The skin plays a crucial role in protecting the integrity of the body's internal milieu. The loss of this largest organ is incompatible with sustained life. In reconstructive surgery or burn management, substitution of the skin is often necessary. In addition to traditional approaches such as split- or full-thickness skin grafts, tissue flaps and free-tissue transfers, skin bioengineering in vitro or in vivo has been developing over the past decades. It applies the principles and methods of both engineering and life sciences toward the development of substitutes to restore and maintain skin structure and function. Currently, these methods are valuable alternatives or complements to other techniques in reconstructive surgery. This review article deals with the evolution and current approaches to the development of in vitro and in vivo epidermis and dermis.
References
1.
Arenholt-Bindslev D., Jepsen A., MacCallum K., Lillie JH (1987). The growth and structure of human oral keratinocytes in culture. J Invest Dermatol88:314-319.
2.
Asselineau D., Bernard BA, Bailly C., Darmon M., Prunieras M. (1986). Human epidermis reconstructed by culture: Is it normal? J Invest Dermatol86:181-186.
3.
Bell E., lvarsson B., Merrill C. (1979). Production of a tissue like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci USA76:1274-1278.
4.
Ben-Bassat H., Eldad A., Chaouat M., Livoff A., Ron N., Ne'eman Z., et al. (1992). Structural and functional evaluation of modifications in the composite skin graft: cryopreserved dermis and cultured keratinocytes. Plast Reconstr Surg89:510-520.
5.
Bettinger DA, Mast B., Gore D. ( 1996). Hyaluronic acid impedes reepithelialization of skin graft donor sites. J Burn Care Rehabil17:302-304.
6.
Beumer GJ, van Blitterswijk CA, Bakker D., Ponec M. (1993). Cell-seeding and in vitro biocompatibility evaluation of polymeric matrices of PEO/PBT copolymers and PLLA. Biomaterials14:598-604.
7.
Billingham RE, Reynolds J. (1953). Transplantation studies on sheets of pure epidermal epithelium and on epidermal cell suspensions. Br J Plast Surg5:25-36.
8.
Boisseau AM, Donatien P., Surleve-Bazeille JE, Amedee J., Harmand MF, Bezian JH, et al. (1992). Production of epidermal sheets in a serum free culture system: a further appraisal of the role of extracellular calcium. J Dermatol Sci3:111-120.
9.
Boyce ST, Hansbrough JF (1988). Biologic attachment, growth and differentiation of cultured human epidermal keratinocytes on a graftable collagen and chondroitin-6-sulfate substrate. Surgery103:421-431.
10.
Boyce ST, Glafkides C., Foreman TJ, Hansbrough JF (1988). Reduced wound contraction after grafting of full-thickness burns with a collagen and chondroitin-6-sulfate (GAG) dermal skin substitute and coverage with biobrane. J Burn Care Rehabil9:364-370.
11.
Boyce ST, Medrano EE, Abdel-Malek Z., Supp AP, Dodick JM. Nordlund JJ, et al. (1993a). Pigmentation and inhibition of wound contraction by cultured skin substitutes with adult melanocytes after transplantation to athymic mice. J Invest Dermatol100:360-365.
12.
Boyce ST, Greenhalgh DG, Kagan RJ, Housinger T., Sorell JM, Childress CP, et al. (1993b). Skin anatomy and antigen expression after burn wound closure with composite grafts of cultured skin cells and biopolymers. Plast Reconstr Surg91:632-641.
13.
Breuing K., Eriksson E., Liu P., Miller DR (1992). Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res52:50-58.
14.
Burke JF, Yannas IC, Quinby WC Jr, Bondoc CC, lung WK ( 1981). Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury. Ann Surg194:413-428.
15.
Burt AM, Pallett CD, Sloane JP, O'Hare MJ, Schafler KF, Yardeni P., et al. (1989). Survival of cultured allografts in patients with burns assessed with probe specific for Y chromosome. Br Med J298(6678):915-917.
16.
