Tissue Engineering von Haut – von der Spalthaut zum gezüchteten Hauttransplantat?

Zusammenfassung

Heutzutage sind Spalt- oder Vollhauttransplantate der Goldstandard in der Behandlung von Substanzdefekten der Haut, deren Erfolge in der Therapie von zum Beispiel Schwerstverbrannten erkennbar sind. Allerdings haben Schwerstverbrannte mit mehr als 50% verbrannter Körperoberfläche nur begrenzte Spenderareale. Des Weiteren haben Hauttransplantate auf chronischen Wunden schlechtere Einheilungsraten als bei Verbrennungspatienten, was z. B. durch Begleiterkrankungen oder vermehrte lokale Infektionen bedingt sein kann. Aufgrund oben genannter Limitationen ist der Bedarf an kostendeckenden, benutzerfreundlichen synthetischen oder gezüchteten Hautersatzmaterialien, die sowohl für akute und chronische Wunden geeignet sind, als auch bei Problempatienten mit Begleiterkrankungen zur Anwendung kommen können, vorhanden. In den letzten 30 Jahren sind eine Vielzahl an unterschiedlichen biologischen und synthetischen Hautersatzmatrizes sowie Produkte mit humanen patienteneigenen Zellen auf den Markt gekommen, an deren Weiterentwicklung ständig gearbeitet wird. Eine Möglichkeit ist die Züchtung eines Hautersatzes in vitro, der sich nach Transplantation in das Wundbett integrieren soll. Eine andere Alternative stellt die Herstellung einer biokompatiblen und bioresorbierbaren Matrix dar, die die ortständigen Zellen rekrutieren kann und zur narbenlosen Heilung anregt. Allerdings können die heute verfügbaren Hautersatzprodukte die Spalt- oder Vollhauttransplantation noch nicht vollständig ersetzen, da noch immer Einschränkungen wie unzureichende Einheilung und/oder mechanische Stabilität des Hautersatzes oder ein Fehlen von differenzierten Strukturen auftreten. An dem Ziel einen Hautersatz herzustellen, der alle funktionellen und strukturellen Fähigkeiten der gesunden menschlichen Haut mit sich bringt und diese vollständig ersetzen kann, wird weiter gearbeitet. Dieser Artikel gibt einen Überblick über die heute verfügbaren Lösungsansätze und Produkte im Feld des Tissue Engineerings von Haut.

Abstract

Today split or full skin grafts are still the gold standard in the treatment of substance defects of the skin. Such results can be seen, for example, in the therapy for burn patients. However, in patients with more than 50% burned skin area, donor sites are limited. Likewise in chronic wound patients inferior take rates of skin grafts as compared to burn wounds are observed. This may be attributed, for example, to accompanying or underlying chronic diseases or a higher rate of local infections. These phenomena also lead to a lack of availability of transplantable skin grafts. Hence the need for cost effective and user friendly synthetic or engineered skin grafts, which can serve for acute and chronic wounds and which can be also used in critically ill patients, is at hand. During the last 30 years a huge number of biological and synthetic skin graft materials and products based on the patient's own cells were launched on the market. Researchers and clinicians are constantly working on further improvements. One possibility is the engineering of skin grafts in vitro, which have to be integrated into the wound bed after transplantation. Another approach is the fabrication of biocompatible and bioresorbable matrices, which can attract host cells and stimulate a wound-healing process without scars. However, the skin graft materials available today cannot yet replace split or full skin grafts completely because of their inherent limitations such as insufficient take rates and/or the lack of mechanical stability and differentiated structures of the grafted artificial skin. Thus researchers in the field of skin tissue engineering are still working on the final goal of developing a skin graft which has all the features of healthy human skin and is capable of replacing human skin completely. This article gives on overview of the currently available solutions and products in the field of skin tissue engineering.

Haut Tissue Engineering - Hautersatz - Keratinozyten - kultivierte autologe Epidermis

skin tissue engineering - skin replacement - keratinocytes - cultured epidermal autografts

