Bio-engineering a prevascularized human tri-layered skin substitute containing a hypodermis
Open accessAbstract
Severe injuries to skin including hypodermis require full-thickness skin replacement. Here, we bioengineered a tri-layered human skin substitute (TLSS) containing the epidermis, dermis, and hypodermis. The hypodermal layer was generated by differentiation of human adipose stem cells (ASC) in a collagen type I hydrogel and combined with a prevascularized dermis consisting of human dermal microvascular endothelial cells and fibroblasts, which arranged into a dense vascular network. Subsequently, keratinocytes were seeded on top to generate the epidermal layer of the TLSS. The differentiation of ASC into adipocytes was confirmed in vitro on the mRNA level by the presence of adiponectin, as well as by the expression of perilipin and FABP-4 proteins. Moreover, functional characteristics of the hypodermis in vitro and in vivo were evaluated by Oil Red O, BODIPY, and AdipoRed stainings visualizing intracellular lipid droplets. Further, we demonstrated that both undifferentiated ASC and mature adipocytes present in the hypodermis influenced the keratinocyte maturation and homeostasis in the skin substitutes after transplantation. In particular, an enhanced secretion of TGF-β1 by these cells affected the epidermal morphogenesis as assessed by the expression of key proteins involved in the epidermal differentiation including cytokeratin 1, 10, 19 and cornified envelope formation such as involucrin. Here, we propose a novel functional hypodermal-dermo-epidermal tri-layered skin substitute containing blood capillaries that efficiently promote regeneration of skin defects. STATEMENT OF SIGNIFICANCE: The main objective of this study was to develop and assess the usefulness of a tri-layered human prevascularized skin substitute (TLSS) containing an epidermis, dermis, and hypodermis. The bioengineered hypodermis was generated from human adipose mesenchymal stem cells (ASC) and combined with a prevascularized dermis and epidermis. The TLSS represents an exceptional model for studying the role of cell-cell and cell-matrix interactions in vitro and in vivo. In particular, we observed that enhanced secretion of TGF-β1 in the hypodermis exerted a profound impact on fibroblast and keratinocyte differentiation, as well as epidermal barrier formation and homeostasis. Therefore, improved understanding of the cell-cell interactions in such a physiological skin model is essential to gain insights into different aspects of wound healing.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
aHSEs can integrate additional cell types including endothelial cells, melanocytes, neuronal cells, lymphatic cells, immune cells, adipocytes, pluripotent stem cells, and skin appendages.
“These include endothelial cells to vascularize the dermis [46] and melanocytes to introduce pigmentation [47]. Furthermore, neuronal cells [48,49], lymphatic cells [50], immune cells (e.g. dermal dendritic cells [51], monocytes [52], T cells [53], and macrophages [54]), adipocytes and adipose tissue [49,55,56], pluripotent stem cells [22,36,57], and skin appendages such as hair follicles or sweat”
From Diversity of human skin three-dimensional organotypic cultures (2024) · cites this paper as [46]
The cited paper supports the adipocyte and adipose-tissue portion: its Introduction describes generating a hypodermal layer from adipose-derived stem cells, and its Discussion describes the resulting tri-layered skin substitute. Citation [49] is also attached to neuronal cells in the citing sentence, but the paper does not report incorporating neuronal cells. The other listed cell types have separate citations and are not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAdipose tissue critically contributes to the regulation of HF cycling.
“suggesting a critical contribution to the regulation of HFs cycling [22].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [22]
The hypodermis layer supports fibroblast proliferation during skin wound healing.
“but also supports fibroblast proliferation during skin wound healing [22, 25].”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [22]
The hypodermis layer contributes to the mechanical and thermoregulatory properties of normal skin.
“The Hypodermis layer not only contributes to the mechanical and thermoregulatory properties of the normal skin”
From The empowering influence of air-liquid interface culture on skin organoid hair follicle development (2025) · cites this paper as [22]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Multilineage Cells from Human Adipose Tissue: Implications for Cell-Based Therapies
