{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T02:52:52Z","timestamp":1791341572504,"version":"4.3.1"},"reference-count":42,"publisher":"The Royal Society","issue":"1445","license":[{"start":{"date-parts":[[2004,5,29]],"date-time":"2004-05-29T00:00:00Z","timestamp":1085788800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Phil. Trans. R. Soc. Lond. B"],"published-print":{"date-parts":[[2004,5,29]]},"abstract":"<jats:p>In man and domestic animals, scarring in the skin after trauma, surgery, burn or sports injury is a major medical problem, often resulting in adverse aesthetics, loss of function, restriction of tissue movement and\/or growth and adverse psychological effects. Current treatments are empirical, unreliable and unpredictable: there are no prescription drugs for the prevention or treatment of dermal scarring. Skin wounds on early mammalian embryos heal perfectly with no scars whereas wounds to adult mammals scar. We investigated the cellular and molecular differences between scar\u2013free healing in embryonic wounds and scar\u2013forming healing in adult wounds. Important differences include the inflammatory response, which in embryonic wounds consists of lower numbers of less differentiated inflammatory cells. This, together with high levels of morphogenetic molecules involved in skin growth and morphogenesis, means that the growth factor profile in a healing embryonic wound is very different from that in an adult wound. Thus, embryonic wounds that heal without a scar have low levels of TGF\u03b21 and TGF\u03b22, low levels of platelet\u2013derived growth factor and high levels of TGF\u03b23. We have experimentally manipulated healing adult wounds in mice, rats and pigs to mimic the scar\u2013free embryonic profile, e.g. neutralizing PDGF, neutralizing TGF\u03b21 and TGF\u03b22 or adding exogenous TGF\u03b23. These experiments result in scar\u2013free wound healing in the adult. Such experiments have allowed the identification of therapeutic targets to which we have developed novel pharmaceutical molecules, which markedly improve or completely prevent scarring during adult wound healing in experimental animals. Some of these new drugs have successfully completed safety and other studies, such that they have entered human clinical trials with approval from the appropriate regulatory authorities. Initial trials involve application of the drug or placebo in a double\u2013blind randomized design, to experimental incision or punch biopsy wounds under the arms of human volunteers. Based on encouraging results from such human volunteer studies, the lead drugs have now entered human patient\u2013based trials e.g. in skin graft donor sites. We consider the evolutionary context of wound healing, scarring and regeneration. We hypothesize that evolutionary pressures have been exerted on intermediate sized, widespread, dirty wounds with considerable tissue damage e.g. bites, bruises and contusions. Modern wounds (e.g. resulting from trauma or surgery) caused by sharp objects and healing in a clean or sterile environment with close tissue apposition are new occurrences, not previously encountered in nature and to which the evolutionary selected wound healing responses are somewhat inappropriate. We also demonstrate that both repair with scarring and regeneration can occur within the same animal, including man, and indeed within the same tissue, thereby suggesting that they share similar mechanisms and regulators. Consequently, by subtly altering the ratio of growth factors present during adult wound healing, we can induce adult wounds to heal perfectly with no scars, with accelerated healing and with no adverse effects, e.g. on wound strength or wound infection rates. This means that scarring may no longer be an inevitable consequence of modern injury or surgery and that a completely new pharmaceutical approach to the prevention of human scarring is now possible. Scarring after injury occurs in many tissues in addition to the skin. Thus scar\u2013improving drugs could have widespread benefits and prevent complications in several tissues, e.g. prevention of blindness after scarring due to eye injury, facilitation of neuronal reconnections in the central and peripheral nervous system by the elimination of glial scarring, restitution of normal gut and reproductive function by preventing strictures and adhesions after injury to the gastrointestinal or reproductive systems, and restoration of locomotor function by preventing scarring in tendons and ligaments.