Skin biomechanics: a potential therapeutic intervention target to reduce scarring

Abstract

Pathological scarring imposes a major clinical and social burden worldwide. Human cutaneous wounds are responsive to mechanical forces and convert mechanical cues to biochemical signals that eventually promote scarring. To understand the mechanotransduction pathways in cutaneous scarring and develop new mechanotherapy approaches to achieve optimal scarring, the current study highlights the mechanical behavior of unwounded and scarred skin as well as intra- and extracellular mechanisms behind keloid and hypertrophic scars. Additionally, the therapeutic interventions that promote optimal scar healing by mechanical means at the molecular, cellular or tissue level are extensively reviewed. The current literature highlights the significant role of fibroblasts in wound contraction and scar formation via differentiation into myofibroblasts. Thus, understanding myofibroblasts and their responses to mechanical loading allows the development of new scar therapeutics. A review of the current clinical and preclinical studies suggests that existing treatment strategies only reduce scarring on a small scale after wound closure and result in poor functional and aesthetic outcomes. Therefore, the perspective of mechanotherapies needs to consider the application of both mechanical forces and biochemical cues to achieve optimal scarring. Moreover, early intervention is critical in wound management; thus, mechanoregulation should be conducted during the healing process to avoid scar maturation. Future studies should either consider combining mechanical loading (pressure) therapies with tension offloading approaches for scar management or developing more effective early therapies based on contraction-blocking biomaterials for the prevention of pathological scarring.

Keywords: Dermal fibrosis; Mechanotransduction; Pressure therapy; Skin biomechanics; Tension therapy; Wound healing.

Graphical Abstract

Figure 1.

Complicated mechanical factors mediate scar progression in keloids. The mechanical stress is the highest in the keloidal tissues, followed by peripheral tissues. The normal unwounded skin represents the lowest mechanical stress. The keloid peripheral tissues and keloidal tissues demonstrate the highest and lowest mechanical strains, respectively. Source: Reprinted with permission from [28]. Open access; SpringerLink.

Figure 2.

The schematic representation of the mechanical stretch-induced formation of hypertrophic scarring through transient receptor potential (TRP) C3 (TRPC3) (a); Piezo proteins like Piezo1 (b); and Yes-associated protein (YAP) (c). (a) TRPC3 channel plays a key role, as a force transducer, in the formation of hypertrophic scar. In response to mechanical stretch, the TRPC3 channel is activated and increases the calcium influx, which triggers nuclear factor-κB (NFκB) phosphorylation. The translocation of activated NFκB into the nucleus takes place subsequently and results in the expression of fibronectin and wound contraction [69]. (b) In hypertrophic scar, mechanical stretch localizes around the fibroblasts membrane, transferring from the matrix to Piezo1, and leading to Piezo1-mediated calcium influx. The Piezo1 activity is associated with enhancement of proliferation, collagen generation and differentiation in the presence of the force [74,75]. (c) Mechanical tension in the wound bed upregulates En1 expression, generating scar-producing En1 lineage–positive fibroblasts. YAP inhibition is related to the suppression of En1 activation in wounds [66]. NFAT: the nuclear factor of activated T cells. (Created with BioRender.com.)

Figure 3.

The effect of mechanical stress on scarring and skin regeneration in a pig wound model. (a) Schematic representation of wounds before and after applying the stress shielding device. The control wound is only under physiologic stress with no device. Then, the wound is shielded by directly placing the device (blue rectangle) over the wound. The red arrows indicate physiological skin stress and its direction. Conversely, the blue arrows represent the tension applied by the device and its direction. The highest stress level caused by para-positioned devices (which are shown by blue rectangles on either side of the long axis of the wound represented by a dotted line in the middle) results in maximal surface scarring, shown by longer red arrows. (b) Schematic representation of different stress states. The white dotted lines show scarring on the skin surface that is also determined in histological images by white lines. (c) Stress shielding significantly decreases cutaneous scarring in high-tension wounds. The unshielded high-tension wounds (right images) are found with considerable scarring and hypertrophy of the epithelial layer in the dermis. These observations resemble human hypertrophic scarring. Conversely, in the stress-shielded high-tension incisions (middle images), there is evidence of scarless wound healing with slight fibrosis and an epithelial layer similar to unwounded skin under physiologic stress (left images). Source: Adopted and reprinted with permission from [122]. Copyright 2021 Wolters Kluwer Health, Inc.

Figure 4.

The presence of mechanical tension across skin wounds worsens scarring. Human skin always experiences tension. But, when an injury occurs, that extra tension causes the wound to spread wide apart and gradually form a scar. (a) The schematic representation of normal skin without scarring. (b) Small-sized wounds are subject to low tension and end up with insignificant scarring. The red arrows indicate low tension and its direction. (c) Severe wounds are associated with increased tension, particularly at the wound edge. The greater the tension in the wound, the greater the scarring, typically in the form of a hypertrophic scar. The longer red arrows represent elevated stress at the wound bed. (d) By contrast, mechanical offloading by either stress-shielding (left) or microporous tape (right) reduces scar formation. The red arrows indicate skin tension and its direction, whereas the blue and green arrows show tension generated by stress-shielding and microporous tape, respectively. (Created with BioRender.com.)