Heparin Microislands in Microporous Annealed Particle Scaffolds for Accelerated Diabetic Wound Healing

Mimicking growth factor-ECM interactions for promoting cell migration is a powerful technique to improve tissue integration with biomaterial scaffolds for the regeneration of damaged tissues. This has been attempted by scaffold-mediated controlled delivery of exogenous growth factors; however, the predetermined nature of this delivery can limit the scaffold's ability to meet each wound's unique spatiotemporal regenerative needs and presents translational hurdles. To address this limitation, we present a new approach to growth factor presentation by incorporating heparin microislands, which are spatially isolated heparin-containing microparticles that can reorganize and protect endogenous local growth factors via heterogeneous sequestration at the microscale in vitro and result in functional improvements in wound healing. More specifically, we incorporated our heparin microislands within microporous annealed particle (MAP) scaffolds, which allows facile tuning of microenvironment heterogeneity through ratiometric mixing of microparticle sub-populations. In this manuscript, we demonstrate the ability of heparin microislands to heterogeneously sequester applied growth factor and control downstream cell migration in vitro. Further, we present their ability to significantly improve wound healing outcomes (epidermal regeneration and re-vascularization) in a diabetic wound model relative to two clinically relevant controls.