{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:05:15Z","timestamp":1785420315470,"version":"3.56.0"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 113-2221-E-008-011-MY3"],"award-info":[{"award-number":["NSTC 113-2221-E-008-011-MY3"]}]},{"award":["NSTC 113-2221-E-008-011-MY3"],"award-info":[{"award-number":["NSTC 113-2221-E-008-011-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Gels"],"abstract":"<jats:p>Deep wounds often lead to severe complications such as persistent infection, biofilm formation, and high patient morbidity. While skin injuries can usually be managed with functional dressings, wounds in deep layers without sufficient treatment may serve as primary entry points for bacterial infection, thereby posing a significant life-threatening risk to patients. With the rising prevalence of chronic diseases and an aging population, effective strategies for enhanced wound healing are still in high demand. In this study, an injectable and thermoresponsive hexamethylene diisocyanate\u2013Pluronic F127 copolymer\u2013hyaluronic acid composite hydrogel loaded with polyhexamethylene biguanide (PHMB) and epidermal growth factor (EGF), named PEHHPG, was developed for joint therapy of deep wounds. PEHHPG self-gels at 37 \u00b0C and stabilizes both agents in the gel matrix. Based on the results of microbial colony assay and analysis of fibroblast growth kinetics, PEHHPG with \u2265200 ppm of PHMB and \u22650.15 \u03bcg\/mL of EGF can eradicate bacteria and enhance cell proliferation in vitro, illustrating the functionalities of PEHHPG. Given the aforementioned effects, together with the recognized advantages of injectable hydrogels such as wound shape\/depth adaptation, low adhesiveness, exudate absorptiveness, and moisture maintenance, the developed PEHHPG is anticipated to be a feasible dressing material for deep wound treatment after further in vivo examinations.<\/jats:p>","DOI":"10.3390\/gels12060539","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T00:49:01Z","timestamp":1781570941000},"page":"539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Development of Antiseptic and Epidermal Growth Factor Co-Loaded Thermoresponsive Composite Hydrogel for Wound Healing: Fabrication, Characterization, and In Vitro Functional Assessment"],"prefix":"10.3390","volume":"12","author":[{"given":"Ting-Jui","family":"Wang","sequence":"first","affiliation":[{"name":"Interdisciplinary Program of Engineering, National Central University, Taoyuan City 320317, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chieh-An","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City 320317, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1895-5385","authenticated-orcid":false,"given":"Yu-Hsiang","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City 320317, Taiwan"},{"name":"Department of Chemical and Materials Engineering, National Central University, Taoyuan City 320317, Taiwan"},{"name":"Department of Medical Research, Cathay General Hospital, Taipei City 10630, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1089\/wound.2015.0635","article-title":"Challenges in the Treatment of Chronic Wounds","volume":"4","author":"Frykberg","year":"2015","journal-title":"Adv. Wound Care"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Shen, A.Z., Taha, M., Ghannoum, M., and Tyring, S.K. (2025). Biofilms and Chronic Wounds: Pathogenesis and Treatment Options. J. Clin. Med., 14.","DOI":"10.3390\/jcm14217784"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/bjd.21612","article-title":"Challenges in the diagnosis and management of wound infection","volume":"187","author":"Malone","year":"2022","journal-title":"Br. J. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1093\/ced\/llad410","article-title":"Wound healing, scarring and management","volume":"49","author":"Sangha","year":"2024","journal-title":"Clin. Exp. Dermatol."},{"key":"ref_5","first-page":"357","article-title":"Complicated and deep bacterial skin and soft tissue infections","volume":"23","author":"Prodinger","year":"2025","journal-title":"J. Dtsch. Dermatol. Ges."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1721727X221141822","DOI":"10.1177\/1721727X221141822","article-title":"Clinical analysis of diagnosis and treatment of necrotizing fasciitis","volume":"20","author":"Yu","year":"2022","journal-title":"Eur. J. Inflamm."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/iwj.13696","article-title":"Diagnosis and treatment of the invasive extension of bacteria (cellulitis) from chronic wounds utilising point-of-care fluorescence imaging","volume":"19","author":"Andersen","year":"2022","journal-title":"Int. Wound J."},{"key":"ref_8","first-page":"366","article-title":"Cellulitis: Current insights into pathophysiology and clinical management","volume":"75","author":"Cranendonk","year":"2017","journal-title":"Neth. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.suc.2020.05.007","article-title":"Bacteria and Antibiotics in Wound Healing","volume":"100","author":"Caldwell","year":"2020","journal-title":"Surg. Clin. N. Am."