Versatile human cardiac tissues engineered with perfusable heart extracellular microenvironment for biomedical applications.

Engineered human cardiac tissues have been utilized for various biomedical applications, including drug testing, disease modeling, and regenerative medicine. However, the applications of cardiac tissues derived from human pluripotent stem cells are often limited due to their immaturity and lack of functionality. Therefore, in this study, we establish a perfusable culture system based on in vivo-like heart microenvironments to improve human cardiac tissue fabrication. The integrated culture platform of a microfluidic chip and a three-dimensional heart extracellular matrix enhances human cardiac tissue development and their structural and functional maturation. These tissues are comprised of cardiovascular lineage cells, including cardiomyocytes and cardiac fibroblasts derived from human induced pluripotent stem cells, as well as vascular endothelial cells. The resultant macroscale human cardiac tissues exhibit improved efficacy in drug testing (small molecules with various levels of arrhythmia risk), disease modeling (Long QT Syndrome and cardiac fibrosis), and regenerative therapy (myocardial infarction treatment). Therefore, our culture system can serve as a highly effective tissue-engineering platform to provide human cardiac tissues for versatile biomedical applications.

Blood-brain barrier-on-a-chip for brain disease modeling and drug testing.

The blood-brain barrier (BBB) is an interface between cerebral blood and the brain parenchyma. As a gate keeper, BBB regulates passage of nutrients and exogeneous compounds. Owing to this highly selective barrier, many drugs targeting brain diseases are not likely to pass through the BBB. Thus, a large amount of time and cost have been paid for the development of BBB targeted therapeutics. However, many drugs validated in in vitro models and animal models have failed in clinical trials primarily due to the lack of an appropriate BBB model. Human BBB has a unique cellular architecture. Different physiologies between human and animal BBB hinder the prediction of drug responses. Therefore, a more physiologically relevant alternative BBB model needs to be developed. In this review, we summarize major features of human BBB and current BBB models and describe organ-on-chip models for BBB modeling and their applications in neurological complications. [BMB Reports 2022; 55(5): 213-219].

Hybrid skin chips for toxicological evaluation of chemical drugs and cosmetic compounds.

Development of drugs and cosmetics for topical application require safety tests in skin models. However, current skin models, such as skin cell sheets and artificial tissue-engineered skin, do not allow sophisticated toxicological evaluations (e.g., sensory irritation, hepatotoxicity). Animal models are prohibited worldwide for testing cosmetics. Therefore, reliable human skin models that recapitulate physiological events in skin tissue need to be established under in vitro settings. In this study, hybrid human skin models that enable delicate toxicological evaluations of drugs and cosmetic compounds are demonstrated. To recapitulate skin cornification, keratinocytes in the top layer of a vertical microfluidic chip were cultured at the air-liquid interface. For the skin-nerve hybrid model, differentiated neural stem cells in 3D collagen were positioned adjacent to and right below the skin layer. This model enables real-time quantitative skin sensitization analysis following chemical treatments by detecting alterations in neuronal activity in combination with a calcium imaging technique. For the skin-liver model, hepatic cells derived from pluripotent stem cells were cultured in 3D collagen distant from the skin layer. Potential hepatotoxicity of cutaneously applied chemicals in this model can be evaluated by quantification of glutathione and reactive oxygen species. Our study suggests that 3D hybrid skin chips would provide useful human skin models in pharmaceutical and cosmetic industries.

Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier.

The neurovascular unit, which consists of vascular cells surrounded by astrocytic end-feet and neurons, controls cerebral blood flow and the permeability of the blood-brain barrier (BBB) to maintain homeostasis in the neuronal milieu. Studying how some pathogens and drugs can penetrate the human BBB and disrupt neuronal homeostasis requires in vitro microphysiological models of the neurovascular unit. Here we show that the neurotropism of Cryptococcus neoformans-the most common pathogen causing fungal meningitis-and its ability to penetrate the BBB can be modelled by the co-culture of human neural stem cells, brain microvascular endothelial cells and brain vascular pericytes in a human-neurovascular-unit-on-a-chip maintained by a stepwise gravity-driven unidirectional flow and recapitulating the structural and functional features of the BBB. We found that the pathogen forms clusters of cells that penetrate the BBB without altering tight junctions, suggesting a transcytosis-mediated mechanism. The neurovascular-unit-on-a-chip may facilitate the study of the mechanisms of brain infection by pathogens, and the development of drugs for a range of brain diseases.