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.
Similar content being viewed by others
References
Tredget EE (1994) The molecular biology of fibroproliferative disorders of the skin: potential cytokine therapeutics. Ann Plast Surg 33(2):152–154
Murray JC (1994) Keloids and hypertrophic scars. Clin Dermatol 12(1):27–37
Juckett G, Hartman-Adams H (2009) Management of keloids and hypertrophic scars. Am Fam Physician 80(3):253–260
Ogawa R, Akaishi S, Hyakusoku H (2009) Differential and exclusive diagnosis of diseases that resemble keloids and hypertrophic scars. Ann Plast Surg 62(6):660–664
Ogawa R, Akaishi S, Izumi M (2009) Histologic analysis of keloids and hypertrophic scars. Ann Plast Surg 62(1):104–105
Broughton G 2nd, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117(7 Suppl):12S–34S
Enoch S, Leaper DJ (2008) Basic science of wound healing. Surgery 26(2):31–37
Martin P, Nunan R (2015) Cellular and molecular mechanisms of repair in acute and chronic wound healing. Br J Dermatol 173(2):370–378
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):81–94
McDonald J, Hascall VC (2002) Hyaluronan minireview series. J Biol Chem 277(7):4575–4579
Dunphy JE (1978) Wound healing. Surg Clin North Am 58(5):907–916
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):349–363
Jenkins RH, Thomas GJ, Williams JD, Steadman R (2004) Myofibroblastic differentiation leads to hyaluronan accumulation through reduced hyaluronan turnover. J Biol Chem 279(40):41453–41460
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):84–92
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):2046–2058
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):953–959
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):377–379
Bertheim U, Hellström S (1994) The distribution of hyaluronan in human skin and mature, hypertrophic and keloid scars. Br J Plast Surg 47(7):483–489
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):68–76
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–e168
Roques C, Téot L (2008) The use of corticosteroids to treat keloids: a review. Int J Low Extrem Wounds 7(3):137–145
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):508–513
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):473–475
Maján JI (2006) Evaluation of a self-adherent soft silicone dressing for the treatment of hypertrophic postoperative scars. J Wound Care 15(5):193–196
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):1003–1007
Carroll W, Patel K (2015) Steroids and fluorouracil for keloids and hypertrophic scars. JAMA Facial Plast Surg 17(2):77–79
Haurani MJ, Foreman K, Yang JJ, Siddiqui A (2009) 5-Fluorouracil treatment of problematic scars. Plast Reconstr Surg 123(1):139–148
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):83–90
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):461–468
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):797–804
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):957–964
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):218–221
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):387–394
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):219–223
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):166–170
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):2648–2657
Seo BF, Jung SN (2016) The immunomodulatory effects of mesenchymal stem cells in prevention or treatment of excessive scars. Stem Cells Int 2016:6937976
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):245–253
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):145
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–376e
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):1377–1382
Abate M, Schiavone C, Salini V (2014) The use of hyaluronic acid after tendon surgery and in tendinopathies. Biomed Res Int 2014:783632
Matarasso SL (2004) Understanding and using hyaluronic acid. Aesthet Surg J 24(4):361–364
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):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):47–53
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):408–415
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):217–221
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):1461–1464
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):648–652
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):2–7
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):130–138
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):341–346
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):520–529
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):5368–5374
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):36–40
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):514–522
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):1960–1965
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
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):305–308
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):361–371
Sund B (2000) New developments in wound care. PJB Publications, London. pp 1–255. (Clinical Report CBS 836.)
Van Loey NE, Bremer M, Faber AW, Middelkoop E, Nieuwenhuis MK (2008) Itching following burns: epidemiology and predictors. Br J Dermatol 158(1):95–100
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):649–656
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):141–149
Aya KL, Stern R (2014) Hyaluronan in wound healing: rediscovering a major player. Wound Repair Regen 22(5):579–593
King SR, Hickerson WL, Proctor KG (1991) Beneficial actions of exogenous hyaluronic acid on wound healing. Surgery 109(1):76–84
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):23–31
Soranzo C, Renier D, Pavesio A (2004) Synthesis and characterization of hyaluronan-based polymers for tissue engineering. Methods Mol Biol 238:25–40
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Riccio, M., Marchesini, A., Senesi, L. et al. Managing Pathologic Scars by Injecting Auto-Cross-linked Hyaluronic Acid: A Preliminary Prospective Clinical Study. Aesth Plast Surg 43, 480–489 (2019). https://doi.org/10.1007/s00266-018-01303-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00266-018-01303-3