Abstract
Abnormal scarring and its accompanying esthetic, functional, and psychological sequelae still pose significant challe nges. To date, there is no satisfactory prevention or treatment option for hypertrophic scars (HSs), which is mostly due to not completely comprehending the mechanisms underlying their formation. That is why the apprehension of regular and controlled physiological processes of scar formation is of utmost importance when facing hypertrophic scarring, its pathophysiology, prevention, and therapeutic approach. When treating HSs and choosing the best treatment and prevention modality, physicians can choose from a plethora of therapeutic options and many commercially available products, among which currently there is no efficient option that can successfully overcome impaired skin healing. This article reviews current therapeutic approach and emerging therapeutic strategies for the management of HSs, which should be individualized, based on an evaluation of the scar itself, patients’ expectations, and practical, evidence-based guidelines. Clinicians are encouraged to combine various prevention and treatment modalities where combination therapy that includes steroid injections, 5-fluorouracil, and pulsed-dye laser seems to be the most effective. On the other hand, the current therapeutic options are usually empirical and their results are unreliable and unpredictable. Therefore, there is an unmet need for an effective, targeted therapy and prevention, which would be based on an action or a modulation of a particular factor with clarified mechanism of action that has a beneficial effect on wound healing. As the extracellular matrix has a crucial role in cellular and extracellular events that lead to pathological scarring, targeting its components mostly by regulating bone morphogenetic proteins may throw up new therapeutic approach for reduction or prevention of HSs with functionally and cosmetically acceptable outcome.
Introduction
Skin is the largest organ in the human body that is in constant contact with the environment with its primary role to adapt to stresses and tension and to protect other systems within the body. When injured, it must rapidly repair itself to maintain the cutaneous integrity and its external defense function. As a response to injury, at the site of tissue disruption, the highly organized process of wound healing instantly begins and ultimately results in the formation of a scar that never obtains the flexibility or the strength of the original tissue (1). The fact that in the developed countries about 100 million people per year form a dermal scar as a consequence of elective operations or injuries puts this problem among the most common in modern medicine and represents a huge cost to each health system (2, 3). We can expect around 30% of these to undergo abnormal growth due to aberrations in physiologic healing that result in hypertrophic scar (HS) or keloid formation, which are frequently accompanied by a number of esthetic, functional, and social impairments and may lead to decreased quality of life (4). Normotrophic, atrophic, hypertrophic, and keloid scars are all various types of scars with its different clinical appearance, etiology, and pathogenesis, demanding different therapeutic approach. The apprehension of regular and controlled physiological processes of scar formation is of the utmost importance when facing hypertrophic scarring, its pathophysiology, prevention, and therapeutic approach.
Methodology
In preparing this work, we used PubMed, Google Scholar, and Web of Science to perform literature searches on HS-related research. Key terms used in the search were “scarring,” “wound healing,” “hypertrophic scar,” “scar management,” “scar prevention,” and “scar treatment.” Review articles were used as an initial source of information and, where relevant, information from primary research papers was obtained.
Wound Healing and Scar Formation
When it comes to deep skin damage, the wound heals in a highly regulated series of dynamic and physiological processes involving various cells, matrix molecules, cytokines, and mediators (5). Wound healing is divided into continuous and overlapping phases including coagulation, inflammatory response phase (the first 48–72 h after the injury); proliferation phase that includes the formation of extracellular matrix (ECM), angiogenesis, and re-epithelization (days 4–21); and final remodeling or maturation phase, which may last up to a year (6, 7). This final regeneration phase results in the formation of a scar with excess collagen and an absence of cutaneous fat and hair follicles (1). Fibrillar collagen, as a main structural component of the ECM, has a crucial role both for the elasticity and the strength of an intact skin and scar tissue (8). Both normal and pathological scars are the result of deposition of collagen type I and III, although collagen synthesis in HSs is two to three times as much as in normotrophic scars (9). Collagen III increases more than type I in the early stages of wound healing but decreases during maturation phase to normal levels (10).