Cairns BA, deSerres S., Brady BA, Hultman CS, Meyer AA (1995). Xenogenic mouse fibroblasts persist in human cultured epidermal grafts: a possible mechanism of graft loss. J Trauma39:75-80.
17.
Carver N., Navsaria HA, Fryer P., Green CJ, Leigh IM (1993). Restoration of basement membrane structure in pigs following keratinocyte autografting. Br J Plast Surg46:384-392.
18.
Compton CC, Gill JM, Bradford DA, Regauer S., Gallico GG, O'Connor NE (1989). Skin regenerated from cultured epithelial autografts on full thickness burn wounds from 6 days to 5 years after grafting. Lab Invest60:600-612.
19.
Compton CC, Hickerson W., Nadire K., Press W. (1993). Acceleration of skin regeneration from cultured epithelial autografts by transplantation to homograft dermis. J Burn Care Rehabil14:653-662.
20.
Cooper ML, Hansbrough JF (1991). Use of a composite skin graft composed of cultured human keratinocytes and fibroblasts and a collagen-GAG matrix to cover full-thickness wounds on athymic mice. Surgery109:198-207.
21.
Cooper ML, Hansbrough JF, Spielvogel RL, Cohen R., Bartel RL, Naughton G. (1991). In vivo optimization of a living dermal substitute employing cultured human fibroblasts on a biodegradable polyglycolic acid or polyglactin mesh. Biomaterials12:243-248.
22.
Cooper ML, Andree C., Hansbrough JF, Zapata-Sirvent LR, Spielvogel RL (1993). Direct comparison of a cultured composite skin substitute containing human keratinocytes and fibroblasts to an epidermal sheet graft containing human keratinocytes on athymic mice. J Invest Dermatol101:811-819.
23.
Cuono C., Langdon R., McGuire J. (1986). Use of cultured autografts and dermal allografts as skin replacement after burn injury. Lancet1:1123-1124.
24.
Cuono CB, Langdon R., Birchall N., Barttelbort S., McGuire J. (1987). Composite autologous-allogenic skin replacement: Development and clinical application. Plast Reconstr Surg80:626-635.
25.
De Luca M., D'Anna F., Bondanza S., Franzi AT, Cancedda R. (1988). Human epithelial cells induce human melanocyte growth in vitro but only skin keratinocytes regulate its proper differentiation in the absence of dermis. J Cell Biol107:1919-1926.
26.
De Luca M., Albanese E., Bondanza S., Megna M., Ugozzoli L., Molina F., et al. (1989). Multicentre experience in the treatment of burns with autologous and allogeneic cultured epithelium, fresh or preserved in a frozen state. Burns15:303-309.
27.
De Luca M., Albanese E., Megna M., Cancedda R., Mangiante PE, Cadoni A., et al. (1990). Evidence that human oral epithelium reconstituted in vitro and transplanted onto patients with defects in the oral mucosa retains properties of the original donor site. Transplantation50:454-459.
28.
Demarchez M., Hartmann DJ, Regnier M., Asselineau D. (1992). The role of fibroblasts in dermal vascularization and remodelling of reconstructed human skin after transplantation onto the nude mouse. Transplantation54:317-326.
29.
Desai MH, Mlakar JM, McCauley RL, Abdullah KM, Rutan RL, Waymack JP, et al. (1991). Lack of long-term durability of cultured keratinocyte burn-wound coverage: a case report. J Burn Care Rehcibil12:540-545.
30.
Edlich RF, Panek PH, Rodeheaver GT, Turnbull VG, Kurtz LD, Edgerton MT (1973). Physical and chemical configuration of sutures in the development of surgical infection. Ann Surg177:679-688.
31.
Ehrenfried A. (1909). Reverdin and other methods of skin grafting. Boston Med Surg J161:911-927.
32.
Eriksson E., Perez N., Slama J., Page C., Andree C., Maguire JH (1996). Treatment of chronic, nonhealing abdominal wound in a liquid environment. Ann Plast Surg36:80-83.
