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Managing Pathologic Scars by Injecting Auto-Cross-linked Hyaluronic Acid: A Preliminary Prospective Clinical Study

  • Michele Riccio
  • Andrea Marchesini
  • Letizia Senesi
  • Edlira Skrami
  • Rosaria Gesuita
  • Francesco De FrancescoEmail author
Original Article Non-Surgical Aesthetic

Abstract

Background

Pathological scars are unattractive and may significantly impair the patient’s quality of life. Current treatments provide inconsistent results, and none may be regarded as definitive. Recently, an auto-cross-linked hyaluronic acid (HA) formulation, IAL-SYSTEM ACP, featuring a long residence time and an enhanced safety profile, has been successfully used to prevent surgical adhesions, treat tendon lesions and rejuvenate the face and the décolletage. This study aims to preliminarily investigate whether IAL-SYSTEM ACP may also be effective in treating pathological scars resulting from burns, trauma or iatrogenic causes.

Methods

Patients presenting one pathological scar were prospectively recruited and treated with two IAL-SYSTEM ACP injections carried out two weeks apart. Scar improvement was measured comparing the patient and observer scar assessment scale (POSAS) scores collected before treatment (T0) and 90 days after the second injection (T90) using nonparametric tests. The effect of age and scar type over score variation was investigated through quantile regression analysis.

Results

Forty-one patients, 10 women and 31 men (median age, 34 years) were recruited. No patient dropped out, and no significant adverse event was observed. At T90, the median observer total score decreased by 11 units (− 77.5%) and the median patient total score decreased by 15 units (− 73.7%). The difference was significant (p < 0.001) in both cases. Traumatic injuries and young patient’s age were the most significant predictors of a positive treatment outcome.

Conclusions

Treatment of pathological scars by two IAL-SYSTEM ACP injections, carried out two weeks apart, may provide significant clinical benefits. These findings should be the subject of further investigations.

Level of Evidence IV

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Keywords

Hypertrophic scar IAL-SYSTEM ACP Auto-cross-linked hyaluronic acid Dermal pliability Dermal thickness 

Notes

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

All subjects provide their informed consent.

