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Tissue Engineering of Skin: A Review.

Introduction

Tissue engineering [TE] is an interdisciplinary field, which includes principles of engineering and life science, it leads to development of biological substitutes that restore, maintain, or improve tissue function [1]. The concept of TE was proposed by many researchers for treatment of tissue defect and organ failure, which is gradually revolutionized [2]. Skin is the largest organ in mammals act as a physical barrier between the human body and the external environment [3]. Skin is directly exposure to harmful microbial, thermal, mechanical, and chemical damages. Loss of skin can occur for many reasons, including disorders, burn and chronic wounds [4]. Since from the decade many skin substitutes such as autografts and allografts have been using to treat burns or other skin defects [5"7] but still lack of complete healing of damaged skin tissue. To solve the skin related defects tissue engineering field has been emerging widely for repair, restore or regenerate damaged tissue by combination with cell source and biomaterial, skin TE has developed from epidermal substitutes to full-thickness skin containing different seed cells. According to their anatomical structures, skin substitute products could be classified into cellular epithelial autografts, engineered dermal and dermo-epidermal composite substitutes [8]. All these products have become a prospective measure for clinical treatment of large full thickness skin defects. Many studies have been focusing onpreparing biomaterial by using different types of polymer, cells and growth factors, these prepared biomaterial used as a support to attachment, growth of cells and also growth factors are necessary for tissue regeneration. The essential prerequisite to qualify a material as a biomaterial is biocompatible, which is the ability of a material to perform with an appropriate host response.

Basically skin composed of epidermis, dermis and subcutaneous layer, normally skin damage alters skin structure each injury induces loss of integrated skin that may result in functional imbalance [9], in case of large full-thickness skin defects or loss of large area of skin arise due to burns, soft tissue trauma and diseases leads to skin necrosis and also even death can occur in some instances [8, 10]. The concept of tissue engineering was first introduced in 1933 and Burke et al, successfully prepared artificial skin with fibroblasts seeded onto collagen scaffolds for the treatment of skin damage in 1980 and clinically it is being utilized today [11]. Recently highly innovative progress in the development and clinical use of highly sophisticated skin tissue substitute have been developed in order to increase their medical safety, durability, elasticity, biocompatibility and clinical efficacy has been reported. This review emphasizes on cells used for skin tissue regeneration, biodegradable polymer material basically which give preliminary supports for cell attachment and growth factor which provide essential nutrients to cells and progress of the skin tissue engineering.

Aim of the Skin Tissue Engineering

The main fundamental aim of the skin TE is to develop novel strategies for replacement of damaged tissue and restore its normal function using a combination of biology, material chemistry and engineering. Many attempts have been adopted to create a three dimensional scaffold, that will support and guide to formation new tissue from different cells. Restoration of skin anatomy needs to go beyond rehabilitation of structural architecture that includes regeneration of skin pigmentation, nerve, vascular plexus, and adnexa. The construction of skin substitutes also needs to consider the genotype of the transplanted skin cells, the material used should be biocompatible, and the complexity of fabrication and maintenance of storage issues [12]. The restoration of an intact barrier and prevention of sepsis are crucial in skin TE particularly in the treatment of large burns. The skin substitute should control fluid loss, infection, contracture and scarring.

Anatomical Structure of Skin

The anatomy of human skin consists of epidermal and dermal layers permeated by a complex vascular and nervous network [13]. The epidermis layer mainly consists of keratinocytes scattered with other cell types like melanocytes and Langerhans cells. The dermis is comprised of papillary and reticular compartments which contain an extracellular matrix made of collagen, reticulum fibers, elastin and glycosaminoglycans. The cellular constituents are mainly fibroblasts [14], which provide constant secretion of the collagen and proteoglycan matrix.

Allo and Autografts

Auto transplantation is the transplantation of organs from one part of the body to another part in the same person. Autologous skin transplantation is currently the clinical gold standard for full-thickness skin wounds including burn injuries [16, 17]. Before grafting, early excision is play significant role in treatment of burn injuries, as heat-denatured proteins of the skin need to be removed to prevent many complications such as infection, multiple organ dysfunction syndrome, hypertrophic scar formation, uncontrolled inflammatory response or contamination with pathogenic microorganisms [18]. In autologous method split skin grafts (SSGs) are harvested with a dermatome from undamaged skin part and applied to full thickness wound. After application of an SSG to a full thickness wound, its capillaries are merge with the capillary network in the excised wound. This graft take is important for a supply of nutrients and graft survival [17, 19]. The split skin donor site will heals within a week and can be used for SSG harvesting up to 4 times but it is important to note that repeated harvesting is associated with scarring at the donor sites as well as lengthy hospital stays. In case of extensive injury donor sites are extremely limited and might leave the patient with too little undamaged skin to harvest enough autologous SSGs. To cover extensive burn areas regarding the limited availability of donor sites, the technique of meshed STSG (split thickness skin graft) was employed [20] this meshing technique is used forcover a larger wounded area at the expense of cosmetic and functional outcome [21]. Another procedure is allograft, which is used for a temporary prevention of fluid loss or contamination of the wound. These allograft are obtained from non-profit European skin banks, these tissue banks are limited worldwide [22]. Allograft substitutes has disadvantage they leave the patients for weeks with wounds, which leads to many complications. Allografts may undergo immunogenic rejection and then site of injury needs to be covered with an autologous SSG [23]. Delayed rejection may occur due to suppressed immune response, but it can be stimulate by the highly immunogenic epithelial cells of the allograft during its vascularization. Natural skin substitute's auto-graft and allo-graft used for wound healing but naturally derived skin substitutes cannot accomplish skin regeneration due to limited donor sites, risk of infection, slow healing and scar formation [24]. To overcome these all problems related to skin defects, TE is the one technique where skin substitute make easier to formation of new tissue, many reports have been demonstrated the role of skin substitute in TE as novel approach towards skin TE.

