Mimicking growth factor-extracellular matrix interactions for promoting cell migration is a powerful technique to improve tissue integration with biomaterial scaffolds for the regeneration of damaged tissues. This is 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, a new approach to growth factor organization is presented that incorporates heparin microislands (μIslands), 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, the heparin μIslands are incorporated within microporous annealed particle scaffolds, which allows facile tuning of microenvironment heterogeneity through ratiometric mixing of microparticle sub-populations. In this manuscript, the ability of heparin μIslands to heterogeneously sequester applied growth factor and control downstream cell migration in vitro is demonstrated. Further, their ability to significantly improve wound healing outcomes (epidermal regeneration and re-vascularization) in a diabetic wound model relative to two clinically relevant controls is presented.

In article number 2104337, Donald Griffin and co-workers present heterogeneously distributed heparin microislands within a microporous annealed particle hydrogel as a new type of bioactive scaffold that can promote extensive cell migration and enhanced healing without the addition of exogenous growth factors. This innovative materials-only approach has high translational potential for biomedical applications requiring accelerated tissue integration.

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 scaffold's ability to meet each wound's 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.