none yet that include the synovial lymphatics. We therefore created a microfluidic chip device that models the synovial-draining lymphatics within the subintimal synovium microenvironment.
Materials and
Methods: Utilizing microfluidic organ-on-chip technology, we engineered an in vitro lymphatic microvessel from primary lymphatic endothelial cells (LEC) within a biomimetic collagen extracellular matrix embedded with primary fibroblast-like synoviocytes (FLS) to create a co-cultured synovial lymphatic system. The effective permeability, drainage capacity, and lymphangiogenesis of the synovium-on-chip were examined under healthy conditions and rheumatoid arthritis conditions induced by inflammatory cytokine stimulation or the inclusion of RA patient-derived FLS. The differential intravasation and extravasation of immune cells within the normal and inflamed synovial lymphatic microenvironment were also studied by hydrostatic pressure induced migration of peripheral blood mononuclear cells (PBMCs).
Results, Conclusions, and Discussions: Functional assays on our synovium-on-chip demonstrated increased lymphatic permeability and drainage under RA inflammation compared to healthy control, accompanied by increased LEC junctional buttoning and alteration of LEC phenotype by interaction with FLS. RA inflammation within the synovium-on-chip additionally induced lymphangiogenesis with greater sprout length as well as synoviocyte invasion seen in vivo with pannus formation. Similarly, increased immune cell retention and differential migration of PBMCs were observed under RA inflammation, in accordance with in vivo observations from our mouse collagen-induced arthritis model. Combined with further verification from in vivo models, our synovium-on-chip model can provide a physiologically accurate representation of lymphatic drainage and activity under disease conditions, informing tissue engineering, drug testing, and high-throughput screening.