Skin Tissue Engineering: Overview

In tissue engineering three elements play important role cells in consideration, the matrices as supporting material and growth factor for development of tissue.

Cells

Cells are the site of the chemical reactions of life and important consideration is locating suitable sources of cells. These sources need to provide a high quantity of cells for regeneration of damaged tissue. Cells are derived from a variety of lineages, from stem cells to differentiated somatic cells [13]. These populations can be classified as local, systemic or progenitor. The cells are generally obtained from the host, close relatives or other individuals. The different cells considered for skin TE include fibroblasts, keratinocytes, adipocytes, melanocytes hair-follicle associated cells and adipocytes derived stem cell [25]. Most of the research has been studied on keratinocyte and fibroblast and other cell types are being investigated for future generations of bioengineered skin substitute. Multiple cell types other than skin cells are involved in the extensive process of wound healing.

Keratinocytes

Keratinocyte is the predominant cell type in the epidermis, which is outermost layer of the skin. They found in basal layer of skin, keratinocytes constitute 95% to 97% of the epidermis and being on the surface of the skin makes them one of the most easily accessed skin cell type. In comparison with the other cells of the dermis and epidermis, keratinocytes are the only type of cell present in undamaged skin splitthickness autografts and healed skin post grafting [26]. They have ability to reconstruct the outer layer epidermis helps in tissue construction. Autologous or allogenic keratinocytes have been grown into sheets made into suspensions or delivered using various dressings ranging from xenogeneic collagen to synthetic polymers in the pursuit of a commercial skin substitute. Most of the cell-based skin substitutes, whether scaffold-free substitutes or cell-seeded scaffolds, rely mainly on keratinocytes for their manufacturing, they are potentially useful as a source of stem cells for both experimental models and engineered therapeutic products. Mathew et al. have studied effect of keratinocytes on the biomechanical characteristics and pore microstructure of tissue engineered skin with superficial or deep dermal fibroblasts to determine any biomaterial-mediated anti-fibrotic influences on tissue engineered skin, which showed keratinocytes had an inhibitory effect on matrix contraction and stiffness of engineered scaffolds with deep dermal fibroblasts. Further keratinocytes also reduced the expression of the ECM crosslinking factors, influences the pore microstructure of the remodelled TE skin [27].

Fibroblasts

Fibroblasts are found in the dermal part of skin produce collagen, growth factors, glycosaminoglycans (GAGs) fibronectin and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals. The dermis is predominantly extracellular matrix with low fibroblast density [28] and dermal region can be further classified into an upper papillary and a lower reticular region. The papillary dermis is characterized by thin randomly orientated collagen fiber bundles that are arranged into ridge-like structures, while the reticular dermis consists of numerous thick, orderly-orientated fiber bundles. The dermal fibroblasts are heterogeneous, the papillary and reticular fibroblasts are known as superficial and deep fibroblasts respectively [29]. Jian et al. have fabricated sponge-like cell scaffolds of different pore sizes by a particulate-leaching technique using porous poly-L-lactic acid and Poly (Lactideco-Glycolide) [PLLA/ PLGA] and investigated pore structures which are suitable for culturing human skin fibroblast cells. An improved method is proposed for measuring the porosity of the scaffold ie plasma technique, which improves cell affinity and resolve the problem of the loss of cells, when cell seeding. Author evaluated the cell attachment on scaffolds finally results showed that pores smaller than 160 pm was suitable for human skin fibroblast cell growth [30]. Many of research had been experimented based on using different cells to re-growth of tissues using different methods recently in vitro generated skin model has been widely increasing in regenerative medicine and studies had demonstrated that skin equivalents are capable to create adequate microenvironments for both fibroblasts and keratinocytes to maintain tissue integrity and final achieve tissue function. In this context Karsten et al. have studied on skin reconstruction and epidermal function through analysing growth conditions of fibroblasts in a 3D scaffold to optimise the dermal microenvironment by providing an authentic dermal matrix for regular tissue reconstruction and function of co-cultured keratinocytes [31]. TE needs maximum number of cells to address the pressing need of skin auto-graft, dermal substitute has been made by culturing fibroblast in vitro and in vivo. Abundant supply of cells are needed to develop engineered autologous substitute, hence micro carrier playing important role in TE field to enhance efficiency of substrates, micro carrier based cultures not only facilitated more practical large-scale cell expansion but also retained the function and viability of cells [32]. Xiaojun et al. prepared micronized acellular dermal matrix (MADM) micro carriers to act as cell culture substrate as well as scaffolds for guided tissue regeneration, which is simple and rapid strategy to repair tissue defects. MADM was used as a cell culture substrate to expand human fibroblasts with cell transplantation vehicle for skin tissue regeneration which eliminatesthe repeated trypsinization and reseeded process [33].

