Biomechanics of aligned cell sheets for arterial tissue engineering
Backman, Daniel Edwin
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Cardiovascular disease remains the leading cause of death in the United States and oftentimes damaged or occluded arteries need to be replaced. Current surgical materials are unsuitable for small diameter, high pressure vessels such as the carotid and coronary artery because they cannot match the mechanical properties of native tissue. Compliance mismatch between the two materials leads to complications such as anastomotic intimal hyperplasia, thrombosis, and aneurysm. Therefore there is significant clinical need for a tissue engineered arterial graft suitable for small diameter, high pressure vessels. An artery is composed of three layers, but the middle layer, the tunica media, is responsible for bearing normal physiological loads. The medial layer features alternating layers of smooth muscle cells and extracellular matrix where each layer has smooth muscle cells and collagen aligned helically along the length of the artery. This structural feature coupled with the composition of the extracellular matrix cause arterial tissue to have a non-linear mechanical response. A tissue engineered vascular graft that recapitulates the native arterial structure may overcome the limitations of current tissue engineered strategies. We hypothesize that a tissue engineered arterial graft can be built by stacking aligned, single layer cell sheets to better mimic native mechanical properties. Cell sheets are confluent layer of cells and extracellular matrix. In the first aim of this work we developed an inexpensive, novel force sensor design capable of measuring small forces (< 1 mN) that we incorporated into a custom-built uniaxial tensile tester. For the second aim we developed a technique for culturing single layer, aligned, bovine vascular smooth cell sheets. We accomplished this by developing a technique for grafting N-isopropylacrylamide, a thermo-responsive polymer, onto the surface of flat and micropatterned poly-dimethylsiloxane (PDMS) substrates. These substrates allow cell sheets to be cultured and then be detached by decreasing the temperature. In the third aim we experimentally characterized the mechanical and structural properties of aligned vascular smooth muscle cell sheets to show that cell orientation can be controlled by the micropattern and that cellular alignment leads mechanical anisotropy. We also successfully modeled the cell sheet mechanical behavior using existing phenomenological models. The results from this work suggest that aligned cell sheets are capable of recapturing the non-linear stress-strain response of native arterial tissue, making them suitable for arterial tissue engineering. The results from this work provide an experimental and computational foundation for future efforts towards building a multi-layered cell sheet based arterial tissue.
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