Abstract
In vitro human tissue engineered human blood vessels (TEBV) that exhibit vasoactivity can be used to test human toxicity of pharmaceutical drug candidates prior to pre-clinical animal studies. TEBVs with 400–800 μM diameters were made by embedding human neonatal dermal fibroblasts or human bone marrow-derived mesenchymal stem cells in dense collagen gel. TEBVs were mechanically strong enough to allow endothelialization and perfusion at physiological shear stresses within 3 hours after fabrication. After 1 week of perfusion, TEBVs exhibited endothelial release of nitric oxide, phenylephrine-induced vasoconstriction, and acetylcholine-induced vasodilation, all of which were maintained up to 5 weeks in culture. Vasodilation was blocked with the addition of the nitric oxide synthase inhibitor L-NG-Nitroarginine methyl ester (L-NAME). TEBVs elicited reversible activation to acute inflammatory stimulation by TNF-α which had a transient effect upon acetylcholine-induced relaxation, and exhibited dose-dependent vasodilation in response to caffeine and theophylline. Treatment of TEBVs with 1 μM lovastatin for three days prior to addition of Tumor necrosis factor – α (TNF-α) blocked the injury response and maintained vasodilation. These results indicate the potential to develop a rapidly-producible, endothelialized TEBV for microphysiological systems capable of producing physiological responses to both pharmaceutical and immunological stimuli.
Highlights
Over 80% of proposed pharmaceutical drug candidates that enter clinical trials fail due to concerns with human efficacy and toxicity[1]
tissue engineered human blood vessels (TEBV) with dense collagen gel matrices were constructed by first embedding human neonatal dermal fibroblasts or mesenchymal stem cells in rat-tail collagen I matrices[15,25]
TEBVs were plastically compressed by suspension on absorbent tissue paper (Fig. 1b) which reduced water volume and increased collagen fiber density (Table S1)
Summary
Over 80% of proposed pharmaceutical drug candidates that enter clinical trials fail due to concerns with human efficacy and toxicity[1]. In addition to facilitating more accurate disease models through interaction with immunological stimuli, human MPS may serve as a bridge in the drug development pipeline between 2D cell culture studies and in vivo animal studies. Three-dimensional (3D) tissue models have the potential to allow us to evaluate human biological interactions and diseases by taking advantage of natural spatiotemporal cues, physiological fluid perfusion, a variety of cell types, and the complex extracellular matrix that are present in tissues but are absent from 2D culture plates[7]. An ideal TEBV for MPS applications would be comprised of human cells in a biological or biodegradable synthetic matrix, have a small inner diameter to reduce fluid volumes, exhibit enough mechanical strength to withstand physiological stresses, and be produced rapidly to facilitate efficient drug screening. The medial wall cells should exhibit a smooth muscle phenotype, be quiescent and be able to contract and relax in response to www.nature.com/scientificreports/
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