{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:57:39Z","timestamp":1790423859474,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["NIH HL56728"],"award-info":[{"award-number":["NIH HL56728"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The most ubiquitous gap junction protein within the body, connexin 43 (Cx43), is a target of interest for modulating the dermal wound healing response. Observational studies found associations between Cx43 at the wound edge and poor healing response, and subsequent studies utilizing local knockdown of Cx43 found improvements in wound closure rate and final scar appearance. Further preclinical work conducted using Cx43-based peptide therapeutics, including alpha connexin carboxyl terminus 1 (\u03b1CT1), a peptide mimetic of the Cx43 carboxyl terminus, reported similar improvements in wound healing and scar formation. Clinical trials and further study into the mode of action have since been conducted on \u03b1CT1, and Phase III testing for treatment of diabetic foot ulcers is currently underway. Therapeutics targeting connexin activity show promise in beneficially modulating the human body\u2019s natural healing response for improved patient outcomes across a variety of injuries.<\/jats:p>","DOI":"10.3390\/ijms19061778","type":"journal-article","created":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T11:21:20Z","timestamp":1529061680000},"page":"1778","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Connexin 43-Based Therapeutics for Dermal Wound Healing"],"prefix":"10.3390","volume":"19","author":[{"given":"Jade","family":"Montgomery","sequence":"first","affiliation":[{"name":"Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA"},{"name":"School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, VA 24061, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam S.","family":"Ghatnekar","sequence":"additional","affiliation":[{"name":"FirstString Research, Inc., Mount Pleasant, SC 29464, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina L.","family":"Grek","sequence":"additional","affiliation":[{"name":"FirstString Research, Inc., Mount Pleasant, SC 29464, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurtis E.","family":"Moyer","sequence":"additional","affiliation":[{"name":"Department of Surgery, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA"},{"name":"Department of Surgery, Carilion Clinic, Roanoke, VA 24016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6021-0796","authenticated-orcid":false,"given":"Robert G.","family":"Gourdie","sequence":"additional","affiliation":[{"name":"Virginia Tech Carilion Research Institute, Roanoke, VA 24016, USA"},{"name":"School of Biomedical Engineering and Sciences, Virginia Tech-Wake Forest University, Blacksburg, VA 24061, USA"},{"name":"Department of Emergency Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA 24016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2018,6,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.cardiores.2003.11.013","article-title":"Gap junctions and the connexin protein family","volume":"62","author":"Sohl","year":"2004","journal-title":"Cardiovasc. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"486","DOI":"10.2174\/157016109789043937","article-title":"Dysfunctions of the diffusional membrane pathways mediated by hemichannels in inherited and acquired human diseases","volume":"7","author":"Schalper","year":"2009","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1096\/fj.00-0566fje","article-title":"Connexin 43 hemi channels mediate Ca2+-regulated transmembrane NAD+ fluxes in intact cells","volume":"15","author":"Bruzzone","year":"2001","journal-title":"FASEB J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"C1504","DOI":"10.1152\/ajpcell.00015.2010","article-title":"Connexin 43 hemichannels mediate the Ca2+ influx induced by extracellular alkalinization","volume":"299","author":"Schalper","year":"2010","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12250","DOI":"10.1074\/jbc.M111.299610","article-title":"Connexin 43 hemichannels contribute to cytoplasmic Ca2+ oscillations by providing a bimodal Ca2+-dependent Ca2+ entry pathway","volume":"287","author":"Wang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.tibtech.2007.12.007","article-title":"Novel therapies for scar reduction and regenerative healing of skin wounds","volume":"26","author":"Rhett","year":"2008","journal-title":"Trends Biotechnol."},{"key":"ref_7","first-page":"205","article-title":"Connexin43 carboxyl-terminal peptides reduce scar progenitor and promote regenerative healing following skin wounding","volume":"4","author":"Ghatnekar","year":"2009","journal-title":"Future Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.febslet.2014.02.048","article-title":"Connexins: Sensors of epidermal integrity that are therapeutic targets","volume":"588","author":"Martin","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1152\/physiol.00058.2012","article-title":"Gap junction remodeling in skin repair following wounding and disease","volume":"28","author":"Churko","year":"2013","journal-title":"Physiology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1196\/annals.1380.005","article-title":"The unstoppable connexin43 carboxyl-terminus: New roles in gap junction organization and wound healing","volume":"1080","author":"Gourdie","year":"2006","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nguyen, D.T., Orgill, D.P., and Murphy, G.F. (2009). Chapter 4: The Pathophysiologic Basis for Wound Healing and Cutaneous Regeneration. Biomaterials For Treating Skin Loss, CRC Press.","DOI":"10.1533\/9781845695545.1.25"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/360179a0","article-title":"Actin cables and epidermal movement in embryonic wound healing","volume":"360","author":"Martin","year":"1992","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/S0960-9822(03)00396-8","article-title":"Wound healing in the PU. 1 null mouse\u2014tissue repair is not dependent on