A Pulsatile Flow System to Engineer Aneurysm and Atherosclerosis Mimetic Extracellular Matrix

• Published in: Advanced science Vol. 7; no. 12; pp. 2000173 - n/a
• Main Authors: Hosseini, Vahid, Mallone, Anna, Mirkhani, Nima, Noir, Jerome, Salek, Mehdi, Pasqualini, Francesco Silvio, Schuerle, Simone, Khademhosseini, Ali, Hoerstrup, Simon P., Vogel, Viola
• Format: Journal Article
• Language: English
• Published: Weinheim John Wiley & Sons, Inc 01.06.2020; John Wiley and Sons Inc; Wiley
• Subjects: Aneurysms; arterial wall diseases; Atherosclerosis; Collagen; Extracellular matrix; Flow velocity; human vascular smooth muscle cells; in vitro 3D tissue models; pulsatile flow; Shear stress; Turbulence models
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202000173

Alterations of blood flow patterns strongly correlate with arterial wall diseases such as atherosclerosis and aneurysm. Here, a simple, pumpless, close‐loop, easy‐to‐replicate, and miniaturized flow device is introduced to concurrently expose 3D engineered vascular smooth muscle tissues to high‐velocity pulsatile flow versus low‐velocity disturbed flow conditions. Two flow regimes are distinguished, one that promotes elastin and impairs collagen I assembly, while the other impairs elastin and promotes collagen assembly. This latter extracellular matrix (ECM) composition shares characteristics with aneurysmal or atherosclerotic tissue phenotypes, thus recapitulating crucial hallmarks of flow‐induced tissue morphogenesis in vessel walls. It is shown that the mRNA levels of ECM of collagens and elastin are not affected by the differential flow conditions. Instead, the differential gene expression of matrix metalloproteinase (MMP) and their inhibitors (TIMPs) is flow‐dependent, and thus drives the alterations in ECM composition. In further support, treatment with doxycycline, an MMP inhibitor and a clinically used drug to treat vascular diseases, halts the effect of low‐velocity flow on the ECM remodeling. This illustrates how the platform can be exploited for drug efficacy studies by providing crucial mechanistic insights into how different therapeutic interventions may affect tissue growth and ECM assembly. Alterations of hemodynamics are associated with vascular wall diseases. A simple, pumpless, close‐loop, easy‐to‐replicate flow device to engineer de novo‐grown disease‐like extracellular matrix of vascular wall tissues is proposed. Mechanistic insights of a clinically practiced matrix metalloproteinase inhibitor used to treat aneurysm and atherosclerosis, and on how the stage of the disease might affect the efficacy of the treatment are gained.