CAREER: Programming Vascularization by Design in Porous Composites

了解血管是如何生长的，对于推进许多领域至关重要，包括组织工程和癌症研究。许多因素影响新血管的生长，包括可获得多少氧气，存在的化学信号，以及这些血管生长所通过的基质(环境)。在这些因素中，矩阵的确切影响最不为人所知。研究材料的硬度和软度、孔的大小和组织等因素的影响，以及这些相互关联的变量如何相互作用来指导血管生长，将有助于更好地设计合适的多孔材料，并推动组织工程领域的发展。该学院早期职业发展计划(Career)项目旨在评估容器在各种材料中的三维生长情况，以规划设计空间。一个经过验证的计算机模型将被开发出来，以预测血管如何在尚未测试的多孔材料中生长。这些成果将加速新的组织工程解决方案的设计，并通过实现快速筛查来潜在地降低其开发成本。了解分支结构在自然界中是如何生长的，以及事物如何在高度多孔的结构中移动，对于包括农业中的植物根生长、癌症中的肿瘤、天然气开采和催化剂上的化学处理在内的各种领域都是至关重要的。该项目的补充性教育计划旨在让服务不足的学生参与科学和技术教育，并通过动手实验向中学生灌输科学好奇心。将通过开发可视化研讨会实现研究界的推广，使研究人员能够跟踪粒子在高度多孔结构中的运动。该项目的首要目标是生成一个预测性标准，使组织再生的多孔材料的设计得到改进，从而优化快速血管形成。基于流体质量传输来确定血管网络模式的模型是一个非常有价值的第一近似值，然而，它们与自然血管树网络的随机性的显著偏差表明，需要进一步纳入材料/基质力学的影响。该项目的研究计划旨在检验这样一个假设，即局部基质顺应性影响血管萌发，而区域架构影响生长，而全球材料顺应性影响血管网络的维持和融合(连接)。所获得的信息可以用来设计生物材料，这种材料可以诱使血管生成反应，而不是用化学刺激淹没系统。研究方法将涉及开发复合材料，使用成像方式来开发3D建筑地图，并使用结构指标和局部机械性能作为输入来模拟血管形成的结果。研究计划是按照三个目标组织的。第一个目标是测量水凝胶顺应性、密度、交联度和时间降解对均相水凝胶体系血管形成的具体影响。研究旨在检验以下假设：任何最能支持血管形成的水凝胶体系都存在最优的水凝胶顺应性，分子量、纤维长度、凝胶密度和交联度的变化都可以独立地调节系统的顺应性，并且只有当血管形成的时间尺度与降解的时间尺度相当时，即当瞬时区域基质顺应性满足支持血管形成所需的要求时，才可能形成血管网络。第二个目标是量化支架孔径大小、硬度和基质细胞种植对双相支架-水凝胶系统中血管形成反应的影响。研究旨在验证以下假设：更大的孔相互连接更有利于增强血管形成，软质多孔支架将允许具有比刚性支架更长的节段长度的血管形成，并且基质细胞的存在可能与支架孔大小相互依赖地影响血管形成，因为更大的孔表面积将导致更多的基质细胞数量，从而产生更强的血管形成信号。第三个目标是开发和验证一个基于计算力学的模型，以模拟两相材料中血管网络的形成，该两相材料包括一种具有可变结构的多孔材料，并被一种水凝胶材料渗透，该水凝胶材料允许使用确定性和概率方法在孔内形成血管。研究旨在验证以下假设：随着时间的推移，水凝胶中血管形成的发展主要受材料密度和整体边界条件的影响，而含有水凝胶的多孔支架的血管形成不仅受到支架孔径大小(区域边界)的显著影响，还受到支架材料的弹性模量的影响。该项目方法的新奇之处在于，在现有的化学和生物过程知识中增加了力学观点，以了解血管形成的机制，并帮助快速探索适用于组织移植的建筑的任何多孔生物材料。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding how blood vessels grow is crucial to advancing many fields, including tissue engineering and cancer research. Many factors influence the growth of new blood vessels, including how much oxygen is available, the chemical signals present and the matrix (environment) through which these vessels are growing. Of these factors, the exact influence of the matrix is the least understood. Studying the influence of factors such as the stiffness and softness of the material, the size and organization of the pores and how these inter-related variables interact to guide vessel growth will enable a better-informed design of suitable porous materials and advance the field of tissue engineering. This Faculty Early Career Development Program (CAREER) project seeks to evaluate the growth of vessels in three dimensions within a variety of materials to map out the design space. A validated computer model will be developed to predict how vessels might grow in as yet untested porous materials. These outcomes will both accelerate the design of new tissue engineering solutions and potentially reduce the cost of their development by enabling rapid screening. Understanding how branching structures grow in nature and how things move through highly porous structures is critical to a variety of fields, including plant root growth in farming, tumors in cancer, natural gas extraction and chemical processing on catalysts. The project's complementary education plan is designed to engage underserved students in science and technical education and instill scientific curiosity in middle school students through hands-on experiments. Research community outreach will be achieved through the development of visualization workshops that will enable researchers to track particle movement through highly porous structures.The overarching goal of this project is to generate a predictive rubric that enables the improved design of porous