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The growth and culture of cardioids is either conducted in suspension culture or heavily relies on Matrigel encapsulation. Despite the significant advancements in cardioid technology, reproducibility remains a major challenge, limiting their widespread use in both basic research and translational applications. Here, for the first time, we employed synthetic, matrix metalloproteinase (MMP)\u2010degradable polyethylene glycol (PEG)\u2010based hydrogels to define the effect of mechanical and\u00a0biochemical\u00a0cues on cardioid development. Successful cardiac differentiation is demonstrated in all the hydrogel conditions, while cardioid cultured in optimized PEG hydrogel (3 wt.% PEG\u20102mM RGD) underwent similar morphological development and comparable tissue functions to those cultured in Matrigel. Matrix stiffness and cell adhesion motif play a critical role in cardioid development, nascent chamber formation, contractile physiology, and endothelial cell gene enrichment. More importantly, synthetic hydrogel improved the reproducibility in cardioid properties compared to traditional suspension culture and Matrigel encapsulation. Therefore, PEG\u2010based hydrogel has the potential to be used as an alternative to Matrigel for human cardioid culture in a variety of clinical applications including cell therapy and tissue engineering.<\/jats:p>","DOI":"10.1002\/adhm.202403997","type":"journal-article","created":{"date-parts":[[2025,5,16]],"date-time":"2025-05-16T05:22:15Z","timestamp":1747372935000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Mechanically and Chemically Defined PEG Hydrogels Improve Reproducibility in Human Cardioid Development"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2271-1079","authenticated-orcid":false,"given":"Yuanhui","family":"Song","sequence":"first","affiliation":[{"name":"Department of Biomedical &amp; Chemical Engineering Syracuse University  Syracuse NY 13244 USA"},{"name":"BioInspired Institute for Material and Living Systems Syracuse University  Syracuse NY 13244 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