Constitutive Modelling of Skin Growth

Skin, like all biological materials, adapts to mechanical cues. When expanded beyond its physiological regime over extended time periods, skin grows. This intuitive knowledge has been leveraged clinically in a widely used surgical technique called tissue expansion, in which a surgeon inserts a balloon-like device and inflates it gradually over months to grow skin for reconstructive purposes. However, it is currently not possible to anticipate how much of the deformation due to the expander is growth and how much of it is elastic strain, and tissue expansion protocols remain arbitrary, based on each physician’s experience and training, leading to an unacceptable frequency of complications. Here we show a continuum mechanics framework to describe skin growth based on the multiplicative split of the deformation gradient in to growth and elastic tensors. We present the corresponding finite element implementation, in which the growth component is an internal variable stored and updated at the integration points of the finite element mesh. The model is applied to study the deformation and growth patterns of skin for different expander shapes, as well as in patient specific scenarios, showing excellent qualitative agreement with clinical experience. Experimental methods to calibrate and validate the translation of the model to the clinical setting are briefly discussed. We expect that the proposed modeling framework will increase our fundamental understanding of how skin grows in response to stretch, and it will soon lead to personalized treatment plans to achieve the desired patterns of skin growth while minimizing complications.

[1]  Serdar Göktepe,et al.  A generic approach towards finite growth with examples of athlete's heart, cardiac dilation, and cardiac wall thickening , 2010 .

[2]  Ellen Kuhl,et al.  On the effect of prestrain and residual stress in thin biological membranes. , 2013, Journal of the mechanics and physics of solids.

[3]  N. Swanson,et al.  Clinical applications of tissue expansion in head and neck surgery , 1990, The Laryngoscope.

[4]  P. Nielsen,et al.  Mechanical characterisation of in vivo human skin using a 3D force-sensitive micro-robot and finite element analysis , 2011, Biomechanics and modeling in mechanobiology.

[5]  Ellen Kuhl,et al.  Improving tissue expansion protocols through computational modeling. , 2018, Journal of the mechanical behavior of biomedical materials.

[6]  Maria A. Holland,et al.  Growth on demand: reviewing the mechanobiology of stretched skin. , 2013, Journal of the mechanical behavior of biomedical materials.

[7]  Ellen Kuhl,et al.  Isogeometric Kirchhoff-Love shell formulations for biological membranes. , 2015, Computer methods in applied mechanics and engineering.

[8]  R. D'Amato,et al.  A Morphometric Study of Mechanotransductively Induced Dermal Neovascularization , 2011, Plastic and reconstructive surgery.

[9]  Robert A. Brown,et al.  Mechanical loading regulates protease production by fibroblasts in three‐dimensional collagen substrates , 2000, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[10]  F. Watt,et al.  Integrin expression during human epidermal development in vivo and in vitro. , 1991, Development.

[11]  J. Bereiter-Hahn,et al.  Signaling of mechanical stretch in human keratinocytes via MAP kinases. , 2000, The Journal of investigative dermatology.

[12]  Jeffrey W Holmes,et al.  Mechanical Strain Alters Gene Expression in an in Vitro Model of Hypertrophic Scarring , 2005, Annals of plastic surgery.

[13]  J. Molenaar,et al.  Surface‐Area Increase in Tissue Expansion , 1988, Plastic and reconstructive surgery.

[14]  Ellen Kuhl,et al.  Growing skin: tissue expansion in pediatric forehead reconstruction , 2012, Biomechanics and modeling in mechanobiology.

[15]  L. Taber Biomechanics of Growth, Remodeling, and Morphogenesis , 1995 .

[16]  En-Jui Lee Elastic-Plastic Deformation at Finite Strains , 1969 .

[17]  Serdar Göktepe,et al.  A multiscale model for eccentric and concentric cardiac growth through sarcomerogenesis. , 2010, Journal of theoretical biology.

[18]  D. Horan,et al.  Tissue expansion: past, present, and future. , 1990, Journal of the American Academy of Dermatology.

[19]  D. Pamplona,et al.  On skin expansion. , 2014, Journal of the mechanical behavior of biomedical materials.

[20]  N Pallua,et al.  Retrospective analysis of tissue expansion in reconstructive burn surgery: evaluation of complication rates. , 2008, Burns : journal of the International Society for Burn Injuries.

