{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T15:07:12Z","timestamp":1793718432681,"version":"4.6.1"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T00:00:00Z","timestamp":1729209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2024-00338179"],"award-info":[{"award-number":["RS-2024-00338179"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2023R1A2C1004544"],"award-info":[{"award-number":["NRF-2023R1A2C1004544"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005006","name":"Asan Institute for Life Sciences, Asan Medical Center","doi-asserted-by":"publisher","award":["2021IL0037"],"award-info":[{"award-number":["2021IL0037"]}],"id":[{"id":"10.13039\/501100005006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-024-74414-4","type":"journal-article","created":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T01:02:11Z","timestamp":1729213331000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Improved lymphangiogenesis around vascularized lymph node flaps by periodic injection of hyaluronidase in a rodent model"],"prefix":"10.1038","volume":"14","author":[{"given":"Hwayeong","family":"Cheon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linhai","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang Ah","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma. Nessa","family":"Gelvosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon Pio","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Yong","family":"Jeon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunsuk Peter","family":"Suh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,18]]},"reference":[{"key":"74414_CR1","doi-asserted-by":"crossref","unstructured":"Schulze, H., Nacke, M., Gutenbrunner, C. & Hadamitzky, C. Worldwide assessment of healthcare personnel dealing with lymphoedema. Health Econ. Rev. 8, 10 (2018).","DOI":"10.1186\/s13561-018-0194-6"},{"key":"74414_CR2","doi-asserted-by":"crossref","unstructured":"Cormier J. N. et al. Lymphedema beyond breast cancer. Cancer 116(22), 5138-5149 (2010).","DOI":"10.1002\/cncr.25458"},{"key":"74414_CR3","doi-asserted-by":"crossref","unstructured":"Warren, A. G., Brorson, H., Borud, L. J. & Slavin, S. A. Lymphedema: A comprehensive review. Ann. Plast. Surg. 59(4), 464\u2013472 (2007).","DOI":"10.1097\/01.sap.0000257149.42922.7e"},{"key":"74414_CR4","doi-asserted-by":"crossref","unstructured":"Greene, A. K., Grant, F. D., Slavin, S. A. & Maclellan, R. A. Obesity-induced lymphedema: Clinical and lymphoscintigraphic features. Plast. Reconstr. Surg. 135(6), 1715\u20131719 (2015).","DOI":"10.1097\/PRS.0000000000001271"},{"key":"74414_CR5","doi-asserted-by":"crossref","unstructured":"Do, J. H., Choi, K. H., Ahn, J. S. & Jeon, J. Y. Effects of a complex rehabilitation program on edema status, physical function, and quality of life in lower-limb lymphedema after gynecological cancer surgery. Gynecol. Oncol. 147(2), 450\u2013455 (2017).","DOI":"10.1016\/j.ygyno.2017.09.003"},{"key":"74414_CR6","doi-asserted-by":"crossref","unstructured":"Pereira, N. et al. Cumulative experience in lymphovenous anastomosis for lymphedema treatment: The learning curve effect on the overall outcome. J. Reconstr. Microsurg. 