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Methodologies in creating skin substitutes

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Abstract

The creation of skin substitutes has significantly decreased morbidity and mortality of skin wounds. Although there are still a number of disadvantages of currently available skin substitutes, there has been a significant decline in research advances over the past several years in improving these skin substitutes. Clinically most skin substitutes used are acellular and do not use growth factors to assist wound healing, key areas of potential in this field of research. This article discusses the five necessary attributes of an ideal skin substitute. It comprehensively discusses the three major basic components of currently available skin substitutes: scaffold materials, growth factors, and cells, comparing and contrasting what has been used so far. It then examines a variety of techniques in how to incorporate these basic components together to act as a guide for further research in the field to create cellular skin substitutes with better clinical results.

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References

  1. Jeschke MG, Patsouris D, Stanojcic M, Abdullahi A, Rehou S et al (2015) Pathophysiologic Response to Burns in the Elderly. EBioMedicine 2:1536–1548

    Article  PubMed  PubMed Central  Google Scholar 

  2. Brem H, Tomic-Canic M (2007) Cellular and molecular basis of wound healing in diabetes. J Clin Investig 117:1219–1222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shahrokhi S, Arno A, Jeschke MG (2014) The use of dermal substitutes in burn surgery: acute phase. Wound repair and regeneration: official publication of the Wound Healing Society [and] the European Tissue Repair Society 22: 14–22

  4. Snyder DL, Sullivan N, Schoelles KM (2012) AHRQ Technology Assessments. Skin Substitutes for Treating Chronic Wounds. Agency for Healthcare Research and Quality (US), Rockville

  5. Branski LK, Herndon DN, Pereira C, Mlcak RP, Celis MM et al (2007) Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial. Crit Care Med 35:2615–2623

    Article  PubMed  Google Scholar 

  6. Mann EA, Baun MM, Meininger JC, Wade CE (2012) Comparison of mortality associated with sepsis in the burn, trauma, and general intensive care unit patient: a systematic review of the literature. Shock 37:4–16

    Article  PubMed  Google Scholar 

  7. D’Avignon LC, Hogan BK, Murray CK, Loo FL, Hospenthal DR et al (2010) Contribution of bacterial and viral infections to attributable mortality in patients with severe burns: an autopsy series. Burns 36:773–779

    Article  PubMed  Google Scholar 

  8. Siddiqui AR, Bernstein JM (2010) Chronic wound infection: facts and controversies. Clin Dermatol 28:519–526

    Article  PubMed  Google Scholar 

  9. Ong YS, Samuel M, Song C (2006) Meta-analysis of early excision of burns. Burns 32:145–150

    Article  PubMed  Google Scholar 

  10. Lavery LA, Fulmer J, Shebetka KA, Regulski M, Vayser D et al (2014) The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J 11:554–560

    Article  PubMed  Google Scholar 

  11. Namdar T, Stollwerck PL, Stang FH, Siemers F, Mailander P et al (2010) Transdermal fluid loss in severely burned patients. Ger Med Sci 8: Doc28

  12. Woodroof EA (2009) The search for an ideal temporary skin substitute: AWBAT. Eplasty 9:e10

    PubMed  PubMed Central  Google Scholar 

  13. Yannas IV, Burke JF (1980) Design of an artificial skin. I. Basic design principles. J Biomed Mater Res 14:65–81

    Article  CAS  PubMed  Google Scholar 

  14. Wang H, Pieper J, Peters F, van Blitterswijk CA, Lamme EN (2005) Synthetic scaffold morphology controls human dermal connective tissue formation. J Biomed Mater Res A 74:523–532

    Article  PubMed  CAS  Google Scholar 

  15. Suzuki S, Matsuda K, Isshiki N, Tamada Y, Ikada Y (1990) Experimental study of a newly developed bilayer artificial skin. Biomaterials 11:356–360

    Article  CAS  PubMed  Google Scholar 

  16. Hoyt LC (2007) Fibroblast Migration Mediated by the Composition of Tissue Engineered Scaffolds. Dissertation, Virginia Commonwealth University. http://scholarscompass.vcu.edu/etd_retro/164

  17. Jensen PJ, Wheelock MJ (1996) The relationships among adhesion, stratification and differentiation in keratinocytes. Cell Death Differ 3:357–371

    CAS  PubMed  Google Scholar 

  18. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127:514–525

    Article  CAS  PubMed  Google Scholar 

  19. Benichou G, Yamada Y, Yun SH, Lin C, Fray M et al (2011) Immune recognition and rejection of allogeneic skin grafts. Immunotherapy 3:757–770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. François B, Lucie G, Roxane P, François AA (2010) How to achieve early vascularization of tissue-engineered skin substitutes. In: C.K. S (ed) Advances in wound care. New Rochelle, Mary Ann Liebert, Inc. p 445–450

  21. Chiu YC, Cheng MH, Engel H, Kao SW, Larson JC et al (2011) The role of pore size on vascularization and tissue remodeling in PEG hydrogels. Biomaterials 32:6045–6051

    Article  CAS  PubMed  Google Scholar 

  22. Lamme EN, de Vries HJ, van Veen H, Gabbiani G, Westerhof W et al (1996) Extracellular matrix characterization during healing of full-thickness wounds treated with a collagen/elastin dermal substitute shows improved skin regeneration in pigs. J Histochem Cytochem 44:1311–1322

    Article  CAS  PubMed  Google Scholar 

  23. Yildirimer L, Thanh NT, Seifalian AM (2012) Skin regeneration scaffolds: a multimodal bottom-up approach. Trends Biotechnol 30:638–648

    Article  CAS  PubMed  Google Scholar 

  24. Klingenberg JM, McFarland KL, Friedman AJ, Boyce ST, Aronow BJ et al (2010) Engineered human skin substitutes undergo large-scale genomic reprogramming and normal skin-like maturation after transplantation to athymic mice. J Invest Dermatol 130:587–601

    Article  CAS  PubMed  Google Scholar 

  25. Sander EA, Lynch KA, Boyce ST (2014) Development of the mechanical properties of engineered skin substitutes after grafting to full-thickness wounds. J Biomech Eng 136:051008

    Article  PubMed  Google Scholar 

  26. Darby IA, Hewitson TD (2007) Fibroblast differentiation in wound healing and fibrosis. In: Kwang WJ (ed) International review of cytology. Academic Press, New York, pp 143–179

    Google Scholar 

  27. Poon R, Nik SA, Ahn J, Slade L, Alman BA (2009) Beta-catenin and transforming growth factor beta have distinct roles regulating fibroblast cell motility and the induction of collagen lattice contraction. BMC Cell Biol 10:38

