Wound healing: an overview of acute, fibrotic and delayed healing

Abstract

Acute wounds normally heal in a very orderly and efficient manner characterized by four distinct, but overlapping phases: hemostasis, inflammation, proliferation and remodeling. Specific biological markers characterize healing of acute wounds. Likewise, unique biologic markers also characterize pathologic responses resulting in fibrosis and chronic non-healing ulcers. This review describes the major biological processes associated with both normal and pathologic healing. The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-beta). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGF beta. Once the wound site is cleaned out, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required. In pathologic conditions such as non-healing pressure ulcers, this efficient and orderly process is lost and the ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. On the opposite end of the spectrum, fibrosis is characterized by excessive matrix deposition and reduced remodeling. Often fibrotic lesions are associated with increased densities of mast cells. By understanding the functional relationships of these biological processes of normal compared to abnormal wound healing, hopefully new strategies can be designed to treat the pathological conditions.

Dextran-shelled oxygen-loaded nanodroplets reestablish a normoxia-like pro-angiogenic phenotype and behavior in hypoxic human dermal microvascular endothelium

“…Approximately 7 million patients are 105 affected by chronic wounds in the United States, and an estimated $25 billion dollars is spent 106 annually on the treatment of these wounds [Castilla et al, 2012]. 107 A typical feature of chronic wounds is unbalanced proteolytic activity, which overwhelms 108 tissue protective mechanisms [Diegelmann et al, 2004;Pepper, 2001]. Within chronic 109 wounds, activated cells such as endothelial, epithelial, and immune cells display increased 110 production of proteases, including cathepsin G, urokinase and neutrophil elastase [Greaves et 111 al., 2013].…”

“…Traditionally, acute wound 86 healing is defined as a complex multi-step and multi-cellular process, distinguished in four 87 phases involving different cell types: i) hemostasis, involving platelets; ii) inflammation, 88 involving neutrophils, monocytes, and macrophages; iii) proliferation, involving 89 keratinocytes, endothelial cells, and fibroblasts; and iv) matrix remodeling, involving 90 keratinocytes, myofibroblasts, and endothelial cells. [Diegelmann et al, 2004]. In particular, 91 during the third and fourth phases, the endothelium plays a pivotal role, since wound 92 microvasculature is rebuilt through angiogenesis to restore the supply of oxygen, blood 93 constituents and nutrients to the regenerating tissue, helping to promote fibroplasia and 94 prevent sustained tissue hypoxia [Eming et al, 2014].…”

“…diabetes, vascular insufficiency, or ageing) 100 or localized (e.g. bacterial infections and dysregulated proteolysis) factors produce persistent 101 pathological inflammation resulting in chronic wound formation [Diegelmann et al, 2004]. A 102 chronic wound is defined as a break in skin epithelial continuity lasting more than 42 days.…”

“…Within chronic 109 wounds, activated cells such as endothelial, epithelial, and immune cells display increased 110 production of proteases, including cathepsin G, urokinase and neutrophil elastase [Greaves et 111 al., 2013]. Furthermore, pro-inflammatory cytokines strongly induce the production of matrix 112 metalloproteinases (MMPs) and down-regulate the levels of tissue inhibitors of 113 metalloproteinases (TIMPs), thereby creating an environment with unbalanced MMP/TIMP 114 ratios [Diegelmann et al, 2004;Pepper, 2001]. Consequently, wound repair mediators 115 become targets of proteases, and the resultant matrix degradation contributes to the delay in 116 re-epithelialization, fibroplasia and angiogenesis [Pepper, 2001;Wells et al, 2015].…”

Phagocytosis and remodeling of collagen matrices

“…Wound healing as well as tissue remodeling depend on the degradation and phagocytosis process initiated by neutrophils and macrophages, followed by the deposition of new extracellular matrix (ECM) by fibroblasts [1]. The remodeling of collagen is also integral in cardiomyopathy, spinal injury associated ulcers, scleroderma, and bone structure conditions such as osteoporosis, osteogenesis imperfecta, and osteoarthritis [1][2][3].…”