Improving Spontaneous Gradient Formation in Hydrogels Using Agent-Based Modeling

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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.