The Critical Role of Myofibroblasts and Other ECM Components
It is suggested today that it is the ECM that has the critical role in the scar formation (7). Major players involved in the ECM production are fibroblasts, myofibroblasts, transforming growth factor-beta (TGF-β), proteoglycans—decorin, laminin, and fibronectin, matrix metalloproteinases (MMPs), and bone morphogenetic proteins (BMPs) (7). A key role in the formation of dense collagen matrix during the maturation phase belongs to myofibroblasts originating from fibroblasts, which disappear by apoptosis during normal wound healing when epithelialization occurs (11–13). Various biological properties of both fibroblasts and myofibroblasts have profound impact on the progression and regression of HS. These complex processes are influenced by a signaling network involving different cytokines and growth factors of which are to mention, TGF-β, epidermal growth factor, platelet-derived growth factor, connective tissue growth factor (CTGF), and vascular endothelial growth factor, which is known as a key factor in angiogenesis essential for wound healing (14, 15). The transition from fibroblasts to myofibroblasts expressing α-smooth muscle actin (SMA) is influenced by cytokines, previously listed growth factors, especially TGF-β whose activity diminishes upon the completion of wound repair, mechanical stress, and cellular fibronectin (16). Myofibroblasts are responsible for the production of type I and III collagen, secretion of profibrotic cytokines, remodeling of an immature ECM, and wound contraction (12, 16, 17). Additionally, they produce MMPs that catalyze the hydrolysis of the main components of ECM as well as the activity of cytokines and growth factors (18, 19). Degradation of fibrillar collagen type I, II, and III is mediated by specific collagenases-1, 2, and 3 (MMP-1, 8, and 13) and gelatinases MMP-2 and MMP-9 (18). MMPs transcription is not only induced by glucocorticosteroids and interleukin (IL)-1 but also regulated by TGF-β and insulin-like growth factor-1 (20, 21). MMPs expression is low in intact skin, but after injuring their expression is increased (19). It has been demonstrated that inhibitors of MMPs slow wound healing in vivo, which indicates that the MMPs are the key regulators of many wound healing processes (19, 22). One of the most important MMPs for the formation of fibrous tissue is procollagen C proteinase-1, BMP1, of the BMP family, which cleaves the carboxylic pro-domain of procollagen I, II, and III to form the insoluble fibrillar collagen of exceptional tensile strength (23–25). Although isolated with other BMP molecules due to their affinity for the heparin, BMP1 does not share the same amino acid sequence homology with other BMPs so it is not an authentic member of the TGF-β superfamily. It belongs to the astacin/BMP1/tolloid-like family of zinc MMPs that are fundamental in the development and formation of the ECM (23, 26). The importance of BMP1 protein was stressed two decades ago by finding that Bmp1−/− mice die shortly after birth from the failure of ventral body wall closure due to abnormal collagen fibrillogenesis (27). To overcome issues of early lethality and functional redundancy in Bmp1−/− mice, Muir et al. (28) recently utilized BTKO mice with floxed Bmp1 and Tll1 alleles and they came to the findings that loss of the BMP1 proteinase activity resulted in delayed wound healing and significantly thinned and fragile skin with unusually densely grouped collagen fibrils. Their experiment confirmed BMP1-like proteinases as essential proteins to the structure and wound healing of the skin. BMP1 proteinases are crucial for the formation of ECM not only by direct influence to its formation but also indirectly by activating TGF-β superfamily members including BMP-2 and BMP-4, profibrotic TGF-β1, and growth and differentiation factors GDF-8/-11 and IGF (24, 26). To date, there are seven different isoforms of the BMP1 protein (25). A substantial progress in the field of fibrotic diseases in human has been made by findings of a number of BMP1 isoforms at the protein level in the circulation of patients with a variety of fibrotic conditions such as chronic kidney disease, acute bone fracture, acute myocardial infarction, but most importantly BMP1-3 isoform known as mammalian tolloid that circulates as an active enzyme in plasma samples of healthy individuals in lower concentrations (29, 30). Grgurevic et al. (29) utilized their findings of BMP1-3 protein and tested its effect in rats with chronic kidney disease where administration of rhBMP1-3 increased fibrosis, while BMP1-3 neutralizing antibody reduced it and was associated with low plasma levels of TGF-β1, CTGF, and decreased expression of decorin, suggesting that this pathway may be therapeutic target for fibrosis. Decorin is a small leucine-rich proteoglycan produced by myofibroblasts that regulates collagen fibrillogenesis, inhibits the proliferation of fibroblasts, and reduces production of TGF-β1 and collagen synthesis in HS fibroblasts whose production is here significantly increased (31–33). Another important proteoglycan that is produced by myofibroblasts, as well as by keratinocytes, endothelial cells, and dermal fibroblasts is cellular fibronectin. It is responsible for the formation of stable collagen I/III fibrillar network through a mechanism involving integrins (34) but it is also vital for regulating the neovascularization of granulation tissue (35).
