Micro‐Engineered Heart Tissues On‐Chip with Heterotypic Cell Composition Display Self‐Organization and Improved Cardiac Function

Advanced Healthcare Materials, vol. 13, pp. e2303664

Abstract

Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety pharmacology. Conventional 3D Engineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs), endothelial (ECs)- and smooth muscle cells (SMCs), together with human cardiac fibroblasts (FBs), underflow, leading to self-organized miniaturized micro-EHTs (µEHTs) with a CM-EC interface reminiscent of the physiological capillary lining. µEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the EC layer altered drug responses in µEHT contraction. This observation suggests a potential barrier-like function of ECs, which may affect the availability of drugs to the CMs. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy.

Authors 9

1. Carla Cofiño‐Fabrés

   University of Twente

   Affiliation as printed

   Department of Applied Stem Cell Technologies TechMed Centre University of Twente Enschede 7522 NB The Netherlands

   Department of Applied Stem Cell Technologies, TechMed Centre, University of Twente, Enschede, 7522 NB The Netherlands

2. Tom Boonen
   Affiliation as printed

   River BioMedics B.V Enschede 7522 NB The Netherlands

   River BioMedics B.V, Enschede, 7522 NB The Netherlands

3. José M. Rivera‐Arbeláez

   Max Planck University of Twente Center for Complex Fluid Dynamics · University of Twente

   Affiliation as printed

   BIOS Lab‐on‐a‐Chip Group MESA+ Institute for Nanotechnology Max Planck Institute for Complex Fluid Dynamics University of Twente Enschede 7522 NB The Netherlands

   Department of Applied Stem Cell Technologies TechMed Centre University of Twente Enschede 7522 NB The Netherlands

   BIOS Lab-on-a-Chip Group, MESA+ Institute for Nanotechnology, Max Planck Institute for Complex Fluid Dynamics, University of Twente, Enschede, 7522 NB The Netherlands

   Department of Applied Stem Cell Technologies, TechMed Centre, University of Twente, Enschede, 7522 NB The Netherlands

4. Minke Rijpkema Aachen Department of Medicine Division of Endocrinology Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden 2300 RC The Netherlands

   Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 2300 RC The Netherlands

5. Lisanne L. Blauw Aachen Department of Medicine Division of Endocrinology Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden 2300 RC The Netherlands

   River BioMedics B.V Enschede 7522 NB The Netherlands

   Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 2300 RC The Netherlands

   River BioMedics B.V, Enschede, 7522 NB The Netherlands

6. Patrick C.N. Rensen Aachen Department of Medicine Division of Endocrinology Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine

   Leiden University · Leiden University Medical Center

   Affiliation as printed

   Department of Medicine Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden 2300 RC The Netherlands

   Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, 2300 RC The Netherlands

7. Verena Schwach

   University of Twente

   Affiliation as printed

   Department of Applied Stem Cell Technologies TechMed Centre University of Twente Enschede 7522 NB The Netherlands

   Department of Applied Stem Cell Technologies, TechMed Centre, University of Twente, Enschede, 7522 NB The Netherlands

8. Marcelo C. Ribeiro

   University of Twente

   Affiliation as printed

   Department of Applied Stem Cell Technologies TechMed Centre University of Twente Enschede 7522 NB The Netherlands

   River BioMedics B.V Enschede 7522 NB The Netherlands

   Department of Applied Stem Cell Technologies, TechMed Centre, University of Twente, Enschede, 7522 NB The Netherlands

   River BioMedics B.V, Enschede, 7522 NB The Netherlands

9. Robert C. J. J. Passier corresponding Aachen Department of Anatomy and Embryology

   Leiden University · Leiden University Medical Center · University of Twente

   Affiliation as printed

   Department of Anatomy and Embryology Leiden University Medical Centre Leiden 2300 RC The Netherlands

   Department of Applied Stem Cell Technologies TechMed Centre University of Twente Enschede 7522 NB The Netherlands

   Department of Anatomy and Embryology, Leiden University Medical Centre, Leiden, 2300 RC The Netherlands

   Department of Applied Stem Cell Technologies, TechMed Centre, University of Twente, Enschede, 7522 NB The Netherlands