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1093\/cid\/cix233","article-title":"Implications of Antibiotic Resistance for Patients\u2019 Recovery from Common Infections in the Community: A Systematic Review and Meta-analysis","volume":"65","author":"Wang","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.nhtm.2017.08.001","article-title":"Pros, cons and future of antibiotics","volume":"4","author":"Weledji","year":"2017","journal-title":"New Horiz. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"122232","DOI":"10.1016\/j.lfs.2023.122232","article-title":"Functional hydrogel-based wound dressings: A review on biocompatibility and therapeutic efficacy","volume":"334","author":"Nasra","year":"2023","journal-title":"Life Sci."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Pintilei, P.S., Binaymotlagh, R., Chronopoulou, L., and Palocci, C. (2025). The Role of Natural Hydrogels in Enhancing Wound Healing: From Biomaterials to Bioactive Therapies. Pharmaceutics, 17.","DOI":"10.3390\/pharmaceutics17101243"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1208\/s12249-019-1328-9","article-title":"pH\/Thermo-Dual Responsive Tunable In Situ Cross-Linkable Depot Injectable Hydrogels Based on Poly(NIsopropylacrylamide)\/Carboxymethyl Chitosan with Potential of Controlled Localized and Systemic Drug Delivery","volume":"20","author":"Khan","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s40820-020-00585-0","article-title":"Injectable Self-Healing Adhesive pH-Responsive Hydrogels Accelerate Gastric Hemostasis and Wound Healing","volume":"13","author":"He","year":"2021","journal-title":"Nano-Micro Lett."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Cid, P., Jim\u00e9nez-Rosado, M., Romero, A., and P\u00e9rez-Puyana, V. (2022). Novel Trends in Hydrogel Development for Biomedical Applications: A Review. Polymers, 14.","DOI":"10.3390\/polym14153023"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"103390","DOI":"10.1016\/j.jddst.2022.103390","article-title":"Recent advances in drug delivery nanocarriers incorporated in temperature-sensitive Pluronic F-127\u2013A critical review","volume":"72","author":"Oluwafemi","year":"2022","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1089\/ten.teb.2021.0026","article-title":"Triblock Copolymer Bioinks in Hydrogel Three-Dimensional Printing for Regenerative Medicine: A Focus on Pluronic F127","volume":"28","author":"Shamma","year":"2022","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.msec.2016.06.091","article-title":"A cell-compatible PEO-PPO-PEO (Pluronic\u00ae)-based hydrogel stabilized through secondary structures","volume":"69","author":"Peng","year":"2016","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/nbt0206-163","article-title":"Designer combination therapy for cancer","volume":"24","author":"Lane","year":"2006","journal-title":"Nat. Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1159\/000318237","article-title":"Polihexanide: A safe and highly effective biocide","volume":"23","author":"Kaehn","year":"2010","journal-title":"Skin Pharmacol. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5","DOI":"10.12968\/jowc.2023.32.1.5","article-title":"Polyhexamethylene biguanide and its antimicrobial role in wound healing: A narrative review","volume":"32","author":"Rippon","year":"2023","journal-title":"J. Wound Care"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1111\/j.1468-3083.2011.04415.x","article-title":"Cytokines, chemokines and growth factors in wound healing","volume":"26","author":"Behm","year":"2012","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s12272-023-01444-3","article-title":"EGF, a veteran of wound healing: Highlights on its mode of action, clinical applications with focus on wound treatment, and recent drug delivery strategies","volume":"46","author":"Shakhakarmi","year":"2023","journal-title":"Arch. Pharm. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gallorini, M., Antonetti Lamorgese Passeri, C., Cataldi, A., Berardi, A.C., and Osti, L. (2022). Hyaluronic Acid Alleviates Oxidative Stress and Apoptosis in Human Tenocytes via Caspase 3 and 7. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158817"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1016\/j.ijbiomac.2020.10.154","article-title":"Hyaluronic acid injection reduces inflammatory and apoptotic markers through modulation of AKT by repressing the oxidative status of neutrophils from osteoarthritic synovial fluid","volume":"165","author":"Wang","year":"2020","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Chyli\u0144ska, N., and Maciejczyk, M. (2025). Hyaluronic Acid and Skin: Its Role in Aging and Wound-Healing Processes. Gels, 11.","DOI":"10.3390\/gels11040281"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1007\/s12026-014-8495-2","article-title":"Tissue integrity signals communicated by high-molecular weight hyaluronan and the resolution of inflammation","volume":"58","author":"Ruppert","year":"2014","journal-title":"Immunol. Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Marinho, A., Nunes, C., and Reis, S. (2021). Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation. Biomolecules, 11.","DOI":"10.3390\/biom11101518"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Chrostek, L., and Cylwik, B. (2025). Hyaluronic Acid in Immune Response. Biomolecules, 15.","DOI":"10.3390\/biom15071008"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3721","DOI":"10.1021\/la400268p","article-title":"Injectable and thermoresponsive self-assembled nanocomposite hydrogel for long-term anticancer drug delivery","volume":"29","author":"Chen","year":"2013","journal-title":"Langmuir"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Russo, E., and Villa, C. (2019). Poloxamer Hydrogels for Biomedical Applications. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11120671"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2400341","DOI":"10.1002\/mame.202400341","article-title":"Temperature Sensitive Pluronic F127-Based Gels Incorporating Natural Therapeutic Agents","volume":"310","author":"Lupu","year":"2025","journal-title":"Macromol. Mater. Eng."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Thang, N.H., Chien, T.B., and Cuong, D.X. (2023). Polymer-Based Hydrogels Applied in Drug Delivery: An Overview. Gels, 9.","DOI":"10.3390\/gels9070523"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5608","DOI":"10.1021\/acsabm.2c00647","article-title":"Hyaluronic Acid-Based Antibacterial Hydrogels for Use as Wound Dressings","volume":"5","author":"Watson","year":"2022","journal-title":"ACS Appl. Bio. Mater."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"928","DOI":"10.3390\/polym3020928","article-title":"Physical and Chemical Characterization of Poly(hexamethylene biguanide) Hydrochloride","volume":"3","author":"Netto","year":"2011","journal-title":"Polymers"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4125","DOI":"10.1021\/acsomega.9b03852","article-title":"Hyaluronic Acid-Cellulose Composites as Patches for Minimizing Bacterial Infections","volume":"5","author":"Lopez","year":"2020","journal-title":"ACS Omega"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Nguyen, D.T., Dinh, V.T., Dang, L.H., Nguyen, D.N., Giang, B.L., Nguyen, C.T., Nguyen, T.B.T., Thu, L.V., and Tran, N.Q. (2019). Dual Interactions of Amphiphilic Gelatin Copolymer and Nanocurcumin Improving the Delivery Efficiency of the Nanogels. Polymers, 11.","DOI":"10.3390\/polym11050814"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/S0168-3659(01)00557-0","article-title":"Temperature-responsive and degradable hyaluronic acid\/Pluronic composite hydrogels for controlled release of human growth hormone","volume":"80","author":"Kim","year":"2002","journal-title":"J. Control. Release"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9351","DOI":"10.1039\/D5TB00588D","article-title":"Thermoresponsive polymers for cell support: Poloxamers as a case study of promise and challenge","volume":"13","author":"Clerkin","year":"2025","journal-title":"J. Mater. Chem. B"},{"key":"ref_41","first-page":"298","article-title":"A bioactive composite hydrogel dressing that promotes healing of both acute and chronic diabetic skin wounds","volume":"34","author":"Shang","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12951-025-03274-5","article-title":"Multifunctional hydrogel targeting senescence to accelerate diabetic wound healing through promoting angiogenesis","volume":"23","author":"Yang","year":"2025","journal-title":"J. Nanobiotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Jin, S., Newton, M.A.A., Cheng, H., Zhang, Q., Gao, W., Zheng, Y., Lu, Z., Dai, Z., and Zhu, J. (2023). Progress of Hydrogel Dressings with Wound Monitoring and Treatment Functions. Gels, 9.","DOI":"10.3390\/gels9090694"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ribeiro, M., Sim\u00f5es, M., Vitorino, C., and Mascarenhas-Melo, F. (2024). Hydrogels in Cutaneous Wound Healing: Insights into Characterization, Properties, Formulation and Therapeutic Potential. Gels, 10.","DOI":"10.3390\/gels10030188"},{"key":"ref_45","first-page":"100288","article-title":"Effect of wound dressing porosity and exudate viscosity on the exudate absorption: In vitro and in silico tests with 3D printed hydrogels","volume":"8","author":"Concheiro","year":"2024","journal-title":"Int. J. Pharm. X"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hsiao, K.H., Huang, C.M., and Lee, Y.H. (2020). Novel Rifampicin and Indocyanine Green Co-Loaded Perfluorocarbon Nanodroplets Provide Effective In Vivo Photo-Chemo-Probiotic Antimicrobility against Pathogen of Acne Vulgaris Cutibacterium acnes. Nanomaterials, 10.","DOI":"10.3390\/nano10061095"}],"container-title":["Gels"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/6\/539\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:31:44Z","timestamp":1781843504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2310-2861\/12\/6\/539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,15]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["gels12060539"],"URL":"https:\/\/doi.org\/10.3390\/gels12060539","relation":{},"ISSN":["2310-2861"],"issn-type":[{"value":"2310-2861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,15]]}}}