Most recently, a breakthrough study that identifies another consequential role of myofibroblast was published (36). Although it has been thought that they are differentiated, this study showed that adipocytes may be regenerated from myofibroblasts during wound healing through activation of adipocyte transcription factors expressed during development, triggered by crucial BMP signaling from the actively growing hair follicles. These findings fortify the importance of BMPs during wound healing and scar formation and identify the myofibroblasts as a plastic cell type that may be manipulated to treat scars in humans.
Molecular Biology of Wound Healing
Transforming growth factor-beta/Smad signaling has a pivotal role in scar-mediated healing. Both TGF-β1 and TGF-β2 enhance scarring, i.e., promote fibrosis, whereas TGF-β3 reduces scarring; they act through binding to dimeric TGF-β receptor complexes (5, 37, 38). Upon activation, this receptor complex phosphorylates Smad2 and Smad3 proteins, which subsequently form dimers with Smad4 that are able to translocate to nucleus and act as a transcription factor that triggers target gene transcription including collagens I and III (39). TGF-β1 and TGF-β2 activate this dimeric receptor complex and thereby downstream Smad signaling, whereas TGF-β3 is a receptor antagonist that inhibits signal transduction (20, 40). Another Smad protein, Smad7, is thought to prevent Smad2/3-receptor interaction and subsequent phosphorylation that makes Smad7 as the negative feedback regulator of this profibrotic signal pathway. Inducing Smad 7 may be promising way to inhibit fibrosis and prevent HS formation (41). Not only that TGF-β influences collagen production directly through Smad signaling but also induces Smad 3 to transcribe proteins that activate the Wnt pathway that induces scarring (37, 42). It has been experimentally shown that targeting TGF-β/Smad pathway influences fibroblast proliferation and ECM deposition in HS (40, 43–45).
The local healing process is also influenced by systemic response to injury whereby increases in Th2 and possibly Th3 response cytokines such as IL-2, IL-4, IL-10, and TGF-β are found in the circulating lymphocytes in fibrotic conditions (46). Among the other momentous mediators of scarring, there are proinflammatory cytokines IL-6 and IL-8 that enhance scarring, and anti-inflammatory cytokine IL-10 that has the opposite effect (47).
We can say that the key to controlled scarring is a balance between proliferative processes in proliferative phase and degradation and remodeling processes in the early stage of maturation. Thus, the imbalance between proinflammatory, profibrotic growth factors such as TGF-β1 and 2 on one side, and antifibrotic factors such as TGF-β3 and MMPs on the other side, results in overabundant wound ECM or the formation of a HS. Under certain conditions, primarily due to imbalance of synthesis and degradation of collagen, normal scar is replaced by pathological fibrous tissue with decreased or absent cutaneous fat and hair follicles, containing the same ECM molecules as the tissue they replace, but in different ratios; increased production of collagen type I and III, fibronectin, and laminin, and decreased expression of the hyaluronic acid and decorin (7, 47, 48).
HSs Versus Keloids
Hypertrophic scars mostly develop within 1–3 months after deep skin injury, surgical procedure or burns, in contrast with keloids that may occur up to 12 months after injury or even develop spontaneously (49). Many factors such as age, genetic factors, race, hormone levels, and immunologic responses of the individuals appear to play a role (50–52). Not least important, are the type of injury, wound size and depth, anatomic region, and mechanical tension on the wound (20). Ogawa and Akaishi (51) proposed that all of this mentioned risk factors promote pathological scar formation by inducing endothelial dysfunction (i.e., vascular hyperpermeability) that prolongs and intensifies inflammation, thereby leading to fibroblast dysfunction. The first challenge when dealing with pathological scarring in daily clinical practice is a classification of a scar. Scars can be classified as mature, immature, linear hypertrophic, widespread hypertrophic, minor and major keloid (53). The diagnosis is usually clinical based upon scar appearance, etiology, and growth pattern. Based on