Few biopharmaceutical preparations developed from biologicals are available for tissue regeneration and scar management. When developing biological treatments with cellular therapy, selection of cell types and establishment of consistent cell banks are crucial steps in whole-cell bioprocessing. Various cell types have been used in treatment of wounds to reduce scar to date including autolog and allogenic skin cells, platelets, placenta, and amniotic extracts. Experience with fetal cells show that they may provide an interesting cell choice due to facility of outscaling and known properties for wound healing without scar. Differential gene profiling has helped to point to potential indicators of repair which include cell adhesion, extracellular matrix, cytokines, growth factors, and development. Safety has been evidenced in Phase I and II clinical fetal cell use for burn and wound treatments with different cell delivery systems. We present herein that fetal cells present technical and therapeutic advantages compared to other cell types for effective cell-based therapy for wound and scar management. 1. Introduction Cell-based therapies are penetrating gently into routine medical care and especially for wound management of skin. They offer the promise of repairing and/or replacing damaged tissue and restoring lost functionality, because ideally, they provide all of the factors necessary for wound healing. Several cell types and tissues have been proposed as starting material including autologous cells, adult stem cells including those derived from bone marrow, and adipose tissue, fetal cells, embryonic stem cells, platelets, and tissues from placental and amniotic fluid. These cell types are used for biological preparations in processing vaccines and medicinal, veterinary, and tissue engineering products [1–41]. As the literature and information is vast on cell-based therapies, this paper will concentrate on fetal cells as the choice in wound and scar management. Firstly, we will define differences between stem, and mesenchymal and fetal cells, as the literature is confusing with these terminologies, followed by a short review of fetal wound healing and associated processes. Importantly, cell choice and the technical specifications to outscale, stability, safety, and delivery are the major hurdles for development of biologicals for better wound treatments and scar management. Fetal skin cells present biological, technical, and therapeutic advantages lending towards possible routine cellular-based therapy for wound and scar management. All of these aspects
A. Limat, D. Mauri, and T. Hunziker, “Successful treatment of chronic leg ulcers with epidermal equivalents generated from cultured autologous outer root sheath cells,” Journal of Investigative Dermatology, vol. 107, no. 1, pp. 128–135, 1996.
A. Kaviani, T. E. Perry, A. Dzakovic, R. W. Jennings, M. M. Ziegler, and D. O. Fauza, “The amniotic fluid as a source of cells for fetal tissue engineering,” Journal of Pediatric Surgery, vol. 36, no. 11, pp. 1662–1665, 2001.
A. Kaviani, T. E. Perry, C. M. Barnes et al., “The placenta as a cell source in fetal tissue engineering,” Journal of Pediatric Surgery, vol. 37, no. 7, pp. 995–999, 2002.
C. H. Wu, G. Y. Chang, W. C. Chang, C. T. Hsu, and R. S. Chen, “Wound healing effects of porcine placental extracts on rats with thermal injury,” British Journal of Dermatology, vol. 148, no. 2, pp. 236–245, 2003.
J. Hohlfeld, A. De Buys Roessingh, N. Hirt-Burri et al., “Tissue engineered fetal skin constructs for paediatric burns,” The Lancet, vol. 366, no. 9488, pp. 840–842, 2005.
A. S. de Buys Roessingh, J. Hohlfeld, C. Scaletta et al., “Development, characterization, and use of a fetal skin cell bank for tissue engineering in wound healing,” Cell Transplantation, vol. 15, no. 8-9, pp. 823–834, 2006.
A. A. Ramelet, N. Hirt-Burri, W. Raffoul et al., “Chronic wound healing by fetal cell therapy may be explained by differential gene profiling observed in fetal versus old skin cells,” Experimental Gerontology, vol. 44, no. 3, pp. 208–218, 2009.
A. Quintin, N. Hirt-Burri, C. Scaletta, C. Schizas, D. P. Pioletti, and L. A. Laurent-Applegate, “Consistency and safety of cell banks for research and clinical use: preliminary analysis of fetal skin banks,” Cell Transplantation, vol. 16, no. 7, pp. 675–684, 2007.