Advanced research has shown that using different cell in skin substitute could be help in complete regeneration of damaged skin. For example Adipose-derived stem cells (ASCs) are alternative sources of multipotent cells and having similar characteristics to bone marrow-derived mesenchyma stem cells (BM-MSCs) [34, 35]. Comparatively ASCs are more abundant than to BM-MSCs hence it is easy to isolate hence which makes attractive source for wound regeneration [36]. Jian ying et al. used adipose-derived stem cells (ADSCs) seeded on electrospinning poly (L-lactide-co-caprolactone)/poloxamer (PLCL/P123) scaffolds by taking a rat skin tissue injury model. The result of the study showed that ADSCs seeded on PLCL/ P123 scaffolds could promote wound healing and have the potential to become a new therapeutic alternative material for skin tissue engineering [37]. Michelle et al. studied on treatment for chronic and acute wounds including burns by using clotted human plasma to obstruct the excessive porosity and surface irregularity of a commercially available scaffold (Integra). In this model, Integra is populated with human adult fibroblasts for the support of keratinocytes and the scaffold's pores are obstructed with clotted human plasma before seeding adult keratinocytes. Aprotinin is added to culture media to inhibit premature breakdown of clotted plasma. The method shortens the preparation time of a composite human skin equivalent (HSE) with a suitable architecture; it influences the keratinocyte attachment and eficient neoepidermization [38]. In another study David et al. constructed the novel immune competent 3D human skin model comprising of dendritic cells co-cultured with keratinocytes and fibroblasts. Characterized data have shown that differentiation of the epidermal layer and formation of an epidermal barrier. This novel skin model will valuable in investigating the mechanisms of allergic contact dermatitis and other skin pathologies in human [39]. In skin TE field there are many different approaches proposed, but none allows the formation of hair follicles [40]. Hair follicles are more complex appendages of the skin and their genesis is promoted by a series of dermal-epidermal interactions. Recently, Costantino et al. studied and developed endogenous human skin equivalent that induces the full morphogenesis of functional dermal and epidermal compartments by using adult human skin cells. Author observed development of appendage-like structures, which was resemble the structure of the first step of hair follicle embryogenesis results suggested that it is possible to generate follicle-like structures in vitro resembling, what occur in vivo in the fetal skin [41].

Materials used for skin tissue engineering

Natural Polymer

Chitosan

Chitosan is one of the perspective natural polysaccharide [42] found in nature particularly in the shell of crustacean, cuticles of insects and cell walls of fungi. Chitosan molecule has amino and hydroxyl groups which can be modified chemically providing a high chemical versatility and is metabolized by certain human enzyme [43]. Chitosan has unique potential as matrices for tissue engineering scaffolds because of its biodegradability, biocompatibility and easily formed into structures under mild processing conditions can be easily chemically modified. The matrices provide a necessary template for physical support to guide the differentiation and proliferation of cells into targeted functional tissues or organs. It can act as an ideal wound dressing as it exhibits a positive charge, film-forming, mild gelation characteristics and a strong tissue-adhesive property with enhance blood coagulation [44]. It accelerates wound healing by enhancing the functions of inflammatory cells such as polymorph nuclear leukocytes, macrophages and fibroblasts [45-47]. Jian biao et al. constructed bilayer structure of chitosan film and sponge as a scaffold of dermis substitute. It was processed successively via the formation of a dense chitosan film by casting method and porous chitosan sponge by lyophilization [48]. To improve scaffold stability Lie et al. fabricated mixture of chitosan and collagen porous scaffolds for skin tissue engineering by freeze-drying method. Glutaraldehyde (GA) was used as crosslinker to treat the scaffolds to improve their biostability [49]. Glutaraldehyde (GA) is significant as crosslinking agent in preparation of chitosan based matrices it helps in enhancing properties. Iyabo Adekogbe and Amyl Ghanem have developed three dimensional scaffolds from chitosan crosslinked with dimethyl 3-3, dithiobis' propionimidate (DTBP) and evaluated the tissue engineering properties of these matrices with respect to uncross linked and GTA-cross linked chitosan matrices [50]. Cell-matrix interactions remain unclear in addition to the scaffold degradation and mechanical characteristics. In this regard Yan et al. have prepared scaffold and evaluated effect of chitosan blending with gelatin on degradation properties, mechanical properties and cell-matrix interactions [51].

Collagen

Collagen is considered as an ideal choice for tissue engineering scaffold because of its fibrous protein in the extracellular matrix (ECM) [52]. Many types of collagen have been discovered, which differ in their three-dimensional structure and their amino acid sequence, in order to meet the functional needs of different tissues [53]. In recent years special attention was paid to collagen, due to its excellent biocompatibility and ability to degrade. Bilayered collagen gels seeded with human fibroblasts in the lower part and human keratinocytes in the upper layer have been used as the dermal matrix of an artificial skin product which is commercialized by Organogenesis in USA under the name of Apligraf[R] [54]. Collagenous product has valuable material because of biocompatibility and biodegradability, hence made collagen as an inevitable source for tissue engineering biomaterials. Recent studies reported collagen widely used in skin tissue regeneration, Elsa et al. prepared collagen based 3D scaffold from type I bovine collagen with uniform pore size of 80|im to determine whether the collagen scaffold material could support in vitro vascularization using human endothelial cells and to know facilitate extrinsic/ intrinsic vascularization when implanted in vivo and data showed that 3D collagen scaffolds can support extrinsic and intrinsic vascularization using two different in vivo animal models, the murine subcutaneous implant model (extrinsic vascularization) and the rat tissue engineering chamber model (intrinsic vascularization) [55]. Curtis et al. have developed integrated fibroblasts, matrigel and micro fabricated biphasic collagen-glycosaminoglycan (GAG) scaffold whose porous features are well-controlled for proliferation of cells [56]. In vivo evaluation of prepared biomaterial is time consuming and limited by ethical consideration so therefore the availability of a library of biomaterials would allow a fast and rational in vitro selection of those biomaterials to be evaluated in vivo, in this concern Lammers et al. developed 48 defined collagen-based biomaterials were characterized and evaluated in vitro using primary human keratinocytes /fibroblasts [57]. Collagen is a major extracellular matrix [ECM] protein of the dermal layer of skin, and early studies on biodegradable polymers for wound dressing or skin tissue engineering focused on collagen. Biocompatibility and biodegradability is an important aspect in in vitro and in vivo, recently collagen based scaffolds have been implementing as biomaterial widely to assess their in vitro biocompatibility and biodegradability in order to use in skin tissue engineering [58]. The structural and functional characteristics of collagen similar to native ECM, hence collagen is using as matrices for wound healing. Satiesh et al. fabricated Collagen hydrolysate composite scaffold (CHCS) with sol-gel transition procedure using tetraethoxysilane as the silica precursor and investigated effectiveness of the CHCS against the traditionally used collagen scaffolds for wound healing therapy [59]. Collagen being mechanically poor hence to enhance their mechanical and morphological properties, blending of collagen with other synthetic material gives excellent blending of collagen and poly[(D,L-lactide)-co-glycolide] electrospun mat with high porosities of 85-90% and extended pore sizes of 90130mm which mimic the ECM morphologically and chemically [60].

