ROS-scavenging hydrogel to promote healing of bacteria infected diabetic wounds

Optimum healing of a cutaneous wound requires a well-orchestrated integration of the complex biological and molecular events of cell migration and proliferation, and of extracellular matrix deposition and remodelling. Cellular responses to inflammatory mediators, growth factors, and cytokines, and to mechanical forces, must be appropriate and precise. However, this orderly progression of the healing process is impaired in chronic wounds, including those due to diabetes. Several pathogenic abnormalities, ranging from disease-specific intrinsic flaws in blood supply, angiogenesis, and matrix turnover to extrinsic factors due to infection and continued trauma, contribute to failure to heal. Yet, despite these obstacles, there is increasing cause for optimism in the treatment of diabetic and other chronic wounds. Enhanced understanding and correction of pathogenic factors, combined with stricter adherence to standards of care and with technological breakthroughs in biological agents, is giving new hope to the problem of impaired healing.

Cancer recurrence after surgical resection remains a significant cause of treatment failure. Here, we have developed an in situ formed immunotherapeutic bioresponsive gel that controls both local tumour recurrence after surgery and development of distant tumours. Briefly, calcium carbonate nanoparticles pre-loaded with the anti-CD47 antibody are encapsulated in the fibrin gel and scavenge H+ in the surgical wound, allowing polarization of tumour-associated macrophages to the M1-like phenotype. The released anti-CD47 antibody blocks the 'don't eat me' signal in cancer cells, thereby increasing phagocytosis of cancer cells by macrophages. Macrophages can promote effective antigen presentation and initiate T cell mediated immune responses that control tumour growth. Our findings indicate that the immunotherapeutic fibrin gel 'awakens' the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread.

After recruitment to the wound bed, monocytes differentiate into macrophages. Macrophages play a central role in all stages of wound healing and orchestrate the wound healing process. Their functional phenotype is dependent on the wound microenvironment, which changes during healing, hereby altering macrophage phenotype. During the early and short inflammatory phase macrophages exert pro-inflammatory functions like antigen-presenting, phagocytosis and the production of inflammatory cytokines and growth factors that facilitate the wound healing process. As such, the phenotype of wound macrophages in this phase is probably the classically activated or the so-called M1 phenotype. During the proliferative phase, macrophages stimulate proliferation of connective, endothelial and epithelial tissue directly and indirectly. Especially fibroblasts, keratinocytes and endothelial cells are stimulated by macrophages during this phase to induce and complete ECM formation, reepithelialization and neovascularization. Subsequently, macrophages can change the composition of the ECM both during angiogenesis and in the remodelling phase by release of degrading enzymes and by synthesizing ECM molecules. This suggests an important role for alternatively activated macrophages in this phase of wound healing. Pathological functioning of macrophages in the wound healing process can result in derailed wound healing, like the formation of ulcers, chronic wounds, hypertrophic scars and keloids. However, the exact role of macrophages in these processes is still incompletely understood. For treating wound repair disorders more should be elucidated on the role of macrophages in these conditions, especially their functional phenotype, to find more therapeutic opportunities. This review summarizes macrophage function in skin injury repair, thereby providing more insight in macrophage function in wound healing and possible interventions in this process. Copyright © 2011 Elsevier GmbH. All rights reserved.