33.
Flaxman BA, Lutzner MA, Van Scott EJ (1967). Cell maturation and tissue organization in epithelial outgrowths from skin and buccal mucosa in vitro. J Invest Dermatol49:322-329.
34.
Font J., Braut-Boucher F., Pichon J., Noel-Hudson MS, Muriel MP, Bonnet M. (1994). A new three-dimensional culture of human keratinocytes: optimization of differentiation. Cell Biol Toxicol10:353-359.
35.
Formanek M., Millesi W., Willheim M., Scheiner O., Kornfehl J. (1996). Optimized growth medium for primary culture of human oral keratinocytes. Int J Oral Maxillofac Surg25:157-160.
36.
Gallico GG, O'Connor NE (1985). Cultured epithelium as a skin substitute. Clin Plast Surg12:149-157.
37.
Gallico GG, O'Connor NE, Compton CL, Kehinde O., Green H. (1984). Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med311:448-451.
38.
Gibson T., Medawar PB (1943). The fate of skin homo-grafts in man. J Anat77:299-310.
39.
Gielen V., Faure M., Mauduit G., Thivolet (1987). Progressive replacement of human cultured epithelial allografts by recipient cells as evidenced by HLA class 1 antigens expression. Dermatologica175:166-170.
40.
Gilchrest BA (1983). In vitro assessment of keratinocyte aging. J Invest Dermatol81:184-189.
41.
Gilchrest BA, Nemore RE, Maciag T. (1980). Growth of human keratinocytes on fibronectin coated plates. Cell Biol Int Rep4:1009-1016.
42.
Gilchrest BA, Calhoun JK, Maciag T. (1982). Attachment and growth of human keratinocytes in a serum-free environment. J Cell Physiol112:197-206.
43.
Green H., Kehinde O., Thomas J. (1979). Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc Natl Acad Sci USA76:5665-5668.
44.
Hafemann B., Hettich R., Ensslen S., Kowol B., Zuhlke A., Ebert R., et al. (1994). Treatment of skin defects using suspensions of in vitro cultured keratinocytes. Burns20:168-172.
45.
Hansbrough JF, Boyce ST, Cooper ML, Foreman TL (1989). Burn wound closure with cultured autologous keratinocytes and fibroblasts attached to a collagen-glycosaminoglycan substrate. J Am Med Assoc262:2125-2130.
46.
Hansbrough JF, Dore C., Hansbrough WB (1992). Clinical trials of a living dermal tissue replacement placed beneath meshed split-thickness skin grafts on excised burn wounds. J Burn Care Rehabil13:519-529.
47.
Hansbrough JF, Morgan JL, Greenleaf GE, Bartel R. (1993). Composite grafts of human keratinocytes grown on a polyglactin mesh-cultured fibroblast dermal substitute function as a bilayer skin replacement in full-thickness wounds on athymic mice. J Burn Care Rehabil14:485-494.
48.
Harriger MD, Warden GD, Greenhalgh DG, Kagan RJ, Boyce ST (1995). Pigmentation and microanatomy of skin regenerated from composite grafts of cultured cells and biopolymers applied to full-thickness burn wounds. Transplantation59:702-707.
49.
Hawley-Nelson P., Sullivan JE, Kung M., Hennings H., Yuspa SH (1980). Optimized conditions for the growth of human epidermal cells in culture. J Invest Dermatol75:176-182.
50.
Heck EL, Bergstrasser PR, Baxter CR (1985). Composite skin graft: Frozen dermal allografts support the engraftment and expansion of autologous epidermis. J Trauma25:106-112.
51.
Hefton JM, Madden MR, Finkelstein JL, Shires GT (1983). Grafting of burn patients with allografts of cultured epidermal cells. Lancet2(8347):428-430.
52.
Heimbach D., Luterman A., Burke J., Cram A., Herndon D., Hunt J., et al. (1988). Artificial dermis for major burns; a multi-center randomized clinical trial. Ann Surg208:313-320.
53.