<\/jats:p>","DOI":"10.1098\/rstb.2004.1475","type":"journal-article","created":{"date-parts":[[2004,5,3]],"date-time":"2004-05-03T17:23:01Z","timestamp":1083604981000},"page":"839-850","source":"Crossref","is-referenced-by-count":672,"title":["Scar\u2013free healing: from embryonic mechanisms to adult therapeutic intervention"],"prefix":"10.1098","volume":"359","author":[{"given":"Mark W. J.","family":"Ferguson","sequence":"first","affiliation":[{"name":"UK Centre for Tissue Engineering, School of Biological Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road, Manchester M13 9PT, UK"},{"name":"Renovo Limited, Manchester Incubator Building, 48 Grafton Street, Manchester M13 9XX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"O'Kane","sequence":"additional","affiliation":[{"name":"Renovo Limited, Manchester Incubator Building, 48 Grafton Street, Manchester M13 9XX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2004,5,29]]},"reference":[{"key":"p_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1995.1141"},{"key":"p_2","unstructured":"Armstrong J. R. & Ferguson M. W. J. 1997 Ontological wound healing studies in Monodelphis domestica from birth to adulthood. In Marsupial biology: recent research new perspectives (ed. N. Saunders & L. Hinds) pp. 254-271. Sydney Australia: University of New South Wales Press Ltd."},{"key":"p_3","doi-asserted-by":"publisher","DOI":"10.1038\/nm1197-1209"},{"key":"p_4","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12289705"},{"key":"p_5","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-7580.1997.19030351.x"},{"key":"p_6","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65217-0"},{"key":"p_7","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.326.7380.88"},{"key":"p_8","doi-asserted-by":"publisher","DOI":"10.1097\/00006534-199811000-00022"},{"key":"p_9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11867"},{"key":"p_10","unstructured":"Cherry G. W. Hughes M. A. Leaper D. J. & Ferguson M. W. J. 2001 Wound healing ch. 6. In Oxford text book of surgery 2nd edn (ed. P. J. Morris & W. C. Wood) pp. 129-159. Oxford University Press."},{"key":"p_11","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0177(199807)212:3<385::AID-AJA6>3.0.CO;2-D"},{"key":"p_12","first-page":"424","article-title":"Expression of TGF-~ and its receptors in murine fetal and adult dermal wounds","volume":"11","author":"Cowin A. J.","year":"2001","journal-title":"Eur. J. Dermatol."},{"key":"p_13","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.4049\/jimmunol.161.4.1983","article-title":"Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines","volume":"161","author":"Erwig L.-P.","year":"1998","journal-title":"J. Immunol."},{"key":"p_14","doi-asserted-by":"publisher","DOI":"10.1097\/00041552-200105000-00007"},{"key":"p_15","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-8278(00)80412-2"},{"key":"p_16","unstructured":"Ferguson M. W. J. & Leigh I. M. 1998 Wound healing. In Rook\/Wilkinson\/Ebling textbook of dermatology 6th edn (ed. R. H. Champion J. L. Burton D. A. Burns & S. M. Breathnach) pp. 337-356. Oxford: Blackwell Science."},{"key":"p_17","doi-asserted-by":"publisher","DOI":"10.1097\/00006534-199604000-00029"},{"key":"p_18","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1468"},{"key":"p_19","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1467"},{"key":"p_20","doi-asserted-by":"publisher","DOI":"10.1097\/00000658-199401000-00011"},{"key":"p_21","doi-asserted-by":"crossref","unstructured":"McCallion R. L. & Ferguson M. W. J. 1996 Fetal wound healing and the development of anti-scarring therapies for adult wound healing. In The molecular and cellular biology of wound repair 2nd edn (ed. R. A. F. Clarke) pp. 561-600. New York: Plenum.","DOI":"10.1007\/978-1-4899-0185-9_18"},{"key":"p_22","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1472"},{"key":"p_23","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2004.1470"},{"key":"p_24","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(02)00839-4"},{"key":"p_25","doi-asserted-by":"crossref","unstructured":"Niesler C. U. & Ferguson M. W. J. 2001 TGF~ superfamily cytokines in wound healing. In TGF ~ and related cytokines in inflammation (ed. S. M. Breit & S. M. Wahl) pp. 173-198. Basel Switzerland: Birkhauser.","DOI":"10.1007\/978-3-0348-8354-2_8"},{"key":"p_26","doi-asserted-by":"publisher","DOI":"10.1016\/S1357-2725(96)00120-3"},{"key":"p_27","doi-asserted-by":"publisher","DOI":"10.1038\/ng1295-409"},{"key":"p_28","unstructured":"Qiu C. X. Brunner G. & Ferguson M. W. J. 2004 Abnormal wound healing and scarring in the TGF~3 null mouse embryo. Development. 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Series B: Biological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2004.1475","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rstb.2004.1475","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:27:22Z","timestamp":1778621242000},"score":1,"resource":{"primary":{"URL":"http:\/\/royalsocietypublishing.org\/rstb\/article\/359\/1445\/839-850\/20394"}},"subtitle":[],"editor":[{"given":"J. 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