Decellularized dermal tissue substitutes

Decellularized dermal tissue substitutes

4

Camilo Chaves 1 , Feras Alshomer 2 , Abdulaziz K. Alhujayri 3,4 , Deepak M. Kalaskar 5 1 Université Paris Sud, Faculté de médecine Paris Sud, le Kremlin Bicêtre, France; 2Plastic and Reconstructive Surgery Division, Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 3Plastic Surgery Division, Department of Surgery, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia; 4King Abdullah International Medical Research Center, Riyadh, Saudi Arabia; 5Division of Surgery and Interventional Science, University College London, London, United Kingdom

4.1

Introduction

Skin is the largest organ in the body being composed of epidermis and dermis together with a collagen-rich extracellular matrix [1]. Impairment of this vital structure by different means is linked to significant disability and at times mortality [2]. This is also associated with a huge economic burden to the healthcare department. In the UK, the annual cost attributable to wound management was estimated at £5.3 billion, accounting for about 4% of total expenditure on public health [3]. Cutaneous defects are caused by different factors including acute trauma, different surgical procedures, tissue ischemia, or burns [4]. Wounds can be categorized depending on the depth of associated cutaneous injury into epidermal wounds, superficial and deep partial thickness wounds, and lastly full thickness wounds [5]. The management of each type of wound can range from simple wound care measures, as in the case of epidermal loss or partial thickness loss, all the way to complex surgical reconstruction, particularly in full thickness skin wounds. This is linked to the extent of tissue loss and involvement in injury mechanism, in which healing properties can occur as epithelial cells migrate from the wound edges or from hair follicles or sweat glands hosting a rich stem cell reserve capable of regeneration [5e7]. With additional extensive damage, this regenerative property is usually lost, with wound healing occurring through secondary contraction as epithelial cells migrate from the edges, leading to extensive scarring and disfigurement [5]. Different skin graft options like autograft, allograft, or xenograft have been utilized to aid in the wound healing process. However, at times they fail to accomplish appropriate healing properties due to limited supply, delayed healing, or associated risk of infection and subsequent scarring [8,9]. Their utility in wound reconstruction usually presents a valuable solution as sole epidermal coverage preventing wound infection and reducing pain. This, however, is challenged by graft fragility and contracture [10]. Further understanding of cutaneous healing shows the importance of dermal layer in optimizing the healing properties. The presence of a dermal layer shows increased rate of reepithelialization and graft taken together with increased resistance to wound contracture and scarring [11,12]. Biomaterials for Skin Repair and Regeneration. https://doi.org/10.1016/B978-0-08-102546-8.00004-2 Copyright © 2019 Elsevier Ltd. All rights reserved.

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Free flap Tissue expansion Distant flaps Local flaps Dermal matrices Skin graft Negative pressure wound therapy Closure by secondary intention Primary closure

Figure 4.1 Shows the modified model of reconstructive ladder incorporating the concept of skin substitutes as a valuable option in complex wound reconstructive plan. Adapted with permission from J.E. Janis, R.K. Kwon, C.E. Attinger, The new reconstructive ladder: modifications to the traditional model. Plast Reconstr Surg 127 (2011) 205Se212S.

The first attempt to produce an artificial skin substitute was in 1974 by Rheinwald and Green. They investigated the potential of cultured keratinocytes for wound coverage. However, it was time consuming, fragile, and had a high risk of graft loss. This was related to the essential presence of a dermal layer to support cell growth and proliferation [13]. This has led to the concept of a cell-matrix tissue engineered construct, with the dermis being crucial in skin tissue engineering as a template guiding cellular interaction and improving wound healing outcomes. Based on the cell-matrix concept described, many advances in skin tissue engineering were attained with significant improvement in the field of wound healing. It was estimated that nearly 200,000 patients were treated with tissue-engineered skin substitutes [14,15]. The utility of different skin substitutes as a valuable reconstructive tool is usually present at situations where limited graft options are available, like in major burns or trauma. Recent advances in tissue engineering also led to the development of various skin coverage alternatives, especially when the situation of the wound precludes the use of many conventional graft options, such as in the case of exposed bones without intact periosteum, exposed cartilage without intact perichondrium, or with exposed tendon without intact paratendon [16,17]. Fig. 4.1 shows the reconstructive ladder algorithm used to guide the reconstructive plan of different wounds.