current guidelines (54), immature scars are morphologically red and raised, are often associated with slight pain and pruritus, and evolve into mature scars that are pale, soft, narrow, and flat. Linear HSs are those scars that we use as a model of HS type with all of their typical characteristics described in Table 1. Extensive HSs present with irregular, highly erythematous surface and have hardened cord-like appearance. They are usually caused by thermal or chemical burns and lead to functional impairment due to contractures. The terms HS and keloid are often used inconsistently and interchangeably. Although there are clinical similarities between two of them, there are many pathological and biochemical differences that suggest that these entities are distinctive (55, 56). HSs are characterized as raised, pink or red scars, sometimes pruritic and painful, within the margins of the original wound (Figures 1A,B), that develop soon after surgery and usually subside with time as opposed to keloids (Figures 1C,D) that spread out of the margins of the wound, may develop months after the trauma, and continue to evolve over time without regression (49, 57). HSs and keloids are also distinguishable based on their histologic characteristics. HSs contain primarily type III collagen bundles that are oriented parallel to the epidermal surface arranged in a wavy pattern with abundant nodules containing myofibroblasts expressing α-SMA and large extracellular collagen filaments. In contrast, keloid tissue is composed of disorganized type I and III thick, eosinophilic collagen bundles that appear randomly oriented to the epithelial surface with no nodules or excess myofibroblasts (9, 56, 58, 59). To note is that HSs go through a remodeling phase, while keloids do not enter this final wound healing phase. Remodeling happens due to the presence of myofibroblasts in HSs that account for various processes during this phase and contraction of the wound. HS myofibroblasts are less responsive to apoptotic signals and produce more ECM components especially type I collagen, whose synthesis is seven times higher than normal (56). Treatment of HS is demanding, often painful, enduring, and mostly unsatisfactory (3). Due to the similar underlying pathophysiology, HSs and keloids may respond to the same treatment modalities. However, HSs are often more responsive and less prone to recurrence, which makes them therapeutically less challenging. To date, multiple invasive and non-invasive therapies have been used and proposed, but none of these has been adequately evaluated in high-quality studies (60). Management of HS has transitioned from invasive methods to intralesional and topical therapies that act at a cellular level (61).
Table 1
| HSs | Keloids |
|---|---|
| Frequent incidence | Rare incidence |
| Posttraumatic | Posttraumatic or spontaneous |
| Develop soon after surgery | May not begin for many months |
| Usually subside with time | Rarely subside with time |
| Remain within the wound boundaries | Spread outside the wound boundaries |
| No predominant anatomical site but often occur when skin creases are at right angle or when scars cross joints | Predominant anatomical sites (chest, shoulders, upper back, earlobes, posterior neck, knees) |
| Pruritic, rarely painful | Pruritic, painful |
| Less association with phototype | More common in darker skin types |
| Genetic predisposition | Less genetic predisposition |
| Improve with appropriate surgery, low recurrence rate | Often worsened by surgery, high recurrence rate |
| Increase collagen synthesis; 7 times higher than normal | Increase collagen synthesis; 20 times higher than normal |
| Collagen type I < III | Collagen type III < I |
| Fine collagen fibers organized into nodules, predominantly parallel | Large, thick collagen fibers, closely packed random to epidermis |
| Flatter collagen fibers in wavy pattern | Fibers lie haphazardly |
| High collagen cross-link | Collagen cross-link twice higher than in HS |
| Myofibroblasts that express α-SMA | Absence of myofibroblasts |
| Fibroblasts: ↑cell number, ↑↑proliferation, ↓↓apoptosis, ↑↑collagen I | ↑↑proliferation, ↑↑collagen I |
| ↑↑TGF-β1, ↑TGF-β2, ↓↓TGF-β3 | ↑↑TGF-β1, ↑↑TGF-β2, ↓↓TGF-β3 |
Differences in HSs and keloids.
↑, increase; ↓, decrease; SMA, smooth muscle actin; TGF-β, transforming growth factor-beta; HSs, hypertrophic scars.