Literatur

• 1 Gallico Gr, O’Connor N, Compton C. et al . Permanent coverage of large burn wounds with autologous cultured human epithelium.  N Engl J Med. 1984;  311 448-451
• 2 Bleiziffer O, Horch RE, Hammon M. et al . T17b murine embryonal endothelial progenitor cells can be induced towards both proliferation and differentiation in a fibrin matrix.  J Cell Mol Med. 2009;  13 926-935
• 3 Nguyen VA, Furhapter C, Obexer P. et al . Endothelial cells from cord blood CD133+CD34+ progenitors share phenotypic, functional and gene expression profile similarities with lymphatics.  J Cell Mol Med. 2009;  13 522-534
• 4 Popescu LM, Gherghiceanu M, Manole CG. et al . Cardiac renewing: interstitial Cajal-like cells nurse cardiomyocyte progenitors in epicardial stem cell niches.  J Cell Mol Med. 2009;  13 866-886
• 5 Sabatier F, Camoin-Jau L, Anfosso F. et al . Circulating endothelial cells, microparticles and progenitors: key players towards the definition of vascular competence.  J Cell Mol Med. 2009;  13 454-471
• 6 Timmermans F, Plum J, Yoder MC. et al . Endothelial progenitor cells: identity defined?.  J Cell Mol Med. 2009;  13 87-102
• 7 van Osch GJ, Brittberg M, Dennis JE. et al . Cartilage repair: past and future – lessons for regenerative medicine.  J Cell Mol Med. 2009;  13 792-810
• 8 Ballyns JJ, Bonassar LJ. Image-guided tissue engineering.  J Cell Mol Med. 2009;  13 1428-1436
• 9 Hutmacher DW, Horch RE, Loessner D. et al . Translating tissue engineering technology platforms into cancer research.  J Cell Mol Med. 2009;  13 1417-1427
• 10 Spadaccio C, Chello M, Trombetta M. et al . Drug releasing systems in cardiovascular tissue engineering.  J Cell Mol Med. 2009;  13 422-439
• 11 Giunta RE, Machens HG. [Science and research in academic plastic surgery in Germany].  Handchir Mikrochir Plast Chir. 2009;  41 359-363
• 12 Langer R, Vacanti JP. Tissue engineering.  Science. 1993;  260 920-926
• 13 Rab M, Koller R, Ruzicka M. et al . Should dermal scald burns in children be covered with autologous skin grafts or with allogeneic cultivated keratinocytes?.  “The Viennese concept”. Burns. 2005;  31 578-586
• 14 Kamolz L, Lumenta D, Kitzinger H. et al . Tissue engineering for cutaneous wounds: An overview of current standards and possibilities.  Eur Surg. 2008;  40 19-26
• 15 Beele H. Artificial skin: past, present and future.  Int J Artif Organs. 2002;  25 163-173
• 16 Horch RE, Kopp J, Kneser U. et al . Tissue engineering of cultured skin substitutes.  J Cell Mol Med. 2005;  9 592-608
• 17 Boyce ST. Design principles for composition and performance of cultured skin substitutes.  Burns. 2001;  27 523-533
• 18 Aubock J. [Skin replacement with cultured keratinocytes].  Z Hautkr. 1988;  63 565-567
• 19 Billingham RE, Medawar PB. A note on the specificity of the corneal epithelium.  J Anat. 1950;  84 50-56
• 20 Medawar PB. The cultivation of adult mammalian skin epithelium in vitro.  Q J Microsc Sci. 1948;  89 187-196
• 21 Karasek MA. Growth and differentiation of transplanted epithelial cell cultures.  J Invest Dermatol. 1968;  51 247-252
• 22 Karasek MA. Culture of human keratinocytes in liquid medium.  J Invest Dermatol. 1983;  81 24s-28s
• 23 Rheinwald JG, Green H. Epidermal growth factor and the multiplication of cultured human epidermal keratinocytes.  Nature. 1977;  265 421-424
• 24 Rennekampff HO, Hansbrough JF, Woods Jr V. et al . Integrin and matrix molecule expression in cultured skin replacements.  J Burn Care Rehabil. 1996;  17 213-221
• 25 Barrandon Y, Green H. Three clonal types of keratinocyte with different capacities for multiplication.  Proc Natl Acad Sci U S A. 1987;  84 2302-2306
• 26 Falanga V, Isaacs C, Paquette D. et al . Wounding of bioengineered skin: cellular and molecular aspects after injury.  J Invest Dermatol. 2002;  119 653-660
• 27 Munster AM. Cultured skin for massive burns A prospective, controlled trial.  Ann Surg. 1996;  224 372-375 ; discussion 375–377
• 28 Horch R, Stark G. Economy of skin grafting in burns.  Hospital – J Eur Assoc Hosp Man. 2001;  3 6-9
• 29 Meana A, Iglesias J, Del Rio M. et al . Large surface of cultured human epithelium obtained on a dermal matrix based on live fibroblast-containing fibrin gels.  Burns. 1998;  24 621-630
• 30 Kamolz L, Andel H, Eisenbock B. et al . The Use of Allogeneic Cultivated Keratinocytes for the Early Coverage of Burns – The Viennese Concept.  Osteosynthesis and Trauma Care. 2007;  15 48-51
• 31 Boyce ST, Supp AP, Wickett RR. et al . Assessment with the dermal torque meter of skin pliability after treatment of burns with cultured skin substitutes.  J Burn Care Rehabil. 2000;  21 55-63