4.2

Definition of dermal substitutes

Various terminologies are used in the literature when dealing with skin substitutes. These names include tissue-engineered skin, skin constructs, biologic skin substitutes,

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bioengineered skin, and skin bioconstructs that often lead to considerable amount of confusion [18]. Most of these terms are often equal and interchangeable. The appropriate definition of skin substitutes was often referred to any product, either produced or artificially processed, including the modification of naturally occurring materials like native dermal tissue that aims to replace damaged skin tissue, either partially or completely, which can be either temporary or permanently, and possesses some resemblance to native skin tissue both at the anatomic and functional level [19].

4.3

The optimal dermal substitute

An ideal skin and dermal substitute should mimic with great similarity the characteristics of normal skin. This is aided with improved understanding of the cutaneous wound healing and normal skin characteristics [20]. The criteria of an ideal skin substitute are outlined in an effort by Van der Veen et al. [21]. In a review paper, the authors showed that an ideal skin substitute should assure prevention of water loss and reduce the incidence of infection. The construct should also be stable and biodegradable at a controlled rate at which formation of new dermis is orchestrated in a timely fashion. Additionally, the ideal skin substitute should support cellular migration and proliferation aiding in the formation of neodermal tissue rather than scar tissue. Lastly, the construct should be flexible and easy to handle and at the same time have the suitable mechanical properties to resist shear and tear. Others have advocated additional characteristics like shelf-life availability and easy storage, low incidence of antigenicity reducing subsequent immune reaction, cost-effectiveness, and resistance to infection. All the factors mentioned for an ideal skin substitute are summarized in Fig. 4.2.

Hypoxia tolerant Broad availability Presence of dermal and epidermal components Rheology comparable to the skin Resistance to infection Suitable cost/effectiveness Easy to prepare Low antigenicity Easy to store Resistance to shear

Figure 4.2 Shows the characteristics of an ideal skin substitute. Adapted with permission from M.C. Ferreira, A.O. Paggiaro, C. Isaac, N. Teixeira Neto, G.B. Santos, Skin substitutes: current concepts and a new classification system, Rev Bras Cienc Poitica 26 (4) (2011) 696e702.

