Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies

Abstract

Excessive scars form as a result of aberrations of physiologic wound healing and may arise following any insult to the deep dermis. By causing pain, pruritus and contractures, excessive scarring significantly affects the patient's quality of life, both physically and psychologically. Multiple studies on hypertrophic scar and keloid formation have been conducted for decades and have led to a plethora of therapeutic strategies to prevent or attenuate excessive scar formation. However, most therapeutic approaches remain clinically unsatisfactory, most likely owing to poor understanding of the complex mechanisms underlying the processes of scarring and wound contraction. In this review we summarize the current understanding of the pathophysiology underlying keloid and hypertrophic scar formation and discuss established treatments and novel therapeutic strategies.

Figure 1

Clinical appearance of hypertrophic scars and keloids. Development of hypertrophic scars after a scald burn (A); hypertrophic scar on lower leg 4 months after surgical procedure (B); keloid on chest after two minor operations (C); keloid on right ear, no history of trauma (D).

Figure 2

Differences between normal wound healing and excessive scar formation over time. Processes of wound repair follow a specific time sequence and can be temporally grouped into three distinct phases: inflammation (I), proliferation (II) and remodeling (III). Platelet degranulation is responsible for the release and activation of an array of potent cytokines, which serve as chemotactic agents for the recruitment of, for example, macrophages, neutrophils, epithelial cells and fibroblasts. In normal wounds, a balance is achieved between new tissue biosynthesis and degradation mediated by apoptosis and remodeling of ECM (A). During excessive scar formation, a dysfunction of the underlying regulatory mechanisms may lead to persistent inflammation, excessive collagen synthesis or deficient matrix degradation and remodeling (B).

Figure 3

The SMAD signal-transduction pathway as a downstream mediator of TGF-β action. The TGF-β receptor consists of type I and type II subunits that are serine-threonine kinases that signal through the SMAD family of proteins. Binding of TGF-β to its cell-surface receptor type II causes phosphorylation of the type I receptor by type II. The type I receptor is then able to phosphorylate and activate the R-SMAD proteins. Once these SMADs are phosphorylated, they form a complex with the common mediator Co-SMAD 4. This SMAD complex translocates to the nucleus, where the activated SMAD complex recruits other transcription factors (TF) that together activate the expression of target genes mediating the biological effects of TGF-β. Inhibitory SMAD 7 is able to prevent phosphorylation of R-SMADs by forming stable associations with activated type I TGF-β receptors and thus provides negative feedback to the actions of TGF-β.