Systems Modeling Guided Bone regeneration

 描述（由申请人提供）：用于支架修复的工程化血管化骨组织仍然是一个重要的临床问题。一个主要的挑战是开发基于协调实验的系统模型。第二个挑战是了解生长因子线索的时间组合的协同效应的潜在机制。骨组织工程的第三个挑战是建立功能良好的血管网络。为了应对这些挑战，我们计划利用我们在生物材料，细胞生物学和计算建模方面的专业知识，开发连贯的实验方案，材料工程和多尺度数学模型，以系统地优化骨再生（称为sBone系统）。这种骨修复过程可能受到许多复杂途径的控制。以经典的BMP-2/IGF-1双生长因子时序组合系统为生物学模型，通过系统生物学研究，提出了BMP-2诱导MSCs的Smad 1/2信号通路，逐渐重塑Runx 2和Osx通路的表达模式，从而使MSCs对IGF-1的晚期信号敏感的假说。我们将首先开发体外多时间尺度模型，用于促进骨再生的生长因子的最佳时间组合，并使用该模型进行计算机筛选和候选生长因子组合的体外验证。第二，我们将在新型预血管化大孔、可生物降解的β-磷酸三钙（β-TCP）基支架内开发一种预测性多尺度骨再生模型，该支架装载有程序化生长因子释放系统。最后，我们将指导骨支架的化学-物理特性的设计，通过在硅片上优化生长因子释放曲线和大孔的几何参数。通过计算机模拟和实验分析的整合，我们将能够使用系统生物学方法来优化从工程血管移植的3D支架中释放生长因子的时间组合，以实现成功的体内骨再生。

 DESCRIPTION (provided by applicant): Engineering vascularized bone tissue for scaffolding repairing remains a significant clinical problem. One major challenge is to develop systematic models based on coordinated experiments. The second challenge is to understand the underlying mechanisms of the synergistic effects of the temporal combinations of growth factor cues. The third challenge in bone tissue engineering is the establishment of a well functional vascular network. In order to address these challenges, we plan to take advantage of our expertise in biomaterials, cell biology and computational modeling to develop coherent experimental protocols, material engineering and multi-scale mathematical models for systematically optimizing bone regeneration (called sBone system). This bone repairing process is likely under the control of many complex pathways. Using the classical BMP-2/IGF-1 dual-growth-factor temporal combination system as the biological model, our systems biology research, led to the hypothesis that BMP-2 induces Smad1/2 signaling pathways of MSCs, gradually remodels the expression pattern of Runx2 and Osx pathways, and thus sensitizes MSCs to the late IGF-1 cue. We will first develop in-vitro multi-temporal scale model for optimal temporal combinations of growth factors to promote bone regeneration, and conduct in-silico screening using the model and in-vitro validation of candidate growth factor combinations. Second, we will develop a predictive multi-scale model of bone regeneration within the novel pre-vascularized macro-porous, biodegradable beta-tricalcium phosphate (β-TCP) based scaffolds loaded with the programmed growth factor release system. And finally we will guide the design of the chemo-physical features of bone scaffolds by in-silico optimization of growth factor release profiles and the geometric parameters of the macro-pores. Through integration of in silico and experimental analyses, we will be able to use systems biology approaches to optimize the temporal combinations of growth factor release from the engineering vessel grafted 3D scaffolds for successful in-vivo bone regeneration.