Zuk, P. A., Zhu, M., Mizuno, H., Huang, J., Futrell, J. W., Katz, A. J., Benhaim, P., Lorenz, H. P., & Hedrick, M. H. (2001) · Tissue Engineering · doi:10.1089/107632701300062859 · Cited by 7,956 · see citing works
Human Adipose Tissue Is a Source of Multipotent Stem Cells
Zuk, P. A., Zhu, M., Ashjian, P. H., Ugarte, D. A. D., Huang, J. I., Mizuno, H., Alfonso, Z. C., Fraser, J. K., Benhaim, P., & Hedrick, M. H. (2002) · Molecular Biology of the Cell · doi:10.1091/mbc.e02-02-0105 · Cited by 6,669 · see citing works
Roberts, A. B., Sporn, M. B., Assoian, R. K., Smith, J. M., Roche, N. S., Wakefield, L. M., Heine, U., Liotta, L. A., Falanga, V., & Kehrl, J. H. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.12.4167 · Cited by 2,867 · see citing works
Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer
Siegel, P. M., & Massagué, J. (2003) · Nature reviews. Cancer · doi:10.1038/nrc1208 · Cited by 1,600 · see citing works
Epithelialization in Wound Healing: A Comprehensive Review
Pastar, I., Stojadinović, O., Yin, N. C., Ramirez, H. A., Nusbaum, A. G., Sawaya, A. P., Patel, S. B., Khalid, L., Isseroff, R. R., & Tomic‐Canic, M. (2014) · Advances in Wound Care · doi:10.1089/wound.2013.0473 · Cited by 1,549 · see citing works
Adipogenesis and metabolic health
Ghaben, A. L., & Scherer, P. E. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0093-z · Cited by 1,395 · see citing works
Vascularization in tissue engineering
Rouwkema, J., Rivron, N. C., & van Blitterswijk, C. (2008) · Trends in biotechnology · doi:10.1016/j.tibtech.2008.04.009 · Cited by 1,218 · see citing works
Jones, K. H., & Senft, J. A. (1985) · Journal of Histochemistry & Cytochemistry · doi:10.1177/33.1.2578146 · Cited by 1,104 · see citing works
Adipose-derived stem cells: Isolation, expansion and differentiation☆
Bunnell, B. A., Flaat, M., Gagliardi, C., PATEL, B., & RIPOLL, C. (2008) · Methods · doi:10.1016/j.ymeth.2008.03.006 · Cited by 1,069 · see citing works
Accelerated Healing of Incisional Wounds in Rats Induced by Transforming Growth Factor-β
Mustoe, T. A., Pierce, G. F., Thomason, A., Gramates, P. H., Sporn, M. B., & Deuel, T. F. (1987) · Science · doi:10.1126/science.2442813 · Cited by 930 · see citing works
Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response
Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. J., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., et al. (1999) · Nature Cell Biology · doi:10.1038/12971 · Cited by 911 · see citing works
Kim, W.-S., Park, B.-S., Sung, J.-H., Yang, J.-M., Park, S.-B., Kwak, S.-J., & Park, J. (2007) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2007.05.018 · Cited by 860 · see citing works
Illouz, Y.-G., & Illouz, Y.-G. (1983) · Plastic & Reconstructive Surgery · doi:10.1097/00006534-198311000-00001 · Cited by 702 · see citing works
Fain, J. N. (2006) · Vitamins and hormones · doi:10.1016/s0083-6729(06)74018-3 · Cited by 679 · see citing works
Adipocyte Lineage Cells Contribute to the Skin Stem Cell Niche to Drive Hair Cycling
Festa, E., Fretz, J. A., Berry, R., Schmidt, B., Rodeheffer, M. S., Horowitz, M. C., & Horsley, V. (2011) · Cell · doi:10.1016/j.cell.2011.07.019 · Cited by 616 · see citing works
Thannickal, V. J., Lee, D. Y., White, E. S., Cui, Z., Larios, J. M., Chacon, R., Horowitz, J. C., Day, R. M., & Thomas, P. E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208544200 · Cited by 606 · see citing works
Advanced Hydrogels as Wound Dressings
Tavakoli, S., & Klar, A. S. (2020) · Biomolecules · doi:10.3390/biom10081169 · Cited by 551 · see citing works
Self-citationThe Potential of Adipose Stem Cells in Regenerative Medicine
Lindroos, B., Suuronen, R., & Miettinen, S. (2010) · Stem Cell Reviews and Reports · doi:10.1007/s12015-010-9193-7 · Cited by 443 · see citing works
Isolation of adipose-derived stem cells and their induction to a chondrogenic phenotype
Estes, B. T., Diekman, B. O., Gimble, J. M., & Guilak, F. (2010) · Nature Protocols · doi:10.1038/nprot.2010.81 · Cited by 429 · see citing works
Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels
Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F., & Rowan, A. E. (2015) · Nature Materials · doi:10.1038/nmat4483 · Cited by 407 · see citing works
Pietenpol, J. A., Holt, J. T., Stein, R. W., & Moses, H. L. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.10.3758 · Cited by 397 · see citing works
Roles of Autocrine TGF-β Receptor and Smad Signaling in Adipocyte Differentiation
Choy, L., Skillington, J., & Derynck, R. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.149.3.667 · Cited by 323 · see citing works
Intradermal adipocytes mediate fibroblast recruitment during skin wound healing
Schmidt, B. A., & Horsley, V. (2013) · Development · doi:10.1242/dev.087593 · Cited by 318 · see citing works