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Parenteau-Bareil R, Gauvin R, Berthod F (2010) Collagen-based biomaterials for tissue engineering applications. Materials 3:1863–1887

    Article  CAS  Google Scholar 

  29. Glowacki J, Mizuno S (2008) Collagen scaffolds for tissue engineering. Biopolymers 89:338–344

    Article  CAS  PubMed  Google Scholar 

  30. Sarkar SD, Farrugia BL, Dargaville TR, Dhara S (2013) Chitosan–collagen scaffolds with nano/microfibrous architecture for skin tissue engineering. J Biomed Mater Res, Part A 101:3482–3492

    Article  CAS  Google Scholar 

  31. Keck M, Haluza D, Lumenta DB, Burjak S, Eisenbock B et al (2011) Construction of a multi-layer skin substitute: simultaneous cultivation of keratinocytes and preadipocytes on a dermal template. Burns 37:626–630

    Article  PubMed  Google Scholar 

  32. Bottcher-Haberzeth S, Biedermann T, Reichmann E (2010) Tissue engineering of skin. Burns 36:450–460

    Article  PubMed  Google Scholar 

  33. O’Brien FJ (2011) Biomaterials & scaffolds for tissue engineering. Mater Today 14:88–95

    Article  CAS  Google Scholar 

  34. Keogh MB, O’Brien FJ, Daly JS (2010) Substrate stiffness and contractile behaviour modulate the functional maturation of osteoblasts on a collagen-GAG scaffold. Acta Biomater 6:4305–4313

    Article  CAS  PubMed  Google Scholar 

  35. Tierney CM, Haugh MG, Liedl J, Mulcahy F, Hayes B et al (2009) The effects of collagen concentration and crosslink density on the biological, structural and mechanical properties of collagen-GAG scaffolds for bone tissue engineering. J Mech Behav Biomed Mater 2:202–209

    Article  PubMed  Google Scholar 

  36. Haugh MG, Jaasma MJ, O’Brien FJ (2009) The effect of dehydrothermal treatment on the mechanical and structural properties of collagen-GAG scaffolds. J Biomed Mater Res A 89:363–369

    Article  PubMed  CAS  Google Scholar 

  37. Wang HM, Chou YT, Wen ZH, Wang ZR, Chen CH et al (2013) Novel biodegradable porous scaffold applied to skin regeneration. PLoS One 8:e56330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Filova E, Rampichova M, Handl M, Lytvynets A, Halouzka R et al (2007) Composite hyaluronate-type I collagen-fibrin scaffold in the therapy of osteochondral defects in miniature pigs. Physiol Res 56(Suppl 1):S5–s16

    PubMed  Google Scholar 

  39. Han CM, Zhang LP, Sun JZ, Shi HF, Zhou J et al (2010) Application of collagen-chitosan/fibrin glue asymmetric scaffolds in skin tissue engineering. J Zhejiang Univ Sci B 11:524–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mohd Hilmi AB, Halim AS, Jaafar H, Asiah AB, Hassan A (2013) Chitosan dermal substitute and chitosan skin substitute contribute to accelerated full-thickness wound healing in irradiated rats. Biomed Res Int 2013:795458

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Ayvazyan A, Morimoto N, Kanda N, Takemoto S, Kawai K et al (2011) Collagen-gelatin scaffold impregnated with bFGF accelerates palatal wound healing of palatal mucosa in dogs. J Surg Res 171:e247–e257

    Article  CAS  PubMed  Google Scholar 

  42. Morimoto N, Kakudo N, Valentin Notodihardjo P, Suzuki S, Kusumoto K (2014) Comparison of neovascularization in dermal substitutes seeded with autologous fibroblasts or impregnated with bFGF applied to diabetic foot ulcers using laser Doppler imaging. J Artif Organs 17:352–357

    Article  PubMed  Google Scholar 

  43. Rnjak-Kovacina J, Wise SG, Li Z, Maitz PK, Young CJ et al (2012) Electrospun synthetic human elastin:collagen composite scaffolds for dermal tissue engineering. Acta Biomater 8:3714–3722

    Article  CAS  PubMed  Google Scholar 

  44. Garg RK, Rennert RC, Duscher D, Sorkin M, Kosaraju R et al. (2014) Capillary Force Seeding of Hydrogels for Adipose-Derived Stem Cell Delivery in Wounds. Stem Cells Transl Med 3:1079–1089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rustad KC, Wong VW, Sorkin M, Glotzbach JP, Major MR et al (2012) Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials 33:80–90

    Article  CAS  PubMed  Google Scholar 

  46. Wong VW, Rustad KC, Galvez MG, Neofytou E, Glotzbach JP et al (2011) Engineered pullulan-collagen composite dermal hydrogels improve early cutaneous wound healing. Tissue Eng Part A 17:631–644

    Article  CAS  PubMed  Google Scholar 

  47. Gaspar A, Moldovan L, Constantin D, Stanciuc AM, Sarbu Boeti PM et al (2011) Collagen-based scaffolds for skin tissue engineering. J Med Life 4:172–177

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Lin HY, Peng CW, Wu WW (2014) Fibrous hydrogel scaffolds with cells embedded in the fibers as a potential tissue scaffold for skin repair. J Mater Sci Mater Med 25:259–269

    Article  CAS  PubMed  Google Scholar 

  49. Damodaran G, Tiong WH, Collighan R, Griffin M, Navsaria H et al (2013) In vivo effects of tailored laminin-332 alpha3 conjugated scaffolds enhances wound healing: a histomorphometric analysis. J Biomed Mater Res A 101:2788–2795

    Article  PubMed  CAS  Google Scholar 

  50. Lu H, Oh HH, Kawazoe N, Yamagishi K, Chen G (2012) PLLA–collagen and PLLA–gelatin hybrid scaffolds with funnel-like porous structure for skin tissue engineering. Sci Technol Adv Mater 13:064210

    Article  CAS  Google Scholar 

  51. You C, Wang X, Zheng Y, Han C (2013) Three types of dermal grafts in rats: the importance of mechanical property and structural design. Biomed Eng Online 12:125

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cui W, Zhu X, Yang Y, Li X, Jin Y (2009) Evaluation of electrospun fibrous scaffolds of poly(dl-lactide) and poly(ethylene glycol) for skin tissue engineering. Mater Sci Eng, C 29:1869–1876

    Article  CAS  Google Scholar 

  53. Sargeant TD, Desai AP, Banerjee S, Agawu A, Stopek JB (2012) An in situ forming collagen-PEG hydrogel for tissue regeneration. Acta Biomater 8:124–132

