Investigation of Hypoxia-Induced Myocardial Injury Dynamics in a Tissue Interface Mimicking Microfluidic Device

Abstract

Myocardial infarction is a major cause of morbidity and mortality worldwide. However, the methodological development of a spatiotemporally controllable investigation of the damage events in myocardial infarction remains challengeable. In the present study, we describe a micropillar array-aided tissue interface mimicking microfluidic device for the dynamic study of hypoxia-induced myocardial injury in a microenvironment-controllable manner. The mass distribution in the device was visually characterized, calculated, and systematically evaluated using the micropillar-assisted biomimetic interface, physiologically relevant flows, and multitype transportation. The fluidic microenvironment in the specifically functional chamber for cell positioning and analysis was successfully constructed with high fluidic relevance to the myocardial tissue. We also performed a microenvironment-controlled microfluidic cultivation of myocardial cells with high viability and regular structure integration. Using the well-established culture device with a tissue-mimicking microenvironment, a further on-chip investigation of hypoxia-induced myocardial injury was carried out and the varying apoptotic responses of myocardial cells were temporally monitored and measured. The results show that the hypoxia directionally resulted in observable cell shrinkage, disintegration of the cytoskeleton, loss of mitochondrial membrane potential, and obvious activation of caspase-3, which indicates its significant apoptosis effect on myocardial cells. We believe this microfluidic device can be suitable for temporal investigations of cell activities and responses in myocardial infarction. It is also potentially valuable to the microcontrol development of tissue-simulated studies of multiple clinical organ/tissue disease dynamics.

Heart-on-a-chip based on stem cell biology

“…Heart models in microsystems presented in literature allow research on the single cells level (Kaneko et al, 2007, Ges et al, 2008, Murthy et al, 2006, Cheng et al, 2006, multicellular cultures (Nguyen et al, 2009, Nguyen et al, 2015, Pong et al, 2011, Annabi et al, 2013, Ren et al, 2013, Grosberg et al, 2011 and 3D tissue tests (Huang et al, 2007b, Horiguchi et al, 2009, Cheah et al, 2010, Chen et al, 2013 (Table 1). These microsystems are more representative experimental models of the in vivo environment, than conventional culture dishes.…”

“…Heart diseases such as arythmia, ischemia or myocardial infraction were analyzed in the heart-on-a-chip (Ren et al, 2013, Grosberg et al, 2011, Klauke et al, 2003. Ischemia was mimic in a PDMS/glass microsystem integrated with gold electrodes (Fig.…”

“…This microsystem could be applied for investigation of novel compounds to modulate excitation beating of adult cardiomyoctes. In turn, Ren et al presented a microsystem for dynamic study of hypoxiainduced myocadrial injury in a controllable microenvironment (Ren et al, 2013). The PDMS microsystem consists of the central microchamber for cell culture and analysis and side microchannels for flow of culture medium (Fig.…”

Precise manipulation of cell behaviors on surfaces for construction of tissue/organs

“…In these organ-on-chips models, some key aspects of organ-level microenvironment are mimicked and applied to cells or organ-like tissues by engineering and integrating the complex components. Various "organ-on-a-chip" systems, such as blood vessel [112][113][114][115][116][117][118][119][120][121][122], lung [123][124][125][126][127][128][129], heart [130][131][132][133][134][135][136][137], kidney [138][139][140][141][142], liver [143][144][145][146][147][148], brain [149,150], and gut [151], have been reported to reproduce target organ structures and functions better than conventional in vitro model systems. In the following section, we will introduce latest progress in "organ-on-a-chip" in the context of precise manipulation of cells on interfaces.…”

The Hypoxia-Reoxygenation Injury Model

“…Chemical hypoxia models that use mitochondrial uncoupling agents or respiration blockers reproduce the rapid onset of ischemia but there is no way to study the recovery processes that occur during reperfusion [6][7][8][9]. The significance of true hypoxia-reoxygenation models is in the capacity for recovery from the hypoxic phase, which makes these models especially useful for ischemia-related experiments.…”