Figure 1
Prevention is the Key
The most significant segment of an approach to hypertrophic scarring is its prevention. Before an elective surgery doctors should be informed if their patients have had previous problems with scarring. When performing surgery, incisions should follow Langer’s lines that correspond to the natural orientation of collagen fibers in the dermis and are parallel to the direction of the underlying muscle fibers (62). Incisions made parallel to Langer’s lines are known to heal better and produce less scarring than those that cut across (63). Also, it is important that all the incisions are closed with minimal tension that they do not cross joint spaces and that midchest incisions are avoided whenever possible (49). For the non-surgical wounds following trauma, it is crucial to debride contaminated ones and remove foreign bodies to minimize the inflammatory response; also, to promote adequate wound management with regular dressing changes to provide wound coverage and moist healing (57, 64). All the predisposed individuals presenting with any inflammatory skin problems as acne or deeper skin infections should be treated correspondingly to minimize inflammation (65). If we cannot avoid surgery in patients at a high risk of HS, immediate silicone-based products such as gels or sheeting with or without corticosteroid injections should be administered. Silicone sheeting is considered as the internationally recommended first-line option of scar management, which should be used after the wound has fully epithelialized (66). They should be applied for 12–24 h/day with daily washing for at least 2 months up to 1–2 years (54). Silicone gel is often preferred to sheeting from the perspective of ease of application and patient compliance especially when applied on the face, mobile areas, and in patients living in humid climates due to sheeting dislodgment. Silicone gel has been shown not to be inferior to sheeting in improving objective and subjective characteristics of scars, but it is superior in the ease of use (67). However, for extensive hypertrophic burn scars pressure garments still represent the first-line prophylactic therapy (68). The type of preventive scar measure that would be applied to a patient depends on the individual’s risk factors and his/her esthetic concerns. After trauma, in patients with moderate risk of scarring it is advised to apply silicone gels or dressings as preferred therapy, with topical products containing onion extracts or hypoallergenic adhesive tape for a few weeks after surgery as acceptable alternatives (69). In low-risk patients, we should just monitor wounds and prescribe silicone sheeting products for worried individuals (70). Other general measures to prevent HS formation include compression therapy, the use of moisturizers, manual massage, and strict UV photoprotection measures during scar formation and maturation phase to avoid hyperpigmentation (71, 72). As a rule, scars should be reevaluated 4–8 weeks after surgery to determine further management.
Scar Evaluation
If eventually scar forms, regardless of whether or not prophylactic measures were applied, it should be evaluated. When assessing scars, their size, color, contour, height (thickness), surface area, surface texture, pliability, location, and subjective symptoms such as itching and pain, and also patient’s perception should be taken into account. It has been indicated that this subjective component of the patient’s view of the scar is as important as objective aspect and it may be very influential in determining the patient’s quality of life (73, 74). Assessment of the scars is a frequent topic of discussion among clinicians because there is no generally accepted evaluation tool, although various ones have been proposed (75–77). None of these, however, seem suitable as a stand-alone tool, suggesting that combination of objective imaging tools and scar scales and questionnaires may be justified to achieve comprehensive documentation in everyday clinical practice (78).
Current Approach to HS Management
When dealing with future scar reduction modalities, it is of great importance for clinicians to not only discuss with patients their concerns, needs, and expectations but also to educate them about possible treatment options and their outcomes. The approach to treatment and its goals should be set for the individual patient based upon scar evaluation, patients’s characteristics, and expectations in order to reduce the scar volume, minimize subjective symptoms, i.e., pain and pruritus, and to improve function and esthetic appearance. As we have mentioned earlier, HSs are characterized by their ability to potentially regress over time. However, this maturation process is slow. So, the goal of the treatment is to stimulate this process to improve objective and subjective symptoms. According to updated international clinical recommendations on scar management (54) and others that adopted them (70), when treating linear or small HS resulting from trauma or surgery, silicone gel sheeting and topical onion extracts are considered as the first-line therapy. If there is no improvement within a month, we can start second-line therapy that is intralesional corticosteroid injections—triamcinolone acetonide 10–40 mg/mL with or without cryosurgery at monthly intervals for 3–4 months. Second-line therapy also includes laser therapy (pulsed-dye laser or fractional laser) and surgical excision in combination with postoperative silicone sheeting or postoperative intralesional corticosteroid/5-fluorouracil (5-FU) injections (79). Corticosteroids suppress healing and abnormal scarring by three mechanisms: vasoconstriction, anti-inflammatory and immunosuppressive effect, and inhibition of keratinocyte and fibroblast proliferation (80). When facing extensive HSs as are the postburn ones, of great importance is acute treatment at specialized burn centers where debridement and possible skin grafting are performed. Afterward, first-line therapy, as in linear HSs, includes silicone sheeting or gel and topical onion extracts. First-line also includes pressure garments that are also the first-line prophylactic therapy measure for postburn scars. Current international guidelines recommend ablative fractional laser, CO2 laser, as promising second-line therapy for this extensive HSs but also for inactive, linear HSs. The abovementioned commonly used and innovative scar-reducing modalities are presented in detail in Table 2.
