Over the past two decades, the increase in prevalence of cardiovascular diseases and the limited availability of autologous blood vessels and saphenous vein grafts have motivated the development of tissue-engineered vascular grafts (TEVGs). However, compliance mismatch and poor mechanical properties of the TEVGs remain as two major issues that need to be addressed. Researchers have investigated the role of various culture conditions and mechanical conditioning in deposition and orientation of collagen fibers, which are the key structural components in the vascular wall; however, the intrinsic complexity of mechanobiological interactions demands implementing new engineering approaches that allow researchers to investigate various scenarios more efficiently. In this study, we utilized a coupled agent-based finite element analysis (AB-FEA) modeling approach to study the effect of various loading modes (uniaxial, biaxial, and equibiaxial), boundary conditions, stretch magnitudes, and growth factor concentrations on growth and remodeling of smooth muscle cell-populated TEVGs, with specific focus on collagen deposition and orientation. Our simulations (12 weeks of culture) showed that biaxial cyclic loading (and not uniaxial or equibiaxial) leads to alignment of collagen fibers in the physiological directions. Moreover, axial boundary conditions of the TEVG act as determinants of fiber orientations. Decreasing the serum concentration, from 10% to 5% or 1%, significantly decreased the growth and remodeling speed, but only affected the fiber orientation in the 1% serum case. In conclusion, in silico tissue engineering has the potential to evolve the future of tissue engineering, as it will allow researchers to conceptualize various interactions and investigate numerous scenarios with great speed. In this study, we were able to predict the orientation of collagen fibers in TEVGs using a coupled AB-FEA model in less than 8 h. Impact Statement Tissue-engineered vascular grafts (TEVGs) hold potential to replace the current gold standard of vascular grafting, saphenous vein grafts. However, developing TEVGs that mimic the mechanical performance of the native tissue remains a challenging task. We developed a computational model of the grafts' remodeling processes and studied the effects of various loading mechanisms and culture conditions on collagen fiber orientation, which is a key factor in mechanical performance of the grafts. We were able to predict the fiber orientations accurately and show that biaxial loading and axial boundary conditions are important factors in collagen fiber organization.
Keywords: AB-FEA; ABM; FEA; In Silico; TEVG; agent-based modeling; coronary artery; finite element analysis; mechanobiology; multiscale modeling; tissue-engineered vascular graft.