Extracellular Matrix Remodeling of Adipose Tissue in Obesity and Metabolic Diseases
Ruiz‐Ojeda, F. J., Méndez-Gutiérrez, A., Aguilera, C. M., & Plaza‐Díaz, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20194888 · Cited by 312 · see citing works
Adipogenesis: cellular and molecular aspects
Fève, B. (2005) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2005.07.007 · Cited by 281 · see citing works
The Role of TGFβ Signaling in Wound Epithelialization
Ramirez, H. A., Patel, S. B., & Pastar, I. (2013) · Advances in Wound Care · doi:10.1089/wound.2013.0466 · Cited by 273 · see citing works
Dermal adipocyte lipolysis and myofibroblast conversion are required for efficient skin repair
Shook, B. A., Wasko, R. R., Mano, O., Rutenberg-Schoenberg, M. L., Rudolph, M. C., Zirak, B., Rivera-Gonzalez, G. C., López-Giráldez, F., Zarini, S., Rezza, A., et al. (2020) · Cell Stem Cell · doi:10.1016/j.stem.2020.03.013 · Cited by 265 · see citing works
Trottier, V., Marceau-Fortier, G., Germain, L., Vincent, C., & Fradette, J. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0031 · Cited by 231 · see citing works
Zieris, A., Prokoph, S., Levental, K. R., Welzel, P. B., Grimmer, M., Freudenberg, U., & Werner, C. (2010) · Biomaterials · doi:10.1016/j.biomaterials.2010.07.021 · Cited by 209 · see citing works
Tissue-engineered dermo-epidermal skin grafts prevascularized with adipose-derived cells
Klar, A. S., Güven, S., Biedermann, T., Luginbühl, J., Sophie Böttcher-haberzeth, A., Meuli‐Simmen, C., Meuli, M., Martín, I., Scherberich, A., & Ernst Reichmann, A. (2014) · Biomaterials · doi:10.1016/j.biomaterials.2014.02.049 · Cited by 177 · see citing works
Self-citationTransforming Growth Factor β1 release by human adipose tissue is enhanced in obesity
Fain, J. N., Tichansky, D. S., & Madan, A. K. (2005) · Metabolism · doi:10.1016/j.metabol.2005.05.024 · Cited by 154 · see citing works
In Vitro 3D Model for Human Vascularized Adipose Tissue
Kang, J. H., Gimble, J. M., & Kaplan, D. L. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2008.0469 · Cited by 144 · see citing works
Isolating adipose-derived mesenchymal stem cells from lipoaspirate blood and saline fraction
Francis, M. P., Sachs, P. C., Elmore, L. W., & Holt, S. E. (2010) · Organogenesis · doi:10.4161/org.6.1.10019 · Cited by 137 · see citing works
Pontiggia, L., Biedermann, T., Meuli, M., Widmer, D., Sophie Böttcher-haberzeth, A., Schiestl, C. M., Schneider, J. J., Braziulis, E., Montaño, I., Meuli‐Simmen, C., et al. (2008) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.254 · Cited by 131 · see citing works
Self-citationCeiling culture of mature human adipocytes: use in studies of adipocyte functions
Zhang, H. H., Kumar, S., Barnett, A., & Eggo, M. C. (2000) · Journal of Endocrinology · doi:10.1677/joe.0.1640119 · Cited by 130 · see citing works
Braziulis, E., Diezi, M., Biedermann, T., Pontiggia, L., Schmucki, M., Hartmann-Fritsch, F., Luginbühl, J., Schiestl, C. M., Meuli, M., & Ernst Reichmann, A. (2011) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2011.0561 · Cited by 123 · see citing works
Self-citationTGF-β1 Accelerates Wound Healing: Reversal of Steroid-Impaired Healing in Rats and Rabbits
Beck, L. S., Deguzman, L., Lee, W. P., Xu, Y., McFatridge, L. A., & Amento, E. P. (1991) · Growth Factors · doi:10.3109/08977199109000293 · Cited by 122 · see citing works
Zhang, L., Chen, S., Guerrero‐Juarez, C. F., Li, F., Tong, Y., Liang, Y., Liggins, M. C., Chen, X., Chen, H., Li, M., et al. (2018) · Immunity · doi:10.1016/j.immuni.2018.11.003 · Cited by 122 · see citing works
Oxygen consumption in undifferentiated versus differentiated adipogenic mesenchymal precursor cells
von Heimburg, D., Hemmrich, K., Zachariah, S., Staiger, H., & Pallua, N. (2005) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2004.12.013 · Cited by 117 · see citing works
Syndecan-1 Is Required to Maintain Intradermal Fat and Prevent Cold Stress
Kasza, I., Suh, Y. K., Wollny, D., Clark, R. J., Roopra, A., Colman, R. J., MacDougald, O. A., Shedd, T. A., Nelson, D. W., Yen, M., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004514 · Cited by 109 · see citing works
Skin Tissue Engineering: Application of Adipose-Derived Stem Cells
Klar, A. S., Zimoch, J., & Biedermann, T. (2017) · BioMed Research International · doi:10.1155/2017/9747010 · Cited by 107 · see citing works
Self-citationRevisiting the regulatory roles of the TGF-β family of cytokines
Fujio, K., Komai, T., Inoue, M., Morita, K., Okamura, T., & Yamamoto, K. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.07.007 · Cited by 106 · see citing works
Adipose Tissue Engineering by Human Adipose-Derived Stromal Cells
Hong, L., Peptan, I. A., Çolpan, A., & Daw, J. L. (2006) · Cells Tissues Organs · doi:10.1159/000095987 · Cited by 104 · see citing works
