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Donor-Derived Engineered Microvessels for Cardiovascular Risk Stratification of Patients with Kidney Failure
Mitesh L Rathod1, Wen Yih Aw1, Stephanie Huang1
1Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill and Raleigh, NC, 27599, 27695, USA.
Insights
Researchers developed a novel microvessel model to study how the uremic environment impacts blood vessel health in chronic kidney disease (CKD) patients. This new model shows increased vascular permeability, aiding in personalized CKD treatment strategies.
Area of Science:
- Biotechnology
- Cardiovascular Research
- Nephrology
Background:
- Cardiovascular disease (CVD) causes approximately 50% of deaths in hemodialysis patients.
- Uremic solute accumulation is a suspected driver of endothelial dysfunction and CVD in chronic kidney disease (CKD).
- Existing in vitro models are insufficient for studying the uremic environment's effects on the endothelium.
Purpose of the Study:
- To develop and validate a novel microfabricated human blood vessel model.
- To assess the impact of the uremic environment on microvascular integrity and permeability.
- To evaluate the potential of this model for risk stratification and personalized treatment in CKD patients.
Main Methods:
- Microfabrication of human blood vessels using donor cells.
- Perfusion of microvessels with donor serum.
- Quantification of vascular permeability in response to uremic serum and indoxyl sulfate.
Main Results:
- The engineered microvessels exhibited increased permeability and irregular cell-cell junctions under uremic conditions.
- The model demonstrated higher sensitivity compared to traditional 2D cell culture assays.
- Uremic serum from CKD patients and uremic pigs significantly affected microvascular integrity.
Conclusions:
- The developed microvessel model effectively replicates the detrimental effects of the uremic environment on vascular integrity.
- This technology offers a promising platform for understanding CKD-related endothelial dysfunction.
- The model has the potential to guide personalized treatment strategies and risk stratification for CKD patients.
Abstract:
Cardiovascular disease is the cause of death in ≈50% of hemodialysis patients. Accumulation of uremic solutes in systemic circulation is thought to be a key driver of the endothelial dysfunction that underlies elevated cardiovascular events. A challenge in understanding the mechanisms relating chronic kidney disease to cardiovascular disease is the lack of in vitro models that allow screening of the effects of the uremic environment on the endothelium. Here, a method is described for microfabrication of human blood vessels from donor cells and perfused with donor serum. The resulting donor-derived microvessels are used to quantify vascular permeability, a hallmark of endothelial dysfunction, in response to serum spiked with pathophysiological levels of indoxyl sulfate, and in response to serum from patients with chronic kidney disease and from uremic pigs. The uremic environment has pronounced effects on microvascular integrity as demonstrated by irregular cell-cell junctions and increased permeability in comparison to cell culture media and healthy serum. Moreover, the engineered microvessels demonstrate an increase in sensitivity compared to traditional 2D assays. Thus, the devices and the methods presented here have the potential to be utilized to risk stratify and to direct personalized treatments for patients with chronic kidney disease.
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