Heparin MicroIslands for Spontaneous Gradient Formation and Improved Diabetic Wound Healing Outcomes

A powerful tool to improve tissue integration with biomaterial scaffolds for the regeneration of damaged tissues is to promote cell migration using chemotactic gradients of growth factors. This approach has been realized by the exogenous delivery of growth factors, which unfortunately also limits the scaffolds ability to meet each wounds unique spatial and temporal regenerative needs. To address this limitation, we present a new approach to gradient generation by incorporating heparin microislands, which are spatially isolated heparin-containing microparticles that create chemotactic microgradients through reorganization of endogenous local growth factors. We incorporated heparin microislands within microporous annealed particle (MAP) scaffolds, which allows us to tune their incorporation ratiometrically to create a heterogenous microenvironment. In this manuscript, we demonstrate the ability of heparin microislands to organize uniform growth factors into spontaneous microgradients and control downstream cell migration in vitro. Further, we present their ability to significantly improve wound healing outcomes (epidermal regeneration and vascularization) in a diabetic wound model relative to two clinically relevant controls.