    Article  CAS  PubMed  Google Scholar 

  54. Gautam S, Chou CF, Dinda AK, Potdar PD, Mishra NC (2014) Surface modification of nanofibrous polycaprolactone/gelatin composite scaffold by collagen type I grafting for skin tissue engineering. Mater Sci Eng C Mater Biol Appl 34:402–409

    Article  CAS  PubMed  Google Scholar 

  55. Stuart K, Panitch A (2008) Influence of chondroitin sulfate on collagen gel structure and mechanical properties at physiologically relevant levels. Biopolymers 89:841–851

    Article  CAS  PubMed  Google Scholar 

  56. McFadden TM, Duffy GP, Allen AB, Stevens HY, Schwarzmaier SM et al (2013) The delayed addition of human mesenchymal stem cells to pre-formed endothelial cell networks results in functional vascularization of a collagen–glycosaminoglycan scaffold in vivo. Acta Biomater 9:9303–9316

    Article  CAS  PubMed  Google Scholar 

  57. Duffy GP, McFadden TM, Byrne EM, Gill SL, Farrell E et al (2011) Towards in vitro vascularisation of collagen-GAG scaffolds. Eur Cell Mater 21:15–30

    CAS  PubMed  Google Scholar 

  58. Corin KA, Gibson LJ (2010) Cell contraction forces in scaffolds with varying pore size and cell density. Biomaterials 31:4835–4845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nimni ME, Cheung D, Strates B, Kodama M, Sheikh K (1987) Chemically modified collagen: a natural biomaterial for tissue replacement. J Biomed Mater Res 21:741–771

    Article  CAS  PubMed  Google Scholar 

  60. Kamel RA, Ong JF, Eriksson E, Junker JP, Caterson EJ (2013) Tissue engineering of skin. J Am Coll Surg 217:533–555

    Article  PubMed  Google Scholar 

  61. Maheshwari G, Brown G, Lauffenburger DA, Wells A, Griffith LG (2000) Cell adhesion and motility depend on nanoscale RGD clustering. J Cell Sci 113(Pt 10):1677–1686

    CAS  PubMed  Google Scholar 

  62. Sethi KK, Yannas IV, Mudera V, Eastwood M, McFarland C et al (2002) Evidence for sequential utilization of fibronectin, vitronectin, and collagen during fibroblast-mediated collagen contraction. Wound Repair Regen 10:397–408

    Article  PubMed  Google Scholar 

  63. Clark RA, Lin F, Greiling D, An J, Couchman JR (2004) Fibroblast invasive migration into fibronectin/fibrin gels requires a previously uncharacterized dermatan sulfate-CD44 proteoglycan. J Invest Dermatol 122:266–277

    Article  CAS  PubMed  Google Scholar 

  64. Bielefeld KA, Amini-Nik S, Whetstone H, Poon R, Youn A et al (2011) Fibronectin and beta-catenin act in a regulatory loop in dermal fibroblasts to modulate cutaneous healing. J Biol Chem 286:27687–27697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bhattarai N, Gunn J, Zhang M (2010) Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev 62:83–99

    Article  CAS  PubMed  Google Scholar 

  66. Koide SS (1998) Chitin-chitosan: properties, benefits and risks. Nutr Res 18:1091–1101

    Article  CAS  Google Scholar 

  67. Hayashi Y, Yamada S, Yanagi Guchi K, Koyama Z, Ikeda T (2012) Chitosan and fish collagen as biomaterials for regenerative medicine. Adv Food Nutr Res 65:107–120

    Article  PubMed  Google Scholar 

  68. Hilmi AB, Halim AS, Hassan A, Lim CK, Noorsal K et al (2013) In vitro characterization of a chitosan skin regenerating template as a scaffold for cells cultivation. Springerplus 2:79

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Shevchenko RV, Eeman M, Rowshanravan B, Allan IU, Savina IN et al (2014) The in vitro characterization of a gelatin scaffold, prepared by cryogelation and assessed in vivo as a dermal replacement in wound repair. Acta Biomater 10:3156–3166

    Article  CAS  PubMed  Google Scholar 

  70. Kang H-W, Tabata Y, Ikada Y (1999) Fabrication of porous gelatin scaffolds for tissue engineering. Biomaterials 20:1339–1344

    Article  CAS  PubMed  Google Scholar 

  71. Takemoto S, Morimoto N, Kimura Y, Taira T, Kitagawa T et al (2008) Preparation of collagen/gelatin sponge scaffold for sustained release of bFGF. Tissue Eng Part A 14:1629–1638

    Article  CAS  PubMed  Google Scholar 

  72. Rnjak J, Wise SG, Mithieux SM, Weiss AS (2011) Severe burn injuries and the role of elastin in the design of dermal substitutes. Tissue Eng Part B Rev 17:81–91

    Article  CAS  PubMed  Google Scholar 

  73. Rnjak-Kovacina J, Wise SG, Li Z, Maitz PKM, Young CJ et al (2011) Tailoring the porosity and pore size of electrospun synthetic human elastin scaffolds for dermal tissue engineering. Biomaterials 32:6729–6736

    Article  CAS  PubMed  Google Scholar 

  74. Almine JF, Bax DV, Mithieux SM, Nivison-Smith L, Rnjak J et al (2010) Elastin-based materials. Chem Soc Rev 39:3371–3379

    Article  CAS  PubMed  Google Scholar 

  75. Jones I, Currie L, Martin R (2002) A guide to biological skin substitutes. Br J Plast Surg 55:185–193

    Article  CAS  PubMed  Google Scholar 

  76. Min JH, Yun IS, Lew DH, Roh TS, Lee WJ (2014) The use of matriderm and autologous skin graft in the treatment of full thickness skin defects. Arch Plast Surg 41:330–336

    Article  PubMed  PubMed Central  Google Scholar 

  77. Haslik W, Kamolz LP, Nathschlager G, Andel H, Meissl G et al (2007) First experiences with the collagen-elastin matrix Matriderm as a dermal substitute in severe burn injuries of the hand. Burns 33:364–368

    Article  CAS  PubMed  Google Scholar 

  78. Nicholas MN, Jeschke MG, Amini-Nik S (2016) Cellularized Bilayer Pullulan-gelatin Hydrogel for Skin Regeneration. Tissue Eng Part A. doi: 10.1089/ten.tea.2015.0536

