Human Vascular Microphysiological System for in vitro Drug Screening

Area of Science:

• Biomedical Engineering
• Vascular Biology
• Toxicology

Background:

• In vitro models are needed to assess pharmaceutical toxicity.
• Tissue engineered blood vessels (TEBVs) offer a potential human-relevant model.
• Existing models may lack the necessary physiological complexity and functionality.

Purpose of the Study:

• To develop and characterize functional, tissue-engineered human blood vessels (TEBVs).
• To evaluate the vasoactive responses of TEBVs to pharmacological and immunological stimuli.
• To assess the potential of TEBVs as a platform for drug toxicity testing.

Main Methods:

• Human neonatal dermal fibroblasts or mesenchymal stem cells were embedded in collagen gel to create TEBVs.
• TEBVs were endothelialized and subjected to perfusion under physiological shear stress.
• Vasoactivity was assessed via responses to phenylephrine, acetylcholine, caffeine, theophylline, and TNF-α.
• Nitric oxide synthase inhibition (L-NAME) and lovastatin treatment were used to probe mechanisms.

Main Results:

• TEBVs supported endothelialization and perfusion within 3 hours, maintaining structural integrity for up to 5 weeks.
• TEBVs exhibited nitric oxide release, vasoconstriction, and vasodilation, mimicking native vessel responses.
• Responses to acetylcholine were modulated by TNF-α, and vasodilation was dose-dependent to caffeine and theophylline.
• Lovastatin treatment protected TEBVs from TNF-α-induced injury and preserved vasodilation.

Conclusions:

• Functional TEBVs can be rapidly produced and exhibit key vasoactive properties.
• TEBVs serve as a viable microphysiological system for evaluating drug and inflammatory responses.
• These engineered vessels hold promise for reducing reliance on animal models in preclinical toxicity testing.