Table 2
| Therapeutic modality (application) | Mechanism of action | Advantages | Disadvantages | Comment | Reference |
|---|---|---|---|---|---|
| Topical agents | |||||
| Silicone gel Silicone sheet | Optimal occlusion and hydration of the stratum corneum; ↓TEWL, subsequent ↓cytokine-mediated signaling from keratinocytes to dermal fibroblasts. Gentle reduction of tension. Static electricity | Easy to use, can be applied at home Non-invasive, safe, tolerated by children Multiple formulations and formats available | Sheets need to be washed daily. Risk of infection 6–12 months constant wear to achieve optimum results. Expensive | Should be avoided on open wounds Gel preferred over sheets on visible areas and in hot climates For prevention of HS; treatment can be considered as additional therapy in active HS Poor study design | (66, 81–83) |
| Onion extract creams | Anti-inflammatory effect, bactericidal, and inhibit fibroblast proliferation Flavonoids (quercetin and kaempferol) in onion extract play the main role in reducing scar formation through inhibition of fibroblast proliferation Induction of MMP-1 Inhibition of TGF-β1 and -β2 and SMAD proteins Improve color, stiffness, and irregularity of the scar | Well-tolerated preventative treatment | Need for early initiation | Onion extract therapy should be used in combination with an occlusive silicon dressing to achieve a satisfying decrease in scar thickness. Now available in form of an occlusive patch that has dual effect | (84–87) |
| Imiquimod 5% cream (alternate night applications for 2 months after surgery) | ↓TNF-α, INF-α, IL-1, IL-4, IL-5, IL-6, IL-8, IL-12, alters the expression of markers for apoptosis; improved scar quality | Minimal recurrence | May cause hyperpigmentation, irritation | Resting period from the treatments usually needed | (88, 89) |
| Intralesional injections | |||||
| Corticosteroid injections; TAC (10–40 mg/mL into papillary dermis every 2–4 weeks until scar is flattened) | Vasoconstrictive, anti-inflammatory, immunosuppressive effect. Inhibition of keratinocyte and fibroblast proliferation, glycosaminoglycan synthesis. ↓MMPs inhibitors | Inhibit the formation of HS. Reduce pain and pruritus | Multiple injections administered by a clinician. Discomfort, painful. Skin atrophy, telangiectasia, hypopigmentation | Monotherapy or in combination with two 15-s cryotherapy cycles prior to application to facilitate the injection through the development of edema, to reduce the pain and improve the result. Clinical benefit of adding 5-FU. TAC treatment can be performed on the day of surgery to prevent the formation of HS in patients at risk | (90–92) |
| 5-FU 50 mg/mL Weekly intervals, 2- or 4-week intervals; 3–6 injections TAC:5-FU 4:45 mg/mL (1:9); 10:37.5 (1:3) | Cell proliferation inhibition, ↑ fibroblast apoptosis, collagen-1 suppression, MMP-2 induction | No systemic side effects | Pain, purpura, burning sensation, transient hyperpigmentation Risk of ulcerations in dark-skinned patients | Alone or with corticosteroids (more effective and less painful); combination of TAC (40 mg/mL) and 5-FU (50 mg/mL) (1:3) injected intralesionally once weekly for 2 months—superior to exclusive weekly injection of TAC 40 mg/mL The addition of the pulsed-dye laser treatments is to be most effective Not recommended during pregnancy, bone marrow suppression, anemia, etc. At the start of treatment as well as after four injections a blood count should be done | (93–95) |
| Interferon therapy (INF-α, β, γ) INF-α2b—3 times weekly INF-γ—intralesionally once per week up to a dosage of 0.05 mg for 10 weeks or 0.01–0.1 mg 3 times a week/3 week | ↑Collagen breakdown, ↓TGF-β (Smad7 pathway), ↓ECM production, ↓ collagen I and III synthesis | No serious toxic effects Dermal cream containing liposome-encapsulated IFN-α2b | Painful when administered intralesionally. Flu-like symptoms. Expensive | Concept of the early topical use of this antifibrogenic agent for the treatment of dermal fibroproliferative disorders | (96, 97) |
| Bleomycin [intralesional multiple injections 0.1 mL (1.5 IU/mL) at a max dose of 6 mL, 2–6 sessions within a month] | Induces apoptosis, ↓TGF-β1—↓ collagen synthesis ↓Height, pliability as well as reduction in erythema, pruritus, and pain | Easy to administer, cheap, high regression rate, minimum complication and recurrence | Sporadically, development of depigmentation and dermal atrophy has been noted. Systemic toxic effects of intralesional injections appear to be rare | Considerable success. Due to its toxicity, clinicians are encouraged to be aware of associated potential problems Larger scale prospective studies needed | (98–100) |
