A microphysiological system of tendon inflammation and fibrosis for drug screening and efficacy testing: MPS Database Engagement

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Abstract The continued advancement of microphysiological systems (MPS) as pre-clinical research tools is vital to overcome the low throughput and inaccuracies inherent in animal models of human disease. The limitations of pre-clinical animal models, most commonly mice, are particularly apparent in inflammatory diseases which are known to have distinct genetic and cytokine responses to inflammation. The establishment of MPS alternatives, however, will require scientific consensus on the protocols and systems best suited to address particular diseases. As the current MPS era is characterized by a proliferation of approaches, the Microphysiological System Data Base (MPS-db) created by the University of Pittsburgh is a valuable tool to hasten the development of MPS standards. Because the success of the MPS-db requires the active participation by MPS developers and users, we seek supplemental funding to contribute the designs, protocols and results for an MPS system that models the interplay between inflammation and fibrosis in tendon healing (UG3TR00287). Importantly, the injury and repair of connective tissue injury is not represented in the current MPS-db but accounts for more than 8.5 million clinical procedures annually, including 2 million major surgeries. Our human tendon-on-a-chip (hToC) model focuses on the early inflammatory stages of tendon repair, where timely interventions may promote scarless healing. The hToC features vascular and collagen compartments which exchange soluble and cellular factors in a simulation of the neovascularized microenvironment established shortly after blood clotting. Monocyte infiltration is hypothesized to play an essential role in the generation of contractile myofibroblasts which progress to senescence and release monocyte activating factors in a positive feedback loop that causes scar tissue. The model uses iPSCs derived from primary human tenocytes to create vascular endothelial cells and monocytes in an isogenic, patient-centric triculture. With supplemental funding we will share: 1) descriptions of the mechanisms of the tendon injury and fibroinflammatory repair process; 2) design details for the hToC including device components and modules for both flow and integrated photonic- based sensing; 3) cell culture and device protocols including phenotypic characteristics and operational parameters such as flow rates for priming of ECs and the introduction of immune cells; 4) The design and rationale for studies under baseline and inflammation/repair conditions; and 5) Results including an analysis of intra-study reproducibility.