Facial skin replacement after burns or other injuries has proved to be a challenging task in wound healing. The application of laboratory-based tissue-expansion techniques is a potential solution to the problem of surface area cover. Considerable progress has been made in approaches to these techniques, including allograft and autograft skin transplantation to replace skin temporarily or permanently. Methods for handling skin wounds, such as transplantation, tissue engineering, and, more recently, stem cell therapies, have advanced in the past few decades. Issues with these techniques still remain, though. Development of new treatments for facial burn or wound victims is still a problem in cultured skin grafts. Hair follicles, sweat glands, and other features of normal skin are absent in cultured skin. Scientists believe stem cells with unique characteristics, including self-renewal and differentiation potential offer a possible way for reconstructing some structures within a wound. Enhanced understanding of these new approaches may help researchers develop novel therapies to overcome the problems in facial wound healing.
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References
1.
SlavinJ. The role of cytokines in wound healing. J Pathol. 1996;178:5–10.
2.
MacNeilS. Progress and opportunities for tissue-engineered skin. Nature. 2007;445:874–880.
3.
EhrlichHP. Understanding experimental biology of skin equivalent: From laboratory to clinical use in patients with burns and chronic wounds. Am J Surg. 2004;187(5A):29S–33S.
4.
BurkeJFYannasIVQuinbyWCJrBondocCCJungWK. Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg. 1981;194:413–428.
5.
GallicoGGIIIO'ConnorNEComptonCCKehindeOGreenH. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med. 1984;311:448–451.
6.
De LucaMAlbaneseEBondanzaS. Multicentre experience in the treatment of burns with autologous and allogenic cultured epithelium, fresh or preserved in a frozen state. Burns. 1989;15:303–309.
7.
GallicoGGIIIO'ConnorNEComptonCCKehindeOGreenH. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med. 1984;311:448–451.
8.
RomagnoliGDe LucaMFarandaF. Treatment of posterior hypospadias by the autologous graft of cultured urethral epithelium. N Engl J Med. 1990;323:527–530.
9.
ClaudinotSNicolasMOshimaHRochatABarrandonY. Long-term renewal of hair follicles from clonogenic multipotent stem cells. Proc Natl Acad Sci U S A. 2005;102:14677–14682.
10.
MathorMBFerrariGDellambraE. Clonal analysis of stably transduced human epidermal stem cells in culture. Proc Natl Acad Sci U S A. 1996;93:10371–10376.
11.
BellEEhrlichHPButtleDJNakatsujiT. Living tissue formed in vitro and accepted as skin-equivalent tissue of full thickness. Science. 1981;211:1052–1054.
12.
RonfardVRivesJMNeveuxYCarsinHBarrandonY. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation. 2000;70:1588–1598.
13.
KhodadadiLShafieyanSAghdamiNBaharvandH. Cell therapy in burn repair. Yakhteh Med J. 2008;10:167–178.
14.
YanagaHUdohYYamauchiT. Cryopreserved cultured epidermal allografts achieved early closure of wounds and reduced scar formation in deep partial-thickness burn wounds (DDB) and split-thickness skin donor sites of pediatric patients. Burns. 2001;27:689–698.
HorchRStarkGBKoppJSpilkerG. Cologne Burn Centre experiences with glycerol-preserved allogeneic skin: Part I: Clinical experiences and histological findings (overgraft and sandwich technique). Burns. 1994;20(suppl 1):S23–S26.
17.
HorchRECorbeiOFormanek-CorbeiBBrand-SaberiBVanscheidtWStarkGB. Reconstitution of basement membrane after ‘sandwich-technique’ skin grafting for severe burns demonstrated by immunohistochemistry. J Burn Care Rehabil. 1998;19:189–202.
18.
NanchahalJDoverROttoWR. Allogeneic skin substitutes applied to burns patients. Burns. 2002;28:254–257.
RouabhiaM. In vitro production and transplantation of immunologically active skin equivalents. Lab Invest. 1996;75:503–517.
21.
RouabhiaMGermainLBergeronJAugerFA. Allogeneic-syngeneic cultured epithelia. A successful therapeutic option for skin regeneration. Transplantation. 1995;59:1229–1235.
22.
ShakespeareP. Burn wound healing and skin substitutes. Burns. 2001;27:517–522.
23.