References

  1. 1.
    Tredget EE (1994) The molecular biology of fibroproliferative disorders of the skin: potential cytokine therapeutics. Ann Plast Surg 33(2):152–154Google Scholar
  2. 2.
    Murray JC (1994) Keloids and hypertrophic scars. Clin Dermatol 12(1):27–37Google Scholar
  3. 3.
    Juckett G, Hartman-Adams H (2009) Management of keloids and hypertrophic scars. Am Fam Physician 80(3):253–260Google Scholar
  4. 4.
    Ogawa R, Akaishi S, Hyakusoku H (2009) Differential and exclusive diagnosis of diseases that resemble keloids and hypertrophic scars. Ann Plast Surg 62(6):660–664Google Scholar
  5. 5.
    Ogawa R, Akaishi S, Izumi M (2009) Histologic analysis of keloids and hypertrophic scars. Ann Plast Surg 62(1):104–105Google Scholar
  6. 6.
    Broughton G 2nd, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117(7 Suppl):12S–34SGoogle Scholar
  7. 7.
    Enoch S, Leaper DJ (2008) Basic science of wound healing. Surgery 26(2):31–37Google Scholar
  8. 8.
    Martin P, Nunan R (2015) Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol 173(2):370–378Google Scholar
  9. 9.
    Sorg H, Tilkorn DJ, Hager S, Hauser J, Mirastschijski U (2017) Skin wound healing: an update on the current knowledge and concepts. Eur Surg Res 58(1–2):81–94Google Scholar
  10. 10.
    McDonald J, Hascall VC (2002) Hyaluronan minireview series. J Biol Chem 277(7):4575–4579Google Scholar
  11. 11.
    Dunphy JE (1978) Wound healing. Surg Clin North Am 58(5):907–916Google Scholar
  12. 12.
    Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA (2002) Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol 3(5):349–363Google Scholar
  13. 13.
    Jenkins RH, Thomas GJ, Williams JD, Steadman R (2004) Myofibroblastic differentiation leads to hyaluronan accumulation through reduced hyaluronan turnover. J Biol Chem 279(40):41453–41460Google Scholar
  14. 14.
    Ferguson EL, Roberts JL, Moseley R, Griffiths PC, Thomas DW (2011) Evaluation of the physical and biological properties of hyaluronan and hyaluronan fragments. Int J Pharm 420(1):84–92Google Scholar
  15. 15.
    Monslow J, Sato N, Mack JA, Maytin EV (2009) Wounding-induced synthesis of hyaluronic acid in organotypic epidermal cultures requires the release of heparin-binding egf and activation of the EGFR. J Invest Dermatol 129(8):2046–2058Google Scholar
  16. 16.
    Meyer LJ, Russell SB, Russell JD, Trupin JS, Egbert BM, Shuster S, Stern R (2000) Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts. J Invest Dermatol. 114(5):953–959Google Scholar
  17. 17.
    Sidgwick GP, Iqbal SA, Bayat A (2013) Altered expression of hyaluronan synthase and hyaluronidase mRNA may affect hyaluronic acid distribution in keloid disease compared with normal skin. Exp Dermatol 22(5):377–379Google Scholar
  18. 18.
    Bertheim U, Hellström S (1994) The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars. Br J Plast Surg 47(7):483–489Google Scholar
  19. 19.
    Ogawa R, Akaishi S, Huang C, Dohi T, Aoki M, Omori Y, Koike S, Kobe K, Akimoto M, Hyakusoku H (2011) Clinical applications of basic research that shows reducing skin tension could prevent and treat abnormal scarring: the importance of fascial/subcutaneous tensile reduction sutures and flap surgery for keloid and hypertrophic scar reconstruction. J Nippon Med Sch 78(2):68–76Google Scholar
  20. 20.
    Moio M, Mataro I, Accardo G, Canta L, Schonauer F (2014) Treatment of hypergranulation tissue with intralesional injection of corticosteroids: preliminary results. J Plast Reconstr Aesthet Surg 67(6):e167–e168Google Scholar
  21. 21.
    Roques C, Téot L (2008) The use of corticosteroids to treat keloids: a review. Int J Low Extrem Wounds 7(3):137–145Google Scholar
  22. 22.
    De Cicco L, Vischioni B, Vavassori A, Gherardi F, Jereczek-Fossa BA, Lazzari R, Cattani F, Comi S, De Lorenzi F, Martella S, Orecchia R (2014) Postoperative management of keloids: low-dose-rate and high-dose-rate brachytherapy. Brachytherapy 13(5):508–513Google Scholar
  23. 23.
    Chang P, Laubenthal KN, Lewis RW 2nd, Rosenquist MD, Lindley-Smith P, Kealey GP (1995) Prospective, randomized study of the efficacy of pressure garment therapy in patients with burns. J Burn Care Rehabil 16(5):473–475Google Scholar
  24. 24.
    Maján JI (2006) Evaluation of a self-adherent soft silicone dressing for the treatment of hypertrophic postoperative scars. J Wound Care 15(5):193–196Google Scholar
  25. 25.
    Khan MA, Bashir MM, Khan FA (2014) Intralesional triamcinolone alone and in combination with 5-fluorouracil for the treatment of keloid and hypertrophic scars. J Pak Med Assoc 64(9):1003–1007Google Scholar
  26. 26.
    Carroll W, Patel K (2015) Steroids and fluorouracil for keloids and hypertrophic scars. JAMA Facial Plast Surg 17(2):77–79Google Scholar