34(9), 735\u2013741 (2018).","DOI":"10.1055\/s-0038-1648220"},{"key":"74414_CR7","doi-asserted-by":"crossref","unstructured":"Rockson, S. G. Lymphedema. Am. J. Med. 110, 288\u2013295 (2001).","DOI":"10.1016\/S0002-9343(00)00727-0"},{"key":"74414_CR8","doi-asserted-by":"crossref","unstructured":"Ciudad, P. et al. Surgical management of lower extremity lymphedema: A comprehensive review. Indian J. Plast. Surg. 52, 81\u201392 (2019).","DOI":"10.1055\/s-0039-1688537"},{"key":"74414_CR9","doi-asserted-by":"crossref","unstructured":"Rosian, K. & Stanak, M. Efficacy and safety assessment of lymphovenous anastomosis in patients with primary and secondary lymphoedema: A systematic review of prospective evidence. Microsurgery 39(8), 763\u2013772 (2019).","DOI":"10.1002\/micr.30514"},{"key":"74414_CR10","doi-asserted-by":"crossref","unstructured":"Moore, H. C. F. Breast cancer survivorship. Semin. Oncol. 47(4), 222\u2013228 (2020).","DOI":"10.1053\/j.seminoncol.2020.05.004"},{"key":"74414_CR11","doi-asserted-by":"crossref","unstructured":"Cheville, A. et al. The impact of arm lymphedema on healthcare utilization during long-term breast cancer survivorship: A population-based cohort study. J. Cancer Surviv. 14(3), 347\u2013355 (2020).","DOI":"10.1007\/s11764-019-00851-0"},{"key":"74414_CR12","doi-asserted-by":"crossref","unstructured":"Dayan, J. H., Ly, C. L., Kataru, R. P. & Mehrara, B. J. Lymphedema: Pathogenesis and novel therapies. Annu. Rev. Med. 69, 263\u2013276 (2018).","DOI":"10.1146\/annurev-med-060116-022900"},{"key":"74414_CR13","doi-asserted-by":"crossref","unstructured":"Jiang, X., Nicolls, M. R., Tian, W. & Rockson, S. G. Lymphatic dysfunction, leukotrienes, and lymphedema. Annu. Rev. Physiol. 80, 49\u201370 (2018).","DOI":"10.1146\/annurev-physiol-022516-034008"},{"key":"74414_CR14","doi-asserted-by":"crossref","unstructured":"Scaglioni, M. F., Fontein, D. B. Y., Arvanitakis, M. & Giovanoli, P. Systematic review of lymphovenous anastomosis (LVA) for the treatment of lymphedema. Microsurgery 37(8), 947\u2013953 (2017).","DOI":"10.1002\/micr.30246"},{"key":"74414_CR15","doi-asserted-by":"crossref","unstructured":"Gallagher, K., Marulanda, K. & Gray, S. Surgical intervention for lymphedema. Surg. Oncol. Clin. N. Am. 27, 195\u2013215  (2018).","DOI":"10.1016\/j.soc.2017.08.001"},{"key":"74414_CR16","doi-asserted-by":"crossref","unstructured":"Allen, R. J. Jr. & Cheng, M. H. Lymphedema surgery: Patient selection and an overview of surgical techniques. J. Surg. Oncol. 113(8), 923\u2013931 (2016).","DOI":"10.1002\/jso.24170"},{"key":"74414_CR17","doi-asserted-by":"crossref","unstructured":"Kung, T. A., Champaneria, M. C., Maki, J. H. & Neligan, P. C. Current concepts in the surgical management of lymphedema. Plast. Reconstr. Surg. 139(4), 1003e\u20131013e (2017).","DOI":"10.1097\/PRS.0000000000003218"},{"key":"74414_CR18","doi-asserted-by":"crossref","unstructured":"Schaverien, M. V. & Coroneos, C. J. Surgical treatment of lymphedema. Plast. Reconstr. Surg. 144(3), 738\u2013758 (2019).","DOI":"10.1097\/PRS.0000000000005993"},{"key":"74414_CR19","doi-asserted-by":"crossref","unstructured":"Ito, R., Zelken, J., Yang, C.-Y., Lin, C.-Y. & Cheng, M.-H. Proposed pathway and mechanism of vascularized lymph node flaps. Gynecol. Oncol. 141, 182\u2013188 (2016).","DOI":"10.1016\/j.ygyno.2016.01.007"},{"key":"74414_CR20","doi-asserted-by":"crossref","unstructured":"Pappalardo, M., Patel, K. & Cheng, M.-H. Vascularized lymph node transfer for treatment of extremity lymphedema: An overview of current controversies regarding donor sites, recipient sites and outcomes. J. Surg. Oncol. 