N. Hirt-Burri, C. Scaletta, S. Gerber, D. P. Pioletti, and L. A. Applegate, “Wound-healing gene family expression differences between fetal and foreskin cells used for bioengineered skin substitutes,” Artificial Organs, vol. 32, no. 7, pp. 509–518, 2008.
L. A. Applegate, C. Scaletta, N. Hirt-Burri, W. Raffoul, and D. Pioletti, “Whole-cell bioprocessing of human fetal cells for tissue engineering of skin,” Skin Pharmacology and Physiology, vol. 22, no. 2, pp. 63–73, 2009.
M. P. Curran and G. L. Plosker, “Bilayered bioengineered skin substitute (Apligraf ): a review of its use in the treatment of venous leg ulcers and diabetic foot ulcers,” BioDrugs, vol. 16, no. 6, pp. 439–455, 2002.
Y. Kuroyanagi, N. Yamada, R. Yamashita, and E. Uchinuma, “Tissue-engineered product: allogeneic cultured dermal substitute composed of spongy collagen with fibroblasts,” Artificial Organs, vol. 25, no. 3, pp. 180–186, 2001.
M. Fimiani, E. Pianigiani, F. C. Di Simplicio et al., “Other uses of homologous skin grafts and skin bank bioproducts,” Clinics in Dermatology, vol. 23, no. 4, pp. 396–402, 2005.
K. W. Ng, H. L. Khor, and D. W. Hutmacher, “In vitro characterization of natural and synthetic dermal matrices cultured with human dermal fibroblasts,” Biomaterials, vol. 25, no. 14, pp. 2807–2818, 2004.
V. Falanga, D. Margolis, O. Alvarez et al., “Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent,” Archives of Dermatology, vol. 134, no. 3, pp. 293–300, 1998.
P. Waymack, R. G. Duff, and M. Sabolinski, “The effect of a tissue engineered bilayered living skin analog, over meshed split-thickness autografts on the healing of excised burn wounds,” Burns, vol. 26, no. 7, pp. 609–619, 2000.
B. Coulomb, C. Lebreton, and L. Dubertret, “Influence of human dermal fibroblasts on epidermalization,” Journal of Investigative Dermatology, vol. 92, no. 1, pp. 122–125, 1989.
B. Coulomb, L. Friteau, J. Baruch et al., “Advantage of the presence of living dermal fibroblasts within in vitro reconstructed skin for grafting in humans,” Plastic and Reconstructive Surgery, vol. 101, no. 7, pp. 1891–1903, 1998.
H. A. Rakhorst, S. J. Posthumus-Van Sluijs, W. M. W. Tra et al., “Fibroblasts accelerate culturing of mucosal substitutes,” Tissue Engineering, vol. 12, no. 8, pp. 2321–2331, 2006.
J. F. Hansbrough, D. W. Mozingo, G. P. Kealey, M. Davis, A. Gidner, and G. D. Gentzkow, “Clinical trials of a biosynthetic temporary skin replacement, dermagraft-transitional covering, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds,” Journal of Burn Care and Rehabilitation, vol. 18, no. 1, pp. 43–51, 1997.
D. J. Wainwright, “Use of an acellular allograft dermal matrix (AlloDerm) in the management of full-thickness burns,” Burns, vol. 21, no. 4, pp. 243–248, 1995.
E. V. Badiavas, D. Paquette, P. Carson, and V. Falanga, “Human chronic wounds treated with bioengineered skin: histologic evidence of host-graft interactions,” Journal of the American Academy of Dermatology, vol. 46, no. 4, pp. 524–530, 2002.
R. L. Sheridan and R. J. Choucair, “Acellular allogenic dermis does not hinder initial engraftment in burn wound resurfacing and reconstruction,” Journal of Burn Care and Rehabilitation, vol. 18, no. 6, pp. 496–499, 1997.
S. Ichioka, S. Kouraba, N. Sekiya, N. Ohura, and T. Nakatsuka, “Bone marrow-impregnated collagen matrix for wound healing: experimental evaluation in a microcirculatory model of angiogenesis, and clinical experience,” British Journal of Plastic Surgery, vol. 58, no. 8, pp. 1124–1130, 2005.