Hennings H., Michael D., Cheng C., Steinert P., Holbrook K., Yuspa SH (1980). Calcium regulation of growth and differentiation of mouse epidermal cells in culture. Cell19:245-254.
54.
Hickerson WL, Compton C., Fletchall S., Smith LR (1994). Cultured epidermal autografts and allodermis combination for permanent wound coverage. Burns20(Suppl 1):S52-S55.
55.
Higgins CR, Navsaria HA, Stringer M., Spitz L., Leigh IM (1994). Use of two stage keratinocyte-dermal grafting to treat the separation site in conjoined twins. J R Soc Med87:108-109.
56.
Hill MW, Mackenzie C. (1984). The influence of differing connective tissue substrates on the maintenance of adult stratified squamous epithelia. Cell Tissue Res237:473-478.
57.
Holbrook KA, Hennings H. (1983). Phenotypic expression of epidermal cells in vitro: A review. J Invest Dermatol81(Suppl 1):11s-24s.
58.
Johnson LF, deSerres S., Herzog S., Peterson HD, Meyer AA (1991). Antigenic cross-reactivity between media supplements for cultured keratinocyte grafts. J Burn Care Rehabil12:306-312.
59.
Johnson MA, Langdon JD (1990). Is skin necessary for intraoral construction with myocutaneous flaps? Br J Oral Maxillofac Surg28:299-301.
60.
Johnson MC, Meyer AA, deSerres S., Herzog S., Peterson HD (1990). Persistence of fetal bovine serum proteins in human keratinocytes. J Burn Care Rehabil11:504-509.
61.
Jones JCR, Goldman AI, Steinart PM, Yuspa S., Goldman RD (1982). Dynamic aspects of the supramolecular organisation of intermediate filament networks in cultured epidermal cells. Cell Motility2:197-213.
62.
Kangesu T. Navsaria HA, Manek S., Fryer PR, Leigh IM, Green CJ (1993a). Kerato-dermal grafts: the importance of dermis for the in vivo growth of cultured keratinocytes. Br J Plast Surg46:401-409.
63.
Kangesu T., Navsaria HA, Manek S., Shurey CB, Jones CR, Fryer PR, et al. (1993b). A porcine model using skin graft chambers for studies on cultured keratinocytes. Br J Plast Surg46:393-400.
64.
Karring T., Lang NP, Löe H. (1975). The role of gingival connective tissue in determining epithelial differentiation. J Periodont Res10:1-11.
65.
Kleinman H., McGarvey ML, Hassell JR, Star VL, Cannon FB, Laurie GW, et al. (1986). Basement membrane complexes with biological activity. Biochemistry25:312-318.
66.
Kumagai N., Nishina H., Tanabe H., Hosaka T., Ishida H., Ogino Y. (1988). Clinical application of autologous cultured epithelia for the treatment of burn wounds and burn scars. Plast Reconstr Surg82:99-108.
67.
Langdon J., Williams DM, Navsaria H., Leigh IM (1991). Autologous keratinocyte grafting: a new technique for intra-oral reconstruction. Br Dent J171:87-90.
68.
Langdon JD, Leigh IM, Navsaria H., Williams DM (1990). Autologous oral keratinocyte grafts in the mouth. Lancet1:1472-1473.
69.
Langdon R., Cuono C., Birchall N., Madri JA, Kuklinska E., McGuire J., et al. (1988). Reconstitution of structure and cell function in human skin grafts derived from cryopreserved allogenic dermis and autologous cultured keratinocytes. J Invest Dermatol91:478-485.
70.
Lerner AB, Halaban R., Klaus SN, Moellmann GE (1987). Transplantation of human melanocytes. J Invest Dermatol89:219-224.
71.
Liu SC, Karasek M. (1978). Isolation and growth of adult human epidermal keratinocytes in cell culture. ) J Invest Dermatol71:157-162.
72.
Lillie JH, MacCallum DK, Jepsen A. (1982). The behaviour of subcultivated stratified squamous epithelial cells on reconstituted extracellular matrices: initial interactions. Eur J Cell Biol29:50-60.
