Growth on demand: reviewing the mechanobiology of stretched skin

Abstract

Skin is a highly dynamic, autoregulated, living system that responds to mechanical stretch through a net gain in skin surface area. Tissue expansion uses the concept of controlled overstretch to grow extra skin for defect repair in situ. While the short-term mechanics of stretched skin have been studied intensely by testing explanted tissue samples ex vivo, we know very little about the long-term biomechanics and mechanobiology of living skin in vivo. Here we explore the long-term effects of mechanical stretch on the characteristics of living skin using a mathematical model for skin growth. We review the molecular mechanisms by which skin responds to mechanical loading and model their effects collectively in a single scalar-valued internal variable, the surface area growth. This allows us to adopt a continuum model for growing skin based on the multiplicative decomposition of the deformation gradient into a reversible elastic and an irreversible growth part. To demonstrate the inherent modularity of this approach, we implement growth as a user-defined constitutive subroutine into the general purpose implicit finite element program Abaqus/Standard. To illustrate the features of the model, we simulate the controlled area growth of skin in response to tissue expansion with multiple filling points in time. Our results demonstrate that the field theories of continuum mechanics can reliably predict the manipulation of thin biological membranes through mechanical overstretch. Our model could serve as a valuable tool to rationalize clinical process parameters such as expander geometry, expander size, filling volume, filling pressure, and inflation timing to minimize tissue necrosis and maximize patient comfort in plastic and reconstructive surgery. While initially developed for growing skin, our model can easily be generalized to arbitrary biological structures to explore the physiology and pathology of stretch-induced growth of other living systems such as hearts, arteries, bladders, intestines, ureters, muscles, and nerves.

Keywords: Finite element analysis; Growth; Mechanobiology; Mechanotransduction; Remodeling; Skin.

Figure 1

Skin expansion in pediatric scalp reconstruction. The patient, a one year-old boy, presented with a giant congenital nevus, left. To grow extra skin for defect repair in situ, tissue expanders are implanted in the frontoparietal and occipital regions of his scalp, middle left. The expanders are gradually filled with saline solution to apply mechanical overstretch and trigger controlled skin growth, middle right. Four months post implantation, the tissue expanders are removed, the nevus is excised, and the defect area is covered by tissue flaps created from the newly grown skin, right.

Figure 2

Histological cross section of human skin. Skin is a composite material of multiple layers: The epidermis, the thin outer layer, has a protective barrier function. It consists primarily of densely packed keratinocytes. The dermis, the inner layer, is the main load-bearing element of skin. Its extracellular matrix consists of loosely interwoven collagen and elastin fibers; its major cells are fibroblasts. The hypodermis, the subcutaneous layer, connects skin to bone and muscle. It consists primarily of adipocytes.

Figure 3

Mechanotransduction of growing skin. Transmembrane mechanosensors in the form of stretch-activated ion channels, integrins, growth factor receptors, and G-protein-coupled receptors translate extracellular signals into intracellular signaling pathways involving calcium (Ca), nitric oxide (NO), mitogen-associated protein kinases (MAPK), Rho GTPases (Rho) and phosphoinositol-3-kinase (PI3K). Biomechanical and biochemical signals converge in the activation of transcription factors that translocate the nucleus and activate mechanoresponsive genes. Increased mitotic activity and increased protein synthesis increase the skin surface area to restore the homeostatic equilibrium state.

Figure 4

Histological sections of non-expanded control, left, expanded normal skin, middle, and expanded scar, left, from pediatric scalp. Skin expansion creates new skin with the same histological appearance as the native skin: The epidermis of the expanded skin displays a similar wrinkling pattern and thickness as the non-expanded skin. The dermis of the expanded skin displays the same thickness as the non-expanded skin. Expanded and non-expanded samples are histologically similar with similar cell-to-matrix volume ratios and a similar collagenous microstructure.

Figure 5

Skin growth upon tissue expansion. The filling volume of all four expanders, rectangular, crescent-shaped, square, and circular, is gradually increased by 150 ml in three steps of 50 ml each, and then gradually removed.

Figure 6

Skin growth upon tissue expansion. The area above all four expanders increases by ~31% in the first step, by ~46% in the second step, by ~25% in the third step, and remains constant upon expander removal. The rectangular expander initiates the largest amount of growth, followed by the crescent-shaped, square, and circular expanders.

Figure 7

Skin growth upon tissue expansion. The expander pressure of all four expanders increases instantly upon inflation and relaxes gradually as skin grows in area and the elastic strain decreases. The rectangular expander is subject to the largest pressured, followed by the crescent-shaped, square, and circular expanders.

Figure 8

Skin growth upon tissue expansion. Spatio-temporal evolution of growth multiplier ϑ^g for rectangular, crescent-shaped, square, and circular expanders, from top to bottom. Snapshots correspond to converged equilibrium states for filling volumes of 50 ml, 100 ml, and 150 ml, and to deflated state with filling volume of 0 ml, from left to right. The color code illustrates the evolution of the growth multiplier ϑ^g, ranging from ϑ^g = 1.00 for the initial ungrown skin, shown in blue, to ϑ^g = 2.25 for the fully grown state, shown in red. Skin growth displays significant regional variations with largest values in the center region and smallest values along the expander edges.

Figure 9

Skin growth upon tissue expansion. Spatio-temporal evolution of normalized von Mises stress σ/σ^max for rectangular, crescent-shaped, square, and circular expanders, from top to bottom. Snapshots correspond to converged equilibrium states for filling volumes of 50 ml, 100 ml, and 150 ml, and to deflated state with filling volume of 0 ml, from left to right. Under the same filling volume and the same base surface area, the rectangular expander initiates the largest stresses, followed by the crescent-shaped, square, and circular expanders. The color code illustrates the evolution of the normalized stress σ/σ^max, ranging from σ/σ^max = 0.00 for the initial ungrown skin, shown in blue, to σ/σ^max = 1.00 for the fully grown state, shown in red.

Figure 10

Skin growth upon tissue expansion in pediatric scalp reconstruction. Spatio-temporal evolution of growth multiplier ϑ^g immediately after filling, bottom row, and after converged growth, top row. Snapshots correspond to filling volumes of 150 ml, 300 ml, and 450 ml, and to deflated state with filling volume of 0 ml, from left to right. The color code illustrates the evolution of the growth multiplier ϑ^g, ranging from ϑ^g = 1.00 for the initial ungrown skin, shown in blue, to ϑ^g = 2.25 for the fully grown state, shown in red. Skin growth displays significant regional variations with largest values in the center region and smallest values along the expander edges.