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      A novel strategy to engineer pre-vascularized 3-dimensional skin substitutes to achieve efficient, functional engraftment

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          Abstract

          Autologous split-thickness skin grafts are the preferred treatment for excised burn wounds, but donor sites for autografting are often limited in patients with extensive burns. A number of alternative treatments are already in use to treat large burns and ulcers. Despite intense efforts to develop tissue-engineered skin, delayed or absent vascularization is one of the major reasons for tissue-engineered skin engraftment failure. To overcome these problems, we developed a scaffold-free 3-dimensional (3D) skin substitute containing vascular networks that combine dermal fibroblasts, endothelial cells, and epidermal keratinocytes based on our layer-by-layer cell coating technique. We transplanted the pre-vascularized 3D skin substitutes onto full-thickness skin defects on severe combined immunodeficiency mice to assess their integration with the host tissue and effects on wound healing. We used non-vascularized 3D skin substitutes as a control. Vessels containing red blood cells were evident in the non-vascularized control by day 14. However, blood perfusion of the human-derived vasculature could be detected within 7 days of grafting. Moreover, the pre-vascularized 3D skin substitutes had high graft survival and their epidermal layers were progressively replaced by mouse epidermis. We propose that a novel dermo-epidermal 3D skin substitute containing blood vessels can promote efficient reconstruction of full-thickness skin defects.

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          Most cited references 24

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          Progress and opportunities for tissue-engineered skin.

          Tissue-engineered skin is now a reality. For patients with extensive full-thickness burns, laboratory expansion of skin cells to achieve barrier function can make the difference between life and death, and it was this acute need that drove the initiation of tissue engineering in the 1980s. A much larger group of patients have ulcers resistant to conventional healing, and treatments using cultured skin cells have been devised to restart the wound-healing process. In the laboratory, the use of tissue-engineered skin provides insight into the behaviour of skin cells in healthy skin and in diseases such as vitiligo, melanoma, psoriasis and blistering disorders.
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            A review of tissue-engineered skin bioconstructs available for skin reconstruction.

            Situations where normal autografts cannot be used to replace damaged skin often lead to a greater risk of mortality, prolonged hospital stay and increased expenditure for the National Health Service. There is a substantial need for tissue-engineered skin bioconstructs and research is active in this field. Significant progress has been made over the years in the development and clinical use of bioengineered components of the various skin layers. Off-the-shelf availability of such constructs, or production of sufficient quantities of biological materials to aid rapid wound closure, are often the only means to help patients with major skin loss. The aim of this review is to describe those materials already commercially available for clinical use as well as to give a short insight to those under development. It seeks to provide skin scientists/tissue engineers with the information required to not only develop in vitro models of skin, but to move closer to achieving the ultimate goal of an off-the-shelf, complete full-thickness skin replacement.
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              Dynamic reciprocity in the wound microenvironment.

              Here, we define dynamic reciprocity (DR) as an ongoing, bidirectional interaction among cells and their surrounding microenvironment. In this review, we posit that DR is especially meaningful during wound healing as the DR-driven biochemical, biophysical, and cellular responses to injury play pivotal roles in regulating tissue regenerative responses. Such cell-extracellular matrix interactions not only guide and regulate cellular morphology, but also cellular differentiation, migration, proliferation, and survival during tissue development, including, e.g., embryogenesis, angiogenesis, as well as during pathologic processes including cancer, diabetes, hypertension, and chronic wound healing. Herein, we examine DR within the wound microenvironment while considering specific examples across acute and chronic wound healing. This review also considers how a number of hypotheses that attempt to explain chronic wound pathophysiology may be understood within the DR framework. The implications of applying the principles of DR to optimize wound care practice and future development of innovative wound healing therapeutics are also briefly considered. © 2011 by the Wound Healing Society.
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                Author and article information

                Contributors
                ds0711@ndmc.ac.jp
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                24 May 2019
                24 May 2019
                2019
                : 9
                Affiliations
                [1 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Division of Traumatology, Research Institute, , National Defense Medical College, ; 3-2 Namiki, Tokorozawa, Saitama 359-8513 Japan
                [2 ]ISNI 0000 0004 0374 0880, GRID grid.416614.0, Division of Bioinformation and Therapeutic Systems, Research Institute, , National Defense Medical College, ; 3-2 Namiki, Tokorozawa, Saitama 359-8513 Japan
                [3 ]ISNI 0000 0004 0373 3971, GRID grid.136593.b, Graduate School of Frontier Biosciences, , Osaka University, ; 1-3 Yamadaoka, Suita, Osaka 565-0871 Japan
                Article
                44113
                10.1038/s41598-019-44113-6
                6534548
                31127144
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Japan Ministry of Defense
                Categories
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                © The Author(s) 2019

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                implants, tissue engineering

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