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Here, we report successful xeno\u2010free isolation, expansion, and cryopreservation of human endothelial cells (EC), fibroblasts (FBs), pericytes (PCs), and keratinocytes (KCs). We further demonstrate the bioprinting of a human skin substitute with a dermal layer containing xeno\u2010free cultured human EC, FBs, and PCs in a xeno\u2010free bioink containing human collagen type I and fibronectin layered in a biocompatible polyglycolic acid mesh and subsequently seeded with xeno\u2010free human KCs to form an epidermal layer. Following implantation of such bilayered skin grafts on the dorsum of immunodeficient mice, KCs form a mature stratified epidermis with rete ridge\u2010like structures. The ECs and PCs form human EC\u2010lined perfused microvessels within 2\u2009weeks after implantation, preventing graft necrosis, and eliciting further perfusion of the graft by angiogenic host microvessels. As proof\u2010of\u2010concept, we generated 12 individual grafts using a single donor of all four cell types. In summary, we describe the fabrication of a bioprinted vascularized bilayered skin substitute under completely xeno\u2010free culture conditions demonstrating feasibility of a xeno\u2010free approach to complex tissue engineering.<\/jats:p>","DOI":"10.1002\/btm2.10324","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T03:40:23Z","timestamp":1650512423000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["<scp>3D<\/scp>\n                    bioprinting of an implantable xeno\u2010free vascularized human skin graft"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5071-5037","authenticated-orcid":false,"given":"Tania","family":"Baltazar","sequence":"first","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine  New Haven Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Surgery Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Vascular Surgery The First Hospital of China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandra","family":"Moncayo","sequence":"additional","affiliation":[{"name":"Department of Chronic Disease Epidemiology Yale University School of Public Health  New Haven Connecticut USA"},{"name":"College of Medicine SUNY Downstate Health Sciences University  Brooklyn New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Merola","sequence":"additional","affiliation":[{"name":"Department of Surgery Yale University School of Medicine  New Haven Connecticut USA"},{"name":"Department of Surgery Columbia University Medical Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Z.","family":"Albanna","sequence":"additional","affiliation":[{"name":"Humabiologics Inc  Phoenix Arizona USA"},{"name":"Department of General Surgery Atrium Health Wake Forest Baptist  Winston\u2010Salem North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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