Role of Skin Substitutes in Burn Wound Reconstruction

Abstract

Skin substitutes have modernised burn wound reconstruction since their use was first pioneered by Burke and Yannas in the 1980s. Skin substitutes offer a solution to the problem of insufficient autologous skin graft availability in major burn wound closure. A growing body of evidence supports the role of skin substitutes in both acute major burns and secondary burn scar resurfacing. Classification of skin substitutes has become increasingly complex given the large variety of synthetic and biologic dermal matrices now available as the result of ongoing advances in regenerative medicine techniques. Classification systems are required to assist clinicians with selection and comparison of outcomes across a wide diversity of skin substitutes. Professor John Greenwood, invented, designed and developed one such dermal substitute, \'Biodegradable Temporising Matrix\', which is approved for use across the globe for reconstruction of major burns and complex wounds. This chapter provides a review of available classification systems for skin substitutes with a summary of the latest evidence in relation to their role and impact on burn wound outcomes. Future developments toward the elusive ‘ideal’ skin substitute may be possible through ongoing research efforts focused on clinical translation of modern skin tissue engineering techniques for burn wound reconstruction.

1. Introduction

The skin is the largest organ of the body and is responsible for many essential functions that no skin substitute has been able to fully replicate to date. Skin substitutes can be defined as any material used to provide biologic wound coverage on a temporary or permanent basis. Skin substitutes may be differentiated from simple, inert, wound dressings in that they possess properties that allow them to enhance repair of skin after injury, expedite regeneration and improve scar quality [1, 2, 3].

Epidermal and superficial partial thickness burns have the potential to heal by epidermal regeneration from adnexal nests of epidermal stem cells with minimal scarring, provided the burn wound remains protected and free from infection. Conventional management of debrided deep dermal and full thickness burns has been to achieve wound closure with autologous skin grafts since they were first introduced in the nineteenth century. Early wound closure minimises the severity of scarring and functional impairment caused by permanent dermal loss. However, autologous skin graft donor site availability is frequently limited in major burn patients, particularly when the total body surface area of burn (TBSA) exceeds 25%. Donor site morbidity from skin autograft harvest includes acute physiological insult to the burn patient, blood loss, pain and additional wounding and scarring. Allograft and xenografts are less desirable than autograft due to inherent issues with delayed graft rejection and risk of infection.

A vast array of skin substitutes have been developed through advances in tissue engineering and biomaterials. Skin substitutes have not yet eliminated the requirement for autologous skin grafting in deep or full thickness burns. However, they have the potential to circumvent some issues associated with autologous graft in terms of availability or lack thereof, donor site morbidity and failure to adequately replace dermal elements in deeper injuries. Skin substitutes can provide clinical benefits in terms of wound healing that have been outlined, as follows [4]:

• Protect the wound from infection and loss of fluid

• Provide a stable and biodegradable template for the synthesis of neodermal tissue

• Either host or enable the influx of cells that will function as dermal cells, producing dermal tissue rather than scar tissue

• Allow ease of handling and resist tear forces

Simplified classification systems can aid clinicians in selection of appropriate skin substitutes for burn wound reconstruction. Robust classifications can also benefit research efforts by allowing comparison of outcomes across a growing range of available skin substitutes, categorised based on their properties.

2. Classification of skin substitutes

Skin substitutes encompass a diverse group of materials and may be classified based on five main properties [5, 6, 7], as outlined with examples in Table 1.

1. Permanence: Temporary or permanent

2. Material source: Biological (either natural biological or constructed biological dermal substitutes), synthetic or mixed (biosynthetic) dermal substitutes

3. Layering: Single layer, bilayer, multilayer

4. Replaced region: Epidermal component only, dermal component only, composite (dermal and epidermal components)

5. Cellularity: Acellular or cellular

Skin substitute properties	Subgroups	Examples of materials used in burn wounds
Permanence	Temporary	Allograft, Amniotic membrane, Biobrane, Suprathel, Alloderm, Apligraf
	Permanent	Biodegradable Temporising Matrix (BTM), Integra, Matriderm
Material source	Biological	Allograft, Amniotic membrane, Alloderm, Apligraf, Matriderm
	Biosynthetic	Integra, Biobrane, Dermagraft
	Synthetic	Biodegradable Temporising Matrix (BTM), Suprathel
Layering	Single layer	Alloderm, Matriderm, Suprathel, Cultured Epithelial autograft
	Bilayer	Biobrane, Integra, BTM
Replaced region	Epidermal	Epicel, Recell, Suprathel, Cultured Epithelial autograft, Biobrane
	Dermal only	Alloderm, Dermagraft, Matriderm
	Composite	Allograft, Apligraf, Integra, BTM
Cellularity	Acellular	Integra, BTM, Matriderm, Biobrane, Suprathel
	Cellular	Allograft, Amniotic membrane, Epicel, Recell, Apligraf, Dermagraft

Table 1.