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4.4

Biomaterials for Skin Repair and Regeneration

Classifications of currently available skin and dermal substitutes

Many types of skin substitutes have been described in the literature with different manufacturing techniques, material constitutes, and intended applications [22]. With this, various classification systems have been proposed to ease clinical applications or investigative fields. Balasubramani et al. [22] described a system that was based solely on the manufacturing process. Balasubramani’s system divided skin substitutes into three classes. Class I skin substitutes included cultured epidermal constructs and their equivalents. Class II skin substitutes were those containing solely dermal constructs that were either derived from processed skin or manufactured extracellular matrix constructs. Finally, class III substitutes were described to include constructs that contain both dermal and epidermal components. This system has a simplified view of different skin substitutes, but it lacks newer constructs made from synthetic materials and does not differentiate between cellular and acellular constructs [23]. Later on Kumar et al. [24] proposed a system that aimed to include various types of skin substitutes with more clinical implications. The system also included three classes with subcategories. Class I constructs mainly aimed to mimic epidermis acting to protect from water loss and reducing risk of infection as a temporary measure encouraging innate healing. This class was subdivided into single or double-layered constructs. For single-layered constructs, materials included were either naturally derived like biomembrane (derived from amniotic and Hevea brasiliensis rubber tree membranes) [25] or synthetic like Tegaderm (polyurethane derived films) [26] and Gelapin (gelatin derived cross-linked with Genipin) [27]. For double-layered constructs, Transcyte was an example containing porcine collagen and nylon mesh covered with silicon sheath and seeded with human neonatal fibroblasts [28]. For class II substitutes, sole epidermal or dermal constructs were included. For epidermal substitutes an example was cultured epithelial autograft [29], whereas for dermal constructs examples are K€ ollagen (fetal bovine collagen derived matrix) [24], Matriderm (fetal bovine collagen derived matrix) [30], Alloderm (human derived acellular collagen matrix) [31], and Permacol (porcine collagen derived matrix) [32]. Many advantages and disadvantages for each type were mentioned. For example, the epidermal constructs help to mimic natural epidermis but are usually fragile, whereas dermal constructs help in angiogenesis and prevent water loss, as well as reduce risk of wound infection [23]. Finally, class III skin substitutes were shown to include materials that are intended to mimic both dermis and epidermis with or without cellular component. Materials in this class include different types of skin grafts, as well as constructs like Integra (acellular bovine derived collagen and glycosaminoglycan covered with a semipermeable silicon film) [33] and Biobrane (nylon mesh and porcine derived dermal collagen covered with silicon film) [34]. The implementation of silicon sheets was shown to act as a temporary coverage preventing active water loss while the underlying matrix incorporates to the grafting site. Although the system is broad, some of the newly described constructs do not fit within classes described nor do their clinical applications show any resemblance with the applications discussed.

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Epidermis Layer to be substituted

Dermis Compound

Temporary Skin substitutes

Durability Permanent

Biologic Product origin

Biosynthetic Synthetic

Figure 4.3 Shows the classification system by Ferreira et al. [35]. The system mentioned uses different letters that are based on three criteria: layer to be replaced, the permanency in the wound, and the grafting material origin. Adapted with permission from M.C. Ferreira, A.O. Paggiaro, C. Isaac, N. Teixeira Neto, G.B. Santos, Skin substitutes: current concepts and a new classification system, Rev Bras Cienc Poitica 26 (4) (2011) 696e702.

To address the limitations in Kumar’s classification system, Ferreira et al. [35] presented a classification system that aimed to help organize different skin substitutes based on their clinical orientation. Their system proposed using different letters based on three criteria: first, layer to be replaced, that was subdivided into epidermal (E), dermal (D) and dermal-epidermal constructs (C); second, the permanency in the wound, that was later divided into temporary (T) and permanent (P); and lastly, the grafting material origin, that was divided into biological (b), biosynthetic (bs), and synthetic (s) as seen in Fig. 4.3. However, cellular constructs were not incorporated into the classification system. E. Davison-Kotler et al. have described a different classification system that classifies various types of skin substitutes in a way to ease the utility and application of different constructs for both clinicians and scientists [23]. In this system, the authors classified skin substitutes based on different factors that are addressed in the classification systems mentioned earlier. The first factor was based on cellularity in which the constructs can be either cellular or acellular. The second factor was layering. By this, the constructs can be composed of a single layer that will intend to replace a single layer of cutaneous defect that is either the epidermis or the dermis, while bilayered constructs intend to replace both. Third factor was replaced region, which can be the dermis or epidermis or both. The fourth factor was based on the materials used.

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Different skin substitutes can be produced from various natural or synthetic materials. The constituting materials also originate from both natural and synthetic origin creating composite constructs. Lastly, different skin substitutes can be classified based on their permanence into biodegradable or nonbiodegradable constituting material. The different classification systems discussed earlier represent how complex skin substitutes are, and distinctive efforts were made to help further simplify their use and application. The below sections will focus on biomechanical properties and will expose the different dermal skin substitutes addressing their characteristics, manufacturing process, and utility.

4.5

Biomechanical properties of normal skin and dermal substitutes

When exploring the biomechanical properties of normal skin, knowledge of the normal anatomical makeup of the skin is essential. Normal skin is composed of epidermis and dermis with the epidermis made of migrating keratinocytes. On the other hand, the dermis, with its reticular and papillary layers, is a complex mixture of collagen, elastin, and ground substance with different glycosaminoglycans (as shown in Fig. 4.4) that are responsible for most of the skin’s biomechanical properties [36].

