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

组织工程涉及到使用支架生物材料来提供一个原生的细胞外基质环境，以实现活细胞功能和组织形成。经验实验已经成为测试和优化特定组织应用的个体生物材料参数的主要方法。然而，如果只使用经验方法，工程过程是昂贵和费力的，以排列所有可能的参数。在这个NSERC研究项目中，我们建议将计算建模整合到组织工程的生物材料设计过程中。计算机模型将用于确定支架材料的哪些参数对于获得具有类似结构和功能特性的工程组织至关重要。人类声带在组织工程中面临着独特的挑战。VF构成复杂的层状细胞外基质结构，具有一定的组织粘弹性范围。当我们说话或唱歌时，VF的机械功能要求特别高，其中褶皱振荡高达2,000 Hz。我们的团队开发了基于主体的初始模型（ABM），以数值模拟水凝胶支架内基本的VF细胞活动。我们还开发了一个高性能的并行计算平台，允许在全VF生理尺度上实现ABM。此外，连续体力学模型（CMM）和有限元模型（FEM）用于研究声音产生的生物力学和气动声学机制，与我们的机械工程师合作。这项NSERC研究计划的长期目标是开发一个多尺度计算平台，用于VF组织工程支架生物材料的合理设计。近期目标是：(1)量化巨噬细胞和成纤维细胞对水凝胶支架的生物学反应；(2)使用我们内部的VF生物反应器量化相同细胞对发音相关机械负荷的机械生物学反应；(3)更新和耦合CMM、FEM和ABM，数值模拟工程VF组织随材料参数和力学载荷的时间演化。多尺度计算建模是一种辅助复杂组织工程的新方法。集体HQP培训活动将包括但不限于生物材料设计、细胞培养、组织学、生物反应器操作、共聚焦显微镜、高通量流式细胞术、蛋白质分离和分析、系统生物学以及计算机建模。博士生3人，硕士生1人，本科生3人。我们的工作将为机械生物学，组织工程学和计算生物学做出重大贡献，最终目标是开发工程化的VF组织，以实现其独特的人类发音功能。

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.