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Abstract This study presents the development and morphology analysis of bioinspired 3D cardiovascular tissue models cultured within a dynamic capillary circuit microfluidic device. This study is significant because our in vitro 3D cardiovascular tissue models retained within a capillary circuit microfluidic device provide a less expensive, more controlled, and reproducible platform for more physiologically-relevant evaluation of cellular response to microenvironmental stimuli. The overall aim of our study is to demonstrate our cardiovascular tissue model (CTM) and vascular tissue model (VTM) actively changed their cellular morphology and exhibited structural reorganization in response to biophysical stimuli provided by microposts within the device tissue culture chambers during a 5-day period. The microfluidic device in this study was designed with the Young–Laplace and Navier–Stokes principles of capillary driven fluid flow and fabricated with 3D stereolithography (SLA) printing. The cardiac tissue model and vascular tissue model presented in this study were developed by encapsulating AC16 cardiomyocytes (CTM) and Human umbilical vein endothelial cells (VTM) in a fibrin hydrogel which were subsequently loaded into a capillary circuit microfluidic device. The cardiovascular tissue models were analyzed with fluorescent microscopy for morphological differences, average tube length, and cell orientation. We determined the VTM displayed capillary-like tube formation and the cells within both cardiovascular tissue models continued to elongate around microposts by day-5 which indicates the microfluidic system provided biophysical cues to guide cell structure and direction-specific organization. 

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Doxorubicin (DOX) is a highly effective anthracycline chemotherapy agent effective in treating a broad range of life-threatening malignancies but it causes cardiotoxicity in many subjects. While the mechanism of its cardiotoxic effects remains elusive, DOX-related cardiotoxicity can lead to heart failure in patients. In this study, we investigated the effects of DOX-induced cardiotoxicity on human cardiomyocytes (CMs) using a three-dimensional (3D) bioprinted cardiac spheroidal droplet based-system in comparison with the traditional two-dimensional cell (2D) culture model. The effects of DOX were alleviated with the addition of N -acetylcysteine (NAC) and Tiron. Caspase-3 activity was quantified, and reactive oxygen species (ROS) production was measured using dihydroethidium (DHE) staining. Application of varying concentrations of DOX (0.4 μM–1 μM) to CMs revealed a dose-specific response, with 1 μM concentration imposing maximum cytotoxicity and 0.22 ± 0.11% of viable cells in 3D samples versus 1.02 ± 0.28% viable cells in 2D cultures, after 5 days of culture. Moreover, a flow cytometric analysis study was conducted to study CMs proliferation in the presence of DOX and antioxidants. Our data support the use of a 3D bioprinted cardiac spheroidal droplet as a robust and high-throughput screening model for drug toxicity. In the future, this 3D spheroidal droplet model can be adopted as a human-derived tissue-engineered equivalent to address challenges in other various aspects of biomedical pre-clinical research. 

In this study, we designed a tissue-engineered neurocardiac model to help us examine the role of neuronal regulation and confirm the importance of neural innervation techniques for the regeneration of cardiac tissue. A three-dimensional (3D) bioprinted neurocardiac scaffold composed of a mixture of gelatin–alginate and alginate–genipin–fibrin hydrogels was developed with a 2:1 ratio of AC16 cardiomyocytes (CMs) and retinoic acid-differentiated SH-SY5Y neuronal cells (NCs) respectively. A unique semi-3D bioprinting approach was adopted, where the CMs were mixed in the cardiac bioink and printed using an anisotropic accordion design to mimic the physiological tissue architecture in vivo. The voids in this 3D structure were methodically filled in using a NC–gel mixture and crosslinked. Confocal fluorescent imaging using microtubule-associated protein 2 (MAP-2) and anticholine acetyltransferase (CHAT) antibodies for labeling the NCs and the MyoD1 antibody for the CMs revealed functional coupling between the two cell types in the final crosslinked structure. These data confirmed the development of a relevant neurocardiac model that could be used to study neurocardiac modulation under physiological and pathological conditions.