Vessel-on-a-Chip: A Powerful Tool for Investigating Endothelial COVID-19 Fingerprints

Abstract

Coronavirus disease (COVID-19) causes various vascular and blood-related reactions, including exacerbated responses. The role of endothelial cells in this acute response is remarkable and may remain important beyond the acute phase. As we move into a post-COVID-19 era (where most people have been or will be infected by the SARS-CoV-2 virus), it is crucial to define the vascular consequences of COVID-19, including the long-term effects on the cardiovascular system. Research is needed to determine whether chronic endothelial dysfunction following COVID-19 could lead to an increased risk of cardiovascular and thrombotic events. Endothelial dysfunction could also serve as a diagnostic and therapeutic target for post-COVID-19. This review covers these topics and examines the potential of emerging vessel-on-a-chip technology to address these needs. Vessel-on-a-chip would allow for the study of COVID-19 pathophysiology in endothelial cells, including the analysis of SARS-CoV-2 interactions with endothelial function, leukocyte recruitment, and platelet activation. "Personalization" could be implemented in the models through induced pluripotent stem cells, patient-specific characteristics, or genetic modified cells. Adaptation for massive testing under standardized protocols is now possible, so the chips could be incorporated for the personalized follow-up of the disease or its sequalae (long COVID) and for the research of new drugs against COVID-19.

Keywords: COVID-19; endothelial dysfunction; long COVID; microfluidic system; personalized COVID-19 follow-up; vessel-on-a-chip model.

Figure 1

Participation of vascular endothelium in COVID−19 pathophysiology. Homeostatic behavior of renin–angiotensin system depends on the balance of ACE/ACE2, and it has a role in several diseases such as heart failure, myocardial infarction, hypertension, kidney diseases, acute lung injury or diabetes mellitus. The interaction of SARS-CoV-2 with ACE2 can alter this balance, inducing endothelial dysfunction that could be on the basis of COVID-19 complications and many of its comorbidities. The situation of long COVID (COVID−19 symptoms persistence without virus infection), characterized by persistent endothelial dysfunction and long-lasting inflammation, could be related with COVID−19 severity and/or with ACE2 expression in tissues such as the endothelium. Abbreviations: ACE(2): angiotensin converting enzyme (2); ACEI: angiotensin converting enzyme inhibitors; Ang(1–7): angiotensin (1–7) peptide; Ang II: angiotensin II; ARB: angiotensin receptor blockers; ARDS: acute respiratory distress syndrome; AT1R: angiotensin type 1 receptor; CHD: coronary heart disease; COVID-19: coronavirus disease; DM: diabetes mellitus; HT: hypertension; MasR: mas receptor; RAS: renin–angiotensin system; ROS: reactive oxygen species; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.

Figure 2

Vessel-on-a-chip (VoC) opportunities in COVID-19 research. VoC models for COVID-19 would allow the study of the pathophysiology of the disease in endothelial cells, analyzing the interaction of SARS-CoV-2 with endothelial function, leukocytes recruitment and platelet activation. In these models, “personalization” could be implemented through induced pluripotent stem cells, the implementation of patient-specific characteristics or genetic modified cells. Point-of-care characteristics should be implemented in the models to guarantee massive testing under standardized protocols. These characteristics could be incorporated for the personalized follow-up of the disease or its sequalae (long COVID) and for the research of new drugs against COVID-19 or to test the effects of common cardiovascular drugs. All of this is now possible thanks to the development of the microfabrication techniques for biomimetical miniaturization, which allow the needed pharmacological relevance in important functions of the endothelium. Abbreviations: EC: endothelial cells, ECM: extracellular matrix, iPSC: induced pluripotent stem cells, R&D: research and development, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2, VoC: vessel-on-a-chip.