Human induced pluripotent stem cell-derived fiber-shaped cardiac tissue on a chip

Abstract

We propose a method for the production of a fiber-shaped three-dimensional (3D) cellular construct of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) for the quantification of the contractile force. By culturing the cardiomyocytes in a patterned hydrogel structure with fixed edges, we succeeded in fabricating hiPS-CM fibers with aligned cardiomyocytes. The fiber generated contractile force along the fiber direction due to the hiPS-CM alignment, and we were able to measure its contractile force accurately. Furthermore, to demonstrate the drug reactivity of hiPS-CM fibers, the changes in the contractile frequency and force following treatment with isoproterenol and propranolol were observed. We believe that hiPS-CM fibers will be a useful tool for pharmacokinetic analyses during drug development.

Engineering Muscle Networks in 3D Gelatin Methacryloyl Hydrogels: Influence of Mechanical Stiffness and Geometrical Confinement

“…Two of the most challenging aspects consist in attaining (i) a proper 3D organization of myotubes into highly packed and aligned structures (as to mimic the native SM tissue) and (ii) an advanced maturation of the myotubes in terms of formation and development of sarcomeres. To address these challenges, different strategies have been developed in the recent past (Almany and Seliktar, 2005; Fuoco et al, 2012, 2015; Manabe et al, 2012; Melchels et al, 2012; Malda et al, 2013; Juhas et al, 2014; Heher et al, 2015; Madden et al, 2015; Kang et al, 2016; Morimoto et al, 2016). In particular, to promote a proper 3D organization of myotubes that could mirror the natural organization of muscle fascicles, bioreactors have been designed to stimulate the constructs loaded with myogenic progenitors either mechanically or electrically (Powell et al, 2002; Manabe et al, 2012; Ito et al, 2014; Heher et al, 2015; Kang et al, 2016).…”

Hydrogel Microchambers Integrated with Organic Electrodes for Efficient Electrical Stimulation of Human iPSC‐Derived Cardiomyocytes

“…Therefore, it is still an open question whether the maturation level of hiPSC‐CMs in this study is enough or not, and further maturation should be investigated in a future work. It should also be noted that the maturation of hiPSC‐CMs in this study would be more convincing by examining expression of other sarcomeric proteins and connexin in conjunction with the genetic expression of maturation markers as well as transmission electron microscopy of sarcomere structures and estimation of contractile forces . However, in the current study they are not investigated since the main purpose of this paper is to demonstrate that the hydrogel microchamber with diagonally‐arranged organic electrodes can be used for efficient electrical stimulation.…”

“…Furthermore, the biocompatibility makes it possible to arrange multiple electrodes in a densely‐packed manner for cost‐effective mass production of matured hiPSC‐CMs (Figure S2, Supporting Information). In this study, we focused on hiPSC‐CM spheroids since they are well‐characterized 3D cultures as opposed to the conventional 2D cell culture, however, other techniques for enhancement of maturation such as line patterning and mechanical loading can also be utilized in the hydrogel microchambers by altering the design and dimension of the microchambers and electrodes.…”

“…[13] Therefore, it is still an open question whether the maturation level of hiPSC-CMs in this study is enough or not, and further maturation should be investigated in a future work. It should also be noted that the maturation of hiPSC-CMs in this study would be more convincing by examining expression of other sarcomeric proteins and connexin [24] in conjunction with the genetic expression of maturation markers [38] as well as transmission electron microscopy of sarcomere structures [13] Macromol. Biosci.…”

“…2019, 19,1900060 and estimation of contractile forces. [38] However, in the current study they are not investigated since the main purpose of this paper is to demonstrate that the hydrogel microchamber with diagonally-arranged organic electrodes can be used for efficient electrical stimulation.…”