The need for a small-diameter bioartificial artery (BAA) is great, particularly for the replacement of diseased coronary arteries where vascular grafts based on synthetic polymers fail due to thrombosis and/or intimal hyperplasia. A BAA is obtained by seeding endothelial cells (EC) onto the luminal surface of a media-equivalent (ME), a tube of reconstituted type I collagen populated and compacted by smooth muscle cells (SMC). While the architecture (strong circumferential alignment of collagen and SMC) of the medial layer in the native artery can be obtained by mechanical constraint of ME compaction via a mandrel placed through its lumen, MEs fabricated to date have not possessed the proper mechanical properties, being too compliant and too weak. The ability to stiffen and strengthen MEs by glycation, the crosslinking of collagen and other cell-secreted extracellular matrix molecules, and use of fibrin instead of collagen to promote ECM synthesis and remodeling, both novel approaches to our knowledge, will be exploited in this research to obtain the target mechanical properties (those of the rat abdominal aorta). A large number of glycation conditions will be systematically studied, and ME fabricated from any conditions that yield the proper mechanical properties and dimensions will then be evaluated for tissue compatibility (i.e. not inducing significant inflammation). Cyclic distention to condition the SMC (i.e. induce the contractile phenotype) will be included at this stage. All ME that pass through this filter will then be seeded with EC. Those yielding an EC monolayer will be exposed to physiological flow to condition the EC and those retaining an intact monolayer will be evaluated for blood compatibility (i.e. not inducing significant platelet activation) and retention of the target mechanical properties. Those that pass through this filter (or the five types of BAA that best approximate the target mechanical properties if more than five) will then be implanted into the rat abdominal aorta, which has dimensions similar to the human coronary artery. The BAA will be retrieved over a series of times for histological assessment if acute failure does not occur. Adult cells will be used to fabricate the BAA instead of commonly used neonatal cells in an attempt to meet the stringent demands of autologous cell usage for patients. In a parallel study, MEs will be fabricated from human SMC. Identification of conditions that yield the target mechanical properties here, combined with success in the rat model described above, would imply a favorable probability that a BAA suitable for the human coronary artery can be attained in a future study.