Stratum corneum

Epidermal layer

Papillary layer

Reticular layer

Figure 4.4 Shows light microscopic histologic section of normal skin. The skin layers are labeled based on their location. (PL): papillary layer, (RL): reticular layer. Adapted with permission from D.L. Bader, C. Bouten, D. Colin, C.W. Oomens, Pressure Ulcer Research: Current and Future Perspectives, Springer Science & Business Media, 2005.

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Skin dermis and various skin substitutes possess viscoelastic behavior when they are stressed to measure the biomechanical properties. Collagen and elastin will display the elasticity while the highly hydrated ground substance disperses the strain with its viscous properties. This viscoelastic behavior can be better displayed using dynamic models like a combination of Maxwell and Voight elements (Standard Linear Solid Models “SLSM”). By adopting this model, it helps to consider the time-dependent effect unlike the traditional linear method resulting in Young’s modulus. The model can be applied by measuring the strain and relaxation in the creep curve. Alternatively, measuring the input and output strain projected by oscillating stress is shown in Fig. 4.5 [37]. Analysis of skin’s biomechanical properties shows different results depending on whether the tests are done under in vitro or in vivo conditions [36]. Additionally, results vary when different tests are made across different axis of skin, showing the

(a)

(b) Resulting strain

Time

Applied stress

(c)

Phase lag λ Amplitude M

Stress

Amplitude M' Strain

Figure 4.5 Basic biomechanical characterization of different skin substitutes. (a) Shows linear standard solid model. (b) Shows typical creep curve. (c) Shows basis of oscillatory tests to assess stress and strain. Adapted with permission from C. Edwards, R. Marks, Evaluation of biomechanical properties of human skin, Clin Dermatol 13 (4) (1995) 375e380.

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skin as an anisotropic structure, which means skin shows different strains with different lines of axial loading. Variable results are also encountered along different populations in terms of age [38]. For example, the tensile strength of skin measured by Vogel et al. showed a mean value of 21 N/mm2 in children that declined to 17 N/mm2 with increasing age. Same decline was observed in skin elasticity from 70 to 20 N/mm2 and in the mean strain at rupture from 75% at birth to 60% in older population [37]. Analysis of the mechanical properties of different dermal substitutes, especially collagen matrixes, showed variable results when the strain was measured when those matrices were incorporated with recipient tissues as compared to fresh ones. To demonstrate that effect, Harely et al. proposed a model in which foam of interconnected struts was analyzed to show the effect of cellular growth on the matrices. By using this model, they showed that the cellular population in fact affected the mechanical properties, as the cellular expression of different matrix byproducts resulted in eventual cross-linking of the dermal substitute and later on resulted in increased brittleness and stiffness of the material [39]. The same phenomena were also seen by Powel and Boyce, when they incorporated polycaprolactone (PCL) and collagen matrix to increase the stiffness of the construct. The authors showed a deleterious effect on the construct’s mechanical properties as cellular growth and proliferation occurred [40]. Similar finding on other matrixes with different compositions were found, in which the mechanical properties were checked before and after cell invasion and showed a significant decrease in tensile strength [41].

4.6

Decellularized dermal substitutes

Meticulous understanding of the wound healing process has led to the recognition of the essential role that extracellular tissue matrix plays in injury repair mechanisms. This had led to the development of different products that simulate and replace lost matrix tissue. Decellularized dermal substitutes represented an essential example of such products as they are biodegradable, able to support cellular growth with the formation of new dermis, and have acceptable mechanical properties that vary depending on the product origin. In the following section, different factors related to construct processing together with critical assessment of different commercially available products are discussed.

