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Clinical Data 3D liver tissues composed of human hepatic stellate cells (HSC), human umbilical vein endothelial cells (HUVEC), and cryopreserved primary human hepatocytes were fabricated directly into 24-well Transwell® plates (Fig 3A). Histologic analyses conducted throughout the maturation and maintenance period show that the bioprinted tissues retained the compartmentalization of parenchymal and non-parenchymal components established at the time of fabrication, and that the tissues condense and remodel over time, yielding stable 3D structures with a minimal thickness of 250 μm in the Z axis, dense tissue-like cellularity, and no evidence of necrosis (Fig 3B). Masson’s trichrome staining of the 3D bioprinted liver tissues revealed defined areas of collagen deposition in the non-parenchymal regions of the tissues, consistent with published evidence that functional endothelial cells produce and secrete extracellular matrix (ECM) during vasculogenesis [31] (Fig 3C). This ECM allows for the formation of a cohesive tissue unit without the use of exogenous scaffolding materials. Immunofluorescent analyses of the tissues showed robust surface expression of the intercellular junctional protein E-cadherin as well as cytoplasm-localized human albumin in the hepatocytes of the parenchymal compartment (Fig 3D). Over time in culture, the endothelial cells form extensive networks, with evidence of lumens by day 21 (Fig 3E). While human and rodent HSCs maintained in standard monolayer culture on plastic undergo activation to a myofibroblast phenotype with concomitant upregulation of smooth muscle actin (α-SMA), the HSC resident in the interior of the 3D liver tissues express desmin and not α-SMA (Fig 3E and 3F), suggesting that they are capable of establishing and maintaining a quiescent state within the 3D multicellular environment [32, 33]. A subpopulation of activated stellate cells, identified by their expression of α-SMA, can be identified at the tissue/media interface (Fig 3F). Lipid storage and glycogen storage, two functions associated with hepatocytes in vivo, were also demonstrated in the bioprinted liver tissues after maturation (Fig 3G and 3H). Comparison of vimentin staining between bioprinted liver tissues and native human liver biopsy shows similar patterns of expression (Fig 4).

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