Improving Spontaneous Gradient Formation in Hydrogels Using Agent-Based Modeling

项目摘要 在这项提案中，我们的目标是设计一种生物材料支架，通过改善糖尿病伤口的愈合速度， 我们发明了一种新的水凝胶生物材料，称为微孔退火颗粒（MAP） 凝胶MAP凝胶由使用微流体生成制成的微米级球形构建块组成， 原位退火以形成稳定的支架。MAP支架已被证明可以改善皮肤和大脑的愈合 通过孔隙度依赖性减少伤口炎症和组织整合。我们专注于 材料改进，以克服糖尿病伤口材料治疗的已知困难; 减少血管生成。具体来说，我们已经开发了肝素“微岛”， 分布在支架内以形成微梯度以促进血管生成。我们假设优化 “肝素微岛”的浓度和间距会导致糖尿病创面血管生成的改善 结束 我们将使用体内和计算机方法评估和优化这些特性。目标1侧重于 合成不同浓度的肝素微粒并定量血管内皮生长 因子（VEGF）梯度产生的颗粒使用一种新的测定在我们的实验室开发。的相对 梯度强度将用于在MAP支架内产生基于试剂的血管生成模型， 不同浓度和比例的肝素岛。目标2侧重于理解 用MAP支架处理的糖尿病伤口内的细胞分布和VEGF浓度。此外，本发明还 使用实验输入来通知模型，我们将运行多个模拟来开发最佳支架 在计算机上加速血管生成的配方。该制剂沿着初始肝素“微岛” 我们开发的MAP支架将应用于糖尿病小鼠（db/db）夹板伤口愈合模型， 评估伤口闭合、血管生成和新组织形成。如果成功，该项目将 工程和临床意义。本项目将开发MAP的第一个计算模型 生物材料支架，并提供关于计算机实验如何为生物材料支架提供信息的见解 发展在更大的范围内，该项目将提供对血管生成反应的更好理解， 我们的新一类生物材料，并产生一个廉价和有效的支架治疗选择， 加速糖尿病伤口愈合 这个项目将扩大我的生物材料培训，并增加计算建模到我的技能。的 弗吉尼亚大学是一所著名的转化研究机构，在生物材料和 系统生物学拟议的研究沿着计划的专业发展活动将使 成为再生生物材料的独立研究员。

Project Summary In this proposal, we aim to engineer a biomaterial scaffold to accelerate diabetic wound closure by improving upon a new sub-class of hydrogel biomaterials we have invented called Microporous Annealed Particle (MAP) gel. MAP gels are composed of micron-scale spherical building blocks made using microfluidic generation and annealed in situ to form a stable scaffold. MAP scaffolds have shown to improve healing in both skin and brain through porosity dependent reduction in wound inflammation and tissue integration. We are focusing on material improvements to counter a known difficulty for material-based treatment of diabetic wounds; diminished angiogenesis. Specifically, we have developed heparin “micro-islands” to be heterogeneously distributed within the scaffold to form microgradients to promote angiogenesis. We hypothesize optimizing the “heparin micro-island” concentration and spacing will lead to improved angiogenesis and diabetic wound closure. We will evaluate and optimize these properties using both in vivo and in silico approaches. Aim 1 focuses on synthesizing heparin microparticles at various concentrations and quantifying the Vascular Endothelial Growth Factor (VEGF) gradient produced by the particles using a novel assay developed in our lab. The relative gradient strengths will be used to produce an agent-based model of angiogenesis within MAP scaffolds with various concentrations and proportions of heparin islands. Aim 2 focuses on understanding the time-scale of cell distribution and VEGF concentration within a diabetic wound treated with a MAP scaffold. Additionally, using experimental inputs to inform the model, we will run multiple simulations to develop the optimal scaffold formulation to accelerate angiogenesis in silico. This formulation along with the initial heparin “micro-island” MAP scaffold we developed will be applied in a diabetic mouse (db/db) splinted wound healing model and assessed for wound closure, angiogenesis, and new tissue formation. If successful, this project will have engineering and clinical implications. This project will develop the first computational model of a MAP biomaterial scaffold and provide insight on how in silico experiments can inform biomaterial scaffold development. On a greater scale, this project will provide a better understanding of the angiogenic response to our new class of biomaterial and produce an inexpensive and effective scaffold treatment option for accelerating diabetic wound healing. This project will expand upon my biomaterials training and add computational modeling to my skillset. The University of Virginia is a renowned institution for translational research, with strengths in Biomaterials and Systems Biology. The proposed research along with planned professional development activities will enable me to become an independent researcher in regenerative biomaterials.