4.6.1

General concepts of tissue decellularization and processing

Different efforts made in the field of tissue decellularization have enabled their application in a broad spectrum of reconstructive surgery and tissue engineering strategies. The purpose of tissue decellularization is to provide a complex threedimensional tissue scaffold that is composed of native extracellular matrix important for cell growth and integration [42]. Maintenance of native extracellular matrix features was indicated to be an ideal goal of any decellularization process [43].

Decellularized dermal tissue substitutes

Decellularization methods

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Process (example)

Decellularization effectiveness and ECM damages

Detergent Chemical

Acid and base

Chemical

Biological (enzyme)

Perfect decellularization Heavy damages

Alcohol Freezing and thawing Physical

Pressurization

Physical

Biological (enzyme)

Minimally decellularization Small damages

Electroporation

Figure 4.6 Summarizes the general techniques of decellularization with their associated effect on remaining extracellular matrix. Adapted with permission from N. Nakamura, T. Kimura, A. Kishida, Overview of the development, applications, and future perspectives of decellularized tissues and organs, ACS Biomater Sci Eng 3 (7) (2016) 1236e1244.

The process of tissue decellularization depends on many factors that include tissue type, cellularity, density, lipid contents, and thickness. Each of these factors dictates the method of decellularization adopted for any particular tissue of interest. Depending on the different factors mentioned, a combination of various methods might be justified [42,43]. This however, might come at the expense of its effect on yielded tissue matrix. An example of which is alcohol, that was used to increase lipid solubilization but was associated with increased collagen cross-linking and residual stiffness of gained matrix [44]. The different methods of tissue decellularization can be roughly grouped into three categories: chemical processing, biologic treatments, and lastly physical processing [42,43]. The techniques mentioned are summarized in Fig. 4.6. Different techniques in tissue decellularization are discussed below. For chemical treatments, many agents were investigated, the first of which were acids and bases utilized in the process of tissue decellularization. Among the agents investigated were peracetic acid, acetic acid, sodium sulfide, and sodium hydroxide among others. Each of those agents has their advantages like minimal effect on the remaining extracellular matrix as seen with peracetic acid treatment, whereas some have a significant effect on remaining matrix as seen with acetic acid treatment and most of the bases [45e47]. Hypertonic and hypotonic solutions were also investigated. Their role resides in DNA disintegration and cellular lysis, thus removing all cellular elements with minimal effect on the remaining matrix [48,49]. Others have investigated various detergents like Triton X-100 or sodium dodecyl sulfate. Their effect resides in cell membrane solubilization and DNA dissociation that was time dependent with increasing exposure leading to better tissue decellularization [50,51]. Other chemical agents like glycerol acting by cellular dehydration and lysis and acetone for lipid removal were investigated. Their use was associated with significant change and damage of the remaining extracellular matrix [51e53].

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For biologic treatments, many enzymes (e.g., nucleases, collagenase, lipase, trypsin, a-galactosidase, and thermolysin) and chelating agents (e.g., ethylene glycol tetra acetic acid “EGTA” and ethylenediaminetetraacetic acid “EDTA”) have been used [42]. Different enzymes act by targeting specific cellular elements making complete tissue decellularization difficult together with remaining tissue or enzyme residues impairing tissue integration with potential effect of immune reaction. For this, their role may be of interest in initial tissue disruption for subsequent decellularizing to take effect [54]. The use of chelating agents also acts by cellular disruption and dissociation from surrounding matrix by metal ion sequestration [55]. However, their solo use is insufficient for complete tissue decellularization [56]. Lastly, for physical processing techniques, many modalities have been investigated. The use of temperature alteration with freeze-thaw cycles is associated with cellular lysis, with increasing cycles associated with a better decellularization process. However, the resulting membranous and intracellular contents usually remain requiring a subsequent treatment technique for their removal [57,58]. The process of freeze-thaw cycles was shown to have a minimal effect on the remaining extracellular matrix [59] with minimal effect on their associated mechanical properties [60,61]. Other physical processing techniques investigated for tissue decellularization were mechanical abrasion and hydrostatic pressure treatments [62,63]. However, their use was associated with invariable damage to the associated tissue matrix [62,63]. Additional effort investigated the use of nonthermal irreversible electroporation (NTIRE), in which electrical pulses are applied at a frequency of microseconds through the tissue of interest causing micropores formation in the cell membrane. The use of this technique usually yields an incomplete decellularization mandating the need for additional treatment and at times incomplete process with an associated immune reaction for remaining residues [64e66]. As seen for the previous described methods, the main goal of the decellularization process is to preserve as much native extracellular matrix as possible. However, this is in effect a challenging task with no specific criteria on how much native matrix should be preserved for a construct to maintain it characteristics [42]. Nevertheless, efforts were made to characterize a decellularized construct for its potential clinical use. Badylak et al. [43] suggested a residual DNA length of less than 200 bp. Additionally, a DNA content of less than 50 ng/mg was considered an ideal value for a decellularized construct.

