Tissue engineering, after decades of exciting progress and monumental breakthroughs, has yet to make a significant impact on patient health. It has become apparent that a dearth of biomaterial scaffolds which possess the material properties of human tissue while remaining bioactive and cytocompatible, has been partly responsible for this lack of clinical translation. Herein, we propose the development of interpenetrating polymer network (IPN) hydrogels as materials that can provide cells with an adhesive extracellular matrix-like 3D microenvironment while possessing the mechanical integrity to withstand physiological forces. These hydrogels can be synthesized from biologically derived or synthetic polymers, the former polymer offering preservation of adhesion, degradability, and microstructure and the latter polymer offering tunability and superior mechanical properties. We review critical advances in the enhancement of mechanical strength, substrate-scale stiffness, electrical conductivity, and degradation in IPN hydrogels intended as bioactive scaffolds in the past 5 years. We also highlight the exciting incorporation of IPN hydrogels into state-of-the-art tissue engineering technologies, such as organ-on-a-chip and bioprinting platforms. These materials will be critical in the engineering of functional tissue for transplant, disease modeling and drug screening.
With new daily discoveries about the long-term impacts of COVID-19 there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID-19. Here we demonstrate the utility of developing a model of endothelial dysfunction that utilizes induced pluripotent stem cell-derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID-19 on the endothelium. We found that treating these cell-laden hydrogels with SARS-CoV-2 spike protein resulted in a significant decrease in the number of vessel-forming cells as well as vessel network connectivity. Following treatment with the anti-inflammatory drug dexamethasone, we were able to prevent SARS-CoV-2 spike protein-induced endothelial dysfunction. In addition, we confirmed release of inflammatory cytokines associated with the COVID-19 cytokine storm. In conclusion, we have demonstrated that even in the absence of immune cells, we are able to use this 3D in vitro model for angiogenesis to reproduce COVID-19 induced endothelial dysfunction seen in clinical settings.
With new daily discoveries about the long‐term impacts of COVID‐19, there is a clear need to develop in vitro models that can be used to better understand the pathogenicity and impact of COVID‐19. Here, we demonstrate the utility of developing a model of endothelial dysfunction that utilizes human induced pluripotent stem cell‐derived endothelial progenitors encapsulated in collagen hydrogels to study the effects of COVID‐19 on the endothelium. These cells form capillary‐like vasculature within 1 week after encapsulation and treating these cell‐laden hydrogels with SARS‐CoV‐2 spike protein resulted in a significant decrease in the number of vessel‐forming cells as well as vessel network connectivity quantified by our computational pipeline. This vascular dysfunction is a unique phenomenon observed upon treatment with SARS‐CoV‐2 SP and is not seen upon treatment with other coronaviruses, indicating that these effects were specific to SARS‐CoV‐2. We show that this vascular dysfunction is caused by an increase in inflammatory cytokines, associated with the COVID‐19 cytokine storm, released from SARS‐CoV‐2 spike protein treated endothelial cells. Following treatment with the corticosteroid dexamethasone, we were able to prevent SARS‐CoV‐2 spike protein‐induced endothelial dysfunction. Our results highlight the importance of understanding the interactions between SARS‐CoV‐2 spike protein and the endothelium and show that even in the absence of immune cells, the proposed 3D in vitro model for angiogenesis can reproduce COVID‐19‐induced endothelial dysfunction seen in clinical settings. This model represents a significant step in creating physiologically relevant disease models to further study the impact of long COVID and potentially identify mitigating therapeutics.
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