P. De Coppi, G. Bartsch, M. M. Siddiqui et al., “Isolation of amniotic stem cell lines with potential for therapy,” Nature Biotechnology, vol. 25, no. 1, pp. 100–106, 2007.
S. S. Osswald, D. M. Elston, and P. S. Vogel, “Giant right plantar keloid treated with excision and tissue-engineered allograft,” Journal of the American Academy of Dermatology, vol. 48, no. 1, pp. 131–134, 2003.
T. Hasegawa, Y. Suga, M. Mizoguchi et al., “Clinical trial of allogeneic cultured dermal substitute for the treatment of intractable skin ulcers in 3 patients with recessive dystrophic epidermolysis bullosa,” Journal of the American Academy of Dermatology, vol. 50, no. 5, pp. 803–804, 2004.
M. Fimiani, E. Pianigiani, F. C. Di Simplicio et al., “Other uses of homologous skin grafts and skin bank bioproducts,” Clinics in Dermatology, vol. 23, no. 4, pp. 396–402, 2005.
E. N. Mostow, G. D. Haraway, M. Dalsing, J. P. Hodde, and D. King, “Effectiveness of an extracellular matrix graft (OASIS Wound Matrix) in the treatment of chronic leg ulcers: a randomized clinical trial,” Journal of Vascular Surgery, vol. 41, no. 5, pp. 837–843, 2005.
W. H. Eaglstein, M. Iriondo, and K. Laszlo, “A composite skin substitute (graftskin) for surgical wounds: a clinical experience,” Dermatologic Surgery, vol. 21, no. 10, pp. 839–843, 1995.
G. G. Gallico, N. E. O'Connor, C. C. Compton, J. P. Remensnyder, O. Kehinde, and H. Green, “Cultured epithelial autografts for giant congenital nevi,” Plastic and Reconstructive Surgery, vol. 84, no. 1, pp. 1–9, 1989.
D. M. Carter, A. N. Lin, and M. C. Varghese, “Treatment of junctional epidermolysis bullosa with epidermal autografts,” Journal of the American Academy of Dermatology, vol. 17, no. 2, pp. 246–250, 1987.
N. Kashiwa, O. Ito, T. Ueda, K. Kubo, H. Matsui, and Y. Kuroyanagi, “Treatment of full-thickness skin defect with concomitant grafting of 6-fold extended mesh auto-skin and allogeneic cultured dermal substitute,” Artificial Organs, vol. 28, no. 5, pp. 444–450, 2004.
J. Still, P. Glat, P. Silverstein, J. Griswold, and D. Mozingo, “The use of a collagen sponge/living cell composite material to treat donor sites in burn patients,” Burns, vol. 29, no. 8, pp. 837–841, 2003.
E. S. Y. Chan, P. K. Lam, C. T. Liew, H. C. H. Lau, R. S. C. Yen, and W. W. K. King, “A new technique to resurface wounds with composite biocompatible epidermal graft and artificial skin,” Journal of Trauma, vol. 50, no. 2, pp. 358–362, 2001.
S. R. Beanes, F. Y. Hu, C. Soo et al., “Confocal microscopic analysis of scarless repair in the fetal rat: defining the transition,” Plastic and Reconstructive Surgery, vol. 109, no. 1, pp. 160–170, 2002.
D. L. Cass, M. Meuli, and N. S. Adzick, “Scar wars: implications of fetal wound healing for the pediatric burn patient,” Pediatric Surgery International, vol. 12, no. 7, pp. 484–489, 1997.
J. R. Armstrong and M. W. J. Ferguson, “Ontogeny of the skin and the transition from scar-free to scarring phenotype during wound healing in the pouch young of a marsupial, Monodelphis domestica,” Developmental Biology, vol. 169, no. 1, pp. 242–260, 1995.
C. Dang, K. Ting, C. Soo, M. T. Longaker, and H. P. Lorenz, “Fetal wound healing current perspectives,” Clinics in Plastic Surgery, vol. 30, no. 1, pp. 13–23, 2003.
S. R. Beanes, C. Dang, C. Soo, and K. Ting, “Skin repair and scar formation: the central role of TGF-beta,” Expert reviews in molecular medicine, vol. 5, no. 8, pp. 1–22, 2003.
