Elsevier

Biomaterials

Volume 28, Issue 34, December 2007, Pages 5100-5113
Biomaterials

Review
Bioengineering skin using mechanisms of regeneration and repair

https://doi.org/10.1016/j.biomaterials.2007.07.031Get rights and content

Abstract

The development and use of artificial skin in treating acute and chronic wounds has, over the last 30 years, advanced from a scientific concept to a series of commercially viable products. Many important clinical milestones have been reached and the number of artificial skin substitutes licensed for clinical use is growing, but they have yet to replace the current “gold standard” of an autologous skin graft. Currently available skin substitutes often suffer from a range of problems that include poor integration (which in many cases is a direct result of inadequate vascularisation), scarring at the graft margins and a complete lack of differentiated structures. The ultimate goal for skin tissue engineers is to regenerate skin such that the complete structural and functional properties of the wounded area are restored to the levels before injury. New synthetic biomaterials are constantly being developed that may enable control over wound repair and regeneration mechanisms by manipulating cell adhesion, growth and differentiation and biomechanics for optimal tissue development. In this review, the clinical developments in skin bioengineering are discussed, from conception through to the development of clinically viable products. Central to the discussion is the development of the next generation of skin replacement therapy, the success of which is likely to be underpinned with our knowledge of wound repair and regeneration.

Section snippets

Great expectations: viable skin replacement therapy

Tissue engineering is a radically different approach to reconstruction of the body following degenerative diseases, trauma or chronic debilitating conditions [1]. Skin wounds, burns and scars represent a major burden upon world healthcare costs. As a result of this, the successful creation in vitro of skin substitutes has been the focus of a concerted research activity for the last 30 or more years, culminating in some success for its translation into the clinical setting ([2], [3], [4],

Bioengineering skin

The skin is the largest organ of the body in vertebrates and is composed of the epidermis and dermis with a complex nerve and blood supply (Fig. 1). A third layer the hypodermis, is composed mainly of fat and a layer of loose connective tissue. These three layers play an important role in protecting the body from any mechanical damage such as wounding. The epidermis is thin and highly cellular, composed mainly of keratinocytes and in the lower epidermal layers, melanocytes, for pigmentation. It

Clinical milestones in skin substitute development

Cadaver skin is sometimes used as a temporary covering to protect a patients recovering wounds but it is in limited supply, costly, and variable in quality with many safety concerns, e.g., viruses, transmissible spongiform encephalopathies, etc. The alternative is to graft and mesh an autologous piece of skin from another unwounded location of the body. Neither of these approaches are ideal and have led to the development of alternative, off-the-shelf commercial products.

The major developments

Clinical Panacea or Poison Chalice?

Although there have been some successes, tissue engineering is not yet delivering significant progress in terms of clinical outcomes and commercialisation [1]. Tissue engineering of skin in particular, has many obvious clinical benefits but many of the expectations, both clinical and commercial, have been unrealistic. Three or four leaders in the industry fell into financial trouble recently, with many of them filing for bankruptcy. The reasons for these failures are multiple, one of the most

Developing skin replacements that utilise the molecules, mechanisms and cell types of normal wound repair

Injury to the skin results in the physical disruption of the normal cellular architecture and triggers wound healing: a process involving inflammation, cell proliferation and migration, cell recruitment, angiogenesis and extracellular matrix (ECM) deposition. Growth factors and cytokines released from inflammatory cells dictate the function of those cells present within the wound [9], [21]. Incorporation of such cytokines and growth factors may be a key factor in the development of new skin

Wound repair and scar formation

Scars are the end point of normal mammalian tissue repair and arise after almost every dermal injury. Scarring can be assessed clinically by using the Vancouver scar scale [48], or the Manchester scar proforma [49] or the Visual Analogue Scale [50]. Scars can form one of three types: atrophic, hypertrophic and keloidal scars. Atrophic scars cause a valley or depression in the skin. Hypertrophic scars are elevated and may subside with time. Interestingly, fibrocytes have been heavily implicated

Wound repair as a scar-free, regenerative process

Foetal wound repair is markedly different from adult wound repair and is essentially a regenerative process, characterised by an absence of scarring and fibrosis ([51], [52] see reviews [51], [52], [9], [53], [54], [55]). This has led to a concerted effort to understand these differences with several animal models being developed in which foetal scarless healing has been described [9].