  79. Lee KY, Mooney DJ (2012) Alginate: properties and biomedical applications. Prog Polym Sci 37:106–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith AM, Hunt NC, Shelton RM, Birdi G, Grover LM (2012) Alginate hydrogel has a negative impact on in vitro collagen 1 deposition by fibroblasts. Biomacromolecules 13:4032–4038

    Article  CAS  PubMed  Google Scholar 

  81. Leng L, McAllister A, Zhang B, Radisic M, Gunther A (2012) Mosaic hydrogels: one-step formation of multiscale soft materials. Adv Mater 24:3650–3658

    Article  CAS  PubMed  Google Scholar 

  82. Fang Y, Al-Assaf S, Phillips GO, Nishinari K, Funami T et al (2008) Binding behavior of calcium to polyuronates: comparison of pectin with alginate. Carbohydr Polym 72:334–341

    Article  CAS  Google Scholar 

  83. Behrens DT, Villone D, Koch M, Brunner G, Sorokin L et al (2012) The epidermal basement membrane is a composite of separate laminin- or collagen IV-containing networks connected by aggregated perlecan, but not by nidogens. J Biol Chem 287:18700–18709

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Masuda R, Mochizuki M, Hozumi K, Takeda A, Uchinuma E et al (2009) A novel cell-adhesive scaffold material for delivering keratinocytes reduces granulation tissue in dermal wounds. Wound Repair Regen 17:127–135

    Article  PubMed  Google Scholar 

  85. Halim AS, Khoo TL, Mohd Yussof SJ (2010) Biologic and synthetic skin substitutes: an overview. Indian J Plast Surg 43:S23–S28

    Article  PubMed  PubMed Central  Google Scholar 

  86. Park GE, Pattison MA, Park K, Webster TJ (2005) Accelerated chondrocyte functions on NaOH-treated PLGA scaffolds. Biomaterials 26:3075–3082

    Article  CAS  PubMed  Google Scholar 

  87. Lou T, Leung M, Wang X, Chang JY, Tsao CT et al (2014) Bi-layer scaffold of chitosan/PCL-nanofibrous mat and PLLA-microporous disc for skin tissue engineering. J Biomed Nanotechnol 10:1105–1113

    Article  CAS  PubMed  Google Scholar 

  88. Smith LL, Niziolek PJ, Haberstroh KM, Nauman EA, Webster TJ (2007) Decreased fibroblast and increased osteoblast adhesion on nanostructured NaOH-etched PLGA scaffolds. Int J Nanomed 2:383–388

    CAS  Google Scholar 

  89. Powell HM, Boyce ST (2009) Engineered human skin fabricated using electrospun collagen-PCL blends: morphogenesis and mechanical properties. Tissue Eng Part A 15:2177–2187

    Article  CAS  PubMed  Google Scholar 

  90. van der Veen VC, van der Wal MB, van Leeuwen MC, Ulrich MM, Middelkoop E (2010) Biological background of dermal substitutes. Burns 36:305–321

    Article  PubMed  Google Scholar 

  91. Akasaka Y, Ono I, Tominaga A, Ishikawa Y, Ito K et al (2007) Basic fibroblast growth factor in an artificial dermis promotes apoptosis and inhibits expression of alpha-smooth muscle actin, leading to reduction of wound contraction. Wound Repair Regen 15:378–389

    Article  PubMed  Google Scholar 

  92. Inoue S, Kijima H, Kidokoro M, Tanaka M, Suzuki Y et al (2009) The effectiveness of basic fibroblast growth factor in fibrin-based cultured skin substitute in vivo. J Burn Care Res 30:514–519

    Article  PubMed  Google Scholar 

  93. Tsuji-Saso Y, Kawazoe T, Morimoto N, Tabata Y, Taira T et al (2007) Incorporation of basic fibroblast growth factor into preconfluent cultured skin substitute to accelerate neovascularisation and skin reconstruction after transplantation. Scand J Plast Reconstr Surg Hand Surg 41:228–235

    Article  PubMed  Google Scholar 

  94. Spyrou GE, Naylor IL (2002) The effect of basic fibroblast growth factor on scarring. Br J Plast Surg 55:275–282

    Article  CAS  PubMed  Google Scholar 

  95. Bodnar RJ (2013) Epidermal growth factor and epidermal growth factor receptor: the Yin and Yang in the treatment of cutaneous wounds and cancer. Adv Wound Care (New Rochelle) 2:24–29

    Article  Google Scholar 

  96. Kuroyanagi M, Yamamoto A, Shimizu N, Ishihara E, Ohno H et al (2014) Development of cultured dermal substitute composed of hyaluronic acid and collagen spongy sheet containing fibroblasts and epidermal growth factor. J Biomater Sci Polym Ed 25:1133–1143

    Article  CAS  PubMed  Google Scholar 

  97. Yamamoto A, Shimizu N, Kuroyanagi Y (2013) Potential of wound dressing composed of hyaluronic acid containing epidermal growth factor to enhance cytokine production by fibroblasts. J Artif Organs 16:489–494

    Article  CAS  PubMed  Google Scholar 

  98. Kondo S, Kuroyanagi Y (2012) Development of a wound dressing composed of hyaluronic acid and collagen sponge with epidermal growth factor. J Biomater Sci Polym Ed 23:629–643

    Article  CAS  PubMed  Google Scholar 

  99. Matsumoto Y, Kuroyanagi Y (2010) Development of a wound dressing composed of hyaluronic acid sponge containing arginine and epidermal growth factor. J Biomater Sci Polym Ed 21:715–726

    Article  CAS  PubMed  Google Scholar 

  100. Biselli-Chicote PM, Oliveira AR, Pavarino EC, Goloni-Bertollo EM (2012) VEGF gene alternative splicing: pro- and anti-angiogenic isoforms in cancer. J Cancer Res Clin Oncol 138:363–370

    Article  CAS  PubMed  Google Scholar 

  101. Caldwell RB, Bartoli M, Behzadian MA, El-Remessy AE, Al-Shabrawey M et al (2005) Vascular endothelial growth factor and diabetic retinopathy: role of oxidative stress. Curr Drug Targets 6:511–524

    Article  CAS  PubMed  Google Scholar 

  102. Lohmeyer JA, Liu F, Kruger S, Lindenmaier W, Siemers F et al (2011) Use of gene-modified keratinocytes and fibroblasts to enhance regeneration in a full skin defect. Langenbecks Arch Surg 396:543–550

    Article  PubMed  Google Scholar 

  103. Xie WG, Lindenmaier W, Gryzybowski S, Machens HG (2005) Influence of vascular endothelial growth factor gene modification on skin substitute grafted on nude mice. Zhonghua Shao Shang Za Zhi 21:203–206