inflammatory cells","volume":"13","author":"Martin","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/S0070-2153(08)60428-7","article-title":"Mechanisms of wound healing in the embryo and fetus","volume":"32","author":"Martin","year":"1996","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1098\/rstb.2004.1475","article-title":"Scar-free healing: From embryonic mechanisms to adult therapeutic intervention","volume":"359","author":"Ferguson","year":"2004","journal-title":"Philos. Trans. R. Soc. Lond. B. Biol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11892-018-0970-z","article-title":"Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads","volume":"18","author":"Davis","year":"2018","journal-title":"Curr. Diabetes Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.yexcr.2012.12.013","article-title":"Cell motility in models of wounded human skin is improved by Gap27 despite raised glucose, insulin and IGFBP-5","volume":"319","author":"Wright","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1111\/j.1600-0625.2012.01532.x","article-title":"The G60S Cx43 mutant enhances keratinocyte proliferation and differentiation","volume":"21","author":"Churko","year":"2012","journal-title":"Exp. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1242\/jcs.084400","article-title":"CASK (LIN2) interacts with Cx43 in wounded skin and their coexpression affects cell migration","volume":"125","author":"Singh","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1016\/j.cub.2003.09.007","article-title":"Targeting connexin43 expression accelerates the rate of wound repair","volume":"13","author":"Qiu","year":"2003","journal-title":"Curr. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/j.bbamem.2011.11.017","article-title":"Connexins in wound healing; perspectives in diabetic patients","volume":"1818","author":"Becker","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1042\/BST20150034","article-title":"Connexin43 plays diverse roles in co-ordinating cell migration and wound closure events","volume":"43","author":"Lorraine","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jdermsci.2015.03.019","article-title":"Connexin 43 deficiency accelerates skin wound healing and extracellular matrix remodeling in mice","volume":"79","author":"Cogliati","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tarzemany, R., Jiang, G., Larjava, H., and H\u00e4kkinen, L. (2015). Expression and function of connexin 43 in human gingival wound healing and fibroblasts. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0115524"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1016\/j.bbamem.2011.09.004","article-title":"Connexins in epidermal homeostasis and skin disease","volume":"1818","author":"Scott","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1091\/mbc.6.11.1491","article-title":"Wounding alters epidermal connexin expression and gap junction-mediated intercellular communication","volume":"6","author":"Goliger","year":"1995","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/S1065-6995(03)00077-5","article-title":"Dynamic changes in connexin expression correlate with key events in the wound healing process","volume":"27","author":"Coutinho","year":"2003","journal-title":"Cell Biol. Int."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1006\/exmp.2001.2406","article-title":"Wound healing: The role of gap junctional communication in rat granulation tissue maturation","volume":"72","author":"Moyer","year":"2002","journal-title":"Exp. Mol. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/wrr.12054","article-title":"Connexin dynamics in the privileged wound healing of the buccal mucosa","volume":"21","author":"Davis","year":"2013","journal-title":"Wound Repair Regen."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14157","DOI":"10.1038\/s41598-017-12672-1","article-title":"Connexin 43 Hemichannels Regulate the Expression of Wound Healing-Associated Genes in Human Gingival Fibroblasts","volume":"7","author":"Tarzemany","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.yexcr.2018.03.031","article-title":"Connexin 43 regulates the expression of wound healing-related genes in human gingival and skin fibroblasts","volume":"367","author":"Tarzemany","year":"2018","journal-title":"Exp. Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5193","DOI":"10.1242\/jcs.03320","article-title":"Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory response, enhanced keratinocyte proliferation and wound fibroblast migration","volume":"119","author":"Mori","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Faniku, C., O\u2019Shaughnessy, E., Lorraine, C., Johnstone, S.R., Graham, A., Greenhough, S., and Martin, P.E.M. (2018). The Connexin Mimetic Peptide Gap27 and Cx43-Knockdown Reveal Differential Roles for Connexin43 in Wound Closure Events in Skin Model Systems. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020604"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1111\/j.0022-202X.2004.22529.x","article-title":"Connexins 26, 30, and 43: Differences among spontaneous, chronic, and accelerated human wound healing","volume":"122","author":"Brandner","year":"2004","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Mendoza-Naranjo, A., Cormie, P., Serrano, A.E., Hu, R., O\u2019Neill, S., Wang, C.M., Thrasivoulou, C., Power, K.T., White, A., and Serena, T. (2012). Targeting Cx43 and N.-Cadherin, Which Are Abnormally Upregulated in Venous Leg Ulcers, Influences Migration, Adhesion and Activation of Rho GTPases. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0037374"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1002\/bjs.10653","article-title":"Upregulation of epidermal gap junctional proteins in patients with venous disease","volume":"105","author":"Kanapathy","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/jid.2014.318","article-title":"The effect of a connexin43-based Peptide on the healing of chronic venous leg ulcers: A multicenter, randomized trial","volume":"135","author":"Ghatnekar","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/jid.2014.444","article-title":"Healing refractory venous ulcers: New treatments offer hope","volume":"135","author":"Kirsner","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.jid.2016.11.006","article-title":"A Multicenter Randomized Controlled Trial Evaluating a Cx43-Mimetic Peptide in Cutaneous Scarring","volume":"137","author":"Grek","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1111\/j.1582-4934.2010.01057.x","article-title":"Connexin 43 mimetic peptide Gap27 reveals potential differences in the role of Cx43 in wound repair between diabetic and non-diabetic cells","volume":"15","author":"Pollok","year":"2011","journal-title":"J. Cell. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1111\/wrr.12275","article-title":"Topical administration of a connexin43-based peptide augments healing of chronic neuropathic diabetic foot ulcers: A multicenter, randomized trial","volume":"23","author":"Grek","year":"2015","journal-title":"Wound Repair Regen."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1016\/j.febslet.2014.02.047","article-title":"Cardiac to cancer: Connecting connexins to clinical opportunity","volume":"588","author":"Grek","year":"2014","journal-title":"FEBS Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5686","DOI":"10.1091\/mbc.e05-08-0737","article-title":"Zonula Occludens-1 Alters Connexin43 Gap Junction Size and Organization by Influencing Channel Accretion","volume":"16","author":"Hunter","year":"2005","journal-title":"Mol. Biol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1516","DOI":"10.1091\/mbc.e10-06-0548","article-title":"Connexin 43 connexon to gap junction transition is regulated by zonula occludens-1","volume":"22","author":"Rhett","year":"2011","journal-title":"Mol. Biol. Cell"},{"key":"ref_45","first-page":"A16380","article-title":"Phosphorylation of Connexin43 at Serine368 is Necessary for Induction of Cardioprotection by a Connexin43 Carboxyl-Terminal Mimetic Peptide","volume":"134","author":"Jiang","year":"2016","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1161\/CIRCRESAHA.110.235747","article-title":"A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury","volume":"108","author":"Palatinus","year":"2011","journal-title":"Circ. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1089\/wound.2011.0341","article-title":"A Connexin43 Mimetic Peptide Promotes Regenerative Healing and Improves Mechanical Properties in Skin and Heart","volume":"2","author":"Ongstad","year":"2013","journal-title":"Adv. Wound Care"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jbiotec.2010.03.015","article-title":"Vascularised human tissue models: A new approach for the refinement of biomedical research","volume":"148","author":"Schanz","year":"2010","journal-title":"J. Biotechnol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.exer.2013.07.001","article-title":"A synthetic connexin 43 mimetic peptide augments corneal wound healing","volume":"115","author":"Moore","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Moore, K., Ghatnekar, G., Gourdie, R.G., and Potts, J.D. (2014). Impact of the Controlled Release of a Connexin 43 Peptide on Corneal Wound Closure in an STZ Model of Type I Diabetes. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086570"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.1097\/PRS.0b013e3181a0741d","article-title":"The connexin43 carboxyl-terminal peptide ACT1 modulates the biological response to silicone implants","volume":"123","author":"Soder","year":"2009","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_52","first-page":"4958","article-title":"Astroglial Connexins as a Therapeutic Target for Alzheimer\u2019s Disease","volume":"23","author":"Yi","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.pharmthera.2017.07.001","article-title":"Inhibitors of connexin and pannexin channels as potential therapeutics","volume":"180","author":"Willebrords","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1124\/pr.115.012062","article-title":"Connexins in Cardiovascular and Neurovascular Health and Disease: Pharmacological Implications","volume":"69","author":"Leybaert","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.semcdb.2015.12.009","article-title":"Translating connexin biology into therapeutics","volume":"50","author":"Becker","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.neuropharm.2013.04.050","article-title":"Peptides and peptide-derived molecules targeting the intracellular domains of Cx43: Gap junctions versus hemichannels","volume":"75","author":"Iyyathurai","year":"2013","journal-title":"Neuropharmacology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00109-017-1506-8","article-title":"Targeting the tight junction protein, zonula occludens-1, with the connexin43 mimetic peptide, \u03b1CT1, reduces VEGF-dependent RPE pathophysiology","volume":"95","author":"Obert","year":"2017","journal-title":"J. Mol. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1186\/s12967-016-1089-0","article-title":"Bridging the gap to therapeutic strategies based on connexin\/pannexin biology","volume":"14","author":"Naus","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.hrthm.2015.07.023","article-title":"Gap junction modifier rotigaptide decreases the susceptibility to ventricular arrhythmia by enhancing conduction velocity and suppressing discordant alternans during therapeutic hypothermia in isolated rabbit hearts","volume":"13","author":"Hsieh","year":"2016","journal-title":"Heart Rhythm"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1778\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:08:50Z","timestamp":1760195330000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/6\/1778"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,15]]},"references-count":59,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["ijms19061778"],"URL":"https:\/\/doi.org\/10.3390\/ijms19061778","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,15]]}}}