| Verapamil (intralesional 2.5 mg/mL) | Stimulates procollagenase synthesis—↓collagen synthesis, ↑collagen breakdown, ↓scar elevation, vascularity, pliability | Low cost, fewer adverse effects | Monotherapy or as adjuvant therapy after excision with or without silicone | (101, 102) | |
| Botulinum toxin A Intralesional injections (2.5 U/mL at 1-month intervals) for 3 months 4–7 days before the surgery | ↓Erythema, itching sensation, and pliability Chemoimmobilization—temporary muscular paralysis, ↓tension vectors on wound edges, enhances scarring of facial wounds. ↓CTGF, ↓TGF-α1 | Acceptable for both doctors and patients Improvement and the rate of therapeutic satisfaction is very high | Expensive | Beneficial for use in young patients for wounds without tissue loss, lying perpendicular to the reduced tension lines of the skin of the face Larger, randomized, control studies are warranted | (103–105) |
| TGF-β and isomers avotermin (hrTGFβ-3) (50–500 ng/100 μg per linear centimeter of wound margin given once) | Significant improvement in scar appearance | Safe and tolerable | Prevention or reduction of scarring following surgery. Ongoing clinical trials | (106–108) | |
| Mannose-6-phosphate | Reduction of fibrosis by inhibiting TGF-β1 and 2 activation | Safe and tolerable | Clinical trial | ||
| Other current therapeutic options | |||||
| Compression therapy | |||||
| Elastic bandages or pressure garments (20–40 mmHg) | Reduction in scar thickness MMP-9 activation; prostanglandin E2↑, subsequent ↑collagenases. Pressure-induced hypoxic effects leading to collagen and fibroblast degeneration | Non-invasive. Can be applied at home Recommended for special locations (e.g., on the ear) | Expensive (custom made). Poor compliance (cause discomfort; 6–24 months constant wear to achieve optimum results). Sweating and swelling of the limbs; dermatitis, pressure erosions, and ulcerations can develop | Treatment of postburn scars and scars in children. Applied when wound is closed. Can be used in combination with silicones. The beneficial effects remain unproven | (109–113) |
| Cryotherapy (monthly sessions) | Induce vascular damage that may lead to anoxia and ultimately tissue necrosis ↓Scar volume, hardness, elevation, erythema | Easy to perform, low cost | Hypopigmentation, pain, moderate atrophy, protracted healing time | Useful on small lesions. Easy to perform. New intralesional cryoneedles have shown ↑ efficacy | (95, 114) |
| Surgery Z- or W-plasty, grafts, or local skin flaps | Interrupt the circle between scar tension and ensuing further thickening of the scar due to permanently stimulated ECM production | Invasive. Risk of recurrence | Z-plasty option for burns. Immediate postsurgical additional treatment needed to prevent regrowth First-line treatment if disabling scar contractures are present. Surgical therapy of HS without tension and without contractures, present less than 1 year, is not recommended | (115) | |
| Laser procedures | |||||
| Ablative lasers (CO2, Er:YAG) | Induction of capillary destruction—generates hypoxemia—alters local collagen production. ↑MMPs Improvement of pigmentation, vascularity, pliability, and scar height | Reach greater depths than a pulsed-dye laser | Mild side effects that include a prickling sensation during treatment and post-treatment erythema Erosions, weeping, and crusting can occur | For inactive HS with height differences, bridge or contracture formation. CO2 shows superior effectiveness. Fractional CO2 is option in postburn HS | (116) |
| Non-ablative lasers; pulsed-dye laser 585/595 nm | Induction of selective capillary destruction—generates hypoxemia—alters local collagen production. ↑MMPs | Minimal side effects, purpura usually persisting for 7–14 days | Expensive. Specialist referral needed. Vascular-specific | Excellent first-line treatment, preventive strategy for HS, reduce erythema primarily | (98, 117, 118) |
| Gold standard: application on the day of suture removal, 44.5 J/cm2 about 1.5–2 ms (every 3–4 weeks) | Reducing erythema, pruritus, pliability, improving skin texture | Depending on the energy density employed, vesicles and crusts may occur | Do not appear to be adequate for thick HS | ||
Treatment options for hypertrophic scars.
↑, increase; ↓, decrease; TEWL, transepidermal water loss; ECM, extracellular matrix; MMP, matrix metalloproteinase; HS, hypertrophic scar; CTGF, connective tissue growth factor; IL, interleukin; 5-FU, 5-fluorouracil; TAC, triamcinolone acetonide; TGF-β, transforming growth factor-beta.
