Improving Spontaneous Gradient Formation in Hydrogels Using Agent-Based Modeling

使用基于代理的建模改善水凝胶中的自发梯度形成

• 批准号: 10467985
• 负责人: Lauren Pruett
• 金额: $ 3.69万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467985
• 关键词: Affect; Alpha Particles; Animal Model; Biocompatible Materials; Biological; Biological Assay; Biological Process; Blood Vessels; Blood flow; Brain; Cells; Cellular Infiltration; Characteristics; Chemicals; Clinical; Computer Models; Data; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Disease; Electrostatics; Engineering; Enzyme-Linked Immunosorbent Assay; Exhibits; Formulation; Gel; Generations; Goals; Growth Factor; Heparin; Histological Techniques; Histology; Hydrogels; Immune; In Situ; In Vitro; Individual; Inflammation; Injectable; Institution; Island; Light; Lower Extremity; Maps; Mechanics; Microfluidics; Microspheres; Modeling; Mus; Muscle; Natural regeneration; Particle Size; Pathologic Neovascularization; Patients; Pattern; Physiological; Platelet-Derived Growth Factor; Play; Population; Porosity; Process; Property; Regenerative Medicine; Research; Research Personnel; Resources; Role; Running; Skin; Skin wound healing; Solid; Splint Device; Structure; System; Systems Biology; Techniques; Thick; Time; Tissues; Training; Translational Research; Universities; Vascular Endothelial Growth Factors; Vascularization; Virginia; Wound models; angiogenesis; base; bioprinting; chemokine; chronic wound; clinical translation; design; diabetic ulcer; diabetic wound healing; experimental study; healing; hydrogel scaffold; immunogenicity; implantation; improved; in silico; in vivo; insight; limb amputation; mouse model; non-diabetic; novel; novel strategies; particle; peripheral blood; porous hydrogel; post stroke; ratiometric; regenerative; response; scaffold; simulation; two-dimensional; wound; wound closure; wound healing; wound treatment; Affect; Alpha Particles; Animal Model; Biocompatible Materials; Biological; Biological Assay; Biological Process; Blood Vessels; Blood flow; Brain; Cells; Cellular Infiltration; Characteristics; Chemicals; Clinical; Computer Models; Data; Development; Diabetes Mellitus; Diabetic Foot Ulcer; Diabetic mouse; Disease; Electrostatics; Engineering; Enzyme-Linked Immunosorbent Assay; Exhibits; Formulation; Gel; Generations; Goals; Growth Factor; Heparin; Histological Techniques; Histology; Hydrogels; Immune; In Situ; In Vitro; Individual; Inflammation; Injectable; Institution; Island; Light; Lower Extremity; Maps; Mechanics; Microfluidics; Microspheres; Modeling; Mus; Muscle; Natural regeneration; Particle Size; Pathologic Neovascularization; Patients; Pattern; Physiological; Platelet-Derived Growth Factor; Play; Population; Porosity; Process; Property; Regenerative Medicine; Research; Research Personnel; Resources; Role; Running; Skin; Skin wound healing; Solid; Splint Device; Structure; System; Systems Biology; Techniques; Thick; Time; Tissues; Training; Translational Research; Universities; Vascular Endothelial Growth Factors; Vascularization; Virginia; Wound models; angiogenesis; base; bioprinting; chemokine; chronic wound; clinical translation; design; diabetic ulcer; diabetic wound healing; experimental study; healing; hydrogel scaffold; immunogenicity; implantation; improved; in silico; in vivo; insight; limb amputation; mouse model; non-diabetic; novel; novel strategies; particle; peripheral blood; porous hydrogel; post stroke; ratiometric; regenerative; response; scaffold; simulation; two-dimensional; wound; wound closure; wound healing; wound treatment

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.

项目摘要 在此提案中，我们旨在设计生物材料的支架，以改善糖尿病伤口闭合 在新的水凝胶生物材料子类中，我们发明了称为微孔退火颗粒（MAP） 凝胶。地图凝胶由使用微流体产生制成的微米尺度球形构建块和 原位退火以形成稳定的脚手架。地图脚手架已显示可改善皮肤和大脑的愈合 通过孔隙率依赖性减少伤口感染和组织整合。我们专注于 材料改进，以应对已知难以基于材料的糖尿病伤口治疗的困难； 血管生成减少。特别是，我们已经开发出肝素“微观”是异质的 分布在支架内以形成微观体以促进血管生成。我们假设优化 “肝素微岛”浓度和间距将导致血管生成和糖尿病伤口的改善 关闭。 我们将使用体内和计算机方法评估和优化这些属性。 AIM 1专注于 以各种浓度合成肝素微粒并量化血管内皮生长 粒子使用我们实验室中开发的新测定法产生的因子（VEGF）梯度。亲戚 梯度强度将用于在MAP支架内产生基于剂的血管生成模型 肝素群岛的各种浓度和比例。 AIM 2专注于了解 用MAP支架处理的糖尿病伤口内的细胞分布和VEGF浓度。此外， 使用实验输入来告知模型，我们将运行多个模拟以开发最佳支架 在硅中加速血管生成的形成。该配方以及最初的肝素“微岛” 我们开发的MAP脚手架将应用于糖尿病小鼠（DB/DB）夹住伤口愈合模型和 评估了伤口闭合，血管生成和新的组织形成。如果成功，这个项目将有 工程和临床意义。该项目将开发地图的第一个计算模型 生物材料脚手架，并提供有关如何在计算机实验中如何通知生物材料支架的洞察力 发展。在更大的范围内，该项目将更好地了解 我们新的生物材料类，并为 加速糖尿病伤口愈合。 该项目将扩展我的生物材料培训，并为我的技能添加计算建模。 弗吉尼亚大学是一家著名的转化研究机构，在生物材料和 系统生物学。拟议的研究以及计划的专业发展活动将使 我成为再生生物材料的独立研究人员。