4.6.2

Sterilization techniques and associated effect on decellularized constructs

Sterilization of produced constructs represents an essential step prior to application. It essentially involves the removal of different pyrogens, endotoxins, and various viral and bacterial DNA materials that might contaminate the produced scaffold [43]. Among the techniques described are ethylene oxide incubation, gamma irradiation, and electron beam irradiation [67,68]. Each of these techniques is associated with certain limitations. The use of ethylene oxide results in various alterations in the mechanical properties of produced scaffold [69], together with an unwanted host immune response after implantation [70]. The use of irradiation is also associated

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with denaturation of the produced native extracellular matrix with subsequent effect on the mechanical properties [67] or cytotoxic transformation or residual lipids in the produced scaffold [71]. Others have investigated the utility of supercritical carbon dioxide in the sterilization process. Its use was associated with reduction in various bacterial and viral residues within produced scaffolds with minimal effect on the remaining extracellular matrix and its associated mechanical properties [72].

4.6.3

Current decellularized dermal substitutes

Different available dermal substitutes with varied composition have been described. Most of these substitutes are an acellular scaffold processed from allogeneic, xenogeneic, or synthetic materials [19]. In this section we will discuss various types of acellular dermal tissue substitutes with special emphasis on their properties and characteristics. Alloderm is a well-known dermal substitute. This product represents a good example of an acellular allogeneic matrix. The product is a freeze-dried human acellular matrix with intact basement membrane that is intended to incorporate easily with the wounds without triggering any immunological rejection [19]. Initially it was intended to be used as dermal substitute, [73] but its uses expanded to include abdominal hernia repair [74e76], and breast reconstruction [77]. It has been used in burn injuries or complex wounds in a one-stage reconstruction procedure with the combination of thin split thickness autologous skin graft application [19,78]. The freeze-dried acellular matrix is usually contained in cryoprotective solution that usually requires 30 min of intraoperative rehydration prior to its application. The manufacturer later released a different variant of Alloderm that was labeled as “ready to use.” This later product eliminates the need for intraoperative rehydration, as it is stored in a preservative solution together with terminal sterilization with radiation [79]. The mechanical properties of Alloderm were evaluated and showed a maximum tensile strength of 20.32 MPa and maximum suture retention strength of 127.2 N with team resistance strength at 84.73 N [80]. The use of Alloderm showed promising functional and esthetic results with appropriate mechanical properties that are close to the normal skin values [19]. GraftJacket is another dermal matrix substitute similar to Alloderm. It is aseptically processed, freeze dried, noncross-linked with high tensile strength. Analysis showed a mean load-to-failure strength to reach about 273 þ 116 N [81]. The product has a shelf life of 2 years in freeze condition. It needs 10 min of prehydration at room temperature with ringer lactate [82]. The material has been used for superficial and deep wounds successfully having the advantage of being premeshed [18]. It has also shown success being used for tendon repair [83,84], ligament reinforcement, capsular augmentation, and periosteal covering, [85] as well as lower extremity wounds [86]. FlexHD, a noncross-linked decellularized human dermis, is produced through hypertonic solution decellularization [87] and is available in prehydrated condition minimizing the need of intraoperative preparation. The construct is processed in aseptic technique with ethanol and peracetic acid treatment [88], and can be stored at room temperature for up to 3 years. The mean tensile strength was shown to reach about 929 N/cm [87]. The main indications for its use were shown in cases of breast and abdominal wall reconstruction as it shows resistance to stretching [82].