Human Eccrine Sweat Gland Cells Can Reconstitute a Stratified Epidermis
Biedermann, T., Pontiggia, L., Sophie Böttcher-haberzeth, A., Tharakan, S. J., Braziulis, E., Schiestl, C. M., Meuli, M., & Ernst Reichmann, A. (2010) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.83 · Cited by 101 · see citing works
Self-citationThomas, P. E., Peters-Golden, M. L., White, E. S., Thannickal, V. J., & Moore, B. B. (2007) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00489.2006 · Cited by 100 · see citing works
Meuli, M., Hartmann-Fritsch, F., Hüging, M., Marino, D., Saglini, M., Hynes, S. L., Neuhaus, K., Manuel, E., Middelkoop, E., Ernst Reichmann, A., et al. (2019) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000005746 · Cited by 100 · see citing works
Nall, A. V., Brownlee, R. E., Colvin, C. P., Schultz, G. S., Fein, D. A., Cassisi, N. J., Nguyen, T. H., & Kalra, A. (1996) · Archives of Otolaryngology - Head and Neck Surgery · doi:10.1001/archotol.1996.01890140057011 · Cited by 99 · see citing works
Bioengineered Skin Substitutes: Advances and Future Trends
Tavakoli, S., & Klar, A. S. (2021) · Applied Sciences · doi:10.3390/app11041493 · Cited by 99 · see citing works
Self-citationMatsumoto, K., Hashimoto, K., Hashiro, M., Yoshimasa, H., & Yoshikawa, K. (1990) · Journal of Cellular Physiology · doi:10.1002/jcp.1041450114 · Cited by 90 · see citing works
Klar, A. S., Güven, S., Zimoch, J., Zapiorkowska, N. A., Biedermann, T., Sophie Böttcher-haberzeth, A., Meuli‐Simmen, C., Martín, I., Scherberich, A., Ernst Reichmann, A., et al. (2015) · Pediatric Surgery International · doi:10.1007/s00383-015-3808-7 · Cited by 89 · see citing works
Self-citationProliferation and differentiation of adipose-derived stem cells on naturally derived scaffolds
Flynn, L. E., Prestwich, G. D., Semple, J. L., & Woodhouse, K. A. (2008) · Biomaterials · doi:10.1016/j.biomaterials.2007.12.028 · Cited by 86 · see citing works
Production of human tissue-engineered skin trilayer on a plasma-based hypodermis
Monfort, A., Soriano‐Navarro, M., García‐Verdugo, J. M., & Izeta, A. (2012) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.548 · Cited by 74 · see citing works
Isolation and Culture of Human Dermal Fibroblasts
Kisiel, M. A., & Klar, A. S. (2019) · Methods in molecular biology · doi:10.1007/978-1-4939-9473-1_6 · Cited by 74 · see citing works
Self-citationDenton, C. P., Khan, K., Hoyles, R. K., Shiwen, X., Leoni, P., Chen, Y., Eastwood, M., & Abraham, D. (2008) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.171 · Cited by 71 · see citing works
Sugihara, H., Toda, S., Yonemitsu, N., & Watanabe, K. S. (2001) · British Journal of Dermatology · doi:10.1046/j.1365-2133.2001.04008.x · Cited by 68 · see citing works
Bortell, R., Owen, T. A., Ignotz, R. A., Stein, G. S., & Stein, J. L. (1994) · Journal of Cellular Biochemistry · doi:10.1002/jcb.240540214 · Cited by 62 · see citing works
Klar, A. S., Michalak-Micka, K., Biedermann, T., Simmen-Meuli, C., Reichmann, E., & Meuli, M. (2018) · Pediatric surgery international (Print) · doi:10.1007/s00383-017-4179-z · Cited by 61 · see citing works
Self-citationGeneration of a Fibrin Based Three-Layered Skin Substitute
Kober, J., Gugerell, A., Schmid, M., Kamolz, L., & Keck, M. K. (2015) · BioMed Research International · doi:10.1155/2015/170427 · Cited by 49 · see citing works
Buschke, S., Stark, H., Cerezo, A., Praetzel‐Wunder, S., Boehnke, K., Kollar, J., Langbein, L., Heldin, C., & Boukamp, P. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-11-0879 · Cited by 47 · see citing works
Mittermayr, R., Slezak, P., Haffner, N., Smolen, D., Hartinger, J., Hofmann, A. T., Schense, J. C., Spazierer, D., Gampfer, J., Goppelt, A., et al. (2015) · Acta Biomaterialia · doi:10.1016/j.actbio.2015.10.028 · Cited by 45 · see citing works
Verseijden, F., Sluijs, S. J. P.-V., van Neck, J. W., Hofer, S. O. P., Hovius, S. E. R., & van Osch, G. J. V. M. (2011) · Journal of Tissue Engineering and Regenerative Medicine · doi:10.1002/term.410 · Cited by 40 · see citing works
Sánchez‐Muñoz, I., Granados, R., Holguín, P., Garcia-Vela, J. A., Casares, C., & Casares, M. (2014) · Tissue Engineering Part A · doi:10.1089/ten.tea.2013.0626 · Cited by 38 · see citing works
Choi, J. H. K., Gimble, J. M., Vunjak‐Novakovic, G., & Kaplan, D. L. (2010) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2009.0760 · Cited by 34 · see citing works
Transforming Growth Factor-β Signaling in Skin: Stromal to Epithelial Cross-Talk
Mauviel, A. (2008) · Journal of Investigative Dermatology · doi:10.1038/jid.2008.385 · Cited by 34 · see citing works
Visualisation of newly synthesised collagen in vitro and in vivo