Van LuynMJVerheulJvan WachemPB. Regeneration of full-thickness wounds using collagen split grafts. J Biomed Mater Res. 1995;29:1425–1436.
24.
CoffeyRJJrDerynckRWilcoxJN. Production and auto-induction of transforming growth factor-alpha in human keratinocytes. Nature. 1987;328:817–820.
25.
KupperTSBallardDWChuaAO. Human keratinocytes contain mRNA indistinguishable from monocyte interleukin 1 alpha and beta mRNA. Keratinocyte epidermal cell-derived thymocyte-activating factor is identical to interleukin 1. J Exp Med. 1986;164: 2095–2100.
26.
GrossmanRMKruegerJYourishD. Interleukin 6 is expressed in high levels in psoriatic skin and stimulates proliferation of cultured human keratinocytes. Proc Natl Acad Sci U S A. 1989;86:6367–6371.
27.
LarsenCGAndersonAOOppenheimJJMatsushimaK. Production of interleukin-8 by human dermal fibroblasts and keratinocytes in response to interleukin-1 or tumour necrosis factor. Immunology. 1989;68:31–36.
28.
KupperTSLeeFColemanDChodakewitzJFloodPHorowitzM. Keratinocyte derived T-cell growth factor (KTGF) is identical to granulocyte macrophage colony stimulating factor (GM-CSF). J Invest Dermatol. 1988;91:185–188.
29.
EisingerMSadanSSilverIAFlickRB. Growth regulation of skin cells by epidermal cell-derived factors: Implications for wound healing. Proc Natl Acad Sci U S A. 1988;85: 1937–1941.
30.
AlsbjornB. In search of an ideal skin substitute. Scand J Plast Reconstr Surg. 1984;18:127–133.
31.
HeimbachDLutermanABurkeJ. Artificial dermis for major burns. A multi-center randomized clinical trial. Ann Surg. 1988;208:313–320.
RheinwaldJGGreenH. Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells. Cell. 1975;6:331–343.
34.
WoodFMKolybabaMLAllenP. The use of cultured epithelial autograft in the treatment of major burn wounds: Eleven years of clinical experience. Burns. 2006;32:538–544.
35.
MunsterAM. Whither (corrected) skin replacement?Burns. 1997;23(1):v. Erratum in Burns. 1997;23(2):195.
36.
RonfardVRivesJMNeveuxYCarsinHBarrandonY. Long-term regeneration of human epidermis on third degree burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation. 2000;70:1588–1598.
37.
VoigtMSchauerMSchaeferDJAndreeCHorchRStarkGB. Cultured epidermal keratinocytes on a microspherical transport system are feasible to reconstitute the epidermis in full-thickness wounds. Tissue Eng. 1999;5:563–572.
38.
WoodleyDTPetersonHDHerzogSR. Burn wounds resurfaced by cultured epidermal autografts show abnormal reconstitution of anchoring fibrils. JAMA. 1988;259:2566–2571.
39.
HerndonDNRutanRL. Comparison of cultured epidermal autograft and massive excision with serial autografting plus homograft overlay. J Burn Care Rehabil. 1992;13:154–157.
40.
BrownKWParkinsonEK. Alteration of the extracellular matrix of cultured human keratinocytes by transformation and during differentiation. Int J Cancer. 1985;35:799–807.
41.
HerzogSRMeyerAWoodleyDPetersonHD. Wound coverage with cultured autologous keratinocytes: Use after burn wound excision, including biopsy followup. J Trauma. 1988;28:195–198.
42.
RouabhiaM. Permanent skin replacement using chimeric epithelial cultured sheets comprising xenogeneic and syngeneic keratinocytes. Transplantation. 1996;61:1290–1300.
BillinghamREReynoldsJ. Transplantation studies on sheets of pure epidermal epithelium and on epidermal cell suspensions. Br J Plast Surg. 1972;5:25–36.
45.
FraulinFOBahoricAHarropARHirukiTClarkeHM. Autotransplantation of epithelial cells in the pig via an aerosol vehicle. J Burn Care Rehabil. 1998;19:337–345.
46.
FredrikssonCKratzGHussF. Transplantation of cultured human keratinocytes in single cell suspension: A comparative in vitro study of different application techniques. Burns. 2008;34:212–219.
47.
