Engineering 3D Bioprinted Cardiac Spheroidal Droplets with Cardiomyocytes and Cardiac Fibroblasts for Tissue Engineering and Drug Cytotoxicity Studies
Engineering is the supreme human endeavor that involves harnessing the scientific understanding of the natural world to design and invent objects to improve the society around us. Biomedical engineering is the implementation of concepts acquired from engineering in biology and medicine that aims to improve human health through the integration of engineering with biomedical sciences. The mission of a biomedical engineer is to develop technologies that help advance the quality of people’s health using various tools and materials with one passion and goal: making the patient’s life longer and easier. Tissue engineering is developed from the field of biomaterials and refers to the application of incorporating scaffolds, cells, and biologically active molecules into functional tissues. Engineered tissue replicates must provide in vivo-like physiological demands and have the ability to enable suitable dynamic and mechanical environments for the hosted cells. Heart disease is the leading cause of death worldwide and in the United States. The most common type is coronary artery disease, which can cause heart-related diseases leading to heart failure. When a plaque first grows within the walls of the coronary arteries, the blood flow to the heart becomes limited. If not treated over time, the heart muscle or myocardium will start to die, causing a heart attack. Tissue engineering aims to fabricate functional constructs that have the potential to regenerate damaged tissues. Two-dimensional cultured-based systems lack cell-cell and cell-matrix interactions, and failure to mimic the in vivo microenvironment of the native heart ultimately increases the need for an in vitro fabrication of three-dimensional (3D) cardiac tissue models for more effective drug toxicity testing and pharmaceutical assays. To surpass the current limitations in tissue engineering approaches, in this study three-dimensional bioprinting technology has been used to design a unique 3D cardiac spheroidal droplet hydrogel scaffold using medium viscosity alginate and gelatin using a CELLINK-BIO X printer. This technique was further scaled up to a high throughput 96-well array set-up with a six-axis robotic arm using a 3D bioprinter (BioAssemblyBot). This study produced morphologically consistent 3D spheroidal droplets with significant porosity and a degree of interconnectivity between the pores. The resultant scaffolds retained structural fidelity after 28 days confirming their use in long-term in vitro cell culture studies, and rheological studies performed on these 3D spheroidal droplets were found to be suitable for in vitro cardiac tissue engineering studies. Cell viability quantification showed a steady turnover of cells in the scaffolds for up to 14 days, and the percent heterocellular coupling (HC) between CMs and cardiac fibroblasts (CFs) was quantified. Based on such an existing premise, we adopted the optimized 3D bioprinted cardiac spheroidal model for testing the effects of cardiotoxicity induced by DOX. This study yielded a mass production of 3D spheroidal droplet scaffolds tailored to study the induced cytotoxic effects of DOX in vitro. We further anticipate using this 3D bioprinted model to facilitate early- phase drug development in preclinical studies with sufficient versatility to evaluate the responses of various drugs and small molecules more efficiently at a relatively low cost. As a more sophisticated and cardiac-relevant in vitro model, we expect to see increased adoption of this model for a better understanding of human biology as well as disease diagnosis and therapeutics.
El Khoury, Raven, "Engineering 3D Bioprinted Cardiac Spheroidal Droplets with Cardiomyocytes and Cardiac Fibroblasts for Tissue Engineering and Drug Cytotoxicity Studies" (2022). ETD Collection for University of Texas, El Paso. AAI30241263.