Oostendorp, C., Uijtdewilligen, P. J. E., Versteeg, E. M. M., Hafmans, T. G. M., van den Bogaard, E. H. J., de Jonge, P. K. J. D., Pirayesh, A., den Hoff, J. W. V., Ernst Reichmann, A., Daamen, W. F., et al. (2016) · Scientific Reports · doi:10.1038/srep18780 · Cited by 27 · see citing works
Human Adipocyte Conditioned Medium Promotes In Vitro Fibroblast Conversion to Myofibroblasts
El-Hattab, M. Y., Nagumo, Y., Gourronc, F. A., Klingelhutz, A. J., Ankrum, J. A., & Sander, E. A. (2020) · Scientific Reports · doi:10.1038/s41598-020-67175-3 · Cited by 25 · see citing works
3-D Adipocyte Differentiation and Peri-adipocyte Collagen Turnover
Chun, T., & Inoue, M. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-800280-3.00002-5 · Cited by 23 · see citing works
Moiemen, N. S., Schiestl, C. M., Hartmann-Fritsch, F., Neuhaus, K., Ernst Reichmann, A., Löw, A., Stenger, C., Sophie Böttcher-haberzeth, A., & Meuli, M. (2021) · Burns Open · doi:10.1016/j.burnso.2021.04.004 · Cited by 16 · see citing works
Oostendorp, C., Meyer, S., Sobrio, M., van Arendonk, J., Ernst Reichmann, A., Daamen, W. F., & Kuppevelt, T. H. V. (2016) · Burns · doi:10.1016/j.burns.2016.10.002 · Cited by 15 · see citing works
Michalak‐Micka, K., Biedermann, T., Ernst Reichmann, A., Meuli, M., & Klar, A. S. (2018) · Pediatric Surgery International · doi:10.1007/s00383-018-4384-4 · Cited by 14 · see citing works
Self-citationMicrovascular Networks and Models, In vitro Formation
Blache, U., Guerrero, J., Güven, S., Klar, A. S., & Scherberich, A. (2017) · Springer eBooks · doi:10.1007/978-3-319-21056-8_9-1 · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 6
- A.S. Klar, S. Güven, T. Biedermann, J. Luginbühl, S. Böttcher-Haberzeth, C. Meuli-Simmen, M. Meuli, I. Martin, A. Scherberich, E. Reichmann, Tissue- engineered dermo-epidermal skin grafts prevascularized with adipose-derived cells, Biomaterials 35 (2014), doi: 10.1016/j.biomaterials.2014.02.049 . · DOI
- D. Marino , J. Luginbühl , S. Scola , M. Meuli , E. Reichmann , Bioengineering Dermo-Epidermal Skin Grafts with Blood and Lymphatic Capillaries, 2014, pp. 1-14 .
- L. Pontiggia, T. Biedermann, M. Meuli, D. Widmer, S. Böttcher-Haberzeth, C. Schiestl, J. Schneider, E. Braziulis, I. Montaño, C. Meuli-Simmen, E. Reich- mann, Markers to evaluate the quality and self-renewing potential of engi- neered human skin substitutes in vitro and after transplantation, J. Invest. Der- matol. 129 (2009) 4 80-4 90, doi: 10.1038/jid.2008.254 . · DOI
- J.N. Fain, D.S. Tichansky, A.K. Madan, Transforming growth factor beta1 release by human adipose tissue is enhanced in obesity, Metabolism 54 (2005) 1546- 1551, doi: 10.1016/j.metabol.2005.05.024 . · DOI
- C. Oostendorp, S. Meyer, M. Sobrio, J. van Arendonk, E. Reichmann, W.F. Daa- men, T.H. van Kuppevelt, Evaluation of cultured human dermal-and dermo- epidermal substitutes focusing on extracellular matrix components: compari- son of protein and RNA analysis, Burns 43 (2017) 520-530, doi: 10.1016/j.burns. 2016.10.002 . · DOI
- M. Meuli, F. Hartmann-Fritsch, M. Hüging, D. Marino, M. Saglini, S. Hynes, K. Neuhaus, E. Manuel, E. Middelkoop, E. Reichmann, C. Schiestl, A cultured autologous dermo-epidermal skin substitute for full-thickness skin defects: a phase I, open, prospective clinical trial in children, Plast. Reconstr. Surg. 144 (2019) 188-198, doi: 10.1097/PRS.0 0 0 0 0 0 0 0 0 0 0 05746 . · DOI
Cited by
Sorted by citations
An Overview of Cellulose Derivatives-Based Dressings for Wound-Healing Management
Tudoroiu, E.-E., Dinu‐Pîrvu, C., Kaya, M. G. A., Popa, L., Anuța, V., Prisada, R. M., & Ghica, M. V. (2021) · Pharmaceuticals · doi:10.3390/ph14121215 · Cited by 191 · see citing works
Wang, Y., Zhang, Y., Li, T., Shen, K., Wang, K. J., Tian, C., & Hu, D. (2023) · Advanced Materials · doi:10.1002/adma.202303642 · Cited by 116 · see citing works
Role of Graphene Oxide in Bacterial Cellulose−Gelatin Hydrogels for Wound Dressing Applications
Khan, M. U. A., Stojanović, G. M., Hassan, R., Anand, T. J. S., Al‐Ejji, M., & Hasan, A. (2023) · ACS Omega · doi:10.1021/acsomega.2c07279 · Cited by 100 · see citing works
Choi, K. Y., Ajiteru, O., Hong, H., Suh, Y. J., Sultan, M. T., Lee, H., Lee, J. S., Lee, Y. J., Lee, O. J., Kim, S. H., et al. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.04.034 · Cited by 86 · see citing works
Design of hydrogel-based scaffolds for in vitro three-dimensional human skin model reconstruction
Tan, S. H., Chua, D. A. C., Tang, J. R. J., Bonnard, C., Leavesley, D. I., & Liang, K. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.09.068 · Cited by 70 · see citing works
Engineering multifunctional bioactive citrate-based biomaterials for tissue engineering
Wang, M., Xu, P., & Lei, B. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.04.027 · Cited by 62 · see citing works
