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

Vahid Hosseini,Ali Khademhosseini,Francesco Silvio Pasqualini,Nima Mirkhani,Simone Schuerle,Viola Vogel,Jerome Noir,Mehdi Salek,Anna Mallone,Simon P Hoerstrup

doi:10.1002/advs.202000173

Abstract

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.

Highlights

Atherosclerosis and aneurysms represent life-threatening pathological changes of the arterial wall,[1,2] and are associated with substantial morbidity and mortality caused by vessel rupture, hemorrhage, thromboembolism, ischemic events, and even leading to sudden death.[3]
Since diseased vessel walls are typically seen in regions of disturbed low velocity blood flow,[23] such as atherosclerotic and aneurysm and associated with alteration of arterial wall extracellular matrix (ECM) proteins, for example, elastin and collagens,[10,24,25,26] we evaluated the effect of flow on ECM assembly in the front and backsides of our tissue flaps
While a number of pump-driven in vitro fluidic cell culture models have been proposed for vascular research,[15,17,58] we introduce here a platform that can impose simultaneously two distinct pulsatile flow conditions on bioengineered 3D tissues (Figure 1)

Summary

Introduction

Atherosclerosis and aneurysms represent life-threatening pathological changes of the arterial wall,[1,2] and are associated with substantial morbidity and mortality caused by vessel rupture, hemorrhage, thromboembolism, ischemic events, and even leading to sudden death.[3]. Collagens (mainly types I, III, IV, V, and VI) and the most abundant type I collagen are highly expressed and assembled into fibrillar networks in diseased arteries compared to normal arteries.[10,11] In contrast, mature elastin fibers that have a halflife time extending to many years in humans get degraded in diseased artery walls,[12,13,14] affecting the mechanical properties of vessel walls These changes have been reported in humans and in animal models, a suitable human cellbased 3D in vitro model to simultaneously grow diseased and healthy vessel wall and to study de novo tissue morphogenesis has not yet been introduced.[5,15,16]. The data suggest for the first time why doxycycline has shown limited therapeutic efficacy in the clinic; because of its role in altering the collagen I, III, and elastin balance

Device Setup and Quantification of the Pulsatile Flow Patterns

Discussion

Experimental Section

Conflict of Interest