    PubMed  Google Scholar 

  104. Wilgus TA, Ferreira AM, Oberyszyn TM, Bergdall VK, DiPietro LA (2008) Regulation of scar formation by vascular endothelial growth factor. Lab Investig J Tech Methods Pathol 88:579–590

    Article  CAS  Google Scholar 

  105. Maurer B, Distler A, Suliman YA, Gay RE, Michel BA et al (2014) Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis. Ann Rheum Dis 73:1880–1887

    Article  PubMed  Google Scholar 

  106. Roberts AB, Flanders KC, Heine UI, Jakowlew S, Kondaiah P et al (1990) Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 327:145–154

    Article  CAS  PubMed  Google Scholar 

  107. Ferguson MW, O’Kane S (2004) Scar-free healing: from embryonic mechanisms to adult therapeutic intervention. Philos Trans R Soc Lond B Biol Sci 359:839–850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Pandit A, Ashar R, Feldman D (1999) The effect of TGF-β delivered through a collagen scaffold on wound healing. J Invest Surg 12:89–100

    Article  CAS  PubMed  Google Scholar 

  109. Penn JW, Grobbelaar AO, Rolfe KJ (2012) The role of the TGF-β family in wound healing, burns and scarring: a review. Int J Burns Trauma 2:18–28

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kim MS, Song HJ, Lee SH, Lee CK (2014) Comparative study of various growth factors and cytokines on type I collagen and hyaluronan production in human dermal fibroblasts. J Cosmet Dermatol 13:44–51

    Article  PubMed  Google Scholar 

  111. Sun W, Lin H, Xie H, Chen B, Zhao W et al (2007) Collagen membranes loaded with collagen-binding human PDGF-BB accelerate wound healing in a rabbit dermal ischemic ulcer model. Growth Factors 25:309–318

    Article  PubMed  CAS  Google Scholar 

  112. Niessen FB, Andriessen MP, Schalkwijk J, Visser L, Timens W (2001) Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars. J Pathol 194:207–216

    Article  CAS  PubMed  Google Scholar 

  113. Nolte SV, Xu W, Rennekampff HO, Rodemann HP (2008) Diversity of fibroblasts–a review on implications for skin tissue engineering. Cells Tissues Organs 187:165–176

    Article  PubMed  Google Scholar 

  114. Shamis Y, Silva EA, Hewitt KJ, Brudno Y, Levenberg S et al (2013) Fibroblasts derived from human pluripotent stem cells activate angiogenic responses in vitro and in vivo. PLoS One 8:e83755

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Kendall RT, Feghali-Bostwick CA (2014) Fibroblasts in fibrosis: novel roles and mediators. Front Pharmacol 5:123

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Andriani F, Margulis A, Lin N, Griffey S, Garlick JA (2003) Analysis of microenvironmental factors contributing to basement membrane assembly and normalized epidermal phenotype. J Invest Dermatol 120:923–931

    Article  CAS  PubMed  Google Scholar 

  117. Benny P, Badowski C, Lane B, Raghunath M (2015) Making More Matrix: Enhancing the deposition of dermal-epidermal junction components in vitro and accelerating organotypic skin culture development, using macromolecular crowding. Tissue Eng Part A 21:183–192

    Article  PubMed  Google Scholar 

  118. Niessen CM (2007) Tight Junctions/Adherens Junctions: basic Structure and Function. J Investig Dermatol 127:2525–2532

    Article  CAS  PubMed  Google Scholar 

  119. Pastar I, Stojadinovic O, Yin NC, Ramirez H, Nusbaum AG et al (2014) Epithelialization in wound healing: a comprehensive review. Adv Wound Care (New Rochelle) 3:445–464

    Article  Google Scholar 

  120. Lamouille S, Xu J, Derynck R (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 15:178–196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Nguyen BP, Ryan MC, Gil SG, Carter WG (2000) Deposition of laminin 5 in epidermal wounds regulates integrin signaling and adhesion. Curr Opin Cell Biol 12:554–562

    Article  CAS  PubMed  Google Scholar 

  122. Falanga V, Butmarc J, Cha J, Yufit T, Carson P (2007) Migration of the epidermal over the dermal component (epiboly) in a bilayered bioengineered skin construct. Tissue Eng 13:21–28

    Article  CAS  PubMed  Google Scholar 

  123. Eming SA, Yarmush ML, Morgan JR (1996) Enhanced function of cultured epithelium by genetic modification: cell-based synthesis and delivery of growth factors. Biotechnol Bioeng 52:15–23

    Article  CAS  PubMed  Google Scholar 

  124. Ghahary A, Ghaffari A (2007) Role of keratinocyte-fibroblast cross-talk in development of hypertrophic scar. Wound Repair Regen 15(Suppl 1):S46–S53

    Article  PubMed  Google Scholar 

  125. Wojtowicz AM, Oliveira S, Carlson MW, Zawadzka A, Rousseau CF et al (2014) The importance of both fibroblasts and keratinocytes in a bilayered living cellular construct used in wound healing. Wound Repair Regen 22:246–255

    Article  PubMed  PubMed Central  Google Scholar 

  126. Maas-Szabowski N, Szabowski A, Stark HJ, Andrecht S, Kolbus A et al (2001) Organotypic cocultures with genetically modified mouse fibroblasts as a tool to dissect molecular mechanisms regulating keratinocyte growth and differentiation. J Invest Dermatol 116:816–820

    Article  CAS  PubMed  Google Scholar 

  127. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Repair Regen 16:585–601

    Article  PubMed  Google Scholar 

  128. Borowiec A-S, Delcourt P, Dewailly E, Bidaux G (2013) Optimal Differentiation of In Vitro Keratinocytes Requires Multifactorial External Control. PLoS One 8:e77507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Falanga V, Sabolinski M (1999) A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen 7:201–207

    Article  CAS  PubMed  Google Scholar 

  130. Dinh TL, Veves A (2006) The efficacy of Apligraf in the treatment of diabetic foot ulcers. Plast Reconstr Surg 117:152S–157S (discussion 158S–159S)

    Article  CAS  PubMed  Google Scholar 

  131. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317

    Article  CAS  PubMed  Google Scholar 

  132. Sasaki M, Abe R, Fujita Y, Ando S, Inokuma D et al (2008) Mesenchymal stem cells are recruited into wounded skin and contribute to wound repair by transdifferentiation into multiple skin cell type. J Immunol 180:2581–2587