GustafsonCJKratzG. Cultured autologous keratinocytes on a cell-free dermis in the treatment of full-thickness wounds. Burns. 1999;25:331–335.
48.
NavarroFAStonerMLParkCS. Sprayed keratinocyte suspensions accelerate epidermal coverage in a porcine microwound model. J Burn Care Rehabil. 2000;21:513–518.
49.
KaiserHWStarkGBKoppJBalcerkiewiczASpilkerGKreyselHW. Cultured autologous keratinocytes in fibrin glue suspension, exclusively and combined with STS-allograft (preliminary clinical and histological report of a new technique). Burns. 1994;20:23–29.
50.
CuonoCBLangdonRBirchallNBarttelbortSMcGuireJ. Composite autologous-allogeneic skin replacement: Development and clinical application. Plast Reconstr Surg. 1987;80:626–637.
51.
McKayIWoodwardBWoodKNavsariaHAHoekstraHGreenC. Reconstruction of human skin from glycerol-preserved allodermis and cultured keratinocyte sheets. Burns. 1994;20(suppl 1):S19–S22.
52.
KangesuTNavsariaHAManekSFryerPRLeighIMGreenCJ. Kerato-dermal grafts: The importance of dermis for the in vivo growth of cultured keratinocytes. Br J Plast Surg. 1993;46:401–409.
53.
LearyTJonesPLApplebyMBlightAParkinsonKStanleyM. Epidermal keratinocyte self-renewal is dependent upon dermal integrity. J Invest Dermatol. 1992;99:422–430.
54.
CoulombBFriteauLBaruchJ. Advantage of the presence of living dermal fibroblasts within in vitro reconstructed skin for grafting in humans. Plast Reconstr Surg. 1998;101:1891–1903.
55.
KrejciNCCuonoCBLangdonRCMcGuireJ. In vitro reconstitution of skin: Fibroblasts facilitate keratinocyte growth and differentiation on acellular reticular dermis. J Invest Dermatol. 1991;97:843–848.
56.
CoulombBLebretonCDubertretL. Influence of human dermal fibroblasts on epidermalization. J Invest Dermatol. 1989;92:122–125.
57.
RheinwaldJGGreenH. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes. Nature. 1977;265:421–424.
58.
GreenHKehindeOThomasJ. Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc Natl Acad Sci U S A. 1979;76:5665–5668.
59.
O'ConnorNEMullikenJBBanks-SchlegelSKehindeOGreenH. Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet. 1981;1:75–78.
60.
BarrandonYGreenH. Three clonal types of keratinocyte with different capacities for multiplication. Proc Natl Acad Sci U S A. 1987;84:2302–2306.
61.
FuchsE. Epidermal differentiation: The bare essentials. J Cell Biol. 1990;111:2807–2814.
CuonoCLangdonRMcGuireJ. Use of cultured epidermal autografts and dermal allografts as skin replacement after burn injury. Lancet. 1986;1:1123–1124.
64.
HuangQDawsonRAPeggDEKearneyJNMacNeilS. Use of peracetic acid to sterilise human donor skin for production of acellular matrices for clinical use. Wound Repair Regen. 2004;12:276–287.
65.
SternRMcPhersonMLongakerMT. Histologic study of artificial skin used in the treatment of full thickness thermal injury. J Burn Care Rehabil. 1990;11:7–13.
66.
BoyceSTGoretskyMJGreenhalghDGKaganRJRiemanMTWardenGD. Comparative assessment of cultured skin substitutes and native skin autograft for treatment of full-thickness burns. Ann Surg. 1995;222:743–752.
67.
BoyceSTKaganRJMeyerNAYakuboffKPWardenGD. The 1999 clinical research award. Cultured skin substitutes combined with Integra Artificial Skin to replace native skin autograft and allograft for closure of full-thickness burns. J Burn Care Rehabil. 1999;20:453–461.
68.
BoyceSTKaganRJYakuboffKP. Cultured skin substitutes reduce donor skin harvesting for closure of excised, full-thickness burns. Ann Surg. 2002;235:269–279.
69.
SuppDMBoyceST. Engineered skin substitutes: Practices and potentials. Clin Dermatol. 2005;23:403–412.
70.
IuchiSDabelsteenSEasleyKRheinwaldJGGreenH. Immortalized keratinocyte lines derived from human embryonic stem cells. Proc Natl Acad Sci U S A. 2006;103:1792–1797.