73.
Lilly GE, Cutcher JL, Jones JC, Armstrong JH (1972). Reaction of oral tissues to suture material. IV. Oral Surg33:152-157.
74.
Livesey SA, Herndon DN, Hollyoak MA, Atkinson YH, Nag A. (1995). Transplanted acellular allograft dermal matrix. Transplantation60:1-9.
75.
Mackenzie IC, Hill MW ( 1984). Connective tissue influences on patterns of epithelial architecture and keratinization in skin and oral mucosa of the adult mouse. Cell Tissue Res235:551-559.
76.
Marks R., Dykes PJ (1983). Cultured epidermal cells and burns. Lancet2(8351):678-679.
77.
Medalie DA, Eming SA, Tompkins RG, Yarmush ML, Krueger GG, Morgan JR (1996). Evaluation of human skin reconstituted from composite grafts of cultured keratinocytes and human acellular dermis transplanted to athymic mice. J Invest Dermatol107:121-127.
78.
Mertz PM, Davis SC, Franzen L., Uchima FD, Pickett MP, Pierschbacher MD, et al. (1996). Effects of an arginine-glycine-aspartic acid peptide-containing artificial matrix on epithelial migration in vitro and experimental second-degree burn wound healing in vivo. J Burn Care Rehabil17:199-206.
79.
Mlinek A., Buchner A. (1975). In vitro cultivation of adult human gingiva. J Periodont Res10:73-78.
80.
Morhenn VB, Benike CJ, Cox AJ, Charron DJ, Engleman EG (1982). Cultured human epidermal cells do not synthesize HLA-DR. ) Invest Dermatol78:32-37.
81.
Munster AM, Weiner SH, Spence RJ (1990). Cultured epidermis for the coverage of massive burn wounds. Ann Surg211:676-680.
82.
Murashita T., Nakayama Y., Hirano T., Ohashi S. (1996). Acceleration of granulation tissue ingrowth by hyaluronic acid in artificial skin. Br J Plast Surg49:58-63.
83.
Navsaria HA, Kangesu T., Manek S., Green CJ, Leigh IM (1994). An animal model to study the significance of dermis for grafting cultured keratinocytes on full thickness wounds. Burns20(Suppl 1):S57-S60.
84.
Nerem RM (1992). Tissue engineering in the USA. Med & Biol Eng & Comput30:CE8-CE12.
85.
O'Connor NE, Mulliken JB, Banks-Schlegel S., Kehinde O., Green H. (1981). Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet1(8211):75-78.
86.
O'Connor NE, Gallico GG, Compton CC, Briggs S., Remensnyder J. (1990). Long term results in major pediatric burns treated with cultured epithelial autografts (abstract). Proc Am Burn Assoc22:174.
87.
Peehl DM, Ham RG (1980). Growth and differentiation of human keratinocytes without a feeder layer or conditioned medium. In Vitro16:516-525.
Phillips TJ, Gilchrest BA (1991). Cultured epidermal allografts as biological wound dressings. Prog Clin Biol Res365:77-94.
90.
Phillips TJ, Gilchrest BA (1992). Clinical applications of cultured epithelium. Epithelial Cell Biol1:39-46.
91.
Prunieras M., Delescluse C., Regnier M. (1976). The culture of skin: a review of theories and experimental methods. J Invest Dermatol67:58-65.
92.
Prunieras M., Regnier M., Fongere S., Woodley D. (1983). Keratinocytes synthesize basal-lamina proteins in culture. J Invest Dermatol81(Suppl):74S-81S.
93.
Rheinwald JG, Green H. (1975). Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. Cell6:331-344.
94.
Rheinwald JG, Green H. (1977). Epidermal growth factor and multiplication of cultured human epidermal keratinocytes. Nature265:421-424.
95.
Rue LW III, Cioffi WG, McManus WF, Pruitt BA Jr (1993). Wound closure and outcome in extensively burned patients treated with cultured autologous keratinocytes. J Trauma34:662-668.