117(7), 1420\u20131431 (2018).","DOI":"10.1002\/jso.25034"},{"key":"74414_CR21","doi-asserted-by":"crossref","unstructured":"Alderfer, L., Wei, A. & Hanjaya-Putra, D. Lymphatic tissue engineering and regeneration. J. Biol. Eng. 12, 32 (2018).","DOI":"10.1186\/s13036-018-0122-7"},{"key":"74414_CR22","doi-asserted-by":"crossref","unstructured":"Mishra, V. K. et al. Identifying the therapeutic significance of mesenchymal stem cells. Cells 9(5), 1145 (2020).","DOI":"10.3390\/cells9051145"},{"key":"74414_CR23","doi-asserted-by":"crossref","unstructured":"Asaad, M. & Hanson, S. E. Tissue engineering strategies for cancer-related lymphedema. Tissue Eng. Part A27(7-8), 489\u2013499 (2021).","DOI":"10.1089\/ten.tea.2020.0378"},{"key":"74414_CR24","doi-asserted-by":"crossref","unstructured":"Tourani, S. S., Taylor, G. I. & Ashton, M. W. Vascularized lymph node transfer: A review of the current evidence. Plast. Reconstr. Surg. 137(3), 985\u2013993 (2016).","DOI":"10.1097\/01.prs.0000475827.94283.56"},{"key":"74414_CR25","unstructured":"Liu, N. F. & Zhang, L. R. Changes of tissue fluid hyaluronan (hyaluronic acid) in peripheral lymphedema. Lymphology 31(4), 173\u2013179 (1998)."},{"key":"74414_CR26","doi-asserted-by":"crossref","unstructured":"Roberts, M. A., Mendez, U., Gilbert, R. J., Keim, A. P. & Goldman, J. Increased hyaluronan expression at distinct time points in acute lymphedema. Lymphat. Res. Biol. 10(3), 122\u2013128 (2012).","DOI":"10.1089\/lrb.2012.0001"},{"key":"74414_CR27","unstructured":"Jeong, H. J. et al. Hyaluronidase treatment of acute lymphedema in a mouse tail model. Lymphology 46(4), 160\u2013172 (2013)."},{"key":"74414_CR28","doi-asserted-by":"crossref","unstructured":"Nekoroski, T., Paladini, R. D., Sauder, D. N., Frost, G. I. & Keller, G. A. A recombinant human hyaluronidase sustained release gel for the treatment of post-surgical edema. Int. J. Dermatol. 53(6), 777\u2013785 (2014).","DOI":"10.1111\/ijd.12304"},{"key":"74414_CR29","doi-asserted-by":"crossref","unstructured":"Roh, K. et al. Therapeutic effects of hyaluronidase on acquired lymphedema using a newly developed mouse limb model. Exp. Biol. Med. 242(6), 584\u2013592 (2017).","DOI":"10.1177\/1535370216688570"},{"key":"74414_CR30","doi-asserted-by":"crossref","unstructured":"Cho, S. et al. Hydrolysis of hyaluronic acid in lymphedematous tissue alleviates fibrogenesis via TH1 cell-mediated cytokine expression. Sci. Rep. 7, 35 (2017).","DOI":"10.1038\/s41598-017-00085-z"},{"key":"74414_CR31","doi-asserted-by":"crossref","unstructured":"Hu, L.-R. & Pan, J. Adipose-derived stem cell therapy shows promising results for secondary lymphedema. World J. Stem Cells 12(7), 612\u2013620 (2020).","DOI":"10.4252\/wjsc.v12.i7.612"},{"key":"74414_CR32","doi-asserted-by":"crossref","unstructured":"Albeiroti, S., Soroosh, A. & de la Motte, C. A. Hyaluronan\u2019s role in fibrosis: A pathogenic factor or a passive player? Biomed Res. Int. 2015, 1\u201310 (2015).","DOI":"10.1155\/2015\/790203"},{"key":"74414_CR33","doi-asserted-by":"crossref","unstructured":"Jung, H. Hyaluronidase: An overview of its properties, applications, and side effects. Arch. Plast. Surg. 47(4), 297\u2013300 (2020).","DOI":"10.5999\/aps.2020.00752"},{"key":"74414_CR34","doi-asserted-by":"crossref","unstructured":"Pastouret, F. et al. Anatomical effects of axillary nodes dissection on rat lymphatic system model: Indocyanine green mapping and dissection. Lymphat. Res. Biol. 14(3), 134\u2013141 (2016).","DOI":"10.1089\/lrb.2015.0031"},{"key":"74414_CR35","doi-asserted-by":"crossref","unstructured":"Chang, D. W., Suami, H. & Skoracki, R. A prospective analysis of 100 consecutive lymphovenous bypass cases for treatment of extremity lymphedema. Plast. Reconstr. Surg. 132(5), 1305\u20131314 (2013).","DOI":"10.1097\/PRS.0b013e3182a4d626"},{"key":"74414_CR36","doi-asserted-by":"crossref","unstructured":"Tammela, T. et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat. Med. 13(12), 1458\u20131466 (2007).","DOI":"10.1038\/nm1689"},{"key":"74414_CR37","doi-asserted-by":"crossref","unstructured":"Honkonen, K. M. et al. Lymph node transfer and perinodal lymphatic growth factor treatment for lymphedema. Ann. Surg. 257(5), 961\u2013967 (2013).","DOI":"10.1097\/SLA.0b013e31826ed043"},{"key":"74414_CR38","doi-asserted-by":"crossref","unstructured":"Visuri, M. T. et al. VEGF-C and VEGF-C156S in the pro-lymphangiogenic growth factor therapy of lymphedema: a large animal study. Angiogenesis 18(3), 313\u2013326 (2015).","DOI":"10.1007\/s10456-015-9469-2"},{"key":"74414_CR39","doi-asserted-by":"crossref","unstructured":"L\u00e4hteenvuo, M. et al. Growth factor therapy and autologous lymph node transfer in lymphedema. Circulation 123(6), 613\u2013620 (2011).","DOI":"10.1161\/CIRCULATIONAHA.110.965384"},{"key":"74414_CR40","doi-asserted-by":"crossref","unstructured":"Jonas, F. et al. The effect of vascular endothelial growth factor C and adipose-derived stem cells on lymphatic regeneration in a rat vascularized lymph node transfer model. J. Reconstr. Microsurg. 39(4), 311\u2013319 (2022).","DOI":"10.1055\/a-1896-5471"},{"key":"74414_CR41","doi-asserted-by":"crossref","unstructured":"Verheul, H. M. W. & Pinedo, H. M. The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGFReceptor kinase inhibitors. Clin. Breast Cancer 1, S80\u2013S84 (2000).","DOI":"10.3816\/CBC.2000.s.015"},{"key":"74414_CR42","doi-asserted-by":"crossref","unstructured":"Roskoski, R. Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit. Rev. Oncol. Hematol. 62(3), 179\u2013213 (2007).","DOI":"10.1016\/j.critrevonc.2007.01.006"},{"key":"74414_CR43","doi-asserted-by":"crossref","unstructured":"Wang, C.-A., Harrell, J. C., Iwanaga, R., Jedlicka, P. & Ford, H. L. Vascular endothelial growth factor C promotes breast cancer progression via a novel antioxidant mechanism that involves regulation of superoxide dismutase 3. Breast Cancer Res. 16(5), 462 (2014).","DOI":"10.1186\/s13058-014-0462-2"},{"key":"74414_CR44","doi-asserted-by":"crossref","unstructured":"Decio, A. et al. Vascular endothelial growth factor C promotes ovarian carcinoma progression through paracrine and autocrine mechanisms. Am. J. Pathol. 184(4), 1050\u20131061 (2014).","DOI":"10.1016\/j.ajpath.2013.12.030"},{"key":"74414_CR45","doi-asserted-by":"crossref","unstructured":"Dalaei, F. et al. Short term treatment of secondary lymphedema with hyaluronidase injections reduces mouse hindlimb lymphedema. J. Plast. Surg. Hand Surg. 58, 40\u201347 (2023).","DOI":"10.2340\/jphs.v58.7791"},{"key":"74414_CR46","doi-asserted-by":"crossref","unstructured":"Schaverien, M. V., Badash, I., Patel, K. M., Selber, J. C. & Cheng, M. H. Vascularized Lymph Node Transfer for Lymphedema. Semin. Plast. Surg. 32(1), 28-35 (2018).","DOI":"10.1055\/s-0038-1632401"},{"key":"74414_CR47","doi-asserted-by":"crossref","unstructured":"Gould, D. J., Mehrara, B. J., Neligan, P., Cheng, M. & Patel, K. M. Lymph node transplantation for the treatment of lymphedema. J. Surg. Oncol. 118(5), 736\u2013742 (2018).","DOI":"10.1002\/jso.25180"},{"key":"74414_CR48","doi-asserted-by":"crossref","unstructured":"Liu, H.