  27. 27.
    Haurani MJ, Foreman K, Yang JJ, Siddiqui A (2009) 5-Fluorouracil treatment of problematic scars. Plast Reconstr Surg 123(1):139–148Google Scholar
  28. 28.
    Payapvipapong K, Niumpradit N, Piriyanand C, Buranaphalin S, Nakakes A (2015) The treatment of keloids and hypertrophic scars with intralesional bleomycin in skin of color. J Cosmet Dermatol 14(1):83–90Google Scholar
  29. 29.
    Wang R, Mao Y, Zhang Z, Li Z, Chen J, Cen Y (2016) Role of verapamil in preventing and treating hypertrophic scars and keloids. Int Wound J. 13(4):461–468Google Scholar
  30. 30.
    Brewin MP, Lister TS (2014) Prevention or treatment of hypertrophic burn scarring: a review of when and how to treat with the pulsed dye laser. Burns 40(5):797–804Google Scholar
  31. 31.
    Nicoletti G, De Francesco F, Mele CM, Cataldo C, Grella R, Brongo S, Accardo M, Ferraro GA, D’Andrea F (2013) Clinical and histologic effects from CO2 laser treatment of keloids. Lasers Med Sci 28(3):957–964Google Scholar
  32. 32.
    Scrimali L, Lomeo G, Nolfo C, Pompili G, Tamburino S, Catalani A, Siragò P, Perrotta RE (2010) Treatment of hypertrophic scars and keloids with a fractional CO2 laser: a personal experience. J Cosmet Laser Ther 12(5):218–221Google Scholar
  33. 33.
    Camacho-Martínez FM, Rey ER, Serrano FC, Wagner A (2013) Results of a combination of bleomycin and triamcinolone acetonide in the treatment of keloids and hypertrophic scars. An Bras Dermatol 88(3):387–394Google Scholar
  34. 34.
    Darougheh A, Asilian A, Shariati F (2009) Intralesional triamcinolone alone or in combination with 5-fluorouracil for the treatment of keloid and hypertrophic scars. Clin Exp Dermatol 34(2):219–223Google Scholar
  35. 35.
    Martin MS, Collawn SS (2013) Combination treatment of CO2 fractional laser, pulsed dye laser, and triamcinolone acetonide injection for refractory keloid scars on the upper back. J Cosmet Laser Ther 15(3):166–170Google Scholar
  36. 36.
    Liu S, Jiang L, Li H, Shi H, Luo H, Zhang Y, Yu C, Jin Y (2014) Mesenchymal stem cells prevent hypertrophic scar formation via inflammatory regulation when undergoing apoptosis. J Invest Dermatol 134(10):2648–2657Google Scholar
  37. 37.
    Seo BF, Jung SN (2016) The immunomodulatory effects of mesenchymal stem cells in prevention or treatment of excessive scars. Stem Cells Int 2016:6937976Google Scholar
  38. 38.
    Svolacchia F, De Francesco F, Trovato L, Graziano A, Ferraro GA (2016) An innovative regenerative treatment of scars with dermal micrografts. J Cosmet Dermatol 15(3):245–253Google Scholar
  39. 39.
    Zhang Q, Liu LN, Yong Q, Deng JC, Cao WG (2015) Intralesional injection of adipose-derived stem cells reduces hypertrophic scarring in a rabbit ear model. Stem Cell Res Ther 18(6):145Google Scholar
  40. 40.
    Brongo S, Nicoletti GF, La Padula S, Mele CM, DʼAndrea F (2012) Use of lipofilling for the treatment of severe burn outcomes. Plast Reconstr Surg 130(2):374e–376eGoogle Scholar
  41. 41.
    Brunelli G, Longinotti C, Bertazzo C, Pavesio A, Pressato D (2005) Adhesion reduction after knee surgery in a rabbit model by Hyaloglide, a hyaluronan derivative gel. J Orthop Res 23(6):1377–1382Google Scholar
  42. 42.
    Abate M, Schiavone C, Salini V (2014) The use of hyaluronic acid after tendon surgery and in tendinopathies. Biomed Res Int 2014:783632Google Scholar
  43. 43.
    Matarasso SL (2004) Understanding and using hyaluronic acid. Aesthet Surg J 24(4):361–364Google Scholar
  44. 44.
    Tezel A, Fredrickson GH (2008) The science of hyaluronic acid dermal fillers. J Cosmet Laser Ther 10(1):35–42. Erratum in: J Cosmet Laser Ther. 2014 16(1):45Google Scholar
  45. 45.
    Pluda S, Pavan M, Galesso D, Guarise C (2016) Hyaluronic acid auto-crosslinked polymer (ACP): reaction monitoring, process investigation and hyaluronidase stability. Carbohydr Res 4(433):47–53Google Scholar
  46. 46.
    de Wit T, de Putter D, Tra WM, Rakhorst HA, van Osch GJ, Hovius SE, van Neck JW (2009) Auto-crosslinked hyaluronic acid gel accelerates healing of rabbit flexor tendons in vivo. J Orthop Res 27(3):408–415Google Scholar
  47. 47.
    Belluco C, Meggiolaro F, Pressato D, Pavesio A, Bigon E, Donà M, Forlin M, Nitti D, Lise M (2001) Prevention of postsurgical adhesions with an autocrosslinked hyaluronan derivative gel. J Surg Res 100(2):217–221Google Scholar
  48. 48.
    Guida M, Acunzo G, Di Spiezio Sardo A, Bifulco G, Piccoli R, Pellicano M, Cerrota G, Cirillo D, Nappi C (2004) Effectiveness of auto-crosslinked hyaluronic acid gel in the prevention of intrauterine adhesions after hysteroscopic surgery: a prospective, randomized, controlled study. Hum Reprod 19(6):1461–1464Google Scholar
  49. 49.
