Engineered Human Vascular Models to Study Endothelial Dysfunction in Infectious Disease

Project Overview

The pathogenesis of numerous emerging viral threats is intricately linked to vascular involvement. Pathogens that affect endothelial cells lining blood vessels have profound systemic consequences, leading to complications such as thrombosis and vascular leakage. While the innate immune response serves as a critical defense against these infections, it can also contribute to endothelial damage, as seen in diseases like COVID-19. The absence of therapies to restore endothelial homeostasis in infectious diseases necessitates new approaches that promote pathogen clearance while minimizing inflammation and collateral tissue damage.

The limitations of in vivo models, characterized by interspecies differences and an inability to accurately mimic human-restricted pathogens and comorbidities, underscore the need for an infectable, physiologically relevant human in vitro model. Unfortunately, existing human models lack the capability to directly visualize host-pathogen interactions in 3D. In this work, we sought to fill this gap by establishing the first human in vitro model to investigate interactions among pathogens, the innate immune system, and endothelium, specifically targeting the development of vasculopathy. We extended our existing 3D bioprinted vascular model to include diseased states mimicking vasculitis and incorporated immune components like monocytes. Both diseased and healthy engineered vessels were treated with SARS-CoV-2 pseudovirus to characterize viral infection of vascular networks. When compared to the inflammatory diseased state (i.e., cells exposed to TNF alpha) we saw an increased in immune cells attachment. Our research establishes a human in vitro model to explore how pathogens interact with the innate immune system and endothelial cells, leading to vasculopathy. These models represent a significant advancement in understanding how infections occur between hosts and pathogens.

Mission Impact

The work generated in this LW builds on two of the lab's core competencies: Advanced Materials and Manufacturing as well as Bioscience and Bioengineering. In this work, with the resources available at Lawrence Livermore National Laboratory (LLNL) (functional vascular beds and infectious diseases expertise), we developed a platform to interrogate the interactions of pathogens, the innate immune system, and endothelium leading to vasculopathy. Establishing an infectable human in vitro model holds paramount importance in unraveling the complexities of severe diseases and devising robust countermeasures. This model marks a significant stride in comprehending host-pathogen interactions, aligning with LLNL's global security objectives. Ultimately, this research strengthens the scientific, technological, and engineering capabilities essential to the NNSA mission, reinforcing the Laboratory's expertise in bioscience and bioengineering. Partnership with Northeastern University is anticipated to aid in developing a pipeline of talent in biomedical and materials engineering.

Publications, Presentations, and Patents

Monica Moya, "Bioprinted functional human vasculature and mechanisms of SARS-CoV-2 vasculitis" (Poster Presentation, 2022 Chemical and Biological Defense Science & Technology Conference, San Francisco, CA, Dec. 6-9, 2022). 

Monica Moya,"Engineering Human Vascular Beds To Study Endothelial Susceptibility To SARS-CoV-2" (Oral Presentation, Tissue Engineering and Regenerative Medicine Annual Conference, Boston, MA  April 11-14, 2023).