ESTRATEGIA DE COMUNICACIÓN: PÚBLICOS DE INTERÉS

Both of these pathological scarring phenotypes have an impact on patients quality of life, with some causing considerable disability and psychological implications. It has a huge clinical burden, as approximately 100 million patients per year in the developed world, develop a scar following surgery (English & Shenefelt 1999; Al-Attar et al. 2006; Gurtner et al. 2008; Gauglitz et al. 2011; Ding & Tredget 2015; Andrews et al. 2016). There are a number of treatment options available for keloids and hypertrophic scars, often one of the first options is surgery to remove the excess scar tissue. Hypertrophic scars do not recur following surgical removal of the scar tissue and may resolve themselves if left for a longer period (English & Shenefelt 1999; Niessen et al. 1999; Broughton et al. 2006b; Bran et al. 2009; Gauglitz et al. 2011; Rabello et al. 2014). In nearly 100% of the cases, keloid scar tissue will reoccur and despite this probability, it is often still the first treatment strategy. However, as surgical excision creates another wound site, many cases have shown the formation of a larger keloid at the original site (Berman & Bieley 1996; English & Shenefelt 1999; Al-Attar et al. 2006; Broughton et al. 2006b; Slemp & Kirschner 2006; Bran et al. 2009; Gauglitz et al. 2011; Rabello et al. 2014) .

In patients known to form keloids or hypertrophic scar, there are a variety of preventative treatment options; these include pressure therapy, silicone gel sheeting, silicone gel and flavonoids (English & Shenefelt 1999; Al-Attar et al. 2006; Slemp & Kirschner 2006; Gauglitz et al. 2011; Gold et al. 2014; Andrews et al. 2016; Trace et al. 2016). These treatment options are prophylactic, so are not suitable on formed keloids or hypertrophic scars, they can only be used in a preventative manner. These treatments often need to be performed for several months, in order to prevent scar

72 formation (Kischer et al. 1975; English & Shenefelt 1999; Gauglitz et al. 2011; Gold et al. 2014). Pressure therapy has been shown to be successful, but requires pressure to be exerted onto the site for 18-24 hours, for several months. It is thought that this pressure impacts on ECM synthesis and degradation, increasing degradation and resulting in decreased presence of chrondroitin sulphate. Additionally, compression therapy has been shown to increase prostaglandin E2 (PGE2) levels, reducing collagen

synthesis. This process resolves the scar, however, due to the discomfort with this therapy, there is a reduced patient compliance (Kischer et al. 1975; Reno et al. 2001; Al-Attar et al. 2006; Broughton et al. 2006b; Gauglitz et al. 2011; Trace et al. 2016). Silicone gel sheeting, or silicone gel in areas of continuous movement, is another recognised therapy. It is thought that the beneficial response is a result of maintained hydration of the wound site (Lyle 2001; Broughton et al. 2006b; Zurada et al. 2006; Atiyeh 2007; Ogawa 2010; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014). This hydration may have a positive effect on the keratinocytes and result in beneficial fibroblast function and response to growth factors and the subsequent reduced deposition of collagen (Niessen et al. 1998; Lyle 2001; Broughton et al. 2006b; Zurada et al. 2006; Atiyeh 2007; Mustoe 2008; Rabello et al. 2014). Flavonoids are a topical cream, which are thought to possess anti-fibrotic properties, through the inhibition of fibroblast proliferation, synthesis of collagen and wound contracture (Atiyeh 2007; Cho et al. 2010; Gauglitz et al. 2011; Kandasamy et al. 2011).

The current therapies available for treating developed scars, include corticosteroids, cryotherapy, scar revision, radiotherapy and laser therapy (Al-Attar et al. 2006; Broughton et al. 2006b; Slemp & Kirschner 2006; Atiyeh 2007; Ogawa 2010; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014; Trace et al. 2016). Corticosteroids are often one of the main initial treatment options, especially for keloids. This dampens the inflammatory response, which reduces the downstream responses, resulting in reduced fibroblast proliferation and collagen deposition. Several applications are typically required and successful scar resolution can occur in 50-100% cases. However, recurrence can occur in up to 50% of cases (Maguire Jr. 1965; Chowdri et al. 1999; Niessen et al. 1999; Roques & Téot 2008; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014). Cryotherapy is of use in small scars and induces damage to the vasculature through spray application of liquid nitrogen. Application has been