Cellulose

Cellulose has been the subject of intensive research because of its sustainability, biodegradability and biosafety. In recent years, it has been used extensively in the biomedical field. Cellulose is widely distributed over a variety of sources, including marine animals (tunicates), plants (wood, cotton, or wheat straw), and bacterial sources, such as algae (Valonia), fungi and even amoeba (protozoa). Cellulose is a fibrous, tough, linear, syndiotactic homopolymer composed of D-anhydroglucopyranose units, which are connected by [beta]-(1-4)-glycosidicbonds [61]. Recently cellulose has been widely using in the field of TE. Farah et al. have fabricated fibrous scaffold of hydroxyethyl cellulose (HEC) /poly (vinyl alcohol) blend by electrospinning technique, composite were cross-linked by glutaraldehyde and characterized its microstructure, morphology, mechanical and thermal properties, cytotoxicity studies on these nanofibrous scaffolds were carried out using by the MTT assays. The cells were able to attach and spread in the nanofibrous scaffold. All data showed these nanofibrous scaffold that supports and proliferates the cells [62]. To enhance mechanical strength of cellulose scaffold Xu et al. fabricated uniaxially aligned electrospun nanofiber nonwovens from cotton cellulose in which cellulose nanocomposites (CNCs) were added to strengthen the scaffold and incorporation of CNCs into the spinning dope resulted in more uniform morphology of the electrospun cellulose/CNCs nano composite nanofibers (ECCnN) this scaffold elucidated from MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) tests and showed nontoxic to human cells. Cell culture experiments demonstrated that cells could proliferate rapidly not only on the surface but also deep inside the ECCNN, this feature made the scaffold can be useful for artificial tissues or organs [63]. Cellulose and its derivatives can also be considered as an ideal scaffold material for skin tissue engineering applications [64]. Based on its derivative Deniz et al. fabricated 3-dimensional electrospun cellulose acetate (CA)/ pullulan (PULL) scaffolds for skin defect in this method CA was used for mechanical strength while PULL was used for 3-dimensionality all data reveals that CA/PULL (50/50) electrospun scaffolds with tunable thickness hold promise for skin tissue engineering applications [65].

Silk Fibroin (SF)

Silks are fibrous proteins, which are spun into fibers by a variety of insects and spiders [66]. Silk fibroin (SF) has been proven as a suitable scaffold material in the area of tissue engineering. Silk fibroin can be effectively used for the fabrication of biomedical composite materials in several forms, including fibers, films [67-70], sponges and hydrogels [71]. Fibroin can support the cells growth, differentiation and intercellular communication between the cells, provide the cells with excellent microenvironment. SF has reactive carboxyl groups and amino groups in its side chains, it can react with amino acid and others small chemical groups to introduce other functional groups. Silk fibroin has been used as a biomaterial for biomedical applications because of its mechanical properties, biocompatibility and biodegradability [72, 73]. SF scaffold can support several cell types such as keratinocytes, and dermal fibroblast cells [74, 75]. Regarding its biocompatibility Witoo et al. have prepared film composed of chitosan (CS) and Silk fibroin (SF) then evaluated feasibility of film for skin tissue engineering application. Biocompatibility of the blend films was determined by cultivation with fibroblast cells, cell proliferation on CS/ SF films was also demonstrated, these results showed possibility of using the CS/ SF films as a supporting material for further study on skin tissue engineering [76]. Dae Hyun et al. prepared silk fibroin(SF)/ alginate(AA) blend sponge for full thickness skin defect in rat and studied wound healing effect of SF, AA, and SF/ AA-blended sponge with that of clinically used Nu Gauze[TM] in full thickness wound model of rats and also evaluated whether the wound healing effect of SF/ AA-blended sponge is mediated by either re-epithelialization or granulation process using histological observation and immune-histochemical analysis for proliferating cell nuclear antigen (PCNA) [77].

Alginate (ALG)

Alginates are polysaccharide refined from brown sea weeds. It is linear copolymer with homopolymeric blocks of (1-4)-linked [beta]-D-mannuronate (M) and its C-5 epimer a-L-guluronate (G) residues, respectively. Recently it has been using in tissue engineering for tissue regeneration some of studies have shown that alginate could be helpful for tissue formation. Alginate can be made as film, sponge and hydrogel recently hydrogel based film by using different composition of sodium alginate/Na???g-itaconic acid/acrylamide which was found to exhibit an intercalative structure and coarse surface and also qualified for skin application [78]. Sponge based scaffold has been using as a skin substitute which offers an alternative approach to create functional skin tissue. Pathum et al. prepared fish collagen/alginate (FCA) sponge scaffold that was functionalized by different molecular weights of chitooligosaccharides (COSs) with the use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride as a crosslinking agent and physicochemical, mechanical, and biological properties evaluated and suggest that the FCA/ COS scaffold is a superior candidate that can be used for skin tissue regeneration [79]. Polymeric ultra thin membranes that are compatible with cells offer tremendous advantages for tissue regeneration recently LBL self-assembly technique was used for wound healing for example Yi et al. used the technique of layer by layer self-assembly for producing free standing nanomembrane by using alginate with chitosan as this alginate is polyanion react with the amino group of chitosan enables it to ionize to a polycation in water, which shows a natural attraction to alginate because the carboxyl group of alginate turns it into a polyanion in water simultaneously. This reaction creates the exact condition necessary for the integration of the two polyelectrolytes on a specific substrate via LBL self-assembly resulted biocompatibility and free-standing nature of the fabricated nano-membrane may be useful wound healing [80].