Classification of skin substitutes by various properties.

This classification system inspired by factorial design reported by Davison-Kotler et al. (Figure 1) [7]. borrows elements from four earlier classification systems which have been summarised in Table 2 [8, 9, 10, 11]. Classification systems can be helpful to both researchers in comparing outcomes of different skin substitutes and to clinicians who need to understand their composition in order to make an appropriate selection based on the clinical scenario faced.

Figure 1.

Skin substitute classification adapted from Davison-Kotler et al. [7].

Classification system author	Description	Categories
Balasubramani [8]	Categorised by the tissue layer the produce replaces	Class I: Substitutes consisting of cultured epidermal equivalent only (e.g., Epicel); Class II: Substitutes consisting of dermal components from processed skin or manufactured with extracellular matrix proteins such as collagen (e.g., Dermagraft); Class III: Composite skin substitutes including both dermal and epidermal components (e.g., Integra)
Kumar [9]	Categorised by the tissue layer the product replaces, layering and material source	Class I: Temporary, impervious, materials that replace epidermal function (e.g., Suprathel); Class II: Epidermal (e.g., Epicel or dermal skin substitutes (e.g., Matriderm or Alloderm); Class III: Composite skin substitutes replacing both layers (e.g., Integra, BTM)
Ferreira [10]	Categorised by location, permanence, and material source with lettering system	Permanence: Permanent (P) assigned to materials which lack degradation; Temporary (T) assigned to materials which degrade over time; Origin: Biological (b) assigned to materials that are autologous, allogeneic, or from another species; Biosynthetic (bs) assigned to materials that are derived from a biological source, however, also contain synthetic, nondegradable materials such as silicone or nylon; Location: Composite (C) indicates the skin substitute replaces both dermal and epidermal components of skin; Dermal (D) indicates the skin substitute replacesthe dermal component of the skin; Epidermal (E) indicates the skin substitutereplaces the epidermal component of the skin
Vyas and Vasconez [11]	Categorised by cellularity, the tissue layer the product replaces and permanence	This review suggested categorisation of skin substitutes based on cellularity in addition to the tissue layer the product is replacing and the permanence of the skin substitute
Davison-Kotler [7]	Incorporated elements from all four above classifications	Algorithmic system fully outlined in Figure 1.; Five properties used to categorise skin substitutes: Permanence: Temporary (biodegradable)/Permanent (nonbiodegradable); Material Source: Natural (i.e., Biological)/Synthetic/Both; Layering: Single layer/Bilayer; Replaced region: Epidermis/Dermis/Both; Cellularity: Acellular/Cellular

Table 2.

Chronological development of skin substitute classification systems.

Classifications have evolved over time in parallel with advancements in skin substitute design. A commonality to all classification systems was an emphasis placed on the tissue layer replaced by the skin substitute in question, be it epidermal, dermal or composite skin replacement. This concept marries well with standard categorisation of burns and other wounds by the depth of injury when planning reconstructive requirements. Earlier classification systems failed to differentiate between products based on permanence [8], material source [8] and cellularity [8, 9, 10]. The omission of these integral features created classification systems that were non-intuitive and confusing, whereby some dissimilar products could be placed in the same category or qualify for multiple categories.

The system outlined by Davison-Kotler et al. [7] allows multiple key properties to be simultaneously incorporated, since all skin substitutes possess a variety of characteristics. This multifactorial classification system allows for clear and comprehensive descriptive categorisation of commercially available skin substitutes with potential to expand to include novel skin substitutes still under development. A glossary to further expand on the examples skin substitutes provided in this chapter is found in Table 3. This list is not exhaustive and many additional commercially products are available but it serves to illustrate the classification systems outlined, with a particular focus on materials utilised commonly in contemporary management of burns and other extensive wounds.

