Solar UV radiation reduces the barrier function of human skin.

The ubiquitous presence of solar UV radiation in human life is essential for vitamin D production but also leads to skin photoaging, damage, and malignancies. Photoaging and skin cancer have been extensively studied, but the effects of UV on the critical mechanical barrier function of the outermost layer of the epidermis, the stratum corneum (SC), are not understood. The SC is the first line of defense against environmental exposures like solar UV radiation, and its effects on UV targets within the SC and subsequent alterations in the mechanical properties and related barrier function are unclear. Alteration of the SC's mechanical properties can lead to severe macroscopic skin damage such as chapping and cracking and associated inflammation, infection, scarring, and abnormal desquamation. Here, we show that UV exposure has dramatic effects on cell cohesion and mechanical integrity that are related to its effects on the SC's intercellular components, including intercellular lipids and corneodesmosomes. We found that, although the keratin-controlled stiffness remained surprisingly constant with UV exposure, the intercellular strength, strain, and cohesion decreased markedly. We further show that solar UV radiation poses a double threat to skin by both increasing the biomechanical driving force for damage while simultaneously decreasing the skin's natural ability to resist, compromising the critical barrier function of the skin.

Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing.

OBJECTIVE: To investigate how epithelial mechanotransduction pathways impact wound repair. BACKGROUND: Mechanical forces are increasingly recognized to influence tissue repair, but their role in chronic wound pathophysiology remains unknown. Studies have shown that chronic wounds exhibit high levels of matrix metalloproteinase 9 (MMP9), a key proteolytic enzyme that regulates wound remodeling. We hypothesized that epithelial mechanosensory pathways regulated by keratinocyte-specific focal adhesion kinase (FAK) control dermal remodeling via MMP9. METHODS: A standard wound model was applied to keratinocyte-specific FAK knockout (KO) and control mice. Rates of wound healing were measured and tissue was obtained for histologic and molecular analyses. Transcriptional and immunoblot assays were used to assess the activation of FAK, intracellular kinases, and MMP9 in vitro. A cell suspension model was designed to validate the importance of FAK mechanosensing, p38, and MMP9 secretion in human cells. Biomechanical testing was utilized to evaluate matrix tensile properties in FAK KO and control wounds. RESULTS: Wound healing in FAK KO mice was significantly delayed compared with controls (closure at 15 days compared with 20 days, P = 0.0003). FAK KO wounds demonstrated decreased dermal thickness and collagen density. FAK KO keratinocytes exhibited overactive p38 and MMP9 signaling in vitro, findings recapitulated in human keratinocytes via the deactivation of FAK in the cell suspension model. Functionally, FAK KO wounds were significantly weaker and more brittle than control wounds, results consistent with the histologic and molecular analyses. CONCLUSIONS: Keratinocyte FAK is highly responsive to mechanical cues and may play a critical role in matrix remodeling via regulation of p38 and MMP9. These findings suggest that aberrant epithelial mechanosensory pathways may contribute to pathologic dermal proteolysis and wound chronicity.

Mechanical force prolongs acute inflammation via T-cell-dependent pathways during scar formation.

Mechanical force significantly modulates both inflammation and fibrosis, yet the fundamental mechanisms that regulate these interactions remain poorly understood. Here we performed microarray analysis to compare gene expression in mechanically loaded wounds vs. unloaded control wounds in an established murine hypertrophic scar (HTS) model. We identified 853 mechanically regulated genes (false discovery rate <2) at d 14 postinjury, a subset of which were enriched for T-cell-regulated pathways. To substantiate the role of T cells in scar mechanotransduction, we applied the HTS model to T-cell-deficient mice and wild-type mice. We found that scar formation in T-cell-deficient mice was reduced by almost 9-fold (P < 0.001) with attenuated epidermal (by 2.6-fold, P < 0.01) and dermal (3.9-fold, P < 0.05) proliferation. Mechanical stimulation was highly associated with sustained T-cell-dependent Th2 cytokine (IL-4 and IL-13) and chemokine (MCP-1) signaling. Further, T-cell-deficient mice failed to recruit systemic inflammatory cells such as macrophages or monocytic fibroblast precursors in response to mechanical loading. These findings indicate that T-cell-regulated fibrogenic pathways are highly mechanoresponsive and suggest that mechanical forces induce a chronic-like inflammatory state through immune-dependent activation of both local and systemic cell populations.