The characteristics of scar-free healing after incisional wounding have been shown in various studies to

Skin substitution by regeneration

Medical interest in regeneration has often focussed on the repair of damaged adult tissues. The challenge faced here would be to incorporate molecules associated with the regeneration process into a smart matrix [8]. Only a few examples exist in vertebrate species of tissues where the initial phase of repair is followed by perfect functional and structural restoration of the organ. Classically, when we consider regeneration in mammals we think of liver regeneration [60], rabbit ear regeneration

Designing biomatrices for wound repair and to promote skin regeneration

Engineering design specification in skin has relied upon the creation of both artificial dermal and epidermal components, which when combined produce a replacement skin, that can be grafted in place (reviewed in [5], [7], [8]). Materials used as artificial ECM to date include those derived from naturally occurring materials and those manufactured synthetically. Examples of natural materials include polypeptides, GAG's, fibronectin, collagen, hydroxyapatites, hyaluronan, chitosan and alginates.

Hydrogel technologies

Most biopolymers form complex, 3D fibrillar matrices in a self-assembly and/or enzyme-catalyzed process. The matrix architecture can be altered by varying solid content or gelation conditions, or by adding molecules that induce fibre aggregation or interfere with the cross-linking mechanisms [103], [104]. The use of synthetic degradable gels is emerging primarily as a way to deliver cells and/or molecules in situ; these are the so-called smart matrices. A predominant approach, pioneered by

Biomechanical considerations in skin substitute design

One of the final prerequisites of bioengineered skin to consider is that it should have appropriate mechanical and handling properties that make it as mechanically durable as skin but with handling properties that allow clinicians to manipulate it in a surgical setting. As discussed earlier, currently available skin substitutes do not mimic normal skin composition. The 3D architecture and mechanical properties of skin replacements are therefore completely different to normal skin. This is in

A new generation of skin replacements

Thirty years of tissue engineering and wound healing research has lead to a relatively clear understanding of the successful approaches and where the future challenges lie in skin bioengineering. The ultimate aim is to rapidly produce a construct that offers the complete restoration of functional skin, ideally involving orchestrated regeneration of all the skin appendages and layers with rapid vascularisation and scar free integration with the surrounding host tissue. Such a construct should

Acknowledgements

The authors are grateful to the BBSRC, MRC and EPSRC for their support of the UK Centre for Tissue Engineering.

References (123)

  • K. Kobayashi et al.

    Ectopic growth of mouse whiskers from implanted lengths of plucked vibrissae follicles

    J Invest Dermatol

    (1989)
  • H. Oshima et al.

    Morphogenesis and renewal of hair follicles from adult multipotent stem cells

    Cell

    (2001)
  • G. Taylor et al.

    Lavker RM Involvement of follicular stem cells in forming not only the follicle but the epidermis

    Cell

    (2000)
  • Y.D Zheng et al.

    Organogenesis from dissociated cells: generation of mature cycling hair follicles from skin-derived cells

    J Invest Dermatol

    (2005)
  • D.J. Whitby et al.

    Immunohistochemical localization of growth factors in fetal wound healing

    Dev Biol

    (1991)
  • J.R. Armstrong et al.

    Ontogeny of the skin and the transition from scar-free to scarring phenotype during wound healing in the pouch young of a marsupial, Monodelphis domestica

    Dev Biol

    (1995)
  • N. Fausto

    Liver regeneration

    Hepatology

    (2000)
  • C.M. Illingworth

    Trapped fingers and amputated finger tips in children

    J Pediatr Surg

    (1974)
  • S.P. Allen et al.