Gelatin

Gelatin is a protein that contains high contents of glycine, proline and hydroxyproline [81, 82], it is a natural polymer derived from collagen [83]. Under specific conditions, such as temperature, solvent or pH, gelatin macromolecules present sufficient flexibility to realize a variety of conformations. This makes it possible to vary also all the gelatin characteristics dependent on its molecular structure [84] due to presence of both acidic and basic function at groups in gelatin macromolecules, it shows large number of structural diversity than other synthetic polymers [85]. It has been used in pharmaceuticals, cosmetics, as well as food products due to its exceptional characteristics [86], which has gained interest in biomedical engineering, mainly because of its biocompatibility and biodegradability [87] being a natural macromolecule that is readily available and does not cause antigenicity [88]. Sang et al. have prepared porous scaffold composed of gelatin/[beta]-glucan and investigated their cell attachment, optimum concentration and morphological characteristics, as a glucan is natural complex carbohydrate that boosts the immune response by activating macrophages cells, the ultimate goal of this study was to culture the fibroblasts and keratinocytes, isolated from a child's foreskin into the prepared sponges to mimic normal human skin [89]. Gelatin offers a unique character in blending with other natural polymer would improve the properties of the resultant scaffold, in this regard Brahatheeswaran et al. fabricated and characterized the gelatin blend with chitosan scaffold using electro spinning technique and also evaluated the properties of the chitosan-gelatin blend such as fiber morphology, diameter, mechanical properties, and porosity depends upon the interaction between the individual components chitosan and gelatine this combination serve as scaffold for skin tissue engineering [90]. In another study Ying et al. prepared and studied thermosensitive artificial skin composed of gelatin-chitosan (Gel-CS) scaffold as dermis and poly (N-isopropylacrylamide) (PNIPAAm) grafted micro porous polyurethane (PU) membrane as epidermis bound together by gelatin was prepared, and its morphological structure, water vapor permeability rate (WVPR) and in vivo biological properties were investigated and resulted artificial skin accelerated wound closer in rat model [91].

Synthetic polymer

Most often utilized biodegradable synthetic polymers for biomaterial in tissue engineering involved poly-lactic acid (PLA), poly-glycolic acid (PGA), poly-lactide-co-glycolide (PLGA), poly vinyl alcohol (PVA) and Polycaprolactone (PCL).Various types of biomaterial designs have been used in TE such as meshes, fibers, sponges, films, scaffold and foams, these designs are preferable because they promote uniform cell distribution, supply of nutrients and the reorganisation cell communities [92]. The use of biodegradable synthetic polymer have been widely studied, mainly due to their good biocompatibility, their chemical versatility and good mechanical property, also take part in good immunogenic reactions and free from disease transmission. They have good biodegrade property and generating monomers of lactic and glycolic acid which are eliminated through the metabolic pathways. The biomaterial shape should also facilitate cell seeding and attachment and promote cell proliferation and differentiation [93]. Arun et al. used poly (L-lactic acid)-co-poly ([epsilon]-caprolactone) (PLACL) with gelatine to prepare nanofibre by using elecrospinning technique used as a substrates for the culture of human dermal fibroblasts and resulted nanofibrous scaffolds show sufficient porous structures and mechanical stability, and loose peripheral regions of the scaffold are favourable for cell infiltration and provide enough space for fibroblast ingrowth for the formation of a dermal substitute for skin tissue regeneration [94]. One challenge in tissue engineering is the design of reproducible three-dimensional (3D) scaffolds that can mimic the structure and biological functions of the extracellular matrix (ECM). PLGA nanofiber have shown that versatile material hence Changhai et al. prepared PLGA nanofibre mat with help of polypropylene auxiliary supporter, which makes the scaffold able to maintain long-term integrity without dimensional shrinkage and studied in-vitro on keratinocyte cells resulted human skin keratinocytes can proliferate on the scaffold and infiltrate into the scaffold [95]. Far fewer works have been reported on nano fibers as tissue engineering scaffold because of use of appropriate material is a key limiting step for the creation of functional engineered tissues and their clinical applications, perhaps because of the poor biological properties of these synthetic materials, hence need hybrid composite material that could meet the demand, therefore introduction of polymers of natural origin with synthetic polymers have been shown that optimize the biological and physicochemical properties in this regard Venzin et al. studied and prepared three dimensional scaffold by using synthetic polymer polyethylene glycol (PEG) with fibrinogen (fib) for skin wound. The histological evaluation showed good biocompatibility of the PEG-fib. It provides initial moisture to the wound bed and is gradually resorbed and replaced by structured skin tissue [96]. Other different polymer composition as biomaterial listed in table.1