Mechanics of Wound Closure: Emerging Tape-Based Wound Closure Technology vs. Traditional Methods.

To date, there is still a lack of understanding of how wound closure methods perform comparatively under daily bodily movement during the course of healing and how they affect the mechanics of healing. The present study is a first step in understanding and objectively quantifying the gap. The study provides both a new method of metrology for noninvasive evaluation of skin mechanics at the onset of wound healing and an emerging tape-based wound closure technology. The latter shows better performance with respect to commonly used staples and sutures, holding the wound intact and providing uniform mechanical support across the incision.

A histological and mechanical analysis of the cardiac lead-tissue interface: implications for lead extraction.

The major risks of pacemaker and implantable cardioverter defibrillator extraction are attributable to the fibrotic tissue that encases them in situ, yet little is known about the cellular and functional properties of this response. In the present research, we performed a histological and mechanical analysis of human tissue collected from the lead-tissue interface to better understand this process and provide insights for the improvement of lead design and extraction. The lead-tissue interface consisted of a thin cellular layer underlying a smooth, acellular surface, followed by a circumferentially organized collagen-rich matrix. 51.8±4.9% of cells were myofibroblasts via immunohistochemistry, with these cells displaying a similar circumferential organization. Upon mechanical testing, samples exhibited a triphasic force-displacement response consisting of a toe region during initial tensioning, a linear elastic region and a yield and failure region. Mean fracture load was 5.6±2.1N, and mean circumferential stress at failure was 9.5±4.1MPa. While the low cellularity and fibrotic composition of tissue observed herein is consistent with a foreign body reaction to an implanted material, the significant myofibroblast response provides a mechanical explanation for the contractile forces complicating extractions. Moreover, the tensile properties of this tissue suggest the feasibility of circumferential mechanical tissue disruption, similar to balloon angioplasty devices, as a novel approach to assist with lead extraction.

UV damage and sun care: deciphering mechanics of skin to develop next generation therapies.

Some ultraviolet radiation (UV) is essential to the body as it stimulates the production of vitamin D, yet overexposure has deleterious consequences for the skin. UV induces structural and cellular changes across the different layers of skin tissue leading to mechanical and oxidative stress. Both are critical parameters that can help us better understand and assess dermatological photodamage. While there is a developing body of research to quantify biomarkers of oxidative stress in skin, our knowledge of the magnitude of mechanical stresses in skin has been limited until recently due to the scarcity of methods to quantify the stress state of the tissue. In this regard, what is really exciting is that thin-film characterization and image correlation techniques have recently been successful in measuring the stress state of the tissue both in vitro and in vivo. In the next decade, quantifying UV-induced damage and the efficacy of sunscreens in preventing and treating photodamage will become an increasing focus in skin science research. An improved understanding of the magnitude of skin stresses will help us to better understand skin damage and appearance processes, such as cracking and wrinkling, and measure with accuracy both short-term and long-term effects of treatments.

Focal adhesion kinase links mechanical force to skin fibrosis via inflammatory signaling.

Exuberant fibroproliferation is a common complication after injury for reasons that are not well understood. One key component of wound repair that is often overlooked is mechanical force, which regulates cell-matrix interactions through intracellular focal adhesion components, including focal adhesion kinase (FAK). Here we report that FAK is activated after cutaneous injury and that this process is potentiated by mechanical loading. Fibroblast-specific FAK knockout mice have substantially less inflammation and fibrosis than control mice in a model of hypertrophic scar formation. We show that FAK acts through extracellular-related kinase (ERK) to mechanically trigger the secretion of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), a potent chemokine that is linked to human fibrotic disorders. Similarly, MCP-1 knockout mice form minimal scars, indicating that inflammatory chemokine pathways are a major mechanism by which FAK mechanotransduction induces fibrosis. Small-molecule inhibition of FAK blocks these effects in human cells and reduces scar formation in vivo through attenuated MCP-1 signaling and inflammatory cell recruitment. These findings collectively indicate that physical force regulates fibrosis through inflammatory FAK-ERK-MCP-1 pathways and that molecular strategies targeting FAK can effectively uncouple mechanical force from pathologic scar formation.