materials for tissue regeneration optimized for rapid vascularization. Models that determine vessel network patterns based on fluid mass transport are an invaluable first approximation, however their significant deviation from the randomness of natural vessel tree networks indicates that the impact of material/matrix mechanics needs to be further incorporated. This project's Research Plan is designed to test the hypothesis that local matrix compliance affects vascular sprouting, while regional architecture affects growth, and global material compliance affects maintenance and inosculation (joining) of vascular networks. The information gained can be used to design biomaterials that can coax an angiogenic response instead of overwhelming the system with chemical stimuli. The research methodology will involve developing composite materials, using imaging modalities to develop 3D architectural maps and using structural metrics and local mechanical properties as inputs to model vascularization outcomes. The Research Plan is organized under three objectives. The FIRST OBJECTIVE is to measure the specific impact of hydrogel compliance, density, crosslinking and temporal degradation on the vascularization of homogenous hydrogel systems. Studies are designed to test the hypotheses that there is an optimal hydrogel compliance for any hydrogel system that best supports vascularization, that variation of molecular weight, fiber length, gel density and crosslinking can all independently modulate the compliance of the system and that vascular network formation is only possible when the time scale of vascularization is comparable to the time scale of degradation, i.e., when instantaneous regional matrix compliance meets the requirements needed to support vascularization. The SECOND OBJECTIVE is to quantify the effect of scaffold pore size, stiffness and stromal cell seeding on vascularization responses within biphasic scaffold-hydrogel systems. Studies are designed to test the hypotheses that larger pore interconnections are better for enhanced vascularization, and that soft porous scaffolds will allow vascularization with longer segment lengths than rigid scaffolds and that the presence of stromal cells might impact vascularization interdependently with scaffold pore size since greater pore surface areas would result in greater stromal cell number and consequently a stronger vascularization signal. The THIRD OBJECTIVE is to develop and validate a computational mechanics-based model to simulate vascular network formation in biphasic materials comprising a porous material with variable architecture and infiltrated with a hydrogel material permitting vascularization within the pores using both deterministic and probabilistic approaches. Studies are designed to test the hypotheses that development of vascularization over time in hydrogels is affected primarily by material density and global boundary conditions, while the vascularization of porous scaffolds containing hydrogels is significantly affected not only by the scaffold pore size (regional boundary), but also by the elastic modulus of the scaffold material. The novelty of the project's approach lies in adding a mechanical perspective to existing knowledge on chemical and biological processes to understand mechanisms of vascularization and aid in the rapid exploration of any porous biomaterial for architectures suitable for tissue grafts.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.