OICC Press Progress in Biomaterials 2194-0517 9 3 (September 2020) 2020 09 25 Hydrogel scaffolds with elasticity-mimicking embryonic substrates promote cardiac cellular network formation 10.1007/s40204-020-00137-0 EN Matthew Alonzo Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), El Paso, US Department of Metallurgical, Materials and Biomedical Engineering, M201 Engineering, The University of Texas at El Paso, El Paso, TX, 79968, US Shweta Anil Kumar Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), El Paso, US Department of Metallurgical, Materials and Biomedical Engineering, M201 Engineering, The University of Texas at El Paso, El Paso, TX, 79968, US Shane Allen Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, US Monica Delgado Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), El Paso, US Department of Metallurgical, Materials and Biomedical Engineering, M201 Engineering, The University of Texas at El Paso, El Paso, TX, 79968, US Fabian Alvarez-Primo Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), El Paso, US Department of Metallurgical, Materials and Biomedical Engineering, M201 Engineering, The University of Texas at El Paso, El Paso, TX, 79968, US Laura Suggs Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, 78712, US Binata Joddar Inspired Materials and Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), El Paso, US Department of Metallurgical, Materials and Biomedical Engineering, M201 Engineering, The University of Texas at El Paso, El Paso, TX, 79968, US Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX, 79968, US Journal Article 2020 09 25 Abstract Hydrogels are a class of biomaterials used for a wide range of biomedical applications, including as a three-dimensional (3D) scaffold for cell culture that mimics the extracellular matrix (ECM) of native tissues. To understand the role of the ECM in the modulation of cardiac cell function, alginate was used to fabricate crosslinked gels with stiffness values that resembled embryonic (2.66 ± 0.84 kPa), physiologic (8.98 ± 1.29 kPa) and fibrotic (18.27 ± 3.17 kPa) cardiac tissues. The average pore diameter and hydrogel swelling were seen to decrease with increasing substrate stiffness. Cardiomyocytes cultured within soft embryonic gels demonstrated enhanced cell spreading, elongation, and network formation, while a progressive increase in gel stiffness diminished these behaviors. Cell viability decreased with increasing hydrogel stiffness. Furthermore, cells in fibrotic gels showed enhanced protein expression of the characteristic cardiac stress biomarker, Troponin-I, while reduced protein expression of the cardiac gap junction protein, Connexin-43, in comparison to cells within embryonic gels. The results from this study demonstrate the role that 3D substrate stiffness has on cardiac tissue formation and its implications in the development of complex matrix remodeling-based conditions, such as myocardial fibrosis.