Dean, J., Hoch, C. C., Wollenberg, B., Navidzadeh, J., Maheta, B. J., Mandava, A., Knoedler, S. A., Sherwani, K., Baecher, H., Schmitz, A. M., et al. (2025) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1461328 · Cited by 45 · see citing works
Oxygenation therapies for improved wound healing: current trends and technologies
Garima, Agarwal, T., Costantini, M., Pal, S., & Kumar, A. (2022) · Journal of Materials Chemistry B · doi:10.1039/d2tb01498j · Cited by 32 · see citing works
Reconstructed Human Skin with Hypodermis Shows Essential Role of Adipose Tissue in Skin Metabolism
Jäger, J., Vahav, I., Thon, M., Waaijman, T., Spanhaak, B., de Kok, M., Bhogal, R. K., Gibbs, S., & Koning, J. J. (2024) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-023-00621-1 · Cited by 27 · see citing works
Huang, X., Niu, X., Ma, Y., Wang, X., Su, T., He, Y., Lu, F., Gao, J., & Chang, Q. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.01.002 · Cited by 25 · see citing works
Köpf, M., Nasehi, R., Kreimendahl, F., Jockenhoevel, S., & Fischer, H. (2022) · International Journal of Bioprinting · doi:10.18063/ijb.v8i4.606 · Cited by 24 · see citing works
Kang, Y., Yeo, M., Derman, I. D., Ravnic, D. J., Singh, Y. P., Alioglu, M. A., Wu, Y. B., Makkar, J., Driskell, R. R., & Ozbolat, I. T. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.10.034 · Cited by 21 · see citing works
Avelino, T. M., Harb, S. V., Adamóski, D., Oliveira, L. C. M., Horinouchi, C. D. D. S., de Azevedo, R. J., Azoubel, R. A., Thomaz, V. K., Batista, F. A. H., d’Ávila, M. A., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-07106-4 · Cited by 20 · see citing works
A sustainable strategy for generating highly stable human skin equivalents based on fish collagen
Tan, S. H., Liu, S., Teoh, S. H., Bonnard, C., Leavesley, D. I., & Liang, K. (2024) · Biomaterials Advances · doi:10.1016/j.bioadv.2024.213780 · Cited by 20 · see citing works
The empowering influence of air-liquid interface culture on skin organoid hair follicle development
Sun, J., Ahmed, I., Brown, J., Khosrotehrani, K., & Shafiee, A. (2025) · Burns & Trauma · doi:10.1093/burnst/tkae070 · Cited by 19 · see citing works
Organoids/organs-on-chips towards biomimetic human artificial skin
Huang, Y., Wu, X., Xu, Y., Yang, N., Xi, P., Wang, Y., Zhu, Y., & Chen, X. (2025) · Burns & Trauma · doi:10.1093/burnst/tkaf029 · Cited by 20 · see citing works
Layer-by-Layer Analysis of In Vitro Skin Models
Footner, E., Firipis, K., Liu, E. I., Baker, C., Foley, P. A., Kapsa, R. M. I., Pirogova, E., O’Connell, C. D., & Quigley, A. F. (2023) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.3c00283 · Cited by 18 · see citing works
Yin, W., Yang, Y., Yue, Z., Wang, R., Bai, L., Lin, Y., Chen, X., & Cai, X. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123780 · Cited by 16 · see citing works
A Comparative Analysis of Biological and Synthetic Skin Models for Drug Transport Studies
Biondo, N. E., Argenta, D. F., & Caon, T. (2023) · Pharmaceutical Research · doi:10.1007/s11095-023-03499-9 · Cited by 16 · see citing works
Advances in tissue engineering and biofabrication for in vitro skin modeling
Wistner, S. C., Rashad, L., & Slaughter, G. E. (2023) · Bioprinting · doi:10.1016/j.bprint.2023.e00306 · Cited by 15 · see citing works
Shukla, A. K., Ahn, M., Gao, J., Lee, D., Yoon, S., Oh, S., Gao, G., Cho, W.-W., & Kim, B. S. (2025) · Biomaterials · doi:10.1016/j.biomaterials.2025.123575 · Cited by 14 · see citing works
Development of carboxymethyl cellulose/gelatin hydrogel loaded with Omega-3 for skin regeneration
Zamani, S., Kolarijani, N. R., Naeiji, M., Vaez, A., Maghsoodifar, H., Douki, S. A. H. S., & Salehi, M. (2024) · Journal of Biomaterials Applications · doi:10.1177/08853282241265769 · Cited by 14 · see citing works
Diversity of human skin three-dimensional organotypic cultures
Jia, Y. Y., & Atwood, S. X. (2024) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2024.102275 · Cited by 12 · see citing works
CD146 expression profile in human skin and pre-vascularized dermo-epidermal skin substitutes in vivo
Nanni, M., Rütsche, D., Bächler, C., Pontiggia, L., Klar, A. S., Moehrlen, U., & Biedermann, T. (2023) · Journal of Biological Engineering · doi:10.1186/s13036-023-00327-x · Cited by 12 · see citing works
Self-citationFabrication of granular decellularized extracellular matrix hydrogels for wound repair
Zhang, K., Prakash, N. R., Davern, J. W., Chrysanthou, A., Guo, Y., Yahiaoui, F., Wang, Y., Blowes, L. M., & Connelly, J. T. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.09.051 · Cited by 11 · see citing works
Chocarro‐Wrona, C., Pleguezuelos‐Beltrán, P., de Andrés, J. L., Antich, C., de Vicente, J., Jiménez, G., Arias‐Santiago, S., Gálvez‐Martín, P., López‐Ruiz, E., & Marchal, J. A. (2025) · Materials Today Bio · doi:10.1016/j.mtbio.2025.101592 · Cited by 11 · see citing works
