Multi-Scale Computational Modeling of Vocal Fold Biomaterials and Engineered Tissue

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Tissue engineering involves the use of scaffold biomaterials to provide a native-like extracellular matrix environment for viable cell functions and tissue formation. Empirical experiments have been a mainstay of testing and optimizing individual biomaterial parameters for specific tissue applications. The engineering process is however costly and laborious to permute all possible parameters if empirical approaches are used exclusively. In this NSERC research program, we propose to integrate computational modeling into the biomaterial design process for tissue engineering. Computer models will be applied to identify which parameters of scaffold materials are crucial to attain an engineered tissue with similar structural and functional property as of its native in long term.******Human vocal folds (VF) possess a unique challenge in tissue engineering. The VF constitute a complex layered extracellular matrix structure with a specific range of tissue viscoelasticity. The mechanical function of VF is distinctively demanding in which the folds oscillate up to 2,000 Hz when we talk or sing. Our team has developed initial agent-based models (ABM) to numerically simulate essential VF cellular activities within hydrogel scaffolds. We also developed a high performance, parallel computing platform that allows the implementation of ABM at a full VF physiological scale. In addition, continuum mechanical models (CMM) and finite element models (FEM) are used to study the biomechanical and aeroacoustic mechanisms of voice production in collaboration with our mechanical engineers. The long-term goal of this NSERC research program is to develop a multi-scale computing platform that will be used for the rational design of scaffold biomaterials for VF tissue engineering. Short term goals are:******(1) to quantify the biological response of macrophages and fibroblasts to hydrogel scaffolds;***(2) to quantify the mechanobiological response of the same cells to phonation-relevant mechanical loadings using our in-house VF bioreactor, and;***(3) to update and couple CMM, FEM and ABM to numerically simulate the time evolution of engineered VF tissue as a function of material parameters and mechanical loadings.******Multiscale computational modeling is a novel approach to aid engineer complex tissues. A collective HQP training activities will include but not limited to biomaterial design, cell culture, histology, bioreactor operation, confocal microscopy, high-throughput flow cytometry, protein isolation and assaying, systems biology as well as computer modeling. Three doctoral, one master's and three undergraduate research trainees will be supported by this NSERC program. Our work will make substantial contribution to mechanobiology, tissue engineering and computational biology towards the ultimate goal of developing engineered VF tissues that will fulfill their unique function for human phonation.