Doctoral Researcher Tampere University 33530 Tampere, Finland
Abstract: Ischemic heart disease (IHD) is the leading cause of death globally. In the disease, the blood flow to the myocardium is reduced or blocked, leading to oxygen deprivation and tissue damage. The primary treatment is reperfusion to restore blood flow and antiarrhythmic medication to prevent arrhythmias. Reperfusion, although necessary for recovery, can lead to worsening of the tissue injury. Previous animal experiments have provided promising results for medical interventions during reperfusion to reduce arrythmias or improve tissue regeneration, but they have failed in human clinical trials, indicating the need for human based models. Understanding the pathophysiology on a cellular lever, e.g., what mechanisms cause the arrythmias, promotes the development of more effective treatments. Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) have been used to study IHD, but the experiments have been conducted mostly with 2D cell models. To better mimic physiological environments, in-vitro disease modelling and preclinical drug testing are being shifted from 2D to more complex 3D systems. Here, we present a novel 3D hypoxia platform, combining engineered heart tissue (EHT) model with a system enabling precise control over oxygen concentrations on the chip. The base of the platform is an OxyGenie mini-incubator (BioGenium Microsystems, Finland) combined with field stimulation electrodes and an EHT-insert. Miniature EHT s are constructed on the EHT-insert lid by embedding 300 000 hiPSC-CMs within fibrinogen. The hypoxia-on-a-chip platform allows electrical stimulation on the tissue, and a way to analyze cardiac functionality real time during hypoxic periods, including assessment of the beating rate, emerging arrythmias and contractile force. Here we show that with our hypoxia-on-a-chip platform, iPSC-CMs and EHT technology can be effectively utilized to study cardiac tissue function under hypoxia. The miniature EHTs start beating spontaneously within the first week of culture and respond to the electrical stimulation. The chip design enables advanced imaging and precise control over temperature and oxygen concentration for real-time monitoring of the oxygen dynamics. Our preliminary results show strong potential for use in IHD modeling.