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SureDerm is another acellular lyophilized noncross-linked human dermis. It has 2 years of shelf-life, should be refrigerated to keep it in usable conditions, and requires 10 min of prehydration prior to application [82]. The material has been popularized to provide a permanent base for skin graft after hypertrophic scars or burn wounds reconstruction [89]. Other options have been made from xenogeneic origin such as Permacol, which is derived from porcine dermis. The material is produced through decellularization by trypsinization [90]. The construct is cross-linked with diisocyanate thus increasing its durability. It is sterilized by gamma irradiation and can be stored at room temperature [82]. The mean tensile strength was shown to reach about 66 N/cm [87]. It is used frequently for ventral hernia repair [91,92]. However, it did not have much success in skin reconstruction due to poor integration mostly related to the cross-linkage process [93,94]. Matriderm is another xenogeneic dermal substitute of decellularized noncross-linked bovine dermis coated with a-elastin hydrolysate. It is readily available as a freeze-dried product and sterilized by gamma irradiation. It can be stored at room temperature and has 5 years of shelf-life [82]. It has been very successful in providing a pliable base for full thickness soft tissue reconstruction [95e97]. SurgiMend is made of noncross-linked fetal bovine decellularized dermis that is rich in type III collagen. It is processed and sterilized with ethylene oxide treatment. The material is readily available with 3 years shelf-life, when stored at room temperature [82]. The mean tensile strength was shown to reach about 432 N/cm [87]. The material does not require much preparation before implantation with only 1 min of prehydration. It has been used successfully in abdominal wall and breast reconstruction with excellent outcomes and low complication rates [98e100]. Strattice is a similar noncross-linked decellularized porcine dermis. It is processed enzymatically to remove the antigenic epitope [101e104]. The construct is sterilized by electron beam radiation, can be stored at room temperature for 18 months, and usually requires 2 min hydration prior to usage [82]. The mean tensile strength was shown to reach about 270 N/cm [87]. It has been used in abdominal and breast reconstruction as well [104,105]. Spear et al. popularized the material as it was described to aid in the correction of different breast deformities with success [106]. OASIS is a decellularized porcine small intestine submucosa. It has been used with good success rate in chronic leg wound repair as it has abundance of collagen, glycosaminoglycans (GAG), and growth factors [107]. Mechanical assessment showed a mean tensile strength to reach about 20.6 MPa when the assessment was done on a dry product. Unfortunately, this value dropped to 7.2 MPa when the material was hydrated [108]. The product showed promising results in wound contraction but not in epidermal differentiation when it was experimented on rats [109] despite showing successful results in vitro for stimulating epidermal growth [110]. The product has 2 years of shelf-life and is sterilized by ethylene oxide treatment [82]. Another example of xenogeneic collagen of porcine origin is EzDerm. The material is marketed as a sterile bioactive dressing material that can be stored at room temperature with a shelf-life of 18 month [82,111]. The material is cross-linked

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with aldehyde treatment [112]. The cross-linking process affects the product interaction with the wound bed after implantation with poor incorporation that usually mandates its removal [113]. This section presented an overview of different examples of decellularized dermal tissues. Newer advancements in material processing and manufacturing are ongoing with newer products being produced with variable characteristics and different clinical applications.

