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This study evaluates the perforator-based adipocutaneous skin paddle (PBASP) from vascularized free muscle flaps as a hypothesis-generating human tissue platform for early localized lymphatic insufficiency. The PBASP, receives arterial and venous perfusion but is not reconnected to physiological lymphatic outflow and was therefore hypothesized to develop changes consistent with early local lymphatic outflow insufficiency. Tissue samples were collected from 15 patients who underwent free muscle flap transfer, with PBASP samples obtained 7\u201314 days post-surgery. Histological, immunofluorescence, molecular, and protein analyses were performed to assess lymphangiogenesis, inflammation, extracellular matrix remodeling, and adipogenesis. PBASP tissue exhibited epidermal thickening, dermal expansion, subcutaneous matrix loosening, and leukocyte infiltration. Immunofluorescence showed a 3.6-fold increase in LYVE-1\u2009+\u2009lymphatic vessel cross-sectional area. Gene expression analysis revealed upregulation of markers like VEGF-C, VEGFR3, IL-6, and MMP-9. ELISA demonstrated increased LYVE-1, IL-6, and COL1A1 protein levels. Together, PBASP tissues showed structural, lymphatic-marker, inflammatory, and early remodeling changes consistent with early localized lymphatic outflow insufficiency. Together, these findings support the PBASP-derived approach as a paired human tissue platform for studying early, localized lymphatic insufficiency and for generating mechanistic hypotheses relevant to secondary lymphedema.<\/jats:p>","DOI":"10.1038\/s41598-026-64775-3","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T20:26:05Z","timestamp":1785961565000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A perforator-based adipocutaneous skin paddle derived from free muscle flap reconstruction as a hypothesis-generating human tissue model of early localized lymphatic insufficiency"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1861-5233","authenticated-orcid":false,"given":"Katja K.","family":"Koll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin M.","family":"Zimmermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Schulte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana C.","family":"Panayi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Hundeshagen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich","family":"Kneser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hirche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"64775_CR1","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1007\/s00520-005-0810-y","volume":"13","author":"SH Ridner","year":"2005","unstructured":"Ridner, S. 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