The ROC skin model: A robust skin equivalent for permeation and live cell imaging studies
Jakobsen, N. D., Kaiser, K., Ebbesen, M. F., Lauritsen, L., Gjerstorff, M. F., Kuntsche, J., & Brewer, J. R. (2022) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2022.106282 · Cited by 11 · see citing works
chari, K. M., Enderami, S. E., Mansour, R. N., Hasanzadeh, E., Mahabadi, J. A., Abazari, M., Asadi, P., & Hojjat, A. (2024) · Regenerative Therapy · doi:10.1016/j.reth.2024.02.011 · Cited by 11 · see citing works
Villata, S., Baruffaldi, D., Cue-López, R., Paoletti, C., Bosch, P., Napione, L., Giovannozzi, A. M., Pirri, C. F., Martínez‐Campos, E., & Frascella, F. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c16397 · Cited by 10 · see citing works
Shin, G. J.-E., Abaci, H. E., & Smith, M. C. (2022) · Frontiers in Pain Research · doi:10.3389/fpain.2022.912977 · Cited by 9 · see citing works
Role of Skin Substitutes in Burn Wound Reconstruction
Concannon, E., Damkat‐Thomas, L., Coghlan, P., & Greenwood, J. E. (2022) · IntechOpen eBooks · doi:10.5772/intechopen.105179 · Cited by 7 · see citing works
Momen, L. T., Abdolmaleki, A., Asadi, A., & Zahri, S. (2023) · Cell and Tissue Banking · doi:10.1007/s10561-023-10109-w · Cited by 7 · see citing works
3D-Bioprinted Skin Tissues for Improving Wound Healing: Current Status and Perspective
Gopakumar, N., Ali, A., Oudda, S., Singam, A., & Park, S. (2024) · Advances in experimental medicine and biology · doi:10.1007/5584_2024_817 · Cited by 6 · see citing works
Li, J., Fu, S., Lu, K. W., Christie, O., Gozelski, M. T., Cottone, M., Cottone, P., Kianian, S., Feng, K., Simon, M., et al. (2021) · Experimental Dermatology · doi:10.1111/exd.14488 · Cited by 6 · see citing works
Carvalho, L. N., Peres, L. C., Alonso‐Goulart, V., dos Santos, B. J., Braga, M. F. A., Campos, F. D. A. R., Palis, G. D. A. P., Quirino, L. S., Guimarães, L. D., Lafetá, S. A., et al. (2024) · Journal of Biomaterials Applications · doi:10.1177/08853282241276799 · Cited by 5 · see citing works
Skin models for studying vector-borne kinetoplastid infections
Hauf, L., & Engstler, M. (2025) · Current Opinion in Microbiology · doi:10.1016/j.mib.2025.102617 · Cited by 5 · see citing works
Neoteric Design of Natural Polymers for Smart Wound-Healing Materials
Mohan, S., Kumar, S., Hariharan, N., Tan, J. S., Sakthivel, N., & Muthulakshmi, L. (2024) · Regenerative Engineering and Translational Medicine · doi:10.1007/s40883-024-00332-6 · Cited by 4 · see citing works
Leveraging Tissue Engineering for Skin Cancer Models
Oudda, S., Ali, A., Chien, A. L.-L., & Park, S. (2022) · Advances in experimental medicine and biology · doi:10.1007/5584_2022_755 · Cited by 3 · see citing works
Moving lab-grown tissues into the clinic: organ-on-a-chip and bioengineered skin systems
Reed-McBain, C. A., Patel, J. D., Reed-McBain, F. L. K., Al‐Adra, D. P., Virumbrales-Muñoz, M., & Ayuso, J. M. (2024) · Frontiers in Lab on a Chip Technologies · doi:10.3389/frlct.2024.1383783 · Cited by 4 · see citing works
Phyto-nanomedicine for the Treatment of Autoimmune and Other Related Skin Disorders
Yadav, D. K., Sucheta, Vijayalakshmi, R., Yadav, R. K., Dubey, A., Minz, S., & Pradhan, M. (2024) · Springer eBooks · doi:10.1007/978-3-031-63677-6_10 · Cited by 3 · see citing works
Zuccotti, A., Al‐Fatyan, F., Ferretti, G. D. S., Bertolini, I., Long, D. T., Şahin, Ö., Rodríguez‐Blanco, J., & Barnoud, T. (2025) · Journal of Cellular Physiology · doi:10.1002/jcp.70006 · Cited by 3 · see citing works
Skin: Structure, Function, and Permeability Studies for Delivery of Active Agents
Hassan, C. M., Habiba, M., Abrar, S., Mammadova, K., & Amjad, A. (2025) · Springer eBooks · doi:10.1007/978-3-031-86087-4_2 · Cited by 2 · see citing works
Potential applications and prospects of nanocellulose in cosmetics
Alias, A. H. D., Yusoff, M. H. M., Razak, N. Q. A., Shuhaimi, M. S. R., Subli, A. N., Salleh, M. S. H., Chin, K.-H., & Shafie, M. H. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-30184-1.00011-9 · Cited by 2 · see citing works
Natural solutions for glowing skin: spices
Özler, E., & Şanlıer, N. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2025.1703354 · Cited by 2 · see citing works
Wang, S., Gao, D., Li, M., Wang, Q., Du, X., & Yuan, S. (2024) · Biomedicines · doi:10.3390/biomedicines12122844 · Cited by 1 · see citing works
Bioprinting a Tri-layered Skin Analogue
GÜNAYDIN, H. M., Fogg, S. M., Moakes, R. J. A., & Grover, L. M. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4510-9_13 · Cited by 1 · see citing works
Will the latest skin substitutes revolutionize the treatment of burns and other wounds?
