Chicago — Mimicking the wound healing environment in embryonic skin may allow adult skin to heal scar-free, according to Mark Ferguson,
D.D.S., Ph.D., professor in the faculty of life sciences at the University of Manchester, England, and chief executive officer
of Renovo Ltd. Dr. Ferguson summarized research in this field at the 15th Annual Meeting of the Wound Healing Society.
Wounds in early mammalian embryos heal without scar formation. During development, the embryo gradually loses this ability
and transitions to an adult wound healing response.
"Mammalian embryos in approximately the first half of gestation heal their wounds with absent scarring, but in the later stages
of gestation and neonatal life, scarring is present," Dr. Ferguson tells Cosmetic Surgery Times. "Scarring is often worse in children and teenagers, due to their enhanced inflammatory response, whilst the quality of scarring
in people over 65 years is often improved as a result of an altered inflammatory and immune response at the wound site."
To gain insights into the mechanisms underlying scar-free wound healing, researchers have analyzed the differences in cellular
and molecular responses to wounding in embryonic and adult wound healing models.
Scar formation
To restore the barrier function of the skin as quickly as possible, closure of skin wounds and repair of missing skin tissue
occur rapidly in adult skin by a mechanism that leads to scarring.
In normal skin formation or in skin regeneration without scarring, extracellular matrix is formed with the collagen bundles
deposited in a basketweave pattern. By contrast, when granulation tissue forms in wound healing, collagen bundles are laid
down in parallel bundles between the margins of the wound. The abnormal architecture of the collagen bundle deposition creates
tissue of weaker tensile strength and produces the characteristic scar.
Scarless healing
Two major differences between embryo and adult are critical in understanding the molecular and cellular environments of scar-free
versus scarring mechanisms of wound healing. First, the immune system of an embryo is not fully developed. Consequently, the
repertoire of inflammatory cells, the extent of inflammatory cell differentiation and the duration of the inflammatory response
in embryonic skin are all considerably diminished compared to adult skin. Second, the embryo is undergoing rapid growth and
differentiation, stimulated by exposure to growth factors and cytokines at levels and combinations not seen in adults.
Embryonic and adult wounds differ significantly in the levels and isoforms of cytokines and growth factors detected in the
wound environment, such as transforming growth factor beta (TGF-Beta), fibroblast growth factor (FGF) and platelet-derived
growth factor (PDGF). In embryos, the cytokine and growth factor repertoire in the wound environment is derived from fibroblasts
and keratinocytes, whereas in adults it is derived from platelets and inflammatory cells.
Embryonic cells express high levels of the TGF-Beta3 isoform, derived from keratinocytes and fibroblasts, and low levels of
the TGF-Beta1 and TGF-Beta2 isoforms, derived from degranulating platelets and inflammatory cells in adult wounds. FGF is
expressed at high levels in embryos, but PDGF expression is not detected. By contrast, TGF-Beta1, TGF-Beta2 and PDGF expression
is high in adult wounds, with little if any expression of TGF-Beta3 or FGF.
Studies of wound healing in animal models suggest a possible therapeutic role for TGF-Beta isoforms. Wound healing studies
in rodents have shown that neutralization of TGF-Beta1 and TGF-Beta2 by antibodies markedly improves scarring. Similarly,
wounds heal with less scarring following topical application of mannose-6-phosphate, which inhibits activation of TGF-Beta1
and of TGF-Beta2. By contrast, addition of exogenous TGF-Beta3 improves scarring in rodent models, and TGF-Beta3 deficiency
in heterozygous null knockout mice results in impaired healing with scar formation.
Scar formation is the final event in the wound healing process, and scars are not considered stable and mature until several
weeks post-wounding. Nevertheless, the first 48 hours appears to be critical in determining the scar outcome. Best results
were obtained in animal models when interventions were made within this window.
A possible explanation is that the small number of master signaling molecules in the initial cytokine cascade triggered by
the wound healing process can profoundly affect the levels and ratios of inflammatory cells and growth factors recruited to
the wound site. In addition, the recruited cells influence the receptor profiles on the target cells, further affecting the
wound healing response and subsequent scar formation.
Evolutionary relics
From an evolutionary perspective, wounds represent a serious threat to the organism, not only due to blood loss, but also
due to tissue damage or infection from the invasion of foreign bodies such as dirt, splinters and bacteria. The adult wound
healing mechanism that evolved to respond to this threat has two fundamental characteristics: First, there is a rapid and
robust inflammatory response, with recruitment of activated macrophages, neutrophils and lymphocytes to the wound site; and
second, there is a fibrotic "walling-off" response to isolate the foreign body, with liquification of adjacent tissue leading
to abscess formation.
Is this response still appropriate?
"A scar is not an evolutionarily optimized end point for today's wounds," Dr. Ferguson says. "The scarring response, with
its massive inflammatory overdrive, is optimized for a very different type of wound than the common sharp, clean wounds seen
today. The scar is induced by this inappropriate inflammatory response."
The scars in most adults have arisen from surgical procedures. The "wounds" were inflicted with a sharp instrument under sterile
conditions, without contamination by foreign bodies. These wounds should therefore be ideal candidates for healing, without
complications, by a regenerative wound healing mechanism rather than a scarring mechanism.
Therapeutic approach
Dr. Ferguson and colleagues reasoned that rapid intervention with appropriate growth factors might prevent cells from initiating
the signalling cascade that leads to wound healing by the scarring pathway. "Wounding" by surgical incision is a planned event
that occurs under controlled conditions, and wounds that result from major trauma, such as automobile accidents, are normally
treated soon after the occurrence. Researchers hypothesized that therapeutic intervention within the first 24 or 48 hours
could alter the local environment in a way that favors the scarless healing pathway.
"The first triggers for wound healing and scarring come from growth factors released by degranulating platelets and inflammatory
cells," Dr. Ferguson says. "These released growth factors set off auto-inductive, auto-catalytic cascades, which after a couple
of days have induced so many other cellular and molecular responses that the cascades are functionally redundant and highly
interactive."
At Renovo Ltd., co-founded by Dr. Ferguson, three products are in clinical development for prevention of scar formation.
"Our therapeutic manipulations of adult wound healing, to prevent or reduce scarring, focus on elevating the levels of TGF-Beta3
or preventing the activation of TGF-Beta1 and TGF-Beta2 or modulating the inflammatory response," Dr. Ferguson says. "In other
words, we make the adult wound environment more like that of an embryonic wound."
The lead candidate is Juvista, human recombinant TGF-Beta3 for intradermal injection at the wound site, which is in phase
2 clinical development for scar prevention. A compound under development for scar improvement is Juvidex, a sterile solution
of mannose-6-phosphate for intradermal injection at a wound site. As a modulator of the inflammatory response, Prevascar (human
recombinant IL-10) is under development as a therapeutic agent to reduce scarring.
"Scarring is no longer an inevitable consequence of surgery or injury," Dr. Ferguson says. "In the next few years, we hope
that there will be powerful new pharmaceutical drugs approved to prevent or improve scarring that would augment the current
excellent repertoire of surgical techniques and bring considerable benefits to both patients and surgeons."
Disclosure: Dr. Ferguson is a co-founder and chief executive officer of Renovo Ltd.
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