    Article  CAS  PubMed  Google Scholar 

  133. Alt E, Yan Y, Gehmert S, Song YH, Altman A et al (2011) Fibroblasts share mesenchymal phenotypes with stem cells, but lack their differentiation and colony-forming potential. Biol Cell 103:197–208

    Article  CAS  PubMed  Google Scholar 

  134. Han Y, Chai J, Sun T, Li D, Tao R (2011) Differentiation of human umbilical cord mesenchymal stem cells into dermal fibroblasts in vitro. Biochem Biophys Res Commun 413:561–565

    Article  CAS  PubMed  Google Scholar 

  135. Fathke C, Wilson L, Hutter J, Kapoor V, Smith A et al (2004) Contribution of bone marrow-derived cells to skin: collagen deposition and wound repair. Stem Cells 22:812–822

    Article  PubMed  PubMed Central  Google Scholar 

  136. Deng W, Han Q, Liao L, Li C, Ge W et al (2005) Engrafted bone marrow-derived flk-(1+) mesenchymal stem cells regenerate skin tissue. Tissue Eng 11:110–119

    Article  CAS  PubMed  Google Scholar 

  137. Basiouny HS, Salama NM, Maadawi ZM, Farag EA (2013) Effect of bone marrow derived mesenchymal stem cells on healing of induced full-thickness skin wounds in albino rat. Int J Stem Cells 6:12–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Badiavas EV, Falanga V (2003) Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol 139:510–516

    Article  PubMed  Google Scholar 

  139. Kern S, Eichler H, Stoeve J, Kluter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301

    Article  CAS  PubMed  Google Scholar 

  140. Souza CM, Mesquita LA, Souza D, Irioda AC, Francisco JC et al (2014) Regeneration of skin tissue promoted by mesenchymal stem cells seeded in nanostructured membrane. Transplant Proc 46:1882–1886

    Article  CAS  PubMed  Google Scholar 

  141. Mizuno H, Nambu M (2011) Adipose-derived stem cells for skin regeneration. Methods Mol Biol 702:453–459

    Article  CAS  PubMed  Google Scholar 

  142. Meruane MA, Rojas M, Marcelain K (2012) The use of adipose tissue-derived stem cells within a dermal substitute improves skin regeneration by increasing neoangiogenesis and collagen synthesis. Plast Reconstr Surg 130:53–63

    Article  CAS  PubMed  Google Scholar 

  143. Schneider RK, Pullen A, Kramann R, Bornemann J, Knuchel R et al (2010) Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents. Differentiation 79:182–193

    Article  CAS  PubMed  Google Scholar 

  144. Kim DW, Staples M, Shinozuka K, Pantcheva P, Kang SD et al (2013) Wharton’s Jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications. Int J Mol Sci 14:11692–11712

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Arno AI, Amini-Nik S, Blit PH, Al-Shehab M, Belo C et al (2014) Human Wharton’s jelly-mesenchymal stem cells promote skin wound healing through paracrine signaling. Stem Cell Res Ther 5:28

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Nicoletti G, Brenta F, Bleve M, Pellegatta T, Malovini A et al (2015) Long-term in vivo assessment of bioengineered skin substitutes: a clinical study. J Tissue Eng Regen Med 9:460–468

    Article  CAS  PubMed  Google Scholar 

  147. Hachiya A, Sriwiriyanont P, Kaiho E, Kitahara T, Takema Y et al (2005) An in vivo mouse model of human skin substitute containing spontaneously sorted melanocytes demonstrates physiological changes after UVB irradiation. J Invest Dermatol 125:364–372

    CAS  PubMed  Google Scholar 

  148. Bielefeld KA, Amini-Nik S, Alman BA (2013) Cutaneous wound healing: recruiting developmental pathways for regeneration. Cell Mol Life Sci 70:2059–2081

    Article  CAS  PubMed  Google Scholar 

  149. Amini-Nik S, Glancy D, Boimer C, Whetstone H, Keller C et al (2011) Pax7 expressing cells contribute to dermal wound repair, regulating scar size through a beta-catenin mediated process. Stem Cells 29:1371–1379

    CAS  PubMed  Google Scholar 

  150. Amini-Nik S, Cambridge E, Yu W, Guo A, Whetstone H et al (2014) beta-Catenin-regulated myeloid cell adhesion and migration determine wound healing. J Clin Invest 124:2599–2610

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bechetoille N, Vachon H, Gaydon A, Boher A, Fontaine T et al (2011) A new organotypic model containing dermal-type macrophages. Exp Dermatol 20:1035–1037

    Article  CAS  PubMed  Google Scholar 

  152. Koh TJ, DiPietro LA (2011) Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 13:e23

    Article  PubMed  PubMed Central  Google Scholar 

  153. Liu Y, Luo H, Wang X, Takemura A, Fang YR et al (2013) In vitro construction of scaffold-free bilayered tissue-engineered skin containing capillary networks. Biomed Res Int 2013:561410

    PubMed  PubMed Central  Google Scholar 

  154. Zhang X, Yang J, Li Y, Liu S, Long K et al (2011) Functional neovascularization in tissue engineering with porcine acellular dermal matrix and human umbilical vein endothelial cells. Tissue Eng Part C Methods 17:423–433

    Article  PubMed  Google Scholar 

  155. Marino D, Luginbuhl J, Scola S, Meuli M, Reichmann E (2014) Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries. Sci Transl Med 6:221ra214

    Article  CAS  Google Scholar 

  156. Sriwiriyanont P, Lynch KA, Maier EA, Hahn JM, Supp DM et al (2012) Morphogenesis of chimeric hair follicles in engineered skin substitutes with human keratinocytes and murine dermal papilla cells. Exp Dermatol 21:783–785

    CAS  PubMed  Google Scholar 

  157. Sriwiriyanont P, Lynch KA, McFarland KL, Supp DM, Boyce ST (2013) Characterization of hair follicle development in engineered skin substitutes. PLoS One 8:e65664

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Moiemen N, Yarrow J, Hodgson E, Constantinides J, Chipp E et al (2011) Long-term clinical and histological analysis of Integra dermal regeneration template. Plast Reconstr Surg 127:1149–1154

    Article  CAS  PubMed  Google Scholar 

  159. Huang S, Xu Y, Wu C, Sha D, Fu X (2010) In vitro constitution and in vivo implantation of engineered skin constructs with sweat glands. Biomaterials 31:5520–5525

    Article  CAS  PubMed  Google Scholar 

  160. Sunami H, Yokota I, Igarashi Y (2014) Influence of the pattern size of micropatterned scaffolds on cell morphology, proliferation, migration and F-actin expression. Biomater Sci 2:399–409