Skin substitute (manufacturer)	Structure	Mechanism of action and limitations
Allograft (N/A)	Human cadaveric split-thickness skin grafts. Available cryopreserved or glycerol preserved.	Vascularises temporarily as per autograft but is a passive temporizer with eventual rejection after 3–4 weeks. Fresh allograft confers risk of disease transmission due to retention of residual DNA.
Amniotic membrane (N/A)	Innermost layer of placenta consisting of epithelial layer, basement layer and avascular stroma, hyaluronan and decorin. Available cryopreserved or glycerol-preserved.	Promotes epithelial cell migration and adhesion with anti-inflammatory and anti-scarring properties. Efficacious in protecting the wound bed and reducing bacterial load but has poor mechanical stability.
Alloderm (Lifecel corporation)	Acellular cadaveric human dermis, processed to remove epidermis and cells	Provides a scaffold for fibroblast and vascular ingrowth, single stage reconstruction with autologous graft. Limitations include antigenicity, availability and shelf life.
Apligraf (Organogenesis Inc.)	Cultured human foreskin-derived neonatal fibroblasts in a bovine type I collagen matrix with stratified keratinocytes	Provides a scaffold for host cell migration and population with barrier function provided by keratinocyte layer. Inconsistent cell survival, collagen composition and vascularisation.
Biobrane (Smith & Nephew)	Silicone membrane bonded to porous nylon mesh impregnated with cross linked T1 porcine collagen peptides	Dermal collagen peptides allow adherence to the wound, semipermeable outer membrane allows exudate drainage and evaporative water loss control, e.g., partial thickness burns/donor sites.
Biodegradable Temporising Matrix (BTM) (Novosorb Polynovo®)	Completely synthetic dermal scaffold composed of impermeable polyurethane seal overlying layer of biodegradable polyurethane foam	Bi-layered dermal matrix widely used in acute and delayed burn wound reconstruction. Robust integration and neo-vascularisation reported even in application to infected or avascular wounds such as exposed tendon.
Cultured Epidermal Autograft (N/A)	Keratinocytes cultured from biopsy of autologous skin. 3-week turnaround for 10,000-fold keratinocyte expansion. Culture process which may use murine fibroblasts and foetal calf serum.	Variable graft take and poor long term graft stability in large and deep burn wounds due to poor regeneration of basement membrane proteins which have key role in epidermal adhesion and skin homeostasis. Processing times long and costly. Culture using animal derived cells carries risk of immunogenicity and prion disease transmission.
Dermagraft (Intercytex Ltd.)	Cryopreserved cultured neonatal dermal fibroblasts on a bioresorbable polyglactin mesh	Provides scaffold of extracellular matrix consisting of growth factors and collagens, tenascin, vitronectin, and GAGs.
Epicel (Vericel Corporation)	Petroleum gauze and autologous keratinocyte sheets co-cultured with murine cells	2–8 mm cell layers thick, indicated for deep dermal and full-thickness burns
Integra (Integra LifeSciences)	Biosynthetic dermal scaffold composed of polysiloxane polymer overlying cross-linked T1 bovine collagen and shark glycosaminoglycan (chondroitin-6-sulphate)	Bi-layered dermal matrix widely used in two-stage acute and delayed burn wound reconstruction. Available in single layer of collagen only for single stage reconstruction. Infection during integration phase generally requires removal or replacement.
Matriderm (Medskin Solutions)	Single layer of non-crosslinked bovine collagen and tendon derived elastin hydrolysate. 1 or 2 mm thick matrices available.	Dermal matrix which provides neodermis for autograft application either as one stage (1 mm construct) or two staged (2 mm construct) procedure.
ReCell (Avita Medical)	Autologous keratinocytes obtained from cultured autologous skin biopsy, suspended in solution that can be sprayed onto wound bed	Accelerated epithelialisation from in vivo wound models but human application and long term wound stability remains controversial and further independent clinical studies ongoing. Fibroblasts and melanocytes also delivered to wound
Suprathel (Polymedics Innovations)	Microporous, absorbable synthetic copolymers, mostly polylactic acid	Similar indications for use as Biobrane with no biologic component.

Table 3.

Glossary with description of skin substitutes in alphabetical order.

