02920nas a2200397   4500000000100000000000100001008004100002260001500043100001800058700001900076700001800095700002100113700002300134700001500157700001900172700002200191700002000213700002300233700001700256700001700273700001700290700002000307700002300327700001500350700001400365700002000379700002200399700002200421700001600443245012800459856007000587300001200657490000700669520183200676022001402508       2024                            d  c2024-02-131 aMaedeh Mozneb1 aAmelia Jenkins1 aSamuel Sances1 aStephany Pohlman1 aMichael J. Workman1 aDylan West1 aBriana Ondatje1 aKareem El-Ghazawi1 aAmanda Woodbury1 aVeronica J. Garcia1 aShachi Patel1 aMadelyn Arzt1 aFelipe Dezem1 aAlex H. Laperle1 aV. Alexandra Moser1 aRitchie Ho1 aNur Yucer1 aJasmine Plummer1 aRobert J. Barrett1 aClive N. Svendsen1 aArun Sharma00aMulti-lineage heart-chip models drug cardiotoxicity and enhances maturation of human stem cell-derived cardiovascular cells  uhttps://pubs.rsc.org/en/content/articlelanding/2024/lc/d3lc00745f  a869-8810 v243 aCardiovascular toxicity causes adverse drug reactions and may lead to drug removal from the pharmaceutical market. Cancer therapies can induce life-threatening cardiovascular side effects such as arrhythmias, muscle cell death, or vascular dysfunction. New technologies have enabled cardiotoxic compounds to be identified earlier in drug development. Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and vascular endothelial cells (ECs) can screen for drug-induced alterations in cardiovascular cell function and survival. However, most existing hiPSC models for cardiovascular drug toxicity utilize two-dimensional, immature cells grown in static culture. Improved in vitro models to mechanistically interrogate cardiotoxicity would utilize more adult-like, mature hiPSC-derived cells in an integrated system whereby toxic drugs and protective agents can flow between hiPSC-ECs that represent systemic vasculature and hiPSC-CMs that represent heart muscle (myocardium). Such models would be useful for testing the multi-lineage cardiotoxicities of chemotherapeutic drugs such as VEGFR2/PDGFR-inhibiting tyrosine kinase inhibitors (VPTKIs). Here, we develop a multi-lineage, fully-integrated, cardiovascular organ-chip that can enhance hiPSC-EC and hiPSC-CM functional and genetic maturity, model endothelial barrier permeability, and demonstrate long-term functional stability. This microfluidic organ-chip harbors hiPSC-CMs and hiPSC-ECs on separate channels that can be subjected to active fluid flow and rhythmic biomechanical stretch. We demonstrate the utility of this cardiovascular organ-chip as a predictive platform for evaluating multi-lineage VPTKI toxicity. This study may lead to the development of new modalities for the evaluation and prevention of cancer therapy-induced cardiotoxicity.  a1473-0189