Polymers and Bioactive Compounds with a Macrophage Modulation Effect for the Rational Design of Hydrogels for Skin Regeneration

The development of biomaterial platforms for dispensing reagents of interest such as antioxidants, growth factors or antibiotics based on functional hydrogels represents a biotechnological solution for many challenges that the biomedicine field is facing. In this context, in situ dosing of therapeutic components for dermatological injuries such as diabetic foot ulcers is a relatively novel strategy to improve the wound healing process. Hydrogels have shown more comfort for the treatment of wounds due to their smooth surface and moisture, as well as their structural affinity with tissues in comparison to hyperbaric oxygen therapy, ultrasound, and electromagnetic therapies, negative pressure wound therapy or skin grafts. Macrophages, one of the most important cells of the innate immune system, have been described as the key not only in relation to the host immune defense, but also in the progress of wound healing. Macrophage dysfunction in chronic wounds of diabetic patients leads to a perpetuating inflammatory environment and impairs tissue repair. Modulating the macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) could be a strategy for helping to improve chronic wound healing. In this regard, a new paradigm is found in the development of advanced biomaterials capable of inducing in situ macrophage polarization to offer an approach to wound care. Such an approach opens a new direction for the development of multifunctional materials in regenerative medicine. This paper surveys emerging hydrogel materials and bioactive compounds being investigated to induce the immunomodulation of macrophages. We propose four potential functional biomaterials for wound healing applications based on novel biomaterial/bioactive compound combination that are expected to show synergistic beneficial outcomes for the local differentiation of macrophages (M1–M2) as a therapeutic strategy for chronic wound healing improvement.