2.1 Skin substitute properties

2.1.1 Permanence

Skin substitutes can be subdivided into two groups with distinct objectives and indications in burn care with regards to their permanence: namely temporary and permanent skin substitutes. Permanence may be defined by biodegradability as described in the classification reported by Davison-Kotler et al. [7]. However, many bilayered skin substitutes such as Integra and Biodegradable Temporising Matrix, (BTM), have a non-biodegradable outer component that requires removal before autografting of a slowly biodegradable scaffold following ingrowth of host cellular material (no polyurethane residues present by 18 months in the case of BTM) [12]. A more intuitive definition preferred by the authors of this chapter has been provided by Ferreira et al. [10] who describes the distinction as follows: Temporary skin substitutes ‘refer to those that remain in the wound for the period of time necessary to modulate and improve the characteristics of the lesion and are replaced by autogenous grafts. Permanent materials are those that restore part or the total structure of the skin and remain on the wound bed even after a possible grafting of autogenous skin for complete coverage of the lesion.’ Similarly, permanence is defined by the FDA as any material persisting more than 30 days in a wound, therefore permanence does not imply infinite presence in a wound.

Temporary skin substitutes do not generally achieve full integration with the wound bed. However, they may temporarily adhere while they promote healing by protecting, reducing water loss and accelerating epithelialisation.

The objective of temporary skin substitutes is to provide a moist environment, protect the wound from water loss and bacterial invasion while limiting the number of dressing changes.

Indications include definitive dressing of superficial or partial thickness burns until epithelialisation, temporary excised burn wound closure while awaiting autografting, protection of widely meshed autografts, ‘test’ graft in questionable wound beds while awaiting burn depth demarcation, donor site dressing to facilitate epithelialisation and pain control.

Examples: Cadaveric allograft, Amniotic membrane, Biobrane, Suprathel

Permanent skin substitutes are generally composed of constructs or scaffolds that become integrated with the wound architecture by hosting or allow ingrowth of dermal cells, before eventual scaffold reabsorption.

The objective of permanent skin substitutes is to provide a stable but biodegradable template for the synthesis of neo-dermis by enabling the influx of cells that produce dermal tissue rather than scar tissue [13, 14]. Epidermal constructs alone have proven to be problematic in the absence of viable dermis due to inadequate long term wound stability. Scar fragility with propensity to mechanical damage and shear demonstrated following cultured epithelial autografting [15] highlighted the challenge of dermal-epidermal junction regeneration. Dermal and dermal-epidermal constructs have been developed in response to these issues, to improve the quality of healing and reduce scarring.

Indications include excised deep partial or full thickness burn wounds.

Examples: Biodegradable Temporising Matrix (BTM), Integra.

2.1.2 Material source

As the name suggests, biologic skin substitutes are made using biological materials from human or animal sources. Synthetic material refer to non-biological materials engineered in a laboratory to replace or support regeneration of one or more components of normal skin structure. Biosynthetic skin substitutes are those made using a combination of biological and synthetic materials. Skin substitutes with biological components may allow replication of a more natural neodermal structure generated by native extracellular matrix and can allow excellent re-epithelialisation, although staged procedures are often necessary due to slow vascularisation. Synthetic skin substitutes offer increased control over scaffold composition and less propensity to loss due to cross-species antigenicity or infective complications [16] as compared with materials with biological origins, following integration with the burn wounds to which they applied.

2.1.3 Layering

Single layered skin substitutes replace either the epidermal (e.g., Suprathel) or dermal (e.g., Matriderm) component of skin, the latter of which requires autologous skin grafting to complete the epidermal reconstruction. Bilayered dermal substitutes are designed to replace or replicate both dermal and epidermal layers during their application whether this is on a temporary basis (e.g., Biobrane) or a permanent basis (e.g., Integra, BTM). In the latter case a two-stage approach is required whereby the impermeable pseudo-epidermal layer is removed or ‘delaminated’ prior to autologous skin graft application for definitive wound closure. A two staged strategy is particularly advantageous in major burn patients by allowing autologous skin harvest to be deferred until such time as the patient has reached a point of physiological stabilisation, resolution of inhalational injury or other concomitant traumatic injury [12] and optimisation of cardiac or other medical comorbidities [17]. This approach also facilitates re-epithelialisation of donor site harvest for repeated harvest in major burn patients who may have a paucity of donor site due to their total body surface area of burn, while permitting mobilisation during the integration phase [18].