-L. et al. Orthotopic transfer of vascularized groin lymph node flap in the treatment of breast cancer-related lymphedema: Clinical results, lymphoscintigraphy findings, and proposed mechanism. J. Plast. Reconstr. Aesthetic Surg. 71(7), 1033\u20131040 (2018).","DOI":"10.1016\/j.bjps.2018.02.015"},{"key":"74414_CR49","doi-asserted-by":"crossref","unstructured":"Maeda, T. et al. Lymphatic reconnection and restoration of lymphatic flow by nonvascularized lymph node transplantation: Real-time fluorescence imaging using indocyanine green and fluorescein isothiocyanate-dextran. Lymphat. Res. Biol. 16(2), 165\u2013173 (2018).","DOI":"10.1089\/lrb.2016.0070"},{"key":"74414_CR50","doi-asserted-by":"crossref","unstructured":"Ishikawa, K. et al. Feasibility of pedicled vascularized inguinal lymph node transfer in a mouse model: A preliminary study. Microsurgery 39(3), 247\u2013254 (2019).","DOI":"10.1002\/micr.30394"},{"key":"74414_CR51","doi-asserted-by":"crossref","unstructured":"Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: The ARRIVE guidelines for reporting animal research. PLoS Biol. 8(6), e1000412 (2010).","DOI":"10.1371\/journal.pbio.1000412"},{"key":"74414_CR52","doi-asserted-by":"crossref","unstructured":"Kwiecien, G. J. et al. Vascularized axillary lymph node transfer: A novel model in the rat. Microsurgery 35(8), 662\u2013667 (2015).","DOI":"10.1002\/micr.22472"},{"key":"74414_CR53","doi-asserted-by":"crossref","unstructured":"Cheon, H., Gelvosa, M. N., Kim, S. A., Song, H. & Jeon, J. Y. Lymphatic channel sheet of polydimethylsiloxane for preventing secondary lymphedema in the rat upper limb model. Bioeng. Transl.  Med. 8(1), e10371 (2023).","DOI":"10.1002\/btm2.10371"},{"key":"74414_CR54","doi-asserted-by":"crossref","unstructured":"Cheon, H. et al. In vivo dynamic and static analysis of lymphatic dysfunction in lymphedema using near-infrared fluorescence indocyanine green lymphangiography. Arterioscler. Thromb. Vasc. Biol. 43(10), 2008\u20132022 (2023).","DOI":"10.1161\/ATVBAHA.123.319188"},{"key":"74414_CR55","doi-asserted-by":"crossref","unstructured":"Cheon, H., Kim, S. A., Kim, B. & Jeon, J. Y. Investigation of optimizing indocyanine green solution for in vivo lymphatic research using near-infrared fluorescence indocyanine green lymphangiography. Sci. Rep. 13, 14966 (2023).","DOI":"10.1038\/s41598-023-40826-x"},{"key":"74414_CR56","doi-asserted-by":"crossref","unstructured":"Yamamoto, T. et al. Characteristic indocyanine green lymphography findings in lower extremity lymphedema: The generation of a novel lymphedema severity staging system using dermal backflow patterns. Plast. Reconstr. Surg. 127(5), 1979\u20131986 (2011).","DOI":"10.1097\/PRS.0b013e31820cf5df"},{"key":"74414_CR57","unstructured":"Chowdhry, M., Rozen, W. M. & Griffiths, M. Lymphatic mapping and preoperative imaging in the management of post-mastectomy lymphoedema. Gland Surg. 5(2), 187\u2013196 (2016)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-74414-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-74414-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-74414-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,18]],"date-time":"2024-10-18T01:03:34Z","timestamp":1729213414000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-74414-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,18]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["74414"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-74414-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.04.18.586511","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,18]]},"assertion":[{"value":"8 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 October 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"24430"}}