Atherosclerotic three-layer nanomatrix vascular sheets for high-throughput therapeutic evaluation.

In vitro atherosclerosis models are essential to evaluate therapeutics before in vivo and clinical studies, but significant limitations remain, such as the lack of three-layer vascular architecture and limited atherosclerotic features. Moreover, no scalable 3D atherosclerosis model is available for making high-throughput assays for therapeutic evaluation. Herein, we report an in vitro 3D three-layer nanomatrix vascular sheet with critical atherosclerosis multi-features (VSA), including endothelial dysfunction, monocyte recruitment, macrophages, extracellular matrix remodeling, smooth muscle cell phenotype transition, inflammatory cytokine secretion, foam cells, and calcification initiation. Notably, we present the creation of high-throughput functional assays with VSAs and the use of these assays for evaluating therapeutics for atherosclerosis treatment. The therapeutics include conventional drugs (statin and sirolimus), candidates for treating atherosclerosis (curcumin and colchicine), and potential gene therapy (miR-146a-loaded liposomes). The high efficiency and flexibility of the scalable VSA functional assays should facilitate drug discovery and development for atherosclerosis.

Gd(ABE-DTTA), a novel contrast agent, at the MRI-effective dose shows absence of deleterious physiological effects in dogs.

The physiological effects of a novel MRI contrast agent, Gd(ABE-DTTA), were investigated in dogs, monitoring parameters in blood samples. Each animal (n = 8 in the short-term, n = 4 in the long-term group) underwent isoflurane anesthesia followed by the generation of myocardial infarction and received a contrast agent at the MRI effective dose. Blood samples were collected 24 and 48 h, and 7, 14, 28, 35, 49 and 56 days after contrast agent administration. No significant changes exceeding the normal range were detected in any of the investigated parameters except in alanine aminotransferase (ALT). ALT enzyme activity increased in the short-term group 24 and 48 h after agent administration as expected from the effect of isoflurane anesthesia. Between days 7 and 56 no elevation in ALT was observed. In dogs no substantial short- or long-term effect was observed on the investigated, physiological parameters after Gd(ABE-DTTA) administration at the MRI effective dose.