71.
McPhersonTBLiangHRecordRDBadylakSF. Galalpha(1,3)Gal epitope in porcine small intestinal submucosa. Tissue Eng. 2000;6:233–239.
72.
MarstonWAHanftJNorwoodPPollakR. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: Results of a prospective randomized trial. Diabetes Care. 2003;26:1701–1705.
73.
KumarRJKimbleRMBootsRPeggSP. Treatment of partial-thickness burns: A prospective randomized trial using Transcyte. ANZ J Surg. 2004;74:622–626.
74.
BelloYMFalabellaAF. The role of graftskin (Apligraf) in difficult-to-heal venous leg ulcers. J Wound Care. 2003;11:182–183.
75.
LipkinSChaikofEIsseroffZSilversteinP. Effectiveness of bilayered cellular matrix in healing of neuropathic diabetic foot ulcers: Results of a multicenter pilot trial. Wounds. 2003;15:230–236.
76.
CarverNNavsariaHGreenCJLeighIM. Acute rejection of cultured keratinocyte allografts in nonimmunosuppressed pigs. Transplantation. 1991;52: 918–921.
77.
BrainAPurkisPCoatesPHackettMNavsariaHLeighI. Survival of cultured allogeneic keratinocytes transplanted to deep dermal bed assessed with probe specific for Y chromosome. BMJ. 1989;298:917–919.
78.
HermansMH. Clinical experience with glycerol-preserved donor skin treatment in partial thickness burns. Burns Incl Therm Inj. 1989;15:57–59.
79.
WainwrightDMaddenMLutermanA. Clinical evaluation of an acellular allograft dermal matrix in full-thickness burns. J Burn Care Rehabil. 1986;17:124–136.
80.
Jarman-SmithMLBodamyaliTStevensC. Porcine collagen crosslinking, degradation and its capability for fibroblast adhesion and proliferation. J Mater Sci Mater Med. 2004;15:925–932.
81.
RalstonDRLaytonCDalleyAJBoyceSGFreedlanderEMac NeilS. The requirement for basement membrane antigens in the production of human epidermal/dermal composites in vitro. Br J Dermatol. 1999;140:605–615.
82.
SahotaPSBurnJLHeatonM. Development of a reconstructed human skin model for angio-genesis. Wound Repair Regen. 2003;11:275–284.
83.
MedalieDAEmingSACollinsMETompkinsRGYarmushMLMorganJR. Differences in dermal analogs influence subsequent pigmentation, epidermal differentiation, basement membrane, and rete ridge formation of transplanted composite skin grafts. Transplantation. 1997;64:454–465.
84.
SwopeVBSuppAPSchwembergerSBabcockGBoyceS. Increased expression of integrins and decreased apoptosis correlate with increased melanocyte retention in cultured skin substitutes. Pigment Cell Res. 2006;19:424–433.
85.
RatnerBDBryantSJ. Biomaterials: Where we have been and where we are going. Annu Rev Biomed Eng. 2004;6:41–75.
86.
FreemanAEIgelHJHerrmanBJKleinfeldKL. Growth and characterization of human skin epithelial cell cultures. In Vitro. 1976;12:352–362.
87.
LiuSCKarasekM. Isolation and growth of adult human epidermal keratinocytes in cell culture. J Invest Dermatol. 1978;71:157–162.
88.
HorchREDebusMWagnerGStarkGB. Cultured human keratinocytes on type I collagen membranes to reconstitute the epidermis. Tissue Eng. 2000;6:53–67.
89.
BryskMMRaimerSSPupoRBellTRajaramanS. Grafting of leg ulcers with undifferentiated keratinocytes. J Am Acad Dermatol. 1991;25(2 part 1):238–244.
90.
PellegriniGRannoRStracuzziG. The control of epidermal stem cells (holoclones) in the treatment of massive full-thickness burns with autologous keratinocytes cultured on fibrin. Transplantation. 1999;68:868–879.
91.
RonfardVBrolyHMitchellV. Use of human keratinocytes cultured on fibrin glue in the treatment of burn wounds. Burns. 1991;17:181–184.
92.
MyersSRGradyJSoranzoC. A hyaluronic acid membrane delivery system for cultured keratinocytes: Clinical “take” rates in the porcine kerato-dermal model. J Burn Care Rehabil. 1997;18:214–222.