Growth Factors for Tissue Regeneration

Growth factors are signaling proteins that influence the metabolism of other cells [102]. It is known that successful tissue growth is often dependent on the delivery of growth factors to cells within regenerating tissues. These tissues are generated by specific cellular response due to growth factor signalling leads to cell actions including cell survival, migration, differentiation or proliferation of a specific subset of cells [103]. There is need of sophisticated growth factor delivery mechanisms to mimic the endogenous profiles of growth factor production during natural tissue morphogenesis or regeneration. Growth factors are necessary for communication between a variety of cells like fibroblasts, myofibroblast, smooth muscle cells, endothelial cells, keratinocytes and immune cells. The exogenous application of growth factors has been proven to affect the wound healing process [104]. The complexity of endogenous growth factor release provides a significant new drug delivery challenge and mimicking the endogenous release profiles within in vitro tissue engineering scaffolds. These should have required maintenance of function of proteins, glycoproteins and other biological molecules during the fabrication of scaffolds, and control of the kinetics of growth factor release [105]. Many studies have confirmed that growth factors are necessary for healing for example, platelet-derived growth factor (PDGF) enhance the wound healing rate in acute wounds and even provide complete healing in chronic wounds [106-108]. There are different types of growth factors involved in the wound healing process such as PDGF, epidermal growth factor (EGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), TGF- [beta][109-112] and keratinocyte growth factor (KGF) [110].

Fibroblast growth factor

For dermal injury there are several fibroblast growth factor used such as FGF-1, -2, -7, -10 and -22 [113]. FGF-1 consider to acidic and FGF-2 to basic FGF and these are produced by inflammatory cells, vascular endothelial cells, fibroblasts and keratinocytes, which are contribute to re-epithelialization, angiogenesis and granulation tissue formation [103, 114]. Haifeng et al. prepared chitosan-gelatin microspheres loaded with bFGF and incorporated into a porous three dimensional chitosan-gelatin scaffold for skin tissue engineering. Human fibroblasts were cultured on the scaffolds with and without bFGF-loaded chitosan-gelatin microspheres (bFGFMS), and investigated the effect of the controlled-release of bFGF from chitosan-gelatin microspheres on human fibroblasts cultured on chitosan-gelatin scaffolds. Cell morphology, cell proliferation, GAG synthesis, and gene expression were examined in vitro and were compared with chitosan-gelatin scaffolds alone [115].

Epidermal growth factor [EGF]

EGF is a growth factor mainly secreted by platelets, macrophages, fibroblasts [113]. This growth factor plays an important role in tissue homeostasis by influencing epithelial cell proliferation, growth, and migration. It also helps in providing nutritional support by enhancing angiogenesis, and is therefore considered as a key player in wound healing and tissue regeneration [116]. Recent studies demonstrated that EGF stimulates keratinocyte division in vitro and epidermal regeneration in vivo [117]. Recently studies have shown encapsulation of EGF with biomaterial enhances the ability of material for skin tissue regeneration in this context Mohammad et al. prepared nanofibers of poly (lacticco-glycolic acid) (PLGA) with gelatin and PLGA encapsulated epidermal growth factor through emulsion electrospinning, all data suggested that capability of encapsulation and controlled release of the protein with desirable bioactivity and hemostasis of the scaffolds show their potential applications in skin tissue engineering and wound dressing [118].

Transforming growth factor [beta]-family(TGF-[beta])

Transforming growth factor-[beta] is a multifunctional regulator of cellular growth, differentiation, and extra cellular matrix (ECM) production [119] and plays a pivotal role in wound healing regulation and scarring. The TGF-[beta] consists of TGF-[beta]1-3, bone morphogenic proteins (BMP) and activins. Among TGF-[beta]1 dominates in cutaneous wound healing they are generated by cells involved macrophages, fibroblasts, keratinocytes and platelets [113]. TGF-[beta] which has the capacity to attract new fibroblasts and macrophages to the wound site, this leads to stimulation of fibroblast proliferation and collagen synthesis [120] and also regulate the immune system [121]. Both TGF-[beta]1 and -[beta]2 both have ability to induce fibroblast-myofibroblast differentiation, ECM deposition, contraction, and scar formation, whereas TGF-3 has the ability to reduce scarring [113]. Ronan et al. have investigated and prepared biomaterial which contain fucoidan with transforming growth factor-[beta] (TGF-[beta]) resulted in a three dimensional in vitro model of wound repair, the fibroblast populated collagen lattice, TGF[[beta].sub.1] reduced the rate of fibroblast repopulation of a wound defect created by punch biopsy. Addition of fucoidan to the model in the presence of TGF[[beta].sub.1] increased the rate of fibroblast repopulation of the wound [122].

Platelet-derived growth factor (PDGF)

PDGF is secreted after tissue damage and promotes cellular reactions throughout all phases of the wound healing process. PDGF categorized into three isoforms: PDGF-AA, -BB, and AB [123] secreted from the [alpha]-granules of the platelet [124], also produced by different cells present in early wound healing i.e. macrophages, keratinocytes, fibroblasts and endothelial cells [124, 125]. By using exogenous PDGF it can be treating for wound and studies have been found that, it could be beneficial for chronic wounds [126,127]. Growth factors derived from platelets play an important role in tissue remodeling including neovascularization. Platelet-rich plasma (PRP) has been utilized and studied for the last four decades. Platelet gel and fibrin sealant, derived from PRP mixed with thrombin and calcium chloride, have been exogenously applied to tissues to promote wound healing. Qiming et al. prepared Poly (L-lactic acid) (PLLA) nanofibrous scaffold for tissue engineering and their effects on PDGF biological functions on tissue neogenesis and vascularization. Scaffold containing PDGF-BB encapsulated in poly (lactide-co-glycolide) microsphere (PLGA MS) of different molecular weight were implanted subcutaneously in vivo, and the implant-tissue constructs were harvested and analyzed by histology, histomorphometry, cDNAarray, and quantitative real-time PCR. This method offers a technology to accurately control growth factor release to promote soft tissue engineering in vivo [128].

Summary of Current Status

Although it is now known as a common term for almost two decades, 'Tissue Engineering' (TE) still can considered to be a comparatively young field of basic and applied multidisciplinary biomedical research. Typical examples of tissue engineered substitutes that have been and still are currently being investigated throughout the world. TE field has been working on different type's tissues such as skin, cartilage, bone, blood vessels, pancreas, heart valves, breast, nerves, trachea, bowel, kidney, lung and liver. Recently in skin tissue engineering field, the biodegradable polymer based material preferred for implantation and implanted material should have characteristic of biocompatibility and biofunctionality. Biocompatibility is concerning about the absence of toxicity, immunogenicity, carcinogenicity, and thrombogenicity [129] and response of cell behaviour towards biomaterial particularly cell attachment on biomaterial which can influence cell reaction through changes in the cytoskeleton. Behaviour of cells and interaction of cells with a biomaterial surface are dependent on properties such as topography, surface charges, and chemistry [130, 131]. Bio-functionality related to mechanical, physical, chemical, thermal and biological propertiesbased on structure of biomaterial mainly focussed on porous and fibrous 3D structure play significant role to improve early implant stability. The high porosity (65-70%) and the broad pores (diameter of 350 to 550[micro]m) sufficient for nutritional supply inside the biomaterial. If the pores are too small, cell migration is limited, resulting in the formation of a cellular capsule around the edges of the biomaterial and limiting extra cellular matrix (ECM) production and neovascularisation of the inner areas of thescaffold. This leads to limit the diffusion of nutrients, resulting in a necrotic region within the biomaterial construct. In many cases if the pores are too large, there is a decrease insurface area, limiting cell adhesion [132, 133] become more fragile but which are improves infiltration of new blood vessels into the scaffold. The critical aspect concerning about determination of blood vessel ingrowths, scaffolds with smaller pores have a greater surface area, which helps in increasing sites for initial cellular attachment post-seeding [134]. Therefore it is very essential to maintain balance between the optimal pore size for cell migration and specific surface area for cell attachment [135, 136]. In contrast, the engineering of more complex tissues consisting of large 3D structures remains a critical challenge because the amount of oxygen required for cell survival is limited to a diffusion distance of approximately 150 mm to 200 mm from the supplying blood vessel, the long term survival and function of these 3D-constructed tissues depend on rapid development of new blood vessels, which provide nutrients and oxygen to the cells not only of the margin but also of the centre of the tissue grafts. In fact, the growth of a new micro vascular system remains one of the major limitations in the successful introduction of tissue engineering products to clinical practice [137]. Many synthetic and natural polymer have been using for preparation of 3D structured biomaterial by using different methods such as solvent casting and particulate leaching, thermally induced phase separation, gas foaming, melt molding and advanced electrospinning and 3D printing. The scalability of the 3D printing technique enables the manufacturing of large specimens in the meter range as well as small specimens of a few millimetres. Rapid Prototype (RP) structures show mechanical properties significantly higher than those of structures fabricated by other well-known techniques such as solvent-casting and particle leaching, gas foaming and thermal-induced phase separation, among others [138]. Today various researches has been accelerated based on cells, more recently advances in research of adult stem cells and embryonic stem cells offer hope for the therapeutic deficiencies in severe burn treatment using existing skin tissue-engineered products. There is rapidly increasing interest in human induced pluripotent stem cells (hiPSCs) as this Nobel-winning technology pioneered by Shinya Yamanaka and his team [139, 140] enables the reprogramming of adult somatic cells to embryonic-stage cells. hiPSCs technology therefore allows for patient- and disease-specific stem cells to be used for the development of therapeutics, including more advanced products for skin grafting and treatment of cutaneous wounds [141]. Nanotechnology can help to reproduce or to repair damaged tissue which makes use of artificially stimulated cell proliferation by using suitable nanomaterial-based scaffolds and growth factors. TE might replace today's conventional treatments, e.g. transplantation of organs or artificial implants. Even though well advanced technique there is still lack in reliable methods to generate durable skin substitute that would enhance the original tissue, which loss during injury and disease.Today worldwide need of fast and good research on fabrication of biomaterial to meet global demand because most of the research on skin substitute still under in vitro stage and far few under in vivo which are clinically has to be proved. There are some commercially available skin substitutes for example in Table 2.

Conclusion

Currently in the field of skin tissue engineering (TE) mainly focussing on three elements, choice of scaffold material, type of cell and growth factor to fulfil the growing demand of skin substitute and most of the tissue engineering substitute could only function as temporary substitute in skin TE . Lack of immediate blood supply and activation of immune rejection are the two major problems facing across the world. Skin cells are of central importance to the future efforts for the complete healing of wounds. Cells survive poorly without extra cellular matrix, which provides the structural template necessary for cell growth, tissue scaffolds have been demonstrated to be useful in skin tissue engineering in variety of wound conditions. These are not only covering the wound also offer a cellular skin with excretive biological components to stimulate re-epithelialisation and formation of granulation tissue. A variety of scaffolds fabricated based on materials ranging from naturally occurring materials and manufactured synthetically. Polymer-based materials have been investigated extensively and significant success has been achieved in a variety of commercial or laboratory-engineered skin substitutes for skin tissue regeneration. However, many problems associated with the current skin substitute, which include contraction, delayed vascularisation, high cost and scarring. Rapid progress in skin tissue engineering based on natural and synthetic polymers provides a solution for re-epithelisation of tissue, which can result in a new biomaterial with appropriate biocompatibility and biofunctionality. Use of stem cells, may give us hope that such a product will be developed in the near future. It is hoped that a combination of appropriate materials and techniques can overcome many of problems in order to eliminate or reduce the risk of failure in skin graft. However, there are still many challenges collectively faced by bioengineers, cell biologists, clinicians and further development will be require in TE area with interactions and collaborations to meet global demand of skin substitute for complete tissue regeneration.

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Anand V. Nasalapure (1), Raju K. Chalannavar (2) (*), Ramesh S. Gani (3), Ravindra B. Malabadi (2), Deepak R. Kasai (4)

(1) Department of Industrial Chemistry, (2) Department of Applied Botany, (3) Department of Industrial Chemistry, (4) Department of Material Science, Mangalore University, Mangalagangotri 574199, Mangalore, Karnataka, India

Received 12 May 2017; Accepted 11 November 2017; Published online 31 December 2017

* Coresponding author: Dr. C. Raju Krishna; drrajkc@gmail. com

Caption: Figure 1: Anatomical structure of skin [15]
Table 1: Other Composition of Biomaterial for Tissue Engineering

Composition              Scaffold      Method
                         type

PLLA-collagen and        3D porous     --
PLLA-gc Latin            scaffold

polyvinylpyrrolidone     Balayer       cryogelation
iodine and gelatin       Ciyogel

Polyethyleneglycol-      Porous        --
polyurethane(PEG-PU)     scaffolds

[beta]-glucanbutyrate-   electrospim   electospinning
[beta]- glucan acetate   mats

Borate bioactive glass   Fibrous       Melting and
and CuO                  scaffold      method casting

Composition                       Description                    Ref

PLLA-collagen and        PLLA woven mesh hybridized with         [97]
PLLA-gc Latin            funnel-like collagen or gelatin
                         sponges to construct PLLA-collagen or
                         PLLA-gelatin hybrid scaffold for skin
                         tissue engineering. The hybrid
                         scaffold was used for in vitro dermal
                         fibroblast culture and in vivo wound
                         healing assessment.

polyvinylpyrrolidone     Made of top layer composed of           [98]
iodine and gelatin       polyvinylpyrrolidone-iodine(PVPI)
                         cryogel and bottom regenerative layer
                         made using gelatincryogel,
                         Incorporation of iodine prevents long
                         term infection The secryogel
                         scaffolds are biocompatible.
                         biodegradable and high fluid
                         absorption capacity also help in
                         faster and better healing of the
                         wound.

Polyethyleneglycol-      A porous PEG-PU scaffold that           [99]
polyurethane(PEG-PU)     facilitates cell delivery and boosts
                         tissue repair was developed through
                         semi-interpenetrating polymer network
                         approach. Study depicted polymeric
                         matrices could be better scaffold for
                         wound tissue regeneration.

[beta]-glucanbutyrate-   Combination of self-organization and    [100]
[beta]-glucan acetate    electrospinning could serve as an
                         alternative method to prepare
                         nanostmctured asymmetric membranes,
                         and bilayer [beta]-glucan ester
                         electrospim membrane (BGE-B)could be
                         used as an efficient wound-healing
                         application

Borate bioactive glass   Wound dressings composed of borate      [101]
and CuO                  bioactive glass microfibers doped
                         with 0-3.0 wt. %CuO were created and
                         evaluated in vitro and in vivo.
                         Stimulate angiogenesis and heal lull-
                         thickness skin defects. They also
                         provide valuable data for
                         understanding the role of the
                         microfibers in healing soft tissue
                         wounds.

Table 2: Commercially Available Skin Substitute

Brand name                  Type skin    Graft type    Cell source
manufacturer                substitute

Permacol / Tissue Science   Dermal skin  Cell free           --
Laboratoriesplc             substitute

Transcyte / Advanced        Dermal       Cell-seeded   Allogenic
BioHealingInc               skin         scaffold      neonatal
                            substitute                 Human dermal
                                                       fibroblasts

CryoSkin / Altrika Ltd      Epidermal    Cell-seeded   Cryopreserved
                            skin         scaffold      monolayer
                            substitute                 of noncultured
                                                       allogeneic

LyphoDerm / CellTranLtd     Epidermal    Cell based    keratinocytes
                            skin                       Freeze-dried
                            substitute                 lysate from.
                                                       cultured
                                                       allogeneic

Permaderm / RegenecinInc    Epidermal    Cell seeded   keratinocytes
                            /Dermal      scaffold      Autologous
                            skin                       cultured
                            substitute                 keratinocytes
                                                       and fibroblasts

Tissue Tech                 Epidermal    Cell-seeded   Autologous
Autograft System / Fidia    /Dermal      scaffold      cultured
Advanced Biopolymers        skin                       keratinocytes
                            substitute                 and fibroblasts

Brand name                  Biomaterial                        ref
manufacturer

Permacol / Tissue Science   Porcine-derived a cellular matrix  [142]
Laboratoriesplc

Transcyte / Advanced        Nylonmeshcoated withporcine
BioHealingInc               dermal collagen and bonded to      [143]
                            asilicone membrane

CryoSkin / Altrika Ltd      Silicone backin
                                                               [144]

LyphoDerm / CellTranLtd     Hydrophilic gel
                                                               [145]

Permaderm / RegenecinInc    Absorbable biopolymer              [146]
                            substrate fabricated from
                            bovine collagen

Tissue Tech                 Dermal substitute including        [147]
Autograft System / Fidia    hyaluronic acid matrix             [148]
Advanced Biopolymers
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Author:Nasalapure, Anand V.; Chalannavar, Raju K.; Gani, Ramesh S.; Malabadi, Ravindra B.; Kasai, Deepak R.
Publication:Trends in Biomaterials and Artificial Organs
Date:Apr 1, 2017
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