• 32 Koller R, Bierochs B, Meissl G. et al . The use of allogeneic cultivated keratinocytes for the early coverage of deep dermal burns – indications, results and problems.  Cell Tissue Bank. 2002;  3 11-14
• 33 Koller R, Bierochs B, Meissl G. et al . The use of stored skin grafts for keratinocyte cultures.  Br J Plast Surg. 2001;  54 87
• 34 Sasaki M, Abe R, Fujita Y. et al . Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type.  J Immunol. 2008;  180 2581-2587
• 35 Wu Y, Chen L, Scott PG. et al . Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis.  Stem Cells. 2007;  25 2648-2659
• 36 Li H, Fu X, Ouyang Y. et al . Adult bone-marrow-derived mesenchymal stem cells contribute to wound healing of skin appendages.  Cell Tissue Res. 2006;  326 725-736
• 37 Takahashi K, Tanabe K, Ohnuki M. et al . Induction of pluripotent stem cells from adult human fibroblasts by defined factors.  Cell. 2007;  131 861-872
• 38 Mansbridge JN. Tissue-engineered skin substitutes in regenerative medicine.  Curr Opin Biotechnol. 2009;  20 563-567
• 39 Page RL, Ambady S, Holmes WF. et al . Induction of stem cell gene expression in adult human fibroblasts without transgenes.  Cloning Stem Cells. 2009;  11 417-426
• 40 Kamolz LP, Kolbus A, Wick N. et al . Cultured human epithelium: human umbilical cord blood stem cells differentiate into keratinocytes under in vitro conditions.  Burns. 2006;  32 16-19
• 41 Mangoldt F. Die Epithelsaat zum Verschluss einer großen Wundfläche.  Med Wochenschr. 1895;  21 798-803
• 42 Kamolz LP, Luegmair M, Wick N. et al . The Viennese culture method: cultured human epithelium obtained on a dermal matrix based on fibroblast containing fibrin glue gels.  Burns. 2005;  31 25-29
• 43 Johnsen S, Ermuth T, Tanczos E. et al . Treatment of therapy-refractive ulcera cruris of various origins with autologous keratinocytes in fibrin sealant.  Vasa. 2005;  34 25-29
• 44 Bannasch H, Unterberg T, Fohn M. et al . Cultured keratinocytes in fibrin with decellularised dermis close porcine full-thickness wounds in a single step.  Burns. 2008;  34 1015-1021
• 45 Larochelle F, Ross G, Rouabhia M. Permanent skin replacement using engineered epidermis containing fewer than 5% syngeneic keratinocytes.  Lab Invest. 1998;  78 1089-1099
• 46 Rouabhia M. Burns and skin transplantation.  Transplant Proc. 1999;  31 889
• 47 Burke JF, Yannas IV, Quinby Jr WC. et al . Successful use of a physiologically acceptable artificial skin in the treatment of extensive burn injury.  Ann Surg. 1981;  194 413-428
• 48 Lal S, Barrow RE, Wolf SE. et al . Biobrane improves wound healing in burned children without increased risk of infection.  Shock. 2000;  14 314-318 ; discussion 318–319
• 49 Branski LK, Herndon DN, Pereira C. et al . Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial.  Crit Care Med. 2007;  35 2615-2623
• 50 Kopp J, Jeschke MG, Bach AD. et al . Applied tissue engineering in the closure of severe burns and chronic wounds using cultured human autologous keratinocytes in a natural fibrin matrix.  Cell Tissue Bank. 2004;  5 89-96
• 51 Ryssel H, Gazyakan E, Germann G. et al . The use of MatriDerm in early excision and simultaneous autologous skin grafting in burns – a pilot study.  Burns. 2008;  34 93-97
• 52 Golinski PA, Zoller N, Kippenberger S. et al . Development of an Engraftable Skin Equivalent based on Matriderm(R) with Human Keratinocytes and Fibroblasts.  Handchir Mikrochir Plast Chir. 2009; 
• 53 Keck M, Haluza D, Burjak S. et al . Cultivation of keratinocytes and preadipocytes on a collagen-elastin scaffold (Matriderm^®): First results of an in vitro study.  Eur Surg. 2009;  41 189-193
• 54 Voigt M, Schauer M, Schaefer DJ. et al . Cultured epidermal keratinocytes on a microspherical transport system are feasible to reconstitute the epidermis in full-thickness wounds.  Tissue Eng. 1999;  5 563-572
• 55 Reimers K, Radtke C, Choi CY. et al . Expression of TNF-related apoptosis-inducing ligand (TRAIL) in keratinocytes mediates apoptotic cell death in allogenic T cells.  Ann Surg Innov Res. 2009;  3 13
• 56 Macri L, Silverstein D, Clark RA. Growth factor binding to the pericellular matrix and its importance in tissue engineering.  Adv Drug Deliv Rev. 2007;  59 1366-1381
• 57 Macri L, Clark RA. Tissue engineering for cutaneous wounds: selecting the proper time and space for growth factors, cells and the extracellular matrix.  Skin Pharmacol Physiol. 2009;  22 83-93
• 58 Horch RE, Bannasch H, Stark GB. Transplantation of cultured autologous keratinocytes in fibrin sealant biomatrix to resurface chronic wounds.  Transplant Proc. 2001;  33 642-644

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