    Article  CAS  Google Scholar 

  161. Phipps MC, Clem WC, Grunda JM, Clines GA, Bellis SL (2012) Increasing the pore sizes of bone-mimetic electrospun scaffolds comprised of polycaprolactone, collagen I and hydroxyapatite to enhance cell infiltration. Biomaterials 33:524–534

    Article  CAS  PubMed  Google Scholar 

  162. Lien SM, Ko LY, Huang TJ (2009) Effect of pore size on ECM secretion and cell growth in gelatin scaffold for articular cartilage tissue engineering. Acta Biomater 5:670–679

    Article  CAS  PubMed  Google Scholar 

  163. Joshi VS, Lei NY, Walthers CM, Wu B, Dunn JC (2013) Macroporosity enhances vascularization of electrospun scaffolds. J Surg Res 183:18–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Annabi N, Nichol JW, Zhong X, Ji C, Koshy S et al (2010) Controlling the porosity and microarchitecture of hydrogels for tissue engineering. Tissue Eng Part B, Rev 16:371–383

    Article  CAS  Google Scholar 

  165. Huss FR, Nyman E, Gustafson CJ, Gisselfalt K, Liljensten E et al (2008) Characterization of a new degradable polymer scaffold for regeneration of the dermis: in vitro and in vivo human studies. Organogenesis 4:195–200

    Article  PubMed  PubMed Central  Google Scholar 

  166. Gong Y, Zhou Q, Gao C, Shen J (2007) In vitro and in vivo degradability and cytocompatibility of poly(l-lactic acid) scaffold fabricated by a gelatin particle leaching method. Acta Biomater 3:531–540

    Article  CAS  PubMed  Google Scholar 

  167. Vlierberghe SV, Cnudde V, Dubruel P, Masschaele B, Cosijns A et al (2007) Porous gelatin hydrogels: 1. Cryogenic formation and structure analysis. Biomacromolecules 8:331–337

    Article  PubMed  CAS  Google Scholar 

  168. O’Brien FJ, Harley BA, Yannas IV, Gibson LJ (2005) The effect of pore size on cell adhesion in collagen-GAG scaffolds. Biomaterials 26:433–441

    Article  PubMed  CAS  Google Scholar 

  169. Ho MH, Kuo PY, Hsieh HJ, Hsien TY, Hou LT et al (2004) Preparation of porous scaffolds by using freeze-extraction and freeze-gelation methods. Biomaterials 25:129–138

    Article  CAS  PubMed  Google Scholar 

  170. Hao R, Wang D, Yao A, Huang W (2011) Preparation and characterization of β-TCP/CS scaffolds by freeze-extraction and freeze-gelation. J Wuhan Univer Technol-Mater Sci Ed 26:371–375

    Article  CAS  Google Scholar 

  171. Atala A, Lanza RP (2001) Methods of tissue engineering. Academic Press, San Diego

  172. Shih HH, Lee KR, Lai HM, Tsai CC, Chang YC (2004) Method of making porous biodegradable polymers. US Patent 6673286

  173. Kang HG, Lee SB, Lee YM (2005) Novel preparative method for porous hydrogels using overrun process. Polym Int 54:537–543

    Article  CAS  Google Scholar 

  174. Kang HG, Kim SY, Lee YM (2006) Novel porous gelatin scaffolds by overrun/particle leaching process for tissue engineering applications. J Biomed Mater Res B Appl Biomater 79:388–397

    Article  PubMed  CAS  Google Scholar 

  175. Zhang Y, Ouyang H, Lim CT, Ramakrishna S, Huang ZM (2005) Electrospinning of gelatin fibers and gelatin/PCL composite fibrous scaffolds. J Biomed Mater Res B Appl Biomater 72:156–165

    Article  PubMed  CAS  Google Scholar 

  176. Yoshimoto H, Shin YM, Terai H, Vacanti JP (2003) A biodegradable nanofiber scaffold by electrospinning and its potential for bone tissue engineering. Biomaterials 24:2077–2082

    Article  CAS  PubMed  Google Scholar 

  177. Heydarkhan-Hagvall S, Schenke-Layland K, Dhanasopon AP, Rofail F, Smith H et al (2008) Three-dimensional electrospun ECM-based hybrid scaffolds for cardiovascular tissue engineering. Biomaterials 29:2907–2914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Li WJ, Laurencin CT, Caterson EJ, Tuan RS, Ko FK (2002) Electrospun nanofibrous structure: a novel scaffold for tissue engineering. J Biomed Mater Res 60:613–621

    Article  CAS  PubMed  Google Scholar 

  179. Boland ED, Matthews JA, Pawlowski KJ, Simpson DG, Wnek GE et al (2004) Electrospinning collagen and elastin: preliminary vascular tissue engineering. Front Biosci 9:1422–1432

    Article  CAS  PubMed  Google Scholar 

  180. Verhulsel M, Vignes M, Descroix S, Malaquin L, Vignjevic DM et al (2014) A review of microfabrication and hydrogel engineering for micro-organs on chips. Biomaterials 35:1816–1832

    Article  CAS  PubMed  Google Scholar 

  181. Yeh J, Ling Y, Karp JM, Gantz J, Chandawarkar A et al (2006) Micromolding of shape-controlled, harvestable cell-laden hydrogels. Biomaterials 27:5391–5398

    Article  CAS  PubMed  Google Scholar 

  182. Chia HN, Wu BM (2015) Recent advances in 3D printing of biomaterials. J Biol Eng 9:4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Koch L, Kuhn S, Sorg H, Gruene M, Schlie S et al (2010) Laser printing of skin cells and human stem cells. Tissue Eng Part C Methods 16:847–854

    Article  CAS  PubMed  Google Scholar 

  184. Michael S, Sorg H, Peck C-T, Koch L, Deiwick A et al (2013) Tissue Engineered Skin Substitutes Created by Laser-Assisted Bioprinting Form Skin-Like Structures in the Dorsal Skin Fold Chamber in Mice. PLoS One 8:e57741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Leng L. BQ, Amini-Nik S, Jeschke M, Guenther A (2013) Skin printer: microfluidic approach for skin regeneration and wound dressing.  US Prov. Patent Application (61817860)

  186. Wüst S, Müller R, Hofmann S (2011) Controlled positioning of cells in biomaterials—approaches towards 3D tissue printing. J Funct Biomater 2:119–154

    Article  PubMed  PubMed Central  Google Scholar 

  187. Dunn JC, Chan WY, Cristini V, Kim JS, Lowengrub J et al (2006) Analysis of cell growth in three-dimensional scaffolds. Tissue Eng 12:705–716