73 delivered through intralesional-needle cryoprobe, which reduces scar volume by approximately 50% (Zouboulis et al. 1993; Zouboulis et al. 2002; Har-Shai et al. 2003; Broughton et al. 2006b; Gauglitz et al. 2011; Trace et al. 2016). Radiotherapy has been a therapeutic option towards keloids for many years and successful treatment probabilities have increased over the years, with approximately 64-98% successful scar resolution. It is thought to inhibit the proliferation of fibroblasts in the keloid, increase the rate of keloid fibroblast apoptosis, decreasing collagen deposition. However, the treatment dose is restricted due to potential side effects, including atrophy and erythema (Levy et al. 1976; Niessen et al. 1999; Ogawa et al. 2003; Al- Attar et al. 2006; Broughton et al. 2006b; Gauglitz et al. 2011; Lee & Park 2015). Laser therapy has been used on keloids, using a pulsed-dye laser. This is also beneficial to early hypertrophic scars. It is also thought to impact on fibroblast proliferation and the downstream functions of the cell, whilst causing minimal contraction of the scar (Alster & Williams 1995; Alster & Nanni 1998; Broughton et al. 2006b; Bouzari et al. 2007; Parrett & Donelan 2010; Gauglitz et al. 2011; Jin et al. 2013). Despite the wide range of treatment options, often requiring multiple applications, there are few studies showing their effectiveness. Additionally, there is a wide range in the chance of a successful outcome, with a high incidence of recurrence for keloid scars; a number of side effects have also been associated with these treatments (Al-Attar et al. 2006; Broughton et al. 2006b; Slemp & Kirschner 2006; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014; Trace et al. 2016).

More recently introduced therapies include interferon (IFN-α-2b) and 5-fluorouracil (5-FU); both of which are injected into the scar tissue site (Al-Attar et al. 2006; Broughton et al. 2006b; Atiyeh 2007; Ogawa 2010; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014; Trace et al. 2016). IFN-α was shown to be decreased in keloids and injection of IFN-α-2b may impair fibroblast function, in particular the deposition of collagen. This is also due to increased collagenase activity. It has also been shown to reduce the proliferative action of fibroblasts, reducing their overall presence at the scar site; although some studies have reported this treatment to be ineffective (Wong et al. 1994; Berman & Flores 1997; Al-Attar et al. 2006; Broughton et al. 2006b; Davison et al. 2006; Slemp & Kirschner 2006; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014). However, there are side effects with application of

74 IFN-α-2b. These are typically flu-like symptoms, including fever, along with pain on injection, in addition it is an expensive therapy (Al-Attar et al. 2006; Broughton et al. 2006b; Slemp & Kirschner 2006; Gauglitz et al. 2011; Rabello et al. 2014). 5-FU increases fibroblast apoptosis in keloids and inflamed hypertrophic scars. This along with an inhibited fibroblast proliferation reduces their presence and the subsequent amount of collagen synthesised (Uppal et al. 2001; Kontochristopoulos et al. 2005; Broughton et al. 2006b; Gauglitz et al. 2011; Wilson 2013; Gold et al. 2014; Rabello et al. 2014; Jones et al. 2015; Shah et al. 2016). It has been shown to more effective when given alongside corticosteroid treatment, with a reduction in scar size by approximately 50% appears to occur in most patients (Asilian et al. 2006; Broughton et al. 2006b; Davison et al. 2009; Gauglitz et al. 2011; Gold et al. 2014; Rabello et al. 2014). Despite the beneficial responses seen, there are a few side effects observed in this treatment, including pain on injection, burning sensation and formation of ulcers (Apikian & Goodman 2004; Kontochristopoulos et al. 2005; Al-Attar et al. 2006; Gauglitz et al. 2011; Trace et al. 2016). More successful treatment options are essential for the resolution of these debilitating pathological scars. Consequently, further understanding of the aetiology and pathogenesis of keloids and hypertrophic scars may elucidate target mechanisms for successful outcomes (Al-Attar et al. 2006; Slemp & Kirschner 2006; Atiyeh 2007; Gauglitz et al. 2011; Rabello et al. 2014; Trace et al. 2016).