{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:56:39Z","timestamp":1792173399299,"version":"4.4.0"},"reference-count":151,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Italian University and Research (MUR)","award":["754345"],"award-info":[{"award-number":["754345"]}]},{"name":"European Union\u2019s Horizon 2020 Research and Innovation Program","award":["754345"],"award-info":[{"award-number":["754345"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Objectives: The optimal healing of skin wounds, deep burns, and chronic ulcers is an important clinical problem. Attempts to solve it have been driving the search for skin equivalents based on synthetic or natural polymers. Methods: Consistent with this endeavor, we used regenerated silk fibroin (SF) from Bombyx mori to produce a novel compound scaffold by welding a 3D carded\/hydroentangled SF-microfiber-based nonwoven layer (C\/H-3D-SFnw; to support dermis engineering) to an electrospun 2D SF nanofiber layer (ESFN; a basal lamina surrogate). Next, we assessed\u2014via scanning electron microscopy, attenuated total reflectance Fourier transform infrared spectroscopy, differential scanning calorimetry, mono- and co-cultures of HaCaT keratinocytes and adult human dermal fibroblasts (HDFs), dsDNA assays, exosome isolation, double-antibody arrays, and angiogenesis assays\u2014whether the C\/H-3D-SFnws\/ESFNs would allow the reconstitution of a functional human skin analog in vitro. Results: Physical analyses proved that the C\/H-3D-SFnws\/ESFNs met the requirements for human soft-tissue-like implants. dsDNA assays revealed that co-cultures of HaCaTs (on the 2D ESFN surface) and HDFs (inside the 3D C\/H-3D-SFnws) grew more intensely than did the respective monocultures. Double-antibody arrays showed that the CD9+\/CD81+ exosomes isolated from the 14-day pooled growth media of HDF and\/or HaCaT mono- or co-cultures conveyed 35 distinct angiogenic\/growth factors (AGFs). However, versus monocultures\u2019 exosomes, HaCaT\/HDF co-cultures\u2019 exosomes (i) transported larger amounts of 15 AGFs, i.e., PIGF, ANGPT-1, bFGF, Tie-2, Angiogenin, VEGF-A, VEGF-D, TIMP-1\/-2, GRO-\u03b1\/-\u03b2\/-\u03b3, IL-1\u03b2, IL-6, IL-8, MMP-9, and MCP-1, and (ii) significantly more strongly stimulated human dermal microvascular endothelial cells to migrate and assemble tubes\/nodes in vitro. Conclusions: Our results showed that both cell\u2013cell and cell\u2013SF interactions boosted the exosomal release of AGFs from HaCaTs\/HDFs co-cultured on C\/H-3D-SFnws\/ESFNs. Hence, such exosomes are an asset for prospective clinical applications as they advance cell growth and neoangiogenesis and consequently graft take and skin healing. Moreover, this new integument analog could be instrumental in preclinical and translational studies on human skin pathophysiology and regeneration.<\/jats:p>","DOI":"10.3390\/cells12141827","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:50:41Z","timestamp":1689123041000},"page":"1827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Human Keratinocytes and Fibroblasts Co-Cultured on Silk Fibroin Scaffolds Exosomally Overrelease Angiogenic and Growth Factors"],"prefix":"10.3390","volume":"12","author":[{"given":"Peng","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7804-6143","authenticated-orcid":false,"given":"Ubaldo","family":"Armato","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2800-5623","authenticated-orcid":false,"given":"Giuliano","family":"Freddi","sequence":"additional","affiliation":[{"name":"Silk Biomaterials S.r.l., 22074 Lomazzo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Chiarini","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5523-4910","authenticated-orcid":false,"given":"Ilaria","family":"Dal Pr\u00e0","sequence":"additional","affiliation":[{"name":"Department of Surgery, Dentistry, Pediatrics & Gynecology, University of Verona Medical School, 37134 Verona, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jval.2017.07.007","article-title":"An Economic Evaluation of the Impact, Cost, and Medicare Policy Implications of Chronic Nonhealing Wounds","volume":"21","author":"Nussbaum","year":"2018","journal-title":"Value Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1089\/wound.2021.0026","article-title":"Human Wound and Its Burden: Updated 2020 Compendium of Estimates","volume":"10","author":"Sen","year":"2021","journal-title":"Adv. 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