{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:18:00Z","timestamp":1791847080482,"version":"4.3.4"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T00:00:00Z","timestamp":1535673600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The neuropeptide substance P (SP) is known to stimulate wound healing by regulating the production of relevant cytokines as well as cell proliferation and migration. However, the therapeutic application of SP is limited by its low stability under biological conditions and oxidation during purification, formulation, and storage. To address this problem, we developed a novel formulation of SP as an SP gel, and investigated its wound healing activity both in vitro and in vivo. SP in SP gel was stable at various temperatures for up to 4 weeks. In vitro, SP gel exhibited more potential as a candidate wound-healing agent than SP alone, as evidenced by the observed increases in the proliferation and migration of human epidermal keratinocytes and human dermal fibroblasts. In vivo experiments showed that SP gel treatment enhanced the healing of full-thickness wounds in mice as compared to SP alone. These results demonstrate the benefits of SP gel as a promising topical agent for wound treatment.<\/jats:p>","DOI":"10.3390\/molecules23092215","type":"journal-article","created":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T10:57:52Z","timestamp":1535713072000},"page":"2215","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Novel Substance P-Based Hydrogel for Increased Wound Healing Efficiency"],"prefix":"10.3390","volume":"23","author":[{"given":"Da Jung","family":"Kim","sequence":"first","affiliation":[{"name":"Research and Development Institute, Biosolution, Seoul Technopark, 232 Gongneung-ro, Nowon-gu, Seoul 01811, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Hae","family":"Jang","sequence":"additional","affiliation":[{"name":"Research and Development Institute, Biosolution, Seoul Technopark, 232 Gongneung-ro, Nowon-gu, Seoul 01811, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song Sun","family":"Jang","sequence":"additional","affiliation":[{"name":"Research and Development Institute, Biosolution, Seoul Technopark, 232 Gongneung-ro, Nowon-gu, Seoul 01811, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jungsun","family":"Lee","sequence":"additional","affiliation":[{"name":"Research and Development Institute, Biosolution, Seoul Technopark, 232 Gongneung-ro, Nowon-gu, Seoul 01811, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.4037\/15597768-1990-3010","article-title":"Physiology of wound healing and risk factors that impede the healing process","volume":"1","author":"Norris","year":"1990","journal-title":"AACN Clin. Issues Crit. Care Nurs."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1056\/NEJM199909023411006","article-title":"Cutaneous wound healing","volume":"341","author":"Singer","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Park, S.A., Raghunathan, V.K., Shah, N.M., Teixeira, L., Motta, M.J., Covert, J., Dubielzig, R., Schurr, M., Isseroff, R.R., and Abbott, N.L. (2014). PDGF-BB does not accelerate healing in diabetic mice with splinted skin wounds. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104447"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature07039","article-title":"Wound repair and regeneration","volume":"453","author":"Gurtner","year":"2008","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.msec.2014.12.068","article-title":"Current wound healing procedures and potential care","volume":"48","author":"Dreifke","year":"2015","journal-title":"Mater. Sci. Eng. C Mater. Boil. Appl."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/wrr.12413","article-title":"Substance P promotes diabetic wound healing by modulating inflammation and restoring cellular activity of mesenchymal stem cells","volume":"24","author":"Park","year":"2016","journal-title":"Wound Repair Regen."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.cyto.2014.12.015","article-title":"Topical application of substance P promotes wound healing in streptozotocin-induced diabetic rats","volume":"73","author":"Kant","year":"2015","journal-title":"Cytokine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.ejphar.2013.04.042","article-title":"Topically applied substance P enhanced healing of open excision wound in rats","volume":"715","author":"Kant","year":"2013","journal-title":"Eur. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/00004630-199609000-00004","article-title":"Substance P has a role in neurogenic mediation of human burn wound healing","volume":"17","author":"Dunnick","year":"1996","journal-title":"J. Burn Care Rehabil."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/0304-3940(95)12062-9","article-title":"Substance P and nitric oxide mediate would healing of ultraviolet photodamaged rat skin: Evidence for an effect of nitric oxide on keratinocyte proliferation","volume":"200","author":"Benrath","year":"1995","journal-title":"Neurosci. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1177\/107110070502601008","article-title":"Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing","volume":"26","author":"Burssens","year":"2005","journal-title":"Foot Ankle Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1111\/j.1067-1927.2004.012110.x-1","article-title":"Nerve growth factor accelerates wound healing in diabetic mice","volume":"12","author":"Muangman","year":"2004","journal-title":"Wound Repair Regen."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0165-5728(96)00143-9","article-title":"Substance P promotes lymphocyte-endothelial cell adhesion preferentially via LFA-1\/ICAM-1 interactions","volume":"71","author":"Vishwanath","year":"1996","journal-title":"J. Neuroimmunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1017\/S1462399409000945","article-title":"Inflammation and neuropeptides: The connection in diabetic wound healing","volume":"11","author":"Pradhan","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4448","DOI":"10.1073\/pnas.1000803107","article-title":"IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin","volume":"107","author":"Theoharides","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","first-page":"1865","article-title":"Degradation of kinins, angiotensins and substance P by polymorphonuclear matrix metalloproteinases MMP 8 and MMP 9","volume":"27","author":"Diekmann","year":"1994","journal-title":"Braz. J. Med. Boil. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1748-1716.1955.tb01249.x","article-title":"Inactivation of substance P by proteolytic enzymes","volume":"34","author":"Pernow","year":"1955","journal-title":"Acta Physiol. Scand."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/1475-2859-13-25","article-title":"Effect of metal catalyzed oxidation in recombinant viral protein assemblies","volume":"13","author":"Valderrama","year":"2014","journal-title":"Microb. Cell Fact."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1002\/jps.20726","article-title":"Evaluation of hydroperoxides in common pharmaceutical excipients","volume":"96","author":"Wasylaschuk","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/0003-2697(80)90220-1","article-title":"Substance P sulfoxide: Separation from substance P by high-pressure liquid chromatography, biological and immunological activities, and chemical reduction","volume":"101","author":"Floor","year":"1980","journal-title":"Anal. Biochem."},{"key":"ref_21","first-page":"804","article-title":"Polysorbate 80: A pharmacological study","volume":"35","author":"Varma","year":"1985","journal-title":"Arzneimittel-Forschung"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Li, L., Ben, Y., Yuan, S., Jiang, S., Xu, J., and Zhang, X. (2012). Efficacy, stability, and biosafety of sifuvirtide gel as a microbicide candidate against HIV-1. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037381"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1002\/psc.643","article-title":"The influence of cell growth media on the stability and antitumour activity of methionine enkephalin","volume":"11","author":"Jakas","year":"2005","journal-title":"J. Pept. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1016\/j.coph.2008.06.002","article-title":"Discovering and improving novel peptide therapeutics","volume":"8","author":"McGregor","year":"2008","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1021\/js970143s","article-title":"Antioxidants for prevention of methionine oxidation in recombinant monoclonal antibody HER2","volume":"86","author":"Lam","year":"1997","journal-title":"J. Pharm. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6008","DOI":"10.1038\/srep06008","article-title":"Serum stable natural peptides designed by mRNA display","volume":"4","author":"Howell","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36617","DOI":"10.1038\/srep36617","article-title":"PEPlife: A repository of the half-life of peptides","volume":"6","author":"Mathur","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1073\/pnas.0407677102","article-title":"Partial d-amino acid substitution: Improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide","volume":"102","author":"Tugyi","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1111\/j.1348-0421.2002.tb02759.x","article-title":"Antimicrobial activity and stability to proteolysis of small linear cationic peptides with d-amino acid substitutions","volume":"46","author":"Hamamoto","year":"2002","journal-title":"Microbiol. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1002\/bip.21057","article-title":"Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides","volume":"90","author":"Linde","year":"2008","journal-title":"Biopolymers"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2924","DOI":"10.1002\/jps.21190","article-title":"Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: Structure and degradation pathways","volume":"97","author":"Kerwin","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1208\/s12249-012-9878-0","article-title":"Effect of polysorbate 80 concentration on thermal and photostability of a monoclonal antibody","volume":"14","author":"Agarkhed","year":"2013","journal-title":"AAPS PharmSciTech"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1016\/j.addr.2011.06.015","article-title":"Molecular origins of surfactant-mediated stabilization of protein drugs","volume":"63","author":"Lee","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"50","DOI":"10.3109\/10837450.2013.862260","article-title":"Investigation of the stabilizing effects of hydroxyethyl cellulose on LDH during freeze drying and freeze thawing cycles","volume":"20","author":"Gieseler","year":"2015","journal-title":"Pharm. Dev. Technol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nprot.2013.002","article-title":"The mouse excisional wound splinting model, including applications for stem cell transplantation","volume":"8","author":"Wang","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1634\/stemcells.2007-0226","article-title":"Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis","volume":"25","author":"Wu","year":"2007","journal-title":"Stem Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"D227","DOI":"10.1093\/nar\/gkp971","article-title":"MEROPS: The peptidase database","volume":"38","author":"Rawlings","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1086\/655661","article-title":"Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor","volume":"202","author":"Veazey","year":"2010","journal-title":"J. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1007\/s00726-014-1804-1","article-title":"Efficacy of the designer antimicrobial peptide SHAP1 in wound healing and wound infection","volume":"46","author":"Kim","year":"2014","journal-title":"Amino Acids"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.biomaterials.2016.06.009","article-title":"Engineered human vascularized constructs accelerate diabetic wound healing","volume":"102","author":"Shen","year":"2016","journal-title":"Biomaterials"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/9\/2215\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:22:27Z","timestamp":1760196147000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/23\/9\/2215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,8,31]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["molecules23092215"],"URL":"https:\/\/doi.org\/10.3390\/molecules23092215","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,8,31]]}}}