[21]  Ellen Kuhl,et al.  On the biomechanics and mechanobiology of growing skin. , 2012, Journal of theoretical biology.

[22]  M. Gurtin,et al.  On the characterization of geometrically necessary dislocations in finite plasticity , 2001 .

[23]  D. Billmire,et al.  Tissue Expander Complications in the Pediatric Burn Patient: A 10-Year Follow-up , 2014, Annals of plastic surgery.

[24]  E. Manders,et al.  Soft-Tissue Expansion: Concepts and Complications , 1984, Plastic and reconstructive surgery.

[25]  G. Cherry,et al.  Histomorphologic evaluation of guinea pig skin and soft tissue after controlled tissue expansion. , 1982, Plastic and reconstructive surgery.

[26]  Elaine Fuchs,et al.  Asymmetric cell divisions promote stratification and differentiation of mammalian skin , 2005, Nature.

[27]  Ellen Kuhl,et al.  Characterization of living skin using multi-view stereo and isogeometric analysis. , 2014, Acta biomaterialia.

[28]  Y C Fung,et al.  Zero-stress states of arteries. , 1988, Journal of biomechanical engineering.

[29]  Behzad Khalatbari,et al.  Ten-year experience in face and neck unit reconstruction using tissue expanders. , 2013, Burns : journal of the International Society for Burn Injuries.

[30]  F. Silver,et al.  Mechanobiology of force transduction in dermal tissue , 2003, Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging.

[31]  R. McCauley Tissue Expansion Reconstruction of the Scalp , 2005 .

[32]  A. McCulloch,et al.  Stress-dependent finite growth in soft elastic tissues. , 1994, Journal of biomechanics.

[33]  Paul Steinmann,et al.  On spatial and material settings of thermo-hyperelastodynamics for open systems , 2003 .

[34]  P. Cordeiro,et al.  An Accelerated Approach to Tissue Expansion for Breast Reconstruction: Experience with Intraoperative and Rapid Postoperative Expansion in 370 Reconstructions , 2003, Plastic and reconstructive surgery.

[35]  A. Sonnenberg,et al.  Unique and redundant functions of integrins in the epidermis , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  Paul Steinmann,et al.  Mass– and volume–specific views on thermodynamics for open systems , 2003, Proceedings of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[37]  Yang Dong,et al.  Repetitive mechanical stretching modulates transforming growth factor-β induced collagen synthesis and apoptosis in human patellar tendon fibroblasts. , 2012, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[38]  P. Scott,et al.  Biochemical, biomechanical, and physical changes in the skin in an experimental animal model of therapeutic tissue expansion. , 1989, The Journal of surgical research.

[39]  David A. Cheresh,et al.  Get a ligand, get a life: integrins, signaling and cell survival , 2002, Journal of Cell Science.

[40]  S. Jonathan Chapman,et al.  Mathematical Models of Avascular Tumor Growth , 2007, SIAM Rev..

[41]  Sidney Fels,et al.  Simulating the three-dimensional deformation of in vivo facial skin. , 2013, Journal of the mechanical behavior of biomedical materials.

[42]  Marc A Ronert,et al.  The beginning of a new era in tissue expansion: self-filling osmotic tissue expander--four-year clinical experience. , 2004, Plastic and reconstructive surgery.

[43]  H. Maibach,et al.  Cell renewal in human epidermis. , 1965, Archives of dermatology.

[44]  S. Baker Fundamentals of expanded tissue , 1991, Head & neck.

[45]  Hung Nguyen-Xuan,et al.  Explicit finite deformation analysis of isogeometric membranes , 2014 .

[46]  D. Ambrosi,et al.  On the mechanics of a growing tumor , 2002 .

[47]  Christopher J. Ploch,et al.  Author ' s personal copy Growing skin : A computational model for skin expansion in reconstructive surgery , 2011 .

[48]  Elaine Fuchs,et al.  Getting under the skin of epidermal morphogenesis , 2002, Nature Reviews Genetics.

[49]  Georges Limbert,et al.  Mathematical and computational modelling of skin biophysics: a review , 2017, Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[50]  Ellen Kuhl,et al.  Multi-view stereo analysis reveals anisotropy of prestrain, deformation, and growth in living skin , 2015, Biomechanics and modeling in mechanobiology.