2.1.4 Replaced region

Skin substitutes can be categorised based on their ability to replace the epidermal, dermal or composite (epidermal and dermal) layers of skin. Epidermal replacement should, in theory, be sufficient for reconstruction of burn wounds and other wound with intact dermal elements. However, deeper dermal and full thickness injuries ultimately require epidermal and dermal reconstruction in order to achieve robust wound healing while minimising scar formation and loss of function. Replication of basement membrane and dermal-epidermal junction are one of several scientific challenges that has yet to be overcome by advanced skin substitute design (discussed in further detail in Section 2.5), in order to attain stable skin coverage for deep tissue injuries [19, 20].

2.1.5 Cellularity

Cellular skin substitutes contain viable cells such as keratinocytes or fibroblasts and as such they may incite an immunogenic host response due to antigenicity. These materials are bioengineered from human sources such as Dermagraft (source material: neonatal foreskin). The inclusion of cellularity as a property of skin substitutes was necessary given its implications for wound indications, risk of rejection, cost and regulatory issues.

2.2 Clinical applications of skin substitutes in acute burn care

To appreciate the use of skin substitutes in acute burn care an understanding of the pathophysiology of burn injury is essential. A burn is a defined an injury to tissues induced by heat, cold, friction, chemical, radiation or electrical energy. With regards to the utilisation of dermal substitutes for cutaneous burn wounds, the three most important factors are depth, size and anatomical location of the cutaneous burn.

2.2.1 Burn depth

Burn depth can be epidermal only, dermal (ranging from superficial to deep dermal) or full thickness. In real terms there are only two burn depths. In the first group the burns are superficial enough to heal spontaneously with acceptable functional and aesthetic outcome. These burns are classified as epidermal, superficial partial thickness and mid-dermal. The treatment is supportive and the corner stay is prevention of infection, which can deepen the burn and the control of pain. Pain control facilitates dressing changes and improves compliance with therapy and mobilisation. These burns heal spontaneously as there is an adequate volume of undamaged residual dermal tissue in the burn bed, as well as nests of epidermal cells located in the invaginated sheaths of adnexal structures. This results in re-epithelisation.

The second group (deep dermal to full thickness burns) undergo prolonged healing with granulation tissue and wound contracture, resulting in secondary intention healing. The treatment priorities for this group of burns is to abort the process of secondary intention healing replace it as closely as possible with primary intention healing. The surgical methods for doing this include excision and direct closure of small burns and burn wound excision with split thickness skin grafting for larger burns.

2.2.2 Burn size

As burn size increases the treatment options become more complex. Small burns of any depth can generally be managed with dressings or relatively minor procedures. For the more superficial burns increasing burns size results in increasing the frequency and volume of dressings, restricting mobility and more likely to cause pain. For deeper burns that require skin grafting the larger the burn the smaller the area of “donor” site for skin graft harvesting. The skin grafts are subsequently “meshed” to allow a greater surface area to be covered. The larger the size of the burn the smaller the donor site area becomes resulting in thinner grafts with wider mesh patterns and subsequent poorer scarring outcomes. Additionally, for burns of over 50% TBSA there may not be enough skin donor site to close the debrided burn wounds. Skin grafts can be harvested from the same donor site, but the area must be healed first, and temporising options are required to cover the debrided wounds.

2.2.3 Anatomical locations

Burns over joints can be challenging to manage. Superficial burns require early mobilisation to prevent stiffness and deeper burns require meticulous debridement and skin grafting and intensive mobilisation. Debrided full thickness burns may result in the exposure of deeper structures such as tendon and bone. This results in unfavourable reconstruction if skin graft is used alone and often skin graft failure.

2.2.4 Skin substitutes replacing the epidermis: treatment of superficial dermal burns

For superficial partial thickness burns where the epidermis and a variable amount of dermis is damaged skin substitutes designed to replace the epidermal layer are of value, particularly in larger burns and burns of the hands and joints. Examples of materials that are commonly used as epidermal substitutes in acute burns include:

• Biobrane

• Suprathel

To be of benefit epidermal substitutes must be applied shortly after the burn injury, preferably within 24–48 hours. The burn wound must be meticulously cleaned and residual debris including particulate matter and detached epidermis removed. Shaving the skin is also recommended as is a through wash with iodine solution. Application under general anaesthetic or sedation is recommended as the preparation may be painful. Mobilisation can begin at 48 hours and once the substitute has adhered. Dressing changes will only require the outer layers to be removed at the substitute should remain intact and undisturbed. Within 2–3 weeks it is expected that the substitute will detach as the skin beneath re-epithelialises. It is imperative to monitor for infection and if this occurs the substitute must be removed and conventional dressings applied. The risk of infection can be reduced with meticulous burn wound preparation and consideration of antibiotics.

