Patient-Specific Bioreactor Model for the Study of Human Ascending Aortic Diseases

Andreas Habertheuer, MD, PhD
Department of Surgery
Division of Cardiac Surgery
Poster Overview

The aortic valve is located between the heart and the aorta (the main artery of the human body) and normally consists of three flaps that regulate blood flow. 1-2% of the US population has a bicuspid aortic valve (BAV), essentially missing one flap which not only makes the valve prone to premature failure but also increases the likelihood of aortic dilatation (aneurysm). The mechanisms underlying BAV disease are complex and poorly understood but are likely a combination of genetic and cellular factors, as well as altered blood flow due to the missing flap. We used aortic cells isolated from a spectrum of patients with or without bicuspid aortic valves to essentially partially re-build the aorta and to study BAV disease using a bioreactor system.

We used two different tubular scaffolds [non-biological (PECUU) vs. biological [fibrin]) to guarantee a 3-dimensional vascular shape and provide ideal conditions for cellular growth and proliferation outside the human body. We observed that fibrin seems to provide a more adequate scaffold for proper growth of human aortic cells as well as deposition of extracellular

 

components such as collagen and elastin. We hope to use this novel and innovative system to elucidate the mechanisms underlying BAV disease.

The aortic valve is located between the heart and the aorta (the main artery of the human body) and normally consists of three flaps that regulate blood flow. 1-2% of the US population has a bicuspid aortic valve (BAV), essentially missing one flap which not only makes the valve prone to premature failure but also increases the likelihood of aortic dilatation (aneurysm). The mechanisms underlying BAV disease are complex and poorly understood but are likely a combination of genetic and cellular factors, as well as altered blood flow due to the missing flap. We used aortic cells isolated from a spectrum of patients with or without bicuspid aortic valves to essentially partially re-build the aorta and to study BAV disease using a bioreactor system.

We used two different tubular scaffolds [non-biological (PECUU) vs. biological [fibrin]) to guarantee a 3-dimensional vascular shape and provide ideal conditions for cellular growth and proliferation outside the human body. We observed that fibrin seems to provide a more adequate scaffold for proper growth of human aortic cells as well as deposition of extracellular components such as collagen and elastin. We hope to use this novel and innovative system to elucidate the mechanisms underlying BAV disease.

Scientific Abstract

The multifactorial nature of bicuspid aortic valve (BAV) aortopathy represents a major barrier to investigation and precludes productive use of a relevant animal model. To address these limitations, we engineered a bioreactor-based culture model to study human primary aortic smooth muscle cells (hSMCs) and their derived extracellular matrix (ECM) in a 3-dimensional environment using non-biological and biological vascular scaffolds. hSMCs were isolated from ascending aortas of BAV patients with varying degrees of aortopathy, embedded in polyester carbonate urethane urea (PECUU)- or fibrin-based tubular scaffolds and subjected to pulsatile flow in a perfusion bioreactor. hSMC-derived ECM was assessed using RT-qPCR, histology, immunofluorescence and 2-photon microscopy. Both PECUU and fibrin-based scaffolds supported cellular growth and proliferation for over four weeks in dynamic culture. Qualitative analyses of ECM revealed more deposition of fibrillar collagen and elastin in fibrin scaffolds when compared to PECUU scaffolds. The biologic porous network of fibrin fibers appears to promote cell growth and proliferation and better facilitate ECM deposition, thus providing a promising model for human aortic diseases. Future experimental strategies will use this bioreactor system to elucidate underlying cellular and molecular mechanisms that distinctly govern BAV aortopathy.

Clinical Implications
The multifactorial nature of BAV aortic disease and the lack of relevant animal models represent a significant barrier to investigation. To this end, we developed a bioreactor-based 3- dimensional cell culture model to study patient-specific mechanisms of BAV aortic disease.
Research Areas
Authors
Andreas Habertheuer, Leonid V Emerel, George R Fercana, Jennifer C Hill, Julie A Phillippi, Marie Billaud, Thomas G Gleason
Principal Investigator
Thomas Gleason

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