    Article  CAS  PubMed  Google Scholar 

  188. Fuchs E (2015) Cell biology: more than skin deep. J Cell Biol 209:629–631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Hennink WE, van Nostrum CF (2002) Novel crosslinking methods to design hydrogels. Adv Drug Deliv Rev 54:13–36

    Article  CAS  PubMed  Google Scholar 

  190. Silva SS, Santos MI, Coutinho OP, Mano JF, Reis RL (2005) Physical properties and biocompatibility of chitosan/soy blended membranes. J Mater Sci Mater Med 16:575–579

    Article  CAS  PubMed  Google Scholar 

  191. Gough JE, Scotchford CA, Downes S (2002) Cytotoxicity of glutaraldehyde crosslinked collagen/poly(vinyl alcohol) films is by the mechanism of apoptosis. J Biomed Mater Res 61:121–130

    Article  CAS  PubMed  Google Scholar 

  192. Sung HW, Huang RN, Huang LL, Tsai CC (1999) In vitro evaluation of cytotoxicity of a naturally occurring cross-linking reagent for biological tissue fixation. J Biomater Sci Polym Ed 10:63–78

    Article  CAS  PubMed  Google Scholar 

  193. Lai JY (2012) Biocompatibility of genipin and glutaraldehyde cross-linked chitosan materials in the anterior chamber of the eye. Int J Mol Sci 13:10970–10985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Haugh MG, Murphy CM, McKiernan RC, Altenbuchner C, O’Brien FJ (2011) Crosslinking and mechanical properties significantly influence cell attachment, proliferation, and migration within collagen glycosaminoglycan scaffolds. Tissue Eng Part A 17:1201–1208

    Article  CAS  PubMed  Google Scholar 

  195. Mironi-Harpaz I, Wang DY, Venkatraman S, Seliktar D (2012) Photopolymerization of cell-encapsulating hydrogels: crosslinking efficiency versus cytotoxicity. Acta Biomater 8:1838–1848

    Article  CAS  PubMed  Google Scholar 

  196. Ward JH, Peppas NA (2001) Preparation of controlled release systems by free-radical UV polymerizations in the presence of a drug. J Control Release 71:183–192

    Article  CAS  PubMed  Google Scholar 

  197. Park JS, Chu JS, Tsou AD, Diop R, Tang Z et al (2011) The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β. Biomaterials 32:3921–3930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689

    Article  CAS  PubMed  Google Scholar 

  199. Humphrey JD, Dufresne ER, Schwartz MA (2014) Mechanotransduction and extracellular matrix homeostasis. Nat Rev Mol Cell Biol 15:802–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Okay O (2010) General Properties of Hydrogels. In: Gerlach G, Arndt K-F (eds) Hydrogel sensors and actuators. Springer, Berlin, Heidelberg, pp 1–14

    Google Scholar 

  201. Kirchmajer DM, Watson CA, Ranson M, Mih Panhuis (2013) Gelapin, a degradable genipin cross-linked gelatin hydrogel. RSC Adv 3:1073–1081

    Article  CAS  Google Scholar 

  202. Orakdogen N, Okay O (2006) Correlation between crosslinking efficiency and spatial inhomogeneity in poly(acrylamide) hydrogels. Polym Bull 57:631–641

    Article  CAS  Google Scholar 

  203. Missirlis D, Spatz JP (2013) Combined effects of PEG hydrogel elasticity and cell-adhesive coating on fibroblast adhesion and persistent migration. Biomacromolecules 15:195–205

    Article  PubMed  CAS  Google Scholar 

  204. Kim BM, Suzuki S, Nishimura Y, Um SC, Morota K et al (1999) Cellular artificial skin substitute produced by short period simultaneous culture of fibroblasts and keratinocytes. Br J Plast Surg 52:573–578

    Article  CAS  PubMed  Google Scholar 

  205. Vitacolonna M, Belharazem D, Hohenberger P, Roessner E (2015) Effect of dynamic seeding methods on the distribution of fibroblasts within human acellular dermis. Cell Tissue Bank 16:605–614

    Article  CAS  PubMed  Google Scholar 

  206. Godbey WT, Hindy SB, Sherman ME, Atala A (2004) A novel use of centrifugal force for cell seeding into porous scaffolds. Biomaterials 25:2799–2805

    Article  CAS  PubMed  Google Scholar 

  207. Killat J, Reimers K, Choi CY, Jahn S, Vogt PM et al (2013) Cultivation of keratinocytes and fibroblasts in a three-dimensional bovine collagen-elastin matrix (Matriderm(R)) and application for full thickness wound coverage in vivo. Int J Mol Sci 14:14460–14474

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  208. Vitacolonna M, Belharazem D, Hohenberger P, Roessner ED (2013) Effect of static seeding methods on the distribution of fibroblasts within human acellular dermis. Biomed Eng Online 12:55

    Article  PubMed  PubMed Central  Google Scholar 

  209. Erickson IE, Kestle SR, Zellars KH, Farrell MJ, Kim M et al (2012) High mesenchymal stem cell seeding densities in hyaluronic acid hydrogels produce engineered cartilage with native tissue properties. Acta Biomater 8:3027–3034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Helmedag MJ, Weinandy S, Marquardt Y, Baron JM, Pallua N et al (2015) The effects of constant flow bioreactor cultivation and keratinocyte seeding densities on prevascularized organotypic skin grafts based on a fibrin scaffold. Tissue Eng Part A 21:343–352

    Article  CAS  PubMed  Google Scholar 

  211. Mohd Hilmi AB, Hassan A, Halim AS (2015) A bilayer engineered skin substitute for wound repair in an irradiation-impeded healing model on rat. Adv Wound Care 4:312–320

    Article  Google Scholar 

  212. Hartwig B, Borm B, Schneider H, Arin MJ, Kirfel G et al (2007) Laminin-5-deficient human keratinocytes: defective adhesion results in a saltatory and inefficient mode of migration. Exp Cell Res 313:1575–1587

    Article  CAS  PubMed  Google Scholar 

  213. Koch L, Deiwick A, Schlie S, Michael S, Gruene M et al (2012) Skin tissue generation by laser cell printing. Biotechnol Bioeng 109:1855–1863

    Article  CAS  PubMed  Google Scholar 

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Nicholas, M.N., Jeschke, M.G. & Amini-Nik, S. Methodologies in creating skin substitutes. Cell. Mol. Life Sci. 73, 3453–3472 (2016). https://doi.org/10.1007/s00018-016-2252-8

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