R. Y. Lin and N. S. Adzick, “The role of the fetal fibroblast and transforming growth factor-β in a model of human fetal wound repair,” Seminars in Pediatric Surgery, vol. 5, no. 3, pp. 165–174, 1996.
M. Shah, D. M. Foreman, and M. W. J. Ferguson, “Neutralisation of TGF-β and TGF-β or exogenous addition of TGF-β to cutaneous rat wounds reduces scarring,” Journal of Cell Science, vol. 108, no. 3, pp. 985–1002, 1995.
M. Shah, D. M. Foreman, and M. W. J. Ferguson, “Control of scarring in adult wounds by neutralising antibody to transforming growth factor β,” The Lancet, vol. 339, no. 8787, pp. 213–214, 1992.
L. Wu, A. Siddiqui, D. E. Morris, D. A. Cox, S. I. Roth, and T. A. Mustoe, “Transforming growth factor β3 (TGFβ3) accelerates wound healing without alteration of scar prominence: histologic and competitive reverse- transcription-polymerase chain reaction studies,” Archives of Surgery, vol. 132, no. 7, pp. 753–760, 1997.
O. Okamoto, S. Fujiwara, M. Abe, and Y. Sato, “Dermatopontin interacts with transforming growth factor β and enhances its biological activity,” Biochemical Journal, vol. 337, no. 3, pp. 537–541, 1999.
K. Kuroda, O. Okamoto, and H. Shinkai, “Dermatopontin expression is decreased in hypertrophic scar and systemic sclerosis skin fibroblasts and is regulated by transforming growth factor- β1, interleukin-4, and matrix collagen,” Journal of Investigative Dermatology, vol. 112, no. 5, pp. 706–710, 1999.
S. Kaiser, P. Schirmacher, A. Philipp et al., “Induction of bone morphogenetic protein-6 in skin wounds. Delayed reepitheliazation and scar formation in BMP-6 overexpressing transgenic mice,” Journal of Investigative Dermatology, vol. 111, no. 6, pp. 1145–1152, 1998.
E. J. Stelnicki, V. Doolabh, S. Lee et al., “Nerve dependency in scarless fetal wound healing,” Plastic and Reconstructive Surgery, vol. 105, no. 1, pp. 140–147, 2000.
K. L. Christman, Q. Fang, A. J. Kim et al., “Pleiotrophin induces formation of functional neovasculature in vivo,” Biochemical and Biophysical Research Communications, vol. 332, no. 4, pp. 1146–1152, 2005.
D. W. Huang, B. T. Sherman, and R. A. Lempicki, “Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources,” Nature Protocols, vol. 4, no. 1, pp. 44–57, 2009.
G. Dennis Jr., B. T. Sherman, D. A. Hosack et al., “DAVID: database for annotation, visualization, and integrated discovery,” Genome Biology, vol. 4, no. 5, p. P3, 2003.
W. Chen, X. Fu, S. Ge et al., “Profiling of genes differentially expressed in a rat of early and later gestational ages with high-density oligonucleotide DNA array,” Wound Repair and Regeneration, vol. 15, no. 1, pp. 147–155, 2007.
EU, “Setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells,” In: Parliament E, editor. Directive 2004/23/EC, 2004.
EU, “Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cells,” In: Parliament E, editor. Directive 2006/17/EC, 2006.
EU, “Implementing Directive 2004/23/EC of the European Parliament and of the Council as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cells,” In: Parliament E, editor. Directive 2006/86/EC, 2006.
M. Heinonen, O. Oila, and K. Nordstr？m, “Current issues in the regulation of human tissue-engineering products in the European Union,” Tissue Engineering, vol. 11, no. 11-12, pp. 1905–1911, 2005.
L. Trommelmans, J. Selling, and K. Dierickx, “A critical assessment of the directive on tissue engineering of the European Union,” Tissue Engineering, vol. 13, no. 4, pp. 667–672, 2007.
PMP/ICH, “Note for guidance on quality of biotechnological products: derivation and characterisation of cell substrates used for production of biotechnological/biological products,” CPMP/ICH/294/95, 2001.
