Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation

Abstract

Significance: Excessive scarring is major clinical and financial burden in the United States. Improved therapies are necessary to reduce scarring, especially in patients affected by hypertrophic and keloid scars. Recent Advances: Advances in our understanding of mechanical forces in the wound environment enable us to target mechanical forces to minimize scar formation. Fetal wounds experience much lower resting stress when compared with adult wounds, and they heal without scars. Therapies that modulate mechanical forces in the wound environment are able to reduce scar size. Critical Issues: Increased mechanical stresses in the wound environment induce hypertrophic scarring via activation of mechanotransduction pathways. Mechanical stimulation modulates integrin, Wingless-type, protein kinase B, and focal adhesion kinase, resulting in cell proliferation and, ultimately, fibrosis. Therefore, the development of therapies that reduce mechanical forces in the wound environment would decrease the risk of developing excessive scars. Future Directions: The development of novel mechanotherapies is necessary to minimize scar formation and advance adult wound healing toward the scarless ideal. Mechanotransduction pathways are potential targets to reduce excessive scar formation, and thus, continued studies on therapies that utilize mechanical offloading and mechanomodulation are needed.

Keywords: mechanotransduction; scar; therapy; wound healing.

Geoffrey C. Gurtner, MD

Figure 1.

Schema of mechanical forces acting on a cell and resulting cellular responses. An illustration of the types of mechanical forces to which cells respond. Far left, a cell adhering to the ECM via adhesion molecules such as integrins. Four types of physical stimuli are depicted: tension (stretching in a plane perpendicular to the cell cross-section), compression (pushing inward), shear (stretching in a plane parallel to the cell cross-section), and osmotic (internal pressure maintaining the turgor of a cell, preventing it from collapsing on itself). The stimuli are color-coded as follows: tension (red), compression (orange), shear (green), and osmotic (blue). These stimuli are transmitted to the cell via mechanoreceptors, such as integrins, ion channels, growth factor receptors, and G-protein coupled receptors. Mechanoreceptors trigger various cellular responses, as depicted and cited earlier. ECM, extracellular matrix. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

Intracellular mechanisms involved in mechanotransduction. External mechanical forces are transmitted across the cell membrane by mechanoreceptors, resulting in the activation of various intracellular signaling pathways. Such mechanoreceptors include stretch-activated ion channels, growth-factor receptors, G-protein coupled receptors, and integrins. In fibroblasts and keratinocytes, two of the key mechanosensitive cells in the skin, mechanical signals transmitted via integrins activate focal adhesion complexes containing FAK. Downstream biochemical pathways, such as calcium regulated targets, nitric oxide (NO) targets, phosphoinositol-3-kinase (PI3K) targets, mitogen-associated protein kinases (MAPKs), and Rho GTPases, all synergize to activate transcription factors that translocate into the nucleus and activate mechanically regulated genes. Adapted and used with permission from Wong et al. (2011). FAK, focal adhesion kinase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 3.

Mechanical tension around cutaneous wound impacts scar formation. Human skin is always under tension. When injured, that tension causes the wound to splay open. This results in a typical scar. Greater tension induces increased scar formation in the form of a hypertrophic scar. Conversely, tension-shielding decreases scar formation. This phenomenon is the basis for the development of the Embrace Advanced Scar Therapy, a tension-shielding silicone sheet-based polymer dressing device. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound