Súčasný prístup k liečbe popáleninovej rany je viac holistický a smeruje k zlepšeniu dlhodobých výsledkov v zmysle stavu a funkcie zhojenej popáleninovej rany a kvality života. Autológne kožné transplantáty čiastočnej alebo plnej hrúbky kože síce predstavujú najlepší definitívny kryt popáleninovej rany, ale ich zdroj je obmedzený, hlavne pri rozsiahlych popáleninách. Navyše, odberové plochy predstavujú ďalšiu morbiditu pa-cienta v zmysle vzniku ďalších rán a jaziev, ako aj ev. potrebu ich prekrytia kožným autotransplantátom, čo je potrebné mať na zreteli pri zvažovaní liečby popáleninovej rany. Tento fakt prispel k nutnosti vývinu rôznych kožných náhrad použiteľných na akútnu popáleninovú ranu, ako aj na následné rekonštrukcie. Tento článok sumarizuje súčasne dostupné kožné náhrady, vyrobené v neziskových kožných bankách ako aj komerčne dostupné. Sú rozdelené podľa typu materiálu na biologické, biosyntetickéa syntetické a postupne opísané.
popáleniny – kožné náhrady – biologické kožné náhrady – syntetické kožné náhrady
Skin substitutes are heterogeneous group of wound coverage materials that aid in wound closure and replace the functions of the skin, either temporarily or permanently, depending on the product characteristics. The ultimate goal is to achieve an ideal skin substitute that provides an effective and scar-free wound healing (1). Ideal properties of skin substitutes are: immediate replacement of both the lost dermis and epidermis, permanent wound coverage, firm adherence to the wound, flexible, can be conformed to irregular wound surfaces, easy to be secured and applied, able to withstand the shear forces, lack of antigenicity, non-toxic, maintain surface fluid layer, barrier to evaporative water loss, barrier to bacteria, decrease pain, long shelf life, easy to store, widely available, cost effective (2, 3). There is still no ideal skin substitute available that fulfills all the above-mentioned features and this remains a challenge for tissue engineering. There are many different classifications of currently available skin-substitute products and they can be summarized as follows.
- Anatomical structure: dermo-epidermal (composite), epidermal, dermal.
- Skin substitute composition regarding cellular component: cellular, acellular.
- Primary biomaterial loading with cellular component occurs: in vitro, in vivo.
- Type of the biomaterial: biological: autologous, xenogeneic, amniotic membranes, allogeneic, synthetic: biodegradable, non-biodegradable, biosynthetic.
- Duration of the cover: permanent, semi-permanent, temporary (3).
Currently available skin substitutes divided according to type of biomaterial and subdivided to anatomical structure are presented in this paper. The biological skin substitutes may allow the construction of a more natural new dermis and allow excellent re-epithelialisation characteristics due to the presence of a basement membrane. Synthetic skin substitutes demonstrate the advantages of increased control over scaffold composition (1). The structure should also approximate dermal and epidermal layer and should include not only a 3D matrix of fibres, but also cells, especially keratinocytes and fibroblasts. The expression of relevant cytokines by living cells is expected as well (4). Indications for use of the skin substitutes are: superficial to second degree burns; clean, excised wound; skin donor sites (2).
BIOLOGICAL SKIN SUBSTITUTES
Dermo-epidermal skin substitutes
Skin autografts (isografts) are harvested and placed on the same individual. Autografts present the only commonly used and reliable method of permanent skin substitute. The most valuable is full-thickness skin, but this can be used only for small defects, because there is a need to have a primary suture or cover the donor site with thin dermoepidermal skin graft after harvesting the autograft. Mostly, dermoepidermal skin grafts are used. They contain all the epidermis and part of dermis (cca 1/3 to 2/3 of its thickness) (4). The donor site heals similarly to the superficial partial thickness wound by keratinocyte migration from hair follicles, sweat glands and edges of the wound. Generally, the thicker the skin graft is, the less contraction there will be at the site of application but the longer it will take to heal the donor site. Depending on the thickness of the dermis, only three to four split-thickness skin harvests are possible from the same site and re-cropping is delayed by the time necessary for re-epithelization. Meshing techniques can be used where grafted skin is uniformly perforated and stretched to cover greater areas of the wound. Although this method allows greater area coverage and reduces mortality rates, the cosmetic and functional outcomes are unsatisfactory. This should be of concern for the autograft application (1, 3, 5).
A xenograft is defined as a tissue graft transferred from one species to another one (2). Xenografts have been used as a temporary replacement for skin loss (6). Frog and lizard skin use was reported in the 16th and 17th century and frog skin is still used currently in Brazil (2). Bromberg suggested the use of xenografts from pigs and dogs in 1965. Xenografts are prepared in tissue banks and are stored in different forms as fresh, frozen, lyofilised, deepidermed, etc. Their antigenicity is markedly higher than in allografts so there is no vascularization of xenografts possible. They are frequently used as a temporary cover for partial-thickness burns without former excision as a biological dressing or for deep burns after excision as a temporary skin subtitute. They are used also to cover micrografts or wide-meshed autografts. As well as antigenicity there is a potencial risk of zoonosis transmission (7).
Since 1910, allogeneic amnion has been used as a biological wound dressing. It has a fragile structure and is technically more difficult to handle. Amniotic membrane is a thin semi-transparent tissue forming the innermost layer of the foetal membrane. It has an avascular stroma, which does not allow amniotic membranes to get incorporated and vascularized, and a thick continuous basement membrane with a full complement of collagen types IV and V and laminin and contains several protein inhibitors (6). There are many advantages of human amniotic membranes: they have no immunogenicity which ensures no rejection, reducing loss of proteins, electrolytes, fluids and energy. They are usually free from toxic material and reduce the risk of infection (impermeable for microorganisms). Morover, amniotic membranes contain active substances (angiogenetic factor, basic fibroblasts’ growth factor – bFGF, hepatocytes’ growth factor – HGF, etc.) Transparency allows some control of the healing process. Another advantage is in avoiding of bulky dressings, minimising pain and need of analgesia associated with dressing changes and acceleration of epithelial regeneration reduces length of hospitalization. Disease transmission remains a possibility as well as in any biological material. Washing with antibiotic solutions, lyophilization, sterilization or long-term glycerol preservation have all been used to free amniotic membranes from bacterial and fungal contamination. Human amnion is primarily used to cover debrided superficial and intermediate depth wounds until they are completely healed. When used for full thickness and contaminated wounds, human amniotic membranes undergo disintegration by bacterial enzymes and more frequent reapplication is needed. Human amniotic membranes can also provide a useful cover for microskin grafts or an overlay of widely meshed autografts promoting early epithelization and rapid wound healing (4, 6).
Human cadaver allografts, Karoskin
Allograft is a tissue graft sourced from a genetically non-identical member of the same species. Whenever available skin donor sites are limited or when the overall patient condition does not permit immediate coverage of excised burn wounds with autologous skin, there may still be a clinical need for human cadaver allograft skin to be used as a temporary biologic dressing. It may also be used as a dressing to cover widely meshed autografts in extensive burns (6). Structurally and functionally, it is the best temporary skin replacement. However, availability is limited due to the risk of transmission of diseases and difficulties associated with handling and transporting the material. For this reason, frozen human allograft skin is more commonly used. Guidelines (European directives) for mandatory screening, testing of acute and chronic infections, and documenting the donors medical history before skin harvesting are issued (8). Allografts stay attached only until rejection occurs (4). After allograft skin has adhered to the wound bed, it is removed and usually will leave a vascularized wound base to accept an autograft, increasing the chance that the autograft will be successful. Although allografts can be obtained from not for-profit skin banks, they can also be purchased as a commercial product, e.g. Karoskin (Karocell Tissue Engineering AB, Karolinska University Hospital, Stockholm, Sweden) (3).
Apligraf/Graftskin (Organogenesis Inc, Canton, MA, USA)is a bilayered living skin equivalent composed of type I bovine collagen, allogeneic keratinocytes and fibroblasts. The cellular components are derived from human neonatal foreskin. The construct is able to produce matrix components, including cytokines and growth factors. Apligraf is similar to human skin in many ways. In addition to being biochemically and metabolically similar, the cell proliferation rate is comparable to that of human skin. Apligraf is only available fresh and has a shelf life of 5 days at room temperature. Indications for clinical use are especially non–healing wounds as venous ulcers or defects caused by atherosclerosis and surgical wounds such as after removal of skin cancers. No signs or symptoms of rejection or toxicity were noted with Apligraft (4, 8).
OrCel (Ortec International Inc, New York, NY, USA) includes cultured allogeneic fibroblasts and keratinocytes obtained from the same neonatal foreskin. Fibroblasts are seeded into a bovine type I collagen sponge, which has a non-porous collagen-gel coating, on top of which keratinocytes are added to form a confluent layer. The product was licensed in 2001 to treat donor sites in burns and recessive dystrophic epidermolysis bullosa. This bilayered product is reported to produce an array of cytokines and growth factors, which are all favourable for host cell migration and wound healing, thus „conditioning“ the wound bed for further treatment with skin grafts. This artificial skin substitute product showed reduced scarring and a shorter healing time was also reported when compared to the acellular bioactive wound dressing Biobrane (9). The product performs a temporary role.
Cultured epithelial autograft plus cultured fibroblasts
Cultured epithelial autograft plus cultured fibroblasts (Lifeskin Culture Technology, Sherman Oaks, CA, USA) is a confluent sheet of keratinocytes plus fibroblasts obtained from neonatal foreskins. It does not present a real barrier function on application. A bilayered structure is developed after application. There are no clinical studies of use in burns yet available (2).
Epidermal skin substitutes
Cultured epithelial autografts (CEA) (Epicel, EPIBASE, EpiDex)
In 1975, Rheinwald and Green described a method of in vitro cultivation of epidermal cells that produced viable keratinocyte sheets. In 1988, CEA became commercially available as Epicel (Genzyme Biosurgery, Cambridge, MA, USA), EPIBASE (Laboratoires Genevrier, Sophia – Antipolis, Nice, France), EpiDex (Modex Therapeutiques, Lausanne, Switzerland) and today CEA are also available from other sources. Epicel is indicated for the treatment of deep dermal or full-thickness wounds requiring skin grafting. The use of Epicel is contraindicated in patients who have a history of previous hypersensitivity or serious toxic reactions to penicillin, streptomycin, or gentamicin. The CEA production process requires a small biopsy of a patient’s skin. It takes 3–5 weeks to produce 1.8 m2 confluent sheets of cells from a 2 cm2 biopsy. They are thin and fragile and should be handled with extreme care during and after application (8). The resulting epithelium is unstable, giving rise to spontaneous blistering many months after grafting, and increased susceptibility to infection and contractures.
Bioseed – S
Bioseed – S (BioTissue Technologies GmbH, Freiburg, Germany) consists of cultivated subconfluent autologous keratinocytes resuspended in a fibrin sealant (Tissucol Duo S Immuno, Baxter). It has mainly been used to treat chronic venous leg ulcers (10). No information regarding the use of this material in burns patients is available, although there is potential for its use in this area. An animal study with analogous material, where autologous keratinocytes were resuspended in autologous fibrin sealant, applied to full-thickness wounds, revealed the usefulness of such application methods resulting in a good epithelization (11). The fibrin improved handling, cell attachment, haemostasis and wound healing.
Sprayed cell suspensions (CellSpray)
Cell spray (Clinical Cell Culture, Perth, Australia) have been applied to wounds with autologous split-thickness grafts meshed 3 : 1 in pigs. In these cases, the cells have been suspended in their growth medium and sprayed directly onto the wound without the use of fibrin. The wound is reported to heal faster and to be of superior quality where cells were sprayed (12).
Allogeneic cultured keratinocytes
In an attempt to overcome the problem posed by the time delay in growing confluent autologous keratinocytes for wound closure, the use of pre-grown allogeneic keratinocytes has also been considered. From a clinical perspective, there is no acute rejection reaction following the application of allogeneic sheets of keratinocytes. Survival appears to be related to the state of the wound bed, and is prolonged where dermis is present. The enhanced healing noted following the application of allogeneic keratinocytes is attributed to the secretion of growth factors and cytokines by the cells. The main use of allogeneic keratinocytes remains as a dressing in chronic open wounds, such as ulcers, or to speed the healing of donor sites (12).
Dermal skin substitutes
Acellular allogeneic dermis (AlloDerm, Karoderm, SureDerm, GraftJacket)
AlloDerm (LifeCell Corporation, Branchburg, NJ, USA), Karoderm (Karocell Tissue Engineering AB, Karolinska University Hospital, Stockholm, Sweden), SureDerm (HANS BIOMED Corporation, Seoul, Korea), GraftJacket (Wright Medical Technology Inc, Arlington, TN, USA) are chemically treated non-toxic cadaver allografts in which the epidermal antigeneic cellular components are removed, leaving an immunologically inert acellular dermal matrix. Clinical studies of AlloDerm have demonstrated that it can accept and maintain the viability of ultra-thin split-thickness autografts. Production of the AlloDerm does not disrupt matrix proteins and preserves the basement membrane complex. It appears that the preservation of the basement membrane complex plays a crucial role in the success of the epithelial growth on AlloDerm. In addition to its use in the treatment of burn patients, AlloDerm has also been used in oral and plastic surgery (8).
Matriderm, Permacol Surgical Implant
These decellularized dermal products are similar to AlloDerm but of animal origin. This reduces risks associated with transferable human viral diseases. Matriderm (Dr Suwelack Skin and Health Care AG, Billerbeck, Germany) is of bovine origin. It has shown promising results when applied simultaneously with split-thickness skin grafts in a single-stage operative procedure (13). Permacol Surgical Implant (Tissue Science Laboratories plc, Aldershot, UK) is a decellularized porcine dermal layer. Its use for dermal reconstruction is limited owing to the slow biointegration and vascularization (14).
OASIS Wound Matrix
OASIS Wound Matrix (Cook Biotech Inc, West Lafayette, IN, USA) is produced from porcine small intestine submucosa and intended for wound closure stimulation in acute, chronic and burn wounds. It is freeze-dried and decellularized to prevent immunological responses. OASIS Wound Matrix has also been shown to support in vitro epidermal differentiation and basement membrane formation (15). It was also evaluated in vivo as a wound dressing in rodent full-thickness wounds where it contributed towards contraction minimization and had no effect on epithelization (16). No results of clinical trials regarding its use in full-thickness wound management have been published yet.
EZ Derm (Brennen Medical Inc, MN, USA) is a reconstituted collagen of porcine origin which is cross-linked with aldehyde to increase its tensile strength. The product does not incorporate into the wound and has to be removed (17).
Collagen matrix alone
Collagen matrix alone consists of collagen matrix dermal analog fabricated with cross linked bovine collagen and denaturated collagen (gelatin). After incorporation, a thin autograft is needed to apply (2).
SYNTHETIC AND BIOSYNTHETIC SKIN SUBSTITUTES
Dermo-epidermal skin substitutes
PolyActive (HC Implants BV, Leiden, The Netherlands) is a bilaminar product based on autologous cultured keratinocytes and fibroblasts seeded into a PolyActive matrix. This porous matrix consists of a soft polyethylene oxide terephthalate component and a hard polybutylene terephthalate component, which prevents contraction of this polymer. PolyActive may find use as a biologically active dressing in the treatment of partial-thickness wounds and also skin graft donor sites providing growth factors necessary to enhance wound healing. The fact that this product features a non-biodegradable synthetic dermal component precludes its use as a permanent skin substitute (3).
TissueTech Autograft System (Laserskin and Hyalograft 3D, Fidia Advanced Biopolymers, Abano Terme, Italy)
This system combines two tissue-engineered biomaterials applied consecutively to the wound: dermal replacement construct – Hyalograft 3D and epidermal substitute – Laserskin. These are based on autologous keratinocytes and fibroblasts, grown on microperforated hyaluronic acid membranes, and described later. This system allowed successful treatment of diabetic foot ulcers, many of which were full-thickness (18).
Epidermal skin substitutes
MySkin (CellTran Ltd, Sheffield, UK) uses subconfluent autologous living keratinocytes which are grown on a silicone support layer with a specially formulated surface coating. The advantage is that proliferatively active keratinocytes could be delivered to the patient with greater time flexibility that cannot be achieved with confluent cultured epithelial sheet grafts. Myskin is indicated for the treatment of neuropathic, pressure and diabetic foot ulcers, superficial burns and skin graft donor sites with positive clinical outcomes (19). It can also be applied to full-thickness wounds in combination with meshed skin grafts but cannot be used alone for deep-wound treatment.
Upside – down membrane delivery systems (Laserskin or Vivoderm)
One of the most innovative membranes used to deliver keratinocytes to the wound in an upside-down manner is Laserskin (Fidia Advanced Biopolymers, Padua, Italy), a membrane delivery system created from a laser-perforated derivative of esterified hyaluronic acid. Keratinocytes are seeded in vitro onto the membrane, and populate the laser-drilled pores. The cell colonies then grow above and below the membrane, which can be peeled off the Petri dish without enzymatic digestion. This has been used for the treatment of vitiligo as well as to resurface Integra described next (12).
Dermal skin substitutes
Integra Dermal Regeneration Template, Terudermis, Pelnac Standard Type/Pelnac Fortified With Mesh Type
Integra Dermal Regeneration Template (Integra Neuro Sciences, Plainsboro, NJ, USA) was approved by the FDA (Food and Drug Administration) for use in the treatment of burns in 1996 and since then has become a „gold standard“ dermal substitute biomaterial (20). This material is indicated for the postexcisional treatment of life-threatening full-thickness or deep partial-thickness thermal injury (8). It is also used for chronic ulcer treatment and full-thickness non-thermal skin wound management. Integra is composed of a bilaminate membrane consisting of a bovine collagen-based dermal analogue crosslinked with chondroitin-6-sulfate and glycosaminoglycan (GAG) extracted from shark cartilage and a temporary epidermal substitute layer of silicone. The porous matrix is designed to serve as a template for infiltration of the patient’s fibroblasts, macrophages, lymphocytes, and capillaries. The outer silicone layer of Integra serves as a temporary epidermis and allows for water flux, protection from microbial invasion, and prevention of burn wound desiccation. Once Integra has been placed on an excised wound, it must remain there for approximately 2 to 3 weeks. After the neodermis has formed, the silicone layer is removed and a thin epidermal autograft may be applied. Integra performs less hypertrophic scarring when compared to control materials. Development of seeding the dermal analog with epidermal cells which could then produce epidermis (a one step skin replacement process) is in progress (2).
Terudermis (Olympus Terumo Biomaterial Corp., Tokyo, Japan) consists of a layer of lyophilized bovine collagen sponge which is cross-linked by dehydrothermal treatment. The collagen layer is bonded to the silicone membrane similar to Integra. The material is designed for deep burns treatment, where bone, muscle or ligament exposure is present as well as for skin flap donor site regeneration. Terudermis, when loaded with cultured fibroblasts, endothelial cells, platelet-derived growth factor and then applied to rodent in vivo models, showed not only angiogenesis enhancement but also the potential to use the material simultaneously with a split-thickness skin graft for a one-step operative procedure (21).
Pelnac Standard Type/Pelnac Fortified With Mesh Type (Gunze Ltd, Medical Materials Center, Kyoto, Japan) consist of superficial silicone film layer and porcine collagen sponge layer. Pelnac Fortified With Mesh Type has additional non-adhesive silicone gauze (TREX, Fuji System Co, Tokyo, Japan). Pelnac is indicated for third grade burn injuries, traumatic skin defects, skin defects after excision of tumours or nevi, and donor sites of skin flaps.
Biobrane (UDL Laboratories Inc, Rockford, IL, USA) has been successfully used as a temporary skin replacement for burn wounds that do or do not require surgical excision, such as partial-thickness burns. It is used as a temporary covering for clean, debrided superficial, partial-thickness burns and donor sites and may be used as a protective covering over meshed autografts. Biobrane is a knitted nylon mesh that is bonded to a thin silicone membrane (trifilament for Biobrane and monofilament for Biobrane-L for reduced adhesiveness to the wound). It also contains porcine collagen. Biobrane has not been used for the treatment of chronic wounds because it has no antimicrobial properties. Fluid accumulation was the only reported complication in the clinical trials (3, 8).
TransCyte (former Dermagraft TC)
TransCyte (Advanced BioHealing Inc, New York, NY and La Jolla, CA, USA) is a human fibroblast-derived temporary skin substitute consisting of a polymer membrane and newborn human fibroblast cells cultured under aseptic conditions in vitro on a porcine collagen coated nylon mesh. The membrane is biocompatible and protects the burn wound surface from environmental assaults. In addition, the membrane is semipermeable, allowing for fluid and gas exchange. As the fibroblasts proliferate within the nylon mesh, they secrete human dermal collagen, matrix proteins, and growth factors. TransCyte is indicated for use as a temporary skin replacement for mid-dermal to indeterminate depth partial-thickness burns; as a temporary covering of surgically excised full-thickness and deep partial-thickness burns prior to autografting (8). Burn wounds treated with TransCyte healed more rapidly than the burn wounds treated with silver sulfadiazine. In addition, burn wound site evaluations revealed less hypertrophic scarring on the TransCyte-treated wounds (22).
Dermagraft (Advanced BioHealing Inc, New York, NY and La Jolla, CA, USA) is a cryopreserved living dermal structure, manufactured by cultivating neonatal allogeneic fibroblasts on a bioabsorbable polymer scaffold. The fibroblasts become confluent within the polymer mesh, secreting growth factors and dermal matrix proteins, thus creating a living dermal structure. The science behind this product is similar to TransCyte because the fibroblasts produce a dermal matrix of collagen, proteins, and growth factors. Dermagraft facilitates healing by stimulating the ingrowth of fibroblasts from the wound bed and re-epithelization from the wound edges. It does not close the wound and, as such, is marketed for stimulating the healing of chronic lesions, such as diabetic foot ulcers, rather than for closing burn wounds. Although Dermagraft has not been used extensively for burns, it has been used beneath meshed split-skin grafts on excised full-thickness wounds (8, 12).
Hyalomatrix PA, Hyalograft 3D (Fidia Advanced Biopolymers, Abano Terme, Italy)
Both products are based on hyaluronic acid derivates. Hyaluronic acid is one of the main polysaccharide components of dermal extracellular matrix and promotes migration and proliferation of skin fibroblasts and keratinocytes. Hyalomatrix PA has a temporary silicone layer which acts like an epidermis, while the dermal component of the construct incorporates into the wound and so prepares it for the subsequent skin grafting. Hyalograft 3D has no pseudo-epidermal layer, but it contains cultured autologous fibroblasts that provide the wound healing with growth factors and cytokines. It also performs „conditioning“ the wound for split skin grafting. Material combinations (e.g. Hyalograft 3D and Laserskin) have been used for deep burns treatment, where enhanced keratinocyte take and reduced hypertrophy and wound contracture rates where observed when compared to exclusive application of keratinocyte cultures (23). Hyalomatrix PA has been used clinically for the treatment of deep partial-thickness burns.
Coladerm H/HM is a term for a hybrid membrane with a specific buble macrostructure, which is composed of bovine atelocollagen I and hyaluronic acid. The material was developed at the Faculty of Chemical and Food Technology, Slovak Technical University, Bratislava in cooperation with the Department of Burns and Reconstructive Surgery, University Hospital Bratislava, Ružinov Hospital Bratislava, Slovak Republic, in order to obtain biosynthetic, biodegradable dermal skin substitute (24). Development of the membrane was the subject of the research project of the Grant Agency for Science no. 96-03-13. Clinical trial is underway at present. Preclinical studies proved optimal properties and minimal cytotoxicity. Material did not produce negative side effects in the experimental animals after implantation (25). After successful testing on experimental animals, it has been progressed to clinical trials. The purpose of the clinical testing of the membrane Coladerm H/HM is to verify the properties of the membrane as a biosynthetic cover for the split – thickness skin graft donor sites and for the treatment of burns; and as a dermal substitute for the treatment of deep burns. The membrane could be used for other purposes in the future, such as cell cultivation in vitro (mainly keratinocytes), as a carrier for cultured keratinocytes and fibroblasts; it can also serve as a three-dimensional matrix for the cultivation of other autologous cells such as chondrocytes or osteo-blasts. The membrane is expected to be used as a temporary mucosal substitute for the mucosal defects after surgery in the oral cavity, as well as resorbable implantable carrier of growth factors, therapeutic agents – particularly antibiotics and for filling the cavities in septic surgery after removal the septic foci.
There is no ideal skin substitute in the market that provides an effective and scar-free wound healing at the present. All the epidermal- and dermal-bioengineered products require either multiple stage operating procedures or autologous skin grafting to achieve a definitive wound epithelization.The components of bioengineered skin replacements are continually being developed and improved. Rapid progress in tissue engineering and different approaches to design a skin substitute biomaterial, including the use of stem cells, may develop an ideal skin substitute product in the near future.
ADRESA PRO KORESPONDENCI:
Darina Oravcová, M.D.
Department of Plastic and Reconstructive Surgery
City Hospital of T. Baťa
Havlíčkovo nábřeží 600, 762 75 Zlín,
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