Restoring skin integrity and balance after injury is vital for survival, serving as a crucial defense mechanism against potential infections by preventing the entry of harmful pathogens. Moreover, proper healing is essential for restoring normal tissue function, allowing damaged tissues to repair and, in an ideal scenario, regenerate. Timely healing helps reduce the risk for complications, such as chronic wounds, which could lead to more severe issues if left untreated. Additionally, pain relief often is associated with effective wound healing as inflammatory responses diminish during the repair process.
The immune system plays a pivotal role in wound healing, influencing various repair mechanisms and ultimately determining the extent of scarring. Although inflammation is present throughout the repair response, recent studies have challenged the conventional belief of an inverse correlation between the intensity of inflammation and regenerative capacity. Inflammatory signals were found to be crucial for timely repair and fundamental processes in regeneration, possibly presenting a paradigm shift in the understanding of immunology.1-4 The complexities of wound healing are exemplified when evaluating and treating postamputation wounds. To address such a task, one needs a firm understanding of the science behind healing wounds and what can go wrong along the way.
Phases of Wound Healing
Wound healing is a complex process that involves a series of sequential yet overlapping phases, including hemostasis/inflammation, proliferation, and remodeling.
Hemostasis/Inflammation—The initial stage of wound healing involves hemostasis, in which the primary objective is to prevent blood loss and initiate inflammation. Platelets arrive at the wound site, forming a provisional clot that is crucial for subsequent healing phases.4-6 Platelets halt bleeding as well as act as a medium for cell migration and adhesion; they also are a source of growth factors and proinflammatory cytokines that herald the inflammatory response.4-7
Inflammation is characterized by the infiltration of immune cells, particularly neutrophils and macrophages. Neutrophils act as the first line of defense, clearing debris and preventing infection. Macrophages follow, phagocytizing apoptotic cells and releasing growth factors such as tumor necrosis factor α, vascular endothelial growth factor, and matrix metalloprotease 9, which stimulate the next phase.4-6,8 Typically, the hemostasis and inflammatory phase starts approximately 6 to 8 hours after wound origin and lasts 3 to 4 days.4,6,7
Proliferation—Following hemostasis and inflammation, the wound transitions into the proliferation phase, which is marked by the development of granulation tissue—a dynamic amalgamation of fibroblasts, endothelial cells, and inflammatory cells.1,4-8 Fibroblasts play a central role in synthesizing collagen, the primary structural protein in connective tissue. They also orchestrate synthesis of vitronectin, fibronectin, fibrin, and tenascin.4-6,8 Simultaneously, angiogenesis takes place, involving the creation of new blood vessels to supply essential nutrients and oxygen to the healing tissue.4,7,9 Growth factors such as transforming growth factor β and vascular endothelial growth factor coordinate cellular activities and foster tissue repair.4-6,8 The proliferation phase extends over days to weeks, laying the groundwork for subsequent tissue restructuring.
Remodeling—The final stage of wound healing is remodeling, an extended process that may persist for several months or, in some cases, years. Throughout this phase, the initially deposited collagen, predominantly type III collagen, undergoes transformation into mature type I collagen.4-6,8 This transformation is critical for reinstating the tissue’s strength and functionality. The balance between collagen synthesis and degradation is delicate, regulated by matrix metalloproteinases and inhibitors of metalloproteinases.4-8 Fibroblasts, myofibroblasts, and other cells coordinate this intricate process of tissue reorganization.4-7