Scar–free healing: from embryonic mechanisms to adult therapeutic intervention
Open accessAbstract
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–free healing in embryonic wounds and scar–forming 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 TGFβ1 and TGFβ2, low levels of platelet–derived growth factor and high levels of TGFβ3. We have experimentally manipulated healing adult wounds in mice, rats and pigs to mimic the scar–free embryonic profile, e.g. neutralizing PDGF, neutralizing TGFβ1 and TGFβ2 or adding exogenous TGFβ3. These experiments result in scar–free 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–blind 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–based 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–improving 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.
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TGFβ1 is almost certainly one of the growth factors downstream of the wound inflammatory response.
“TGFβ1 is almost certainly one of the growth factors downstream of the wound inflammatory response, and knockdown of this signaling axis has been shown to reduce scarring (109).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [109]
Knockdown of the TGFβ1 signaling axis reduces scarring.
“knockdown of this signaling axis has been shown to reduce scarring (109).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [109]
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- Authors
- Ferguson, M. W. J., & O'Kane, S.
- Affiliations
- University of Manchester (GB)
- Renovo Limited, Manchester Incubator Building, 48 Grafton Street, Manchester M13 9XX, UK
- Corresponding author
- Ferguson, Mark W. J.
- ORCID
- Ferguson, Mark W. J.
- Venue
- Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences
- Publisher
- The Royal Society
- Published
- 2004-05-29
- Volume
- 359
- Issue
- 1445
- Pages
- 839-850
- ISSN
- 0962-8436 (ISSN-L)
- 1471-2970
- PMC
- PMC1693363
- OpenAlex
- W2161106805
- Cited by
- 812
- References
- 40
- Citations by year
- 2026: 12 · 2025: 26 · 2024: 29 · 2023: 26 · 2022: 31 · 2021: 40 · 2020: 41 · 2019: 44 · 2018: 59 · 2017: 37 · 2016: 57 · 2015: 40 · 2014: 36 · 2013: 29 · 2012: 46
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Dermatology › Dermatologic Treatments and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- dermal scarring, embryonic wound healing, TGF-beta3, TGF-β1, TGF-beta2, platelet-derived growth factor, inflammation, skin regeneration, skin graft donor site
- MeSH terms
- Cicatrix, Embryo, Mammalian, Biological Evolution, Humans, Platelet-Derived Growth Factor, Regeneration, Skin, Skin Physiological Phenomena, Wound Healing, Transforming Growth Factor beta, Transforming Growth Factor beta1, Transforming Growth Factor beta2, Transforming Growth Factor beta3
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