4.6.4

Indications and limitations of available decellularized dermal substitutes

The main goal when developing new decellularized dermal substitutes is to have a material that resembles the various aspects of normal skin. All the previously mentioned substitutes were developed based on this goal to be utilized in different tissue reconstruction applications. Ideally, a dermal substitute should be cost-effective, easy to use and store, nonimmunogenic, degradable with time, strong enough to provide the structural support till complete wound healing with preservation of heat and vapor while providing the necessary pain relief. Different decellularized dermal substitutes have been utilized extensively in various defects’ reconstruction. For instance, deep burns and/or extensive burns are some of the indications for using a dermal substitute. Besides the advantages of early wound coverage (decreased pain, wound bacterial colonization, vapor and heat loss), it can provide structural support when limited donor sites are available, thus decreasing donor site morbidities and minimizing the possibilities of having hypertrophic scars or contracting deforming scars [73,95e97,109]. Decellularized dermal substitutes have also been used extensively in other surgical applications such as breast reconstruction, where they have been applied in different formats to provide the needed structural support and implant coverage, especially in cases where the mastectomy skin flaps were thin or there was a deficiency in the muscles to cover the implants. Dermal substitutes help to properly position the breast implants or tissue expanders with subsequent tissue capsule formation [77,105,106,114] as shown in Fig. 4.7. The different applications mentioned represented brief examples of the vast applications of decellularized dermal substitutes in tissue reconstruction. The use of different dermal matrixes was extended to include various applications in abdominal wall and ventral hernia reconstruction, especially in cases of infected wounds with variable outcomes and complication rates related to fistulas, recurrence, and infections [74,75,115e117]. Dermal matrixes have been used as well in head and neck reconstruction, in cases postparotoidectomy to prevent Frey syndrome, in primary and revision rhinoplasty, in cleft lip deformity correction and in cleft palate repair, and velopharyngeal insufficiency and oronasal fistula repair [118e125]. However, in spite of all the aforementioned advantages, these products also have a number of downsides. Having high costs is one of the major disadvantages limiting their utilization in the various methods of reconstruction [126,127]. This is of greater

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Pectoralis m. Pectoralis major m.

Implant Acellular dermal matrix

(a)

(b)

Acellular dermal matrix

(a) Acellular dermal matrix coverage of implant (anteroposterior). (b) Acellular dermal matrix coverage of implant (lateral). m muscle

Elevation of the pectoralis muscle in preparation for placement of implant and acellular dermal matrix

Pectoralis m.

Inframammary fold

Acellular dermal matrix

Figure 4.7 Shows an example of the use of dermal substitutes in breast reconstruction. Adapted with permission from S.A. Macadam, P.A. Lennox, Acellular dermal matrices: use in reconstructive and aesthetic breast surgery, Can J Plast Surg 20 (2) (2012) 75e89.

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concern when the material requires multiple stages of reconstruction like when using Alloderm [126,127]. Another disadvantage is the reports of immunogenic and allergic reactions, as well as infection transmission, especially with the xenogeneic materials [128,129]. With these points in mind, many dermal substitute biomaterials have to prove their efficacy on the long run, as there is limited data currently demonstrating long-term outcomes [130,131]. To this point, its applications although promising are not limitation free.

4.7

Conclusion

Skin is a complex organ. Cutaneous defects and their coverage represent important healthcare issues since antiquity. Decellularized substitutes offer a three-dimensional native extracellular matrix required for cell growth and integration. Biological, chemical, and physical decellularization methods have specific advantages and disadvantages but no optimal method is available. The ideal method should allow perfect removal of cellular material while preserving the components, structure, and mechanical properties of the extracellular matrix of the skin. Although several decellularized skin substitutes are on the market, their main issues are host cytotoxicity, immunogenic reaction, infection transmission, availability, and price, all of which reside on the processing and manufacturing techniques that are to this time not limitation free. With further development of tissue engineering, processed matrixes gathered with new technologies like 3D printing should aim to offer off-the-shelf and personalized dermal substitutes in the near future that provide optimal fast dermal regeneration, reduced scar contraction, and the best esthetical result for patients. Until then, decellularized substitutes will remain an important tool in the surgical arsenal for dermal reconstruction.

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