    Smit X, van Neck JW, Afoke A, Hovius SE (2004) Reduction of neural adhesions by biodegradable autocrosslinked hyaluronic acid gel after injury of peripheral nerves: an experimental study. J Neurosurg 101(4):648–652Google Scholar
  50. 50.
    Atzei A, Calcagni M, Breda B, Fasolo G, Pajardi G, Cugola L (2007) Clinical evaluation of a hyaluronan-based gel following microsurgical reconstruction of peripheral nerves of the hand. Microsurgery 27(1):2–7Google Scholar
  51. 51.
    Riccio M, Battiston B, Pajardi G, Corradi M, Passaretti U, Atzei A, Altissimi M, Vaienti L, Catalano F, Del Bene M, Fasolo P, Ceruso M, Luchetti R, Landi A; Study Group on Tendon Adhesion of Italian Society of Hand Surgery (2010) Efficiency of hyaloglide in the prevention of the recurrence of adhesions after tenolysis of flexor tendons in zone II: a randomized, controlled, multicentre clinical trial. J Hand Surg Eur 35(2):130–138Google Scholar
  52. 52.
    Alessandrini A, Di Bartolo C, Pavesio A, Pressato D (2006) ACP gel: a new hyaluronic acid-based injectable for facial rejuvenation. Preclinical data in a rabbit model. Plast Reconstr Surg 118(2):341–346Google Scholar
  53. 53.
    Alessandrini A, Tretyakova K (2018) The rejuvenating effect and tolerability of an auto-cross-linked hyaluronic acid on décolletage: a pilot prospective study. Aesthetic Plast Surg 42(2):520–529Google Scholar
  54. 54.
    Renier D, Bellato P, Bellini D, Pavesio A, Pressato D, Borrione A (2005) Pharmacokinetic behaviour of ACP gel, an autocrosslinked hyaluronan derivative, after intraperitoneal administration. Biomaterials 26(26):5368–5374Google Scholar
  55. 55.
    Wohlrab J, Wohlrab D, Neubert RH (2013) Comparison of noncross-linked and cross-linked hyaluronic acid with regard to efficacy of the proliferative activity of cutaneous fibroblasts and keratinocytes in vitro. J Cosmet Dermatol 12(1):36–40Google Scholar
  56. 56.
    van de Kar AL, Corion LU, Smeulders MJ, Draaijers LJ, van der Horst CM, van Zuijlen PP (2005) Reliable and feasible evaluation of linear scars by the patient and observer scar assessment scale. Plast Reconstr Surg 116(2):514–522Google Scholar
  57. 57.
    Draaijers LJ, Tempelman FR, Botman YA, Tuinebreijer WE, Middelkoop E, Kreis RW, van Zuijlen PP (2004) The patient and observer scar assessment scale: a reliable and feasible tool for scar evaluation. Plast Reconstr Surg 113(7):1960–1965Google Scholar
  58. 58.
    R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available from https://www.R-project.org/. Accessed 19 December 2017
  59. 59.
    Bell L, McAdams T, Morgan R, Parshley PF, Pike RC, Riggs P, Carpenter JE (1988) Pruritus in burns: a descriptive study. J Burn Care Rehabil 9(3):305–308Google Scholar
  60. 60.
    Bakker A, Maertens KJ, Van Son MJ, Van Loey NE (2013) Psychological consequences of pediatric burns from a child and family perspective: a review of the empirical literature. Clin Psychol Rev 33(3):361–371Google Scholar
  61. 61.
    Sund B (2000) New developments in wound care. PJB Publications, London. pp 1–255. (Clinical Report CBS 836.)Google Scholar
  62. 62.
    Van Loey NE, Bremer M, Faber AW, Middelkoop E, Nieuwenhuis MK (2008) Itching following burns: epidemiology and predictors. Br J Dermatol 158(1):95–100Google Scholar
  63. 63.
    Verhaegen PD, van Zuijlen PP, Pennings NM, van Marle J, Niessen FB, van der Horst CM, Middelkoop E (2009) Differences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: an objective histopathological analysis. Wound Repair Regen 17(5):649–656Google Scholar
  64. 64.
    Gebhardt C, Averbeck M, Diedenhofen N, Willenberg A, Anderegg U, Sleeman JP, Simon JC (2010) Dermal hyaluronan is rapidly reduced by topical treatment with glucocorticoids. J Invest Dermatol 130(1):141–149Google Scholar
  65. 65.
    Aya KL, Stern R (2014) Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen 22(5):579–593Google Scholar
  66. 66.
    King SR, Hickerson WL, Proctor KG (1991) Beneficial actions of exogenous hyaluronic acid on wound healing. Surgery 109(1):76–84Google Scholar
  67. 67.
    Hoffmann A, Hoing JL, Newman M, Simman R (2013) Role of hyaluronic acid treatment in the prevention of Keloid scarring. J Am Coll Clin Wound Spec. 4(2):23–31Google Scholar
  68. 68.
    Soranzo C, Renier D, Pavesio A (2004) Synthesis and characterization of hyaluronan-based polymers for tissue engineering. Methods Mol Biol 238:25–40Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery 2019

Authors and Affiliations

  1. 1.SOD Chirurgia Ricostruttiva e Chirurgia della Mano (Department of Reconstructive Surgery and Hand Surgery)AOU “Ospedali Riuniti”AnconaItaly
  2. 2.Centre of Epidemiology, Biostatistics and Medical Information Technology“Politecnica delle Marche” UniversityAnconaItaly

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