    A role for retinoic acid in regulating the regeneration of deer antlers

    Dev Biol

    (2002)
  • L.D. Clark et al.

    A new murine model for mammalian wound repair and regeneration

    Clin Immunol Immunopathol

    (1998)
  • S. Frank et al.

    Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing

    J Biol Chem

    (1995)
  • V. Mironov et al.

    Organ printing: computer-aided jet-based 3D tissue engineering

    Trends Biotechnol

    (2003)
  • Y.K. Luu et al.

    Development of a nanostructured DNA delivery scaffold via electrospinning of PLGA and PLA-PEG block copolymers

    J Control Release

    (2003)
  • M. Li et al.

    Electrospun protein fibers as matrices for tissue engineering

    Biomaterials

    (2005)
  • J.G. Rheinwald et al.

    Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinising colonies from single cells

    Cell

    (1975)
  • E. Bell et al.

    Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro

    PNAS

    (1979)
  • I.V. Yannas et al.

    Design of an artificial skin. I. Basic design principles

    J Biomed Mater Res

    (1980)
  • M. Ehrenreich et al.

    Update on dermal substitutes

    Acta Dermatovenerol Croat

    (2006)
  • S. MacNeil

    Progress and opportunities for tissue-engineered skin

    Nature

    (2007)
  • A.D. Metcalfe et al.

    Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration

    J R Soc Interface

    (2007)
  • M.W.J. Ferguson et al.

    Scar-free healing: from embryonic mechanisms to adult therapeutic intervention

    Philos Trans R Soc London B Biol Sci

    (2004)
  • R.A. Clarke et al.

    Tissue engineering for cutaneous wounds

    J Invest Dermatol

    (2007)
  • Y. Ikada

    Challenges in tissue engineering

    J R Soc Interface

    (2006)
  • A.D. Metcalfe et al.

    Characterizing regeneration in the vertebrate ear

    J Anat

    (2006)
  • A.H. Beare et al.

    Location of injury influences the mechanisms of both regeneration and repair within the MRL/MpJ mouse

    J Anat

    (2006)
  • A.D. Metcalfe et al.

    Harnessing wound healing and regeneration for tissue engineering

    Biochem Soc Trans

    (2005)
  • J.G. Rheinwald et al.

    Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes

    Nature

    (1977)
  • J.F. Burke et al.

    Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury

    Ann Surg

    (1981)
  • F.A. Navarro et al.

    Sprayed keratinocyte suspensions accelerate epidermal coverage in a porcine microwound model

    J Burn Care Rehabil

    (2000)
  • D.B. Haddow et al.

    Plasma-polymerized surfaces for culture of human keratinocytes and transfer of cells to an in vitro wound-bed model

    J Biomed Mater Res

    (2003)
  • A.K. Tausche et al.

    An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers

    Wound Repair Regen

    (2003)
  • M. Moustafa et al.

    A new autologous keratinocyte dressing treatment for non-healing diabetic neuropathic foot ulcers

    Diabet Med

    (2004)
  • A.J. Singer et al.

    Cutaneous wound healing

    N Engl J Med

    (1999)
  • J.S. Vande Berg et al.

    Fibroblast senescence in pressure ulcers

    Wound Repair Regen

    (1998)
  • M.W. Lingen

    Role of leukocytes and endothelial cells in the development of angiogenesis in inflammation and wound healing

    Arch Pathol Lab Med

    (2001)
  • R. Gillitzer et al.

    Chemokines in cutaneous wound healing

    J Leukoc Biol

    (2001)
  • R. Bucala et al.

    Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair

    Mol Med

    (1994)
  • J.E. Dunphy

    The healing of wounds

    Can J Surg

    (1967)
  • L. Yang et al.

    Identification of fibrocytes in postburn hypertrophic scar

    Wound Repair Regen

    (2005)
  • T.E. Quan et al.

    The role of circulating fibrocytes in fibrosis

    Curr Rheumatol Rep

    (2006)
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