Abstract
Current in vivo and in vitro models fail to accurately recapitulate the human heart microenvironment for biomedical applications. This study explores the use of cardiac spheroids (CSs) to biofabricate advanced in vitro models of the human heart. CSs were created from human cardiac myocytes, fibroblasts and endothelial cells (ECs), mixed within optimal alginate/gelatin hydrogels and then bioprinted on a microelectrode plate for drug testing. Bioprinted CSs maintained their structure and viability for at least 30 d after printing. Vascular endothelial growth factor (VEGF) promoted EC branching from CSs within hydrogels. Alginate/gelatin-based hydrogels enabled spheroids fusion, which was further facilitated by addition of VEGF. Bioprinted CSs contracted spontaneously and under stimulation, allowing to record contractile and electrical signals on the microelectrode plates for industrial applications. Taken together, our findings indicate that bioprinted CSs can be used to biofabricate human heart tissues for long term in vitro testing. This has the potential to be used to study biochemical, physiological and pharmacological features of human heart tissue.
Highlights
Cardiovascular disease (CVD) is the leading cause of morbidity and death in the modern world.[1,2,3,4] More physiological models to study the human heart microenvironment may advance how to detect, prevent and treat CVD in the future.[5]
This allowed optimal alginate crosslinking while preventing the gelatin from liquifying at higher temperatures
In this study we have shown that bioprinted cardiac spheroids comprising human cardiac endothelial cells, fibroblasts and iPSC-derived cardiomyocytes represent the optimal microenvironment for cells to grow in for long term studies (Figures 1-2 and S1)
Summary
Cardiovascular disease (CVD) is the leading cause of morbidity and death in the modern world.[1,2,3,4] More physiological models to study the human heart microenvironment may advance how to detect, prevent and treat CVD in the future.[5]. [5, 6] These include in vitro cardiac models utilizing human cells to test their molecular, cellular and extracellular response when they are exposed to pathophysiological conditions, currently limited by their ability to replicate the complex cardiac tissue environment.[1, 5, 7] Advanced bioengineered cardiac in vitro models can assist in improving current treatments by better replicating the cardiac tissue microenvironment under physiological and pathological conditions..[5] Current in vitro models which utilize monolayer cell cultures are limited by cells growing as a monolayer on a flat surface contrary to the three-dimensional nature of tissue.
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