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

组织工程涉及使用支架生物材料来提供用于活细胞功能和组织形成的天然样细胞外基质环境。经验性实验一直是测试和优化特定组织应用的单个生物材料参数的支柱。然而，如果仅使用经验方法，则工程过程是昂贵且费力的，以置换所有可能的参数。在这个NSERC研究计划中，我们建议将计算建模集成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是获得与其天然组织在长期内具有相似结构和功能特性的工程组织的关键。人类声带（VF）在组织工程中具有独特的挑战。VF构成具有特定范围的组织粘弹性的复杂分层细胞外基质结构。VF的机械功能要求特别高，当我们说话或唱歌时，褶皱振荡高达2，000 Hz。我们的团队已经开发了初始的基于代理的模型（ABM），以数值模拟水凝胶支架内的基本VF细胞活动。我们还开发了一个高性能，并行计算平台，允许在一个完整的VF生理规模的ABM的实施。此外，连续力学模型（CMM）和有限元模型（FEM）用于研究与我们的机械工程师合作的声音产生的生物力学和航空声学机制。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。短期目标是：（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）使用我们的内部VF生物反应器量化相同细胞对发声相关机械负荷的机械生物学反应;（3）更新和耦合CMM，有限元和ABM数值模拟工程VF组织的时间演变作为材料参数和机械载荷的函数。多尺度计算模型是一种新的帮助设计复杂组织的方法。HQP集体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、蛋白质分离和测定、系统生物学以及计算机建模。三名博士，一名硕士和三名本科生研究实习生将由这个NSERC计划支持。我们的工作将为机械生物学，组织工程和计算生物学做出实质性贡献，最终目标是开发工程化VF组织，以实现其独特的人类发声功能。

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.