Eisenstein, M. S. (2025) · Nature · doi:10.1038/d41586-025-02648-x · Cited by 1 · see citing works
Homaeigohar, S., & Boccaccini, A. R. (2025) · Royal Society of Chemistry eBooks · doi:10.1039/9781837677627-00001 · Cited by 1 · see citing works
Nanocellulose Source and Morphology Impact on Properties of Composite Gelatin Hydrogel Scaffolds
Reid, J. V., Hazelton, N., Hill, S. J., Guen, M.-J. L., & Wise, L. M. (2025) · Tissue Engineering Part A · doi:10.1177/19373341251410203 · Cited by 1 · see citing works
Skin Substitutes: An Overview of Current State of the Art
Kocivnik, N. (2024) · World Congress on Medical Physics and Biomedical Engineering, September 7 - 12, 2009, Munich, Germany · doi:10.1007/978-3-031-49068-2_2 · Cited by 1 · see citing works
Nanni, M., Rütsche, D., Bächler, C., Pontiggia, L., Klar, A. S., Moehrlen, U., & Biedermann, T. (2024) · Figshare · doi:10.6084/m9.figshare.26565372
Self-citationYadav, N., Nautiyal, V., Widyowati, R., Ekasari, W., Asif, A. H., & Bhatt, H. (2026) · Springer eBooks · doi:10.1007/978-981-95-7358-5_2
Overview of skin structure and its normal physiology
Ali, A., Sharif, A., Khan, H. M., Abdel‐Daim, M. M., Khan, M. T., Shehzadi, N., Riaz, S., Akhtar, B., & Raza, Z. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-45193-5.00006-5
Smart colorimetric wound dressing for real-time infection detection and monitoring
Pisheh, H. R., Rezaeian, R., Sani, M., & Mohammadi, H. (2026) · Journal of Biological Engineering · doi:10.1186/s13036-026-00656-7
Agudelo, C. G., Karchalla, L. M., Chandler, Z. D., & McNutt, P. M. (2026) · Journal of Functional Biomaterials · doi:10.3390/jfb17080374 · Cited by 1 · see citing works
Tomšů, J., Doubková, M., Brož, A., Blanquer, A., Hadraba, D., Trávníčková, M., Šuca, H., Šupová, M., Jenčová, V., & Bacakova, L. (2026) · Journal of Tissue Engineering · doi:10.1177/20417314261478553
Risueño, I., Amigo-Morán, L., de Aranda-Izuzquiza, G., Gago-López, N., Quílez, C., Valencia, L., & Velasco, D. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-16110-0.00029-7
- Authors
- Zimoch, J., Zielinska, D., Michalak-Micka, K., Rütsche, D., Böni, R., Biedermann, T., & Klar, A. S.
- Affiliations
- University of Zurich (CH)
- The White House (US)
- Corresponding author
- Klar, Agnes S.
- Venue
- Acta Biomaterialia
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 134
- Pages
- 215-227
- ISSN
- 1742-7061 (ISSN-L)
- OpenAlex
- W3154026603
- Cited by
- 57
- References
- 71
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 17 · 2023: 8 · 2022: 9 · 2021: 2
- FWCI
- 8.52
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Acta Biomaterialia (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- SSRN Electronic Journal (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (179012, CRSII5_173868)
- Universität Zürich
- Fondation Gaydoul
- Olga Mayenfisch Stiftung
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- subcutaneous tissue, adipose-derived stem cells, adipogenesis, type I collagen gel, dermal microvascular endothelial cells, fibroblasts, keratinocyte maturation, epidermal barrier formation, TGF-β1, wound healing, full-thickness skin defect, adipose tissue regeneration, cell-cell interactions
- MeSH terms
- Fibroblasts, Humans, Skin, Keratinocytes, Skin, Artificial, Dermis, Tissue Engineering, Subcutaneous Tissue, Endothelial Cells, Bioengineering
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
