By Jessica Lu
Scarring of the skin can be caused by burns, surgery, and injury. In severe cases, it causes patients long-term functional and psychological problems. In the developed world, it is estimated that 100 million patients acquire scars from surgery every year. Many burns also leave scars and painful contractures which need major surgery (Marshall et al., 2018). In the United States, 500 000 patients are treated for burns every year, costing up to $7.5 billion. Much of this is spent on scar treatment. This places a huge burden on the healthcare system, making it important to find effective treatments for scarring (Marshall et al., 2018).
Scar formation exists on a spectrum. On the one hand, there is scarless regeneration. In the centre is normal wound healing, where scarring exists but is not pathological. On the other hand, there is pathological scarring, for example, hypertrophic and keloid scarring (Marshall et al., 2018). Hypertrophic scars are more raised than normal scars, or cause contracture. Keloid scars occur when the scarring response is abnormally severe and extends beyond the original bounds of the injury. Pathological scars can cause loss of function, restriction of tissue movement or growth, and psychological effects (Marshall et al., 2018).
Considering the middle of the spectrum first, normal wound healing in humans is typically split into three stages: inflammation, proliferation, and remodelling (Marshall et al., 2018). Inflammation occurs immediately after injury. During this phase, a platelet and fibrin clot forms to prevent blood loss. Neutrophils are recruited to the wound to kill microbes. Monocytes localise to the wound, then differentiate into macrophages which phagocytose debris and produce cytokines. Next, various cell types proliferate, such as fibroblasts, myofibroblasts and keratinocytes and endothelial cells. This allows the formation of new tissue. Fibroblasts and myofibroblasts produce collagen, which forms a substantial part of the mature scar. Finally, remodelling occurs two to three weeks after injury and lasts for a year or more. In this stage, many cells undergo apoptosis or migrate away from the wound site, leaving collagen and other ECM proteins behind. The ECM is remodelled by metalloproteinases secreted by fibroblasts, macrophages, and endothelial cells. Immature scars have a ratio of 2:1 of type I to type III collagen. As the scar matures, the ratio transitions to 4:1, which is the ratio typically found in normal skin. The strength of the final scar is at most 75-80% of unwounded skin (Barnes et al., 2018).
Looking at the ends of the spectrum, on one end, study of scarless healing may provide insight into how to prevent scar formation. Many models indicate that healed foetal wounds are almost identical to uninjured tissue. It was initially assumed that this was due to the intrauterine environment, but it was later found that scarless healing is intrinsic to foetal tissue, regardless of the external environment. The transition from scarless regeneration to scarring healing occurs at 24 weeks of gestation in humans. Unlike adult wound healing, in the early stage of foetal wound healing the inflammatory reaction is limited, with lower levels of neutrophils, macrophages and several cytokines (Marshall et al., 2018). On the opposite end of the spectrum, hypertrophic scar formation is characterised by excessive inflammatory cytokines, including IL-1β, IL-6 and TNF-α. These cytokines cause the inhibition of collagenase activity, leading to abnormal collagen composition and scarring. There is an imbalance between ECM synthesis and degradation (Shirakami, Yamakawa & Hayashida, 2020).
A variety of current treatments for scarring exist, including dressings, pressure, topical treatments, surgical revision, steroids and laser therapy (Marshall et al., 2018; Shirakami, Yamakawa & Hayashida, 2020). Clinical evidence for many active agents commonly used in topical treatments is lacking (Tran et al., 2020), and none of these treatments are fully effective (Marshall et al., 2018). It is impossible to regenerate healthy tissue once scar tissue has matured, making it crucial to find effective strategies to prevent aberrant scar formation in the first place (Marshall et al., 2018).
The most common non-invasive treatments for hypertrophic scars are pressure, silicone sheet, and silicone gel therapies. Pressure is thought to act by reducing blood flow and therefore oxygen and nutrients to the scarred tissue, reducing collagen production. The application of a silicone sheets or silicone gel onto the hypertrophic scar helps increase the skin temperature and hydrate the scar. However, these treatments have limitations. Due to the shape of the human body, in some areas it is difficult to exert pressure. Silicone sheets may debond from moving joints, whereas silicone gel may be rubbed off easily during daily activities (Chow et al., 2021; Shirakami, Yamakawa & Hayashida, 2020). In the future, these limitations could be mitigated by combining these three treatments. A pressure sleeve could be integrated with a customised, 3D silicone insert, preventing silicone sheet displacement. Silicone gel can be applied onto the silicone insert to further speed up recovery (Chow et al., 2021).
Another potential future treatment to prevent hypertrophic scarring is anti-inflammatory therapy. Persistent inflammation is possibly a cause of hypertrophic scarring. One possibility is injection of the protein TSG-6, which inhibits the expression of inflammatory cytokines and prevents fibroblast apoptosis. This may prevent excess collagen being deposited (Shirakami, Yamakawa & Hayashida, 2020). Another possibility is targeting the chemokine receptor CXCR/4. An antagonist of CXCR4 was found to lower the number of macrophages and myofibroblasts and reduce scar formation (Wilgus, 2020).
Overall, although scarring is a major problem for patients and the healthcare system, there is still no fully effective treatment. There are also still important unanswered questions about the cellular and molecular processes involved in wound healing. More research into how scarless healing occurs in the early gestation foetus may help develop more effective novel treatments.
Barnes, L. A., Marshall, C. D., Leavitt, T., Hu, M. S., Moore, A. L., Gonzalez, J. G., Longaker, M. T. & Gurtner, G. C. (2018) Mechanical Forces in Cutaneous Wound Healing: Emerging Therapies to Minimize Scar Formation. Advances in Wound Care. 7 (2), 47-56. Available from: doi: 10.1089/wound.2016.0709.
Chow, L., Yick, K., Sun, Y., Leung, M. S. H., Kwan, M., Ng, S., Yu, A., Yip, J. & Chan, Y. (2021) A Novel Bespoke Hypertrophic Scar Treatment: Actualizing Hybrid Pressure and Silicone Therapies with 3D Printing and Scanning. International Journal of Bioprinting. 7 (1). Available from: doi: 10.18063/ijb.v7i1.327.
Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H. P. & Longaker, M. T. (2018) Cutaneous Scarring: Basic Science, Current Treatments, and Future Directions. Advances in Wound Care. 7 (2), 29-45. Available from: doi: 10.1089/wound.2016.0696.
Shirakami, E., Yamakawa, S. & Hayashida, K. (2020) Strategies to prevent hypertrophic scar formation: a review of therapeutic interventions based on molecular evidence. Burns & Trauma. 8 (tkz003). Available from: doi: 10.1093/burnst/tkz003.
Tran, B., Wu, J. J., Ratner, D. & Han, G. (2020) Topical Scar Treatment Products for Wounds: A Systematic Review. Dermatologic Surgery. 46 (12), 1564–1571. Available from: doi: 10.1097/DSS.0000000000002712.
Wilgus, T. (2020) Inflammation as an orchestrator of cutaneous scar formation: a review of the literature. Plastic and Aesthetic Research. Available from: doi: 10.20517/2347-9264.2020.150.