[51]  Arun K Gosain,et al.  Tissue expansion in pediatric patients. , 2005, Clinics in plastic surgery.

[52]  Lingling Sheng,et al.  Bone Marrow–derived Mesenchymal Stem Cells Transplantation Accelerates Tissue Expansion by Promoting Skin Regeneration During Expansion , 2011, Annals of surgery.

[53]  Arun K Gosain,et al.  Pediatric Tissue Expansion: Indications and Complications , 2003, The Journal of craniofacial surgery.

[54]  J. McGrath,et al.  Anatomy and Organization of Human Skin , 2008 .

[55]  Thomas A. Mustoe, MD, FACS,et al.  Animal models of human tissue expansion. , 1989, Plastic and reconstructive surgery.

[56]  Ellen Kuhl,et al.  Quantification of Strain in a Porcine Model of Skin Expansion Using Multi-View Stereo and Isogeometric Kinematics. , 2017, Journal of visualized experiments : JoVE.

[57]  G Pennati,et al.  An Axisymmetric Computational Model of Skin Expansion and Growth , 2007, Biomechanics and modeling in mechanobiology.

[58]  S C Cowin,et al.  Strain or deformation rate dependent finite growth in soft tissues. , 1996, Journal of biomechanics.

[59]  Ellen Kuhl,et al.  Stretching skin: The physiological limit and beyond. , 2012, International journal of non-linear mechanics.

[60]  Ellen Kuhl,et al.  The Incompatibility of Living Systems: Characterizing Growth-Induced Incompatibilities in Expanded Skin , 2015, Annals of Biomedical Engineering.

[61]  J. Reichelt Mechanotransduction of keratinocytes in culture and in the epidermis. , 2007, European journal of cell biology.

[62]  Paul Steinmann,et al.  Computational Modelling of Isotropic Multiplicative Growth , 2005 .

[63]  P. Cordeiro,et al.  A Single Surgeon’s 12-Year Experience with Tissue Expander/Implant Breast Reconstruction: Part I. A Prospective Analysis of Early Complications , 2006, Plastic and reconstructive surgery.

[64]  Thomas Boudou,et al.  A hitchhiker's guide to mechanobiology. , 2011, Developmental cell.

[65]  G. Schultz,et al.  Interactions between extracellular matrix and growth factors in wound healing , 2009, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[66]  M. Ottensmeyer,et al.  In vivo acceleration of skin growth using a servo-controlled stretching device. , 2010, Tissue engineering. Part C, Methods.

[67]  Anthony Atala,et al.  Stretch and Growth: The Molecular and Physiologic Influences of Tissue Expansion , 2002, Plastic and reconstructive surgery.

[68]  Frederick Grinnell,et al.  Fibroblast biology in three-dimensional collagen matrices. , 2003, Trends in cell biology.

[69]  C. G. Neumann THE EXPANSION OF AN AREA OF SKIN BY PROGRESSIVE DISTENTION OF A SUBCUTANEOUS BALLOON: Use of the Method for Securing Skin for Subtotal Reconstruction of the Ear , 1957, Plastic and reconstructive surgery.

[70]  J D Humphrey,et al.  Perspectives on biological growth and remodeling. , 2011, Journal of the mechanics and physics of solids.

[71]  Fiona M. Watt,et al.  Distinct fibroblast lineages determine dermal architecture in skin development and repair , 2013, Nature.

[72]  Adrian Buganza Tepole,et al.  Computational systems mechanobiology of wound healing , 2017 .

[73]  S. E. Logan,et al.  Continuous versus Conventional Tissue Expansion: Experimental Verification of a New Technique , 1991, Plastic and reconstructive surgery.

[74]  Arun K Gosain,et al.  Refinements of Tissue Expansion for Pediatric Forehead Reconstruction: A 13-Year Experience , 2009, Plastic and reconstructive surgery.

[75]  David R. Garrod,et al.  Desmosomal adhesion regulates epithelial morphogenesis and cell positioning , 2001, Nature Cell Biology.

[76]  A. Gosain,et al.  Giant Nevus Sebaceus: Definition, Surgical Techniques, and Rationale for Treatment , 2012, Plastic and reconstructive surgery.