Scar free wound healing – a new reality?

By Madeleine Eaton

Scars – we all have them. But while some may think of scars as a memory of a past incident, they have a high clinical burden. It is estimated that 100 million patients a year develop surgical scars (and that isn’t counting the millions more who get small scars from everyday incidents).¹ When we are injured, scar tissue forms to close the wound, made of a buildup of collagen and fibrous tissue.² Fibroblasts in the skin lay parallel collagen layers in this process to quickly repair the wound but without the tensile strength or flexibility of real skin.¹ While in evolutionary terms this can prevent infection and blood loss, scar tissue lacks many of the normal features of skin like sensing temperature or pain. Scars also occur not only on our skin but also on organs: heart tissue scarring impacts its ability to pump for example.² Additionally, scars have larger physiological and psychological implications, causing pain, sleep issues, self-esteem issues and diminished quality of life for patients.³

Currently, there are a limited range of treatments available for scar treatment ranging from topical steroid creams to laser or cryotherapy⁴. Scar treatment with silicone in particular has been shown to be effective in diminishing the texture and appearance of scars. By increasing skin hydration, it regulates collagen production by fibroblasts and balances excess collagen breakdown. A meta-analysis of published data on silicone scar treatment found that there was a significant improvement in flexibility and pigmentation of scars compared to no treatment, showing the usefulness of such treatments.⁵ However, achieving the ultimate goal of healing without scarring is difficult⁶: the skin needs to regain its appendages like hair and secretory glands, its mechanical properties like strength, and its complex structure. This is a much harder goal to work towards.

While these treatments tend to address already formed scars after their potentially damaging effects, another way to address the problem could be to prevent scarring in the first place. Recent work by a group at Stanford University showed a key chemical signal provoking the scarring process, prompting hope that we may be able to target this with drugs. It’s been known since the 1970s that fetal organisms heal without any scars. In fact, humans only begin to scar after 24 weeks.⁷ This means that if you operate on a fetus in the womb the baby is born without any sign of the original injury – regenerating normal collagen pattern and skin structures/properties.⁷ This then led researchers to investigate the differences in normal and fetal skin causing this.

In 2015, the team at Stanford were looking at fibroblast cells (cells in the skin forming connective tissue).⁸ They found that a specific lineage of fibroblasts formed most of the scar tissue in mice, and when knocked out the mice exhibited less scarring.⁹ By identifying the gene that caused this, they learned that these fibroblast cells were ‘switched on’ to producing scar tissue by the process of wound formation. This could be why embryos don’t scar. The mechanical force of skin splitting in the uterine environment versus in an adult human with tight skin is different.⁹ More research showed that this was the case. For example, fibroblasts grown in a soft material didn’t begin to express the scar fibroblast gene.⁹ They also found that increasing tension provoked production of a protein called YAP, a signal for beginning the scar response. Wounded mice that were treated with a YAP blocker repaired their wounds with normal collagen and grew normal skin appendages like hair

follicles and sweat glands.¹⁰ While these results are promising, they aren’t perfect. While the repair of the mice wounds was much better than normal, there still wasn’t full regeneration of normal skin structure/properties like nerves.

However, these results are extremely promising for new clinical trials of YAP blockers in humans to help address scarring. In fact, an FDA approved YAP blocker is already on the market for macular dystrophy treatment (Verteporfin), meaning it would be easier to begin clinical testing for reduction of fibrosis and scarring in humans.¹¹ The possibilities of a treatment such as this are very wide. It could mean that doctors could administer the drug during surgery or use it to treat existing scars and could relegate scarring to a thing of the past.

With all these elements in mind, it is evident how this new research into fibroblast biology could aid new drug development to prevent scarring or rid patients of painful existing scars. Due to their potentially damaging psychological and physiological implications on millions of people, achieving the complex goal of scarless wound healing at large is extremely sought after. While more work is needed to achieve this, the current work is a big step in the right direction.

References:

1. Marshall C, Hu M, Leavitt T, Barnes L, Lorenz H, Longaker M. Cutaneous Scarring: Basic Science, Current Treatments, and Future Directions. Advances in Wound Care [Internet]. 2018;7(2):29-45. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5792238/
2. Healing without scars [Internet]. Hsci.harvard.edu. 2018 [cited 23 May 2022]. Available from: https://hsci.harvard.edu/news/healing-without-scars
3. Puri N, Talwar A. The efficacy of silicone gel for the treatment of hypertrophic scars and keloids. Journal of Cutaneous and Aesthetic Surgery [Internet]. 2009;2(2):104. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918339/
4. Scars – Treatment [Internet]. nhs.uk. 2020 [cited 23 May 2022]. Available from: https://www.nhs.uk/conditions/scars/treatment/
5. Wang F, Li X, Wang X, Jiang X. Efficacy of topical silicone gel in scar management: A systematic review and meta-analysis of randomised controlled trials. International Wound Journal [Internet]. 2020;17(3):765-773. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949016/
6. Molteni M. In mouse experiments, scientists unlock the key to scar-free skin healing [Internet]. STAT. 2021 [cited 23 May 2022]. Available from:
7. Larson B, Longaker M, Lorenz H. Scarless Fetal Wound Healing: A Basic Science Review. Plastic and Reconstructive Surgery [Internet]. 2010;126(4):1172-1180. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229131/ Fibroblast [Internet]. Genome.gov. 2022 [cited 23 May 2022]. Available from: https://www.genome.gov/genetics-glossary/Fibroblast#:~:text=A%20fibroblast%20is%20a%20type,the%20structural%20framework%20of%20tissues
8. Fibroblast [Internet]. Genome.gov. 2022 [cited 23 May 2022]. Available from: https://www.genome.gov/genetics-glossary/Fibroblast#:~:text=A%20fibroblast%20is%20a%20type,the%20structural%20frame work%20of%20tissues
9. Rinkevich Y, Walmsley G, Hu M, Maan Z, Newman A, Drukker M et al. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science [Internet]. 2015;348(6232). Available from: https://www.science.org/doi/10.1126/science.aaa2151
10. Mascharak S, Desjardins-Park H, Davitt M. Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring. Science [Internet]. 2021 [cited 23 May 2022];372(6540). Available from: https://www.science.org/doi/full/10.1126/science.aba2374
11. Clark R. https://www.nejm.org/doi/full/10.1056/NEJMcibr2107204. New England Journal of Medicine [Internet]. 2021 [cited 23 May 2022];385:469-471. Available from: https://www.nejm.org/doi/full/10.1056/NEJMcibr2107204