93.
MatouskovaEBucekSVogtovaD. Treatment of burns and donor sites with human allogeneic keratinocytes grown on acellular pig dermis. Br J Dermatol. 1997;136:901–907.
94.
ChesterDLBaldersonDSPapiniRP. A review of keratinocyte delivery to the wound bed. J Burn Care Rehabil. 2004;25:266–275.
95.
GrantINgRLWoodwardBBevanSGreenCMartinR. Demonstration of epidermal transfer from a polymer membrane using genetically marked porcine keratinocytes. Burns. 2001;27:1–8.
96.
KirsnerRSFalangaVEaglsteinWH. The biology of skin grafts. Skin grafts as pharmacologic agents. Arch Dermatol. 1993;129:481–483.
97.
DvorankovaBSmetanaKJrKonigovaR. Cultivation and grafting of human keratinocytes on a poly(hydroxyethyl methacrylate) support to the wound bed: A clinical study. Biomaterials. 1998;19:141–146.
98.
HaddowDBFranceRMShortRD. Comparison of proliferation and growth of human keratinocytes on plasma copolymers of acrylic acid/1,7-octadiene and self-assembled monolayers. J Biomed Mater Res. 1999;47:379–387.
99.
HechtJHoefterEAHechtJ. Cultivated keratinocytes on micro-carriers: In vitro studies of a new carrier system [in German]. Handchir Mikrochir Plast Chir. 1997;29:101–106.
100.
MacNeilSH. Progress and opportunities for tissue-engineered skin. Nature. 2007;445:874–880.
101.
GhazizadehSTaichmanLB. Multiple classes of stem cells in cutaneous epithelium: A lineage analysis of adult mouse skin. EMBO J. 2001;20:1215–1222.
102.
RoSRannalaB. A stop-EGFP transgenic mouse t o detect clonal cell lineages generated by mutation. EMBO Rep. 2004;5:914–920.
103.
CotsarelisGSunTTLavkerRM. Label-retaining cells reside in the bulge area of pilosebaceous unit: Implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61:1329–1337.
104.
KobayashiKRochatABarrandonY. Segregation of keratinocyte colony-forming cells in the bulge of the rat vibrissa. Proc Natl Acad Sci U S A. 1993;90:7391–7395.
105.
TumbarTGuaschGGrecoV. Defining the epithelial stem cell niche in skin. Science. 2004;303:359–363.
106.
ItoMYangZAndlT. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature. 2007;447:316–320.
107.
NishimuraEKJordanSAOshimaH. Dominant role of the niche in melanocyte stem-cell fate determination. Nature. 2002;416:854–860.
108.
RinnJLWangJKAllenN. A dermal HOX transcriptional program regulates site-specific epidermal fate. Genes Dev. 2008;22:303–307.
109.
TomaJGAkhavanMFernandesKJ. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol. 2001;3:778–784.
110.
FernandesKJMcKenzieIAMillP. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol. 2004;6:1082–1093.
111.
MillsAAZhengBWangXJVogelHRoopDRBradleyA. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398:708–713.
112.
TruongABKretzMRidkyTWKimmelRKhavariPA. p63 regulates proliferation and differentiation of developmentally mature keratinocytes. Genes Dev. 2006;20:3185–3197.
113.
YiRPoyMNStoffelMFuchsE. A skin microRNA promotes differentiation by repressing ‘stemness’. Nature. 2008;452:225–229.
114.
GatUDasGuptaRDegensteinLFuchsE. De novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin. Cell. 1998;95:605–614.
115.
AndlTReddySTGaddaparaTMillarSE. WNT signals are required for the initiation of hair follicle development. Dev Cell. 2002;2:643–653.
116.
Lo CelsoCProwseDMWattFM. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development. 2004;131:1787–1799.
YamaguchiYItamiSWatabeH. Mesenchymal-epithelial interactions in the skin: Increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation. J Cell Biol. 2004;165:275–285.
119.
AasenTRayaABarreroMJ. Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol. 2008;126:1276–1284.
120.
ZhouQBrownJKanarekARajagopalJMeltonDA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:627–632.
121.
MorrellNTLeuchtPZhaoL. Liposomal packaging generates Wnt protein with in vivo biological activity. PLoS One. 2008;3:e2930.
