Development of an Aged Full-Thickness Skin Model Using Flexible Skin-on-a-Chip Subjected to Mechanical Stimulus Reflecting the Circadian Rhythm

The skin is subject to both intrinsic aging caused by metabolic processes in the body and extrinsic aging caused by exposure to environmental factors. Intrinsic aging is an important obstacle to in vitro experimentation as its long-term progression is difficult to replicate. Here, we accelerated aging of a full-thickness skin equivalent by applying periodic mechanical stimulation, replicating the circadian rhythm for 28 days. This aging skin model was developed by culturing a full-thickness, three-dimensional skin equivalent with human fibroblasts and keratinocytes to produce flexible skin-on-a-chip. Accelerated aging associated with periodic compressive stress was evidenced by reductions in the epidermal layer thickness, contraction rate, and secretion of Myb. Increases in β-galactosidase gene expression and secretion of reactive oxygen species and transforming growth factor-β1 were also observed. This in vitro aging skin model is expected to greatly accelerate drug development for skin diseases and cosmetics that cannot be tested on animals.

Identification of biological processes and potential inhibitors for aging skin

Aging is a critical risk factor for developing many diseases such as skin diseases. Aging skin is caused by the decline of regenerative potential and function of tissues. Here, we aim to discover the biological function and pathways of the skin from aged people. The GSE39170 dataset was originally created by the Illumina Genome Analyzer II (Homo sapiens). The biological pathways were analyzed by the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG), Gene Ontology (GO), and Reactome. KEGG and GO results showed the extracellular matrices (ECMs) were mostly affected in the aging skin. Moreover, we discovered the top ten interacting proteins including FBN1, SPARC, THBS1, DCN, COL1A2, VCAN, LOX, SERPING1, FSTL1, and FBLN5 were involved in the aging skin. Further, we predicted several inhibitors that had the ability to block the aging process by L1000fwd analysis. Thus, this study provides further insights into the mechanism of aging skin.

Structural and Functional Changes and Possible Molecular Mechanisms in Aged Skin

Skin aging is a complex process influenced by intrinsic and extrinsic factors. Together, these factors affect the structure and function of the epidermis and dermis. Histologically, aging skin typically shows epidermal atrophy due to decreased cell numbers. The dermis of aged skin shows decreased numbers of mast cells and fibroblasts. Fibroblast senescence contributes to skin aging by secreting a senescence-associated secretory phenotype, which decreases proliferation by impairing the release of essential growth factors and enhancing degradation of the extracellular matrix through activation of matrix metalloproteinases (MMPs). Several molecular mechanisms affect skin aging including telomere shortening, oxidative stress and MMP, cytokines, autophagic control, microRNAs, and the microbiome. Accumulating evidence on the molecular mechanisms of skin aging has provided clinicians with a wide range of therapeutic targets for treating aging skin.

Anatomy and Histologic of Intrinsic Aging Skin

Aging is an inevitable and dynamic biological process that is characterized by the progressive deterioration of body systems and declines in physiological reserve capacity. Aging skin has distinct two types: intrinsic and extrinsic. Intrinsic changes reduce collagen production, blood flow, amount of skin lipid, and loss of rete ridges. Intrinsic aging or chronological aging is cannot be restored to the skin with characterized by sagging skin and some expression of excess wrinkling lines. Intrinsic aging changes in thickness and characteristics of the epidermis, dermis, and hypodermis. Histologically, epidermis thinner by leveling off the dermo-epidermal junction. In the dermis, collagen fibers become thicker and irregular than younger skin, reducing the elasticity of the skin, while hypodermis reduces lipid volume.

Assessment of Mechanical Stress Induced by Radiofrequency Currents on Skin Interfaces

The epidermal-dermal (ED) and dermal-subcutaneous (DS) junctions are the most prominent skin interfaces, which are known to be of primary importance in different dermatological and aesthetic conditions. These interfaces are strongly modified in aging skin, and their effective targeting can lead to improvement of skin appearance in aging and by cellulite. Application of radiofrequency (RF) currents to the skin can selectively produce mechanical stress on these interfaces. Here, we assess the stresses induced by RF currents of different frequencies on EDJ and DSJ and discuss possible applications of the interfacial therapy in aesthetic medicine.