96.
Sedmak DD, Orosz CG (1991). The role of vascular endothelial cells in transplantation. Arch Pathol Lab Med115:260-265.
97.
Spalteholz W. (1893). Die Verteilung der Blutge fabe in der haut. Arch Anat Physiol Anat Abt2:1-54.
98.
Suzuki S., Matsuda K., Isshiki N., Tamada Y., Yoshioka K., Ikada Y. (1990). Clinical evaluation of a new bilayer "artificial skin" composed of collagen sponge and silicone layer. Br J Plast Surg43:47-54.
99.
Svensjø T., Winkler T., Yao P., Eriksson E. (1996). Growth factor delivery to full-thickness porcine wounds with hEGF-transfected fibroblasts. In: Proceedings, 51st Annual Session, Owen H. Wangensteen Surgical Forum, Clinical Congress, October 6-11, San Francisco, CA. Vol. XLVII. Chicago, IL: American College of Surgeons, pp. 715-717.
100.
Taichman L., Reilly S., Garant PR (1979). In vitro cultivation of human oral keratinocytes. Arch Oral Biol24:335-341.
101.
Tenchini ML, Ranzati C., Malcovati M. (1992). Culture techniques for human keratinocytes. Burns18(Suppl 1):S11-S16.
102.
Thivolet J., Faure M., Demidem A., Mauduit G. (1986). Long-term survival and immunological tolerance of human epidermal allografts produced in culture. Transplantation42:274-280.
103.
Tittlekow M., Scott R. (1986). New techniques for the in vitro culture of human skin keratinocytes and perspectives on their use for grafting of patients with extensive burns. Mayo Clin Proc61:771-777.
104.
Tsao MC, Walthall BJ, Ham RG (1982). Clonal growth of normal epidermal keratinocytes in defined medium. J Cell Physiol110:219-229.
105.
Vogt PM, Thompson S., Andree C., Liu P., Breuing K., Hatzis D., et al. (1994). Genetically modified keratinocytes transplanted to wound reconstitute the epidermis. Proc Natl Acad Sci USA91:9307-9311.
106.
Wainwright D., Madden M., Luterman A., Hunt J., Monafo W., Heimbach D., et al. (1996). Clinical evaluation of an acellular allograft dermal matrix in full-thickness burns. J Burn Care Rehabil17:124-136.
107.
Warden G. (1993). The fifth quinquennium: 1989-1993. J Burn Care Rehabil14:247-251.
108.
Woodley DT, Peterson HD, Herzog SR, Stricklin GP, Burgeson RE, Briggaman RA, et al. (1988). Burn wounds resurfaced by cultured epidermal autografts show abnormal reconstitution of anchoring fibrils. J Am Med Assoc259:2566-2571.
109.
Woodley DT, Briggaman RA, Herzog SR, Meyers AA, Peterson HD, Keefe EJ (1990). Characterization of "neo-dermis" formation beneath cultured human epidermal autografts transplanted on muscle fascia. J Invest Dermatol95:20-26.
110.
Worst PKM, Mackenzie IC, Fusenig NE (1982). Reformation of organized epidermal structure by transplantation of suspensions and cultures of epidermal and dermal cells. Cell Tissue Res225:65-77.
111.
Yannas IV, Burke JF (1980a). Design of an artificial skin. I. Basic design principles. J Biomed Mater Res14:65-81.
112.
Yannas IV, Burke JF (1980b). Design of an artificial skin. II. Control of chemical composition. J Biomed Mater Res14:107-131.
113.
Yannas IV, Burke JF, Orgill DP, Skrabut EM (1982). Wound tissue can utilize a polymeric template to synthesize a functional extension of skin. Science215:174-176.
114.
Yannas IV, Hansbrough JF, Ehrlich HP (1984). What criteria should be used for designing artificial skin replacements and how well do the current grafting materials meet these criteria? J Trauma24(9 Suppl):S29-S39.