Epidermal substitutes play an important role in the management of burns that are destined to heal themselves by preventing infection (which may convert the burn into a deep dermal/full thickness injury that will not heal by itself) and treating pain (allowing patients to tolerate dressing changes, early mobilisation and expediting hospital discharge).

2.2.5 Skin substitutes replacing the dermis: treatment of full thickness burns

The early definitive closure of burn wounds is problematic when the total body surface area exceeds 50% as burn are begins to exceed the available skin donor site area. Dermal substitutes in this setting are used to actively temporise the wound bed until split skin grafting can be performed. Examples of dermal substitutes commonly used in acute burns include:

• Integra

• Biodegradable Temporising Matrix (BTM)

The dermal matrix strategy was developed to combat these issues. Pioneered by Burke and Yannis [1, 2], the strategy involved producing a scaffold to allow autologous tissue in growth and establish a neo-dermis. The material developed, Integra, is a cross-linked type 1 collagen scaffold supported by shark chondroitin-6-suplahte glycosaminoglycan. It is physiologically closed with a bonded pseudo-epidermis of silicone. The expense of the product and issues arising from placing non-vascularised biological material on the surface of a wound in an immune compromised patient and anticipating neovascularisation without infection has resulted in variable usability and success in acute burns. The cost of this product often limits its use to very large burn wounds or as a ‘patch-up’ to cover persistent wounds that remain following primary auto-grafting procedures.

The development of biodegradable polymers and, at the start of this millennium, a completely synthetic, biodegradable polyurethane dermal matrix was designed and developed in Adelaide, Australia, using biodegradable polymer developed in Melbourne, Australia; this is known as the NovoSorb Biodegradable Temporising Matrix (BTM; Polynovo). The synthetic composition means that is not prone to infection by micro-organisms and if it does occur it is localised, not requiring removal or replacement [16]. The loss of skin graft over integrated BTM is uncommon and as also observed with Integra, the appearance of the meshed graft is considerably improved compared to autografting alone. The presence of a ‘neo-dermis’ provides a bed across which interstitial epithelialisation can occur without needing granulation tissue and so the cosmetic appearance is improved. In fact, the thinner the graft, the better the appearance and the less obvious the mesh pattern. The presence of a ‘neo-dermis’ provides a bed across which interstitial epithelialisation can occur without needing granulation tissue and so the cosmetic appearance is improved. In fact, the thinner the graft, the better the appearance and the less obvious the mesh pattern

2.3 Clinical applications of skin substitutes in secondary burn wound resurfacing

The long-term outcome of scarring for survivors of large burn injuries is unpredictable. Skin grafted areas can form unstable pathological scars resulting in itch, pain and reduced function, particularly if the burn scar cross joints. Additionally, the aesthetic appearance is less than ideal.

A method to treat this involves scar excision and re-surfacing using dermal substitutes and split skin grafting. The introduction of skin substitute is beneficial in two ways. Firstly, the secondary contracture associated with using split skin grafts is reduced when using a dermal interface. Secondly the scar quality and pliability is improved when split skin grafting is used in conjunction with skin grafting. Frequently used skin substitutes in secondary burn wound reconstruction include:

• Matriderm

• Integra

• Biodegradable temporizing matrix

The surgical technique for scar excision remains constant but the choice of dermal substitute is dependent upon surgeon preference, size of defect and patient choice.

2.3.1 Matriderm

The application of Matriderm involves a single stage procedure, which may be preferable to the staged reconstruction required for both Integra and BTM. The wound bed requires meticulous preparation and application of Matriderm. It can be challenging to use over large defects and is sheet split skin grafting rather than meshed is generally required and therefore requires available and good quality donor sites [5, 8].

2.3.2 Integra

Integra requires a two-stage application, firstly the excision of the scar application of the dermal substitute. Then, once integrated, delamination and application of split skin grafting. Timing between the two procedures varies dependent upon integration. As burn resurfacing is an elective surgery the risk of infection with Integra is somewhat mitigated in comparison to its use in acute burn wound care. The functional and aesthetic outcome of Integra has been observed to be reliable [1, 2, 3, 5, 8].

2.3.3 Biodegradable Temporising Matrix

Similar to Integra BTM is a two-stage procedure. The patient can be managed in an outpatient setting until integration is completed. The risk of infection in an elective setting is minimal due to the synthetic nature of the product and the aesthetic and functional outcomes are comparable with the more established dermal substitutes [12, 16, 17, 18].

