ReviewBioengineering skin using mechanisms of regeneration and repair
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.
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