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Review
. 2020 Sep;10(9):200223.
doi: 10.1098/rsob.200223. Epub 2020 Sep 30.

Wound healing: cellular mechanisms and pathological outcomes

Holly N Wilkinson  1 , Matthew J Hardman  1
Affiliations
Review

Wound healing: cellular mechanisms and pathological outcomes

Holly N Wilkinson et al. Open Biol. 2020 Sep.

Abstract

Wound healing is a complex, dynamic process supported by a myriad of cellular events that must be tightly coordinated to efficiently repair damaged tissue. Derangement in wound-linked cellular behaviours, as occurs with diabetes and ageing, can lead to healing impairment and the formation of chronic, non-healing wounds. These wounds are a significant socioeconomic burden due to their high prevalence and recurrence. Thus, there is an urgent requirement for the improved biological and clinical understanding of the mechanisms that underpin wound repair. Here, we review the cellular basis of tissue repair and discuss how current and emerging understanding of wound pathology could inform future development of efficacious wound therapies.

Keywords: ageing; chronic wounds; diabetes; skin; tissue repair; wound healing.

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Conflict of interest statement

We declare we have no competing interests.

Figures

Figure 1.
Figure 1.
The stages of wound repair and their major cellular components. Wound repair begins with haemostasis, where a platelet plug prevents blood loss and a preliminary fibrin matrix is formed. Inflammation then ensues to remove debris and prevent infection, commencing with neutrophil influx, which is promoted by histamine release from mast cells. Monocytes arrive later and differentiate into tissue macrophages to clear remaining cell debris and neutrophils. During the proliferative phase, keratinocytes migrate to close the wound gap, blood vessels reform through angiogenesis, and fibroblasts replace the initial fibrin clot with granulation tissue. Macrophages and regulatory T cells (Tregs) are also vital for this stage of healing. Finally, the deposited matrix is remodelled further by fibroblasts, blood vessels regress and myofibroblasts cause overall wound contraction.
Figure 2.
Figure 2.
Factors contributing to chronic wound healing. Chronic wounds become infiltrated with bacteria that exacerbates inflammation. Chronic wound keratinocytes show aberrant activation causing hyperproliferation and impaired migration. A large proportion of chronic wound cells (e.g. macrophages and fibroblasts) become senescent, producing a senescence-associated secretory phenotype (SASP) that perpetuates senescence, triggers reactive oxygen species (ROS) release and heightens inflammation. High amounts of advanced glycation end products (AGEs) also contribute to inflammation and cellular senescence in the wound environment. Together these features cause excessive tissue breakdown and impair cellular functions to prevent normal healing. re-ep = re-epithelialization.
Figure 3.
Figure 3.
Traditional and novel chronic wound treatments and their major tissue effects. Debridement of infected and necrotic tissue, followed by tailored dressing use, is common in wound treatment, with the aim of reducing microbial burden, dampening inflammation and providing a more suitable environment for healing. Antimicrobial therapies are emerging to disrupt biofilms and selectively remove pathogenic, rather than commensal, organisms. EPS = extracellular polymeric substance. QS = quorum sensing. ABs = antibiotics. Cell therapies such as mesenchymal stem cells (MSCs) can benefit multiple aspects of wound repair. re-ep = re-epithelialization. Finally, targeting chronic wound senescence with senolytics (e.g. metformin or CXCR2 antagonists) may be a viable option to reduce inflammation and promote healing.
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