2.4 Future advances toward an ideal dermal substitute

2.4.1 Ideal skin substitute

The ideal skin substitute does not yet exist. The following features have been proposed as desirable properties to consider in the development of novel skin substitutes [5, 6].

• Inexpensive and cost-effective

• Easy to store with long shelf life

• Non-antigenic or low antigenicity

• Durable and resistant to shear but flexible

• Prevents evaporative water loss

• Tolerant of hypoxia

• Presence of dermal and epidermal components

• Provides a bacterial barrier and resist infection

• Rheology comparable to skin—drapes and conforms well

• Easy to prepare, secure and store

• Grows with patient growth (suitable for paediatric wounds)

• Avoids scar hypertrophy/contracture

• Single stage application

2.4.2 Scientific challenges and future advances

Several scientific and regulatory challenges must be overcome in the development of the aspirational ideal skin substitute. Creating an anatomical and physiological substitute for normal skin is a challenge faced by burns and trauma patients that has involved tissue bioengineers, polymer chemists, cellular and molecular biologists, surgeons, nurses, and therapists. A critical challenge in skin substitute design has been replication or regeneration of basement membrane the undulating dermal-epidermal junction which it produces through a process of paracrine dialogue between fibroblasts and keratinocytes. This specialised junction is responsible for limiting shear by establishing a molecular bond that anchors the cellular epidermis to the extracellular matrix of the dermis [19, 20].

As such, epidermal-only substitutes may offer a clinical adjunct to expedite reepithelialisation in conjunction with other wound reconstruction strategies but are insufficient in replication of autologous skin graft due to their limited expansion rate, mechanical fragility on handling, tendency to blister in vivo and vulnerability to shear after application. Reconstructive strategies using novel composite epidermal-dermal constructs [21, 22, 23], although challenging to engineer, offer theoretically increased wound stability compared with combining separate dermal and epidermal substitutes which lack the critical component of a functional dermal-epidermal junction required for long term graft stability. A randomised comparison of an engineered skin substitute with autograft [22] (autologous keratinocytes and fibroblasts attached to a collagen-based scaffold) in 15 paediatric patients demonstrated reduced mortality and requirements for donor skin harvesting, for autografting of full- thickness burns of greater than 50% TBSA. A pre-clinical study of a fibrin-based human skin substitute [23] with epidermal and dermal components (fibroblasts cultured in fibrin gel with keratinocytes seeded on top) carried out on in vitro deep burn necrotic tissue showed similar outcomes compare with split-thickness skin graft, concluding that this could potentially represent a viable management option for deep burn injuries, without the need for autologous skin graft. The challenge of further clinical research efforts will be to evaluate and compare between the ever-growing variety of reconstructive strategies that have been made possible due to the wide array of skin substitute products now commercially available.

New frontiers of research are being forged through clinical translation of advanced tissue bio-engineering techniques combined with 3D printing technology [24, 25, 26] to produce novel bi-layered and even tri-layered constructs with hypodermis [25]. Positive clinical results obtained with autologous and allogeneic TESSs based on human adult skin cells and human mesenchymal stem cells regarding successful engraftment (60–90% in the majority of studies [24]) safety, re-epithelialization and wound healing rates, are promising. Takami et al. has developed a TESS composed of autologous cultured keratinocytes, fibroblasts, and cadaveric de-cellularised allogenic dermal matrix.

This skin substitute demonstrated at 96% graft survival rate in four patients with debrided full thickness burn wounds with no delayed graft loss [27]. Although many tissue engineered skin substitutes (TESS) remain at pre-clinical development stage, they offer hope that the ultimate goal of developing an ideal skin substitute is attainable through further clinical research efforts.

3. Conclusion

This chapter outlines classification systems for skin substitutes and their evolution over time in line with advances in skin engineering technology, evidence supporting their clinical applications with regards to acute and secondary burn wound reconstruction and future advances toward the aspirational goal of developing an ideal dermal substitute.

Conflict of interest

Professor John Greenwood designed and developed the skin substitute known as Novosorb Biodegradable Temporising Matrix (BTM) and has a small residual shareholding with the company that manufactures this product, Polynovo.

Dr. Elizabeth Concannon and Dr. Lindsay Damkat-Thomas have no conflicts of interest to declare.