A tissue-engineered valve needs to incorporate the complex microstructure of the native aortic valve if it is to be as durable as existing bioprosthetic valves. Native aortic valve cusps contain large collagen fiber bundles surrounded by tubes of elastin, linked together by elastin sheets and struts. They also contain glycosaminoglycans (GAGs) that bind water and give the valve cusp a gelatinous consistency. Our approach to tissue engineering the aortic valve is to fabricate the cusp from the building blocks described above. We have developed collagen fiber bundles using the principle of directed collagen gel shrinkage, a GAG matrix by crosslinking high molecular weight hyaluronan with divinyl sulfone, and elastin sheets and tubes by culturing neonatal aortic fibroblasts on the appropriate substrates. To make collagen fiber bundles, cells are mixed with solubilized fibrillar collagen and cast into silicon rubber wells fitted with microporous holders to entrap the gel and hold it in place. As the cells interact with the collagen fibrils, they contract and compact the gel. Since the gel is constrained in the longitudinal direction, it can contract only laterally, forming well-aligned, strong (> 1 MPa) collagen fiber bundles. Elastin sheaths from naturally around the collagen fiber bundles and atop the hyaluronan gel when the neonatal aortic fibroblasts are cultured for more than 4 weeks. The individual building blocks of the aortic valve cusp, designed and fabricated according to patterns dictated by the microstructure of the native aortic valve, will be stacked together to make the final composite, tissue-engineered aortic valve cusp.
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