Conclusion
Scarring and its accompanying esthetic, functional, and psychological sequelae still pose major challenges. To date, there is no satisfactory prevention or treatment option for HS, which is mostly due to not completely comprehending the mechanisms underlying their formation. A predominant role in hypertrophic scarring prevention and treatment still maintain silicone sheeting or gel. The efficacy and safety of this gold-standard, non-invasive therapy has been demonstrated in many clinical studies, but to date, exact mechanisms by which they improve HS are yet to be fully agreed upon. Second most validated and more specialized scar treatment is intralesional corticosteroid injections, especially in combination with other therapeutic modalities like 5-FU, which augment the result and reduce the side effects of corticosteroids. Current therapeutic approaches with their empirical effects are unreliable and unpredictable. Therefore, there is an unmet need for an effective, targeted therapy and prevention, which would be based on an action or a modulation of a specific factor with clarified mechanism of action that has a beneficial effect on wound healing. As the ECM is involved in cellular and extracellular events that lead to pathological scarring, targeting its components mostly by regulating BMPs may throw up new therapeutic approach for reduction or prevention of pathological scarring or HSs with functionally and cosmetically acceptable outcome.
Statements
Author contributions
ZM and AJ performed the literature review and wrote the manuscript. ID-Č participated in literature search and review. KK and RČ provided assistance in preparation of the tables. LG and BM revised the manuscript critically. All authors read and approved the final version of the submitted manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial and financial relationships that could be construed as a potential conflict of interest.
References
1
BorthwickLAWynnTAFisherAJ. Cytokine mediated tissue fibrosis. Biochim Biophys Acta (2013) 1832:1049–60.10.1016/j.bbadis.2012.09.014
2
SenCKGordilloGMRoySKirsnerRLambertLHuntTKet alHuman skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen (2009) 17:763–71.10.1111/j.1524-475X.2009.00543.x
3
GauglitzGGKortingHCPavicicTRuzickaTJeschkeMG. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med (2011) 17:113–25.10.2119/molmed.2009.00153
4
BockOSchmid-OttGMalewskiPMrowietzU. Quality of life of patients with keloid and hypertrophic scarring. Arch Dermatol Res (2006) 297:433–8.10.1007/s00403-006-0651-7
5
WernerSGroseR. Regulation of wound healing by growth factors and cytokines. Physiol Rev (2003) 83:835–70.10.1152/physrev.00031.2002
6
LiJChenJKirsnerR. Pathophysiology of acute wound healing. Clin Dermatol (2007) 25:9–18.10.1016/j.clindermatol.2006.09.007
7
XueMJacksonCJ. Extracellular matrix reorganization during wound healing and its impact on abnormal scarring. Adv Wound Care (New Rochelle) (2015) 4:119–36.10.1089/wound.2013.0485
8
KadlerKEHolmesDFTrotterJAChapmanJA. Collagen fibril formation. Biochem J (1996) 316:1–11.10.1042/bj3160001
9
LinaresHAKischerCWDobrkovskyMLarsonDL. The histiotypic organization of the hypertrophic scar in humans. J Invest Dermatol (1972) 59:323–31.10.1111/1523-1747.ep12627386
10
GaySVijantoJRaekallioJPenttinenR. Collagen types in early phases of wound healing in children. Acta Chir Scand (1977) 144:205–11.
11
SarrazyVBilletFMicallefLCoulombBDesmouliereA. Mechanisms of pathological scarring: role of myofibroblasts and current developments. Wound Repair Regen (2011) 19:s10–5.10.1111/j.1524-475X.2011.00708.x
12
HinzB. The role of myofibroblasts in wound healing. Curr Res Transl Med (2016) 64:171–7.10.1016/j.retram.2016.09.003
13
MicallefLVedrenneNBilletFCoulombBDarbyIADesmouliereA. The myofibroblast, multiple origins for major roles in normal and pathological tissue repair. Fibrogenesis Tissue Repair (2012) 5:S5.10.1186/1755-1536-5-s1-s5
14
LianNLiT. Growth factor pathways in hypertrophic scars: molecular pathogenesis and therapeutic implications. Biomed Pharmacother (2016) 84:42–50.10.1016/j.biopha.2016.09.010
15
DiPietroLA. Angiogenesis and wound repair: when enough is enough. J Leukoc Biol (2016) 100:979–84.10.1189/jlb.4MR0316-102R
16
GabbianiG. The myofibroblast in wound healing and fibrocontractive diseases. J Pathol (2003) 200:500–3.10.1002/path.1427
17
Bochaton-PiallatMLGabbianiGHinzB. The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Research (2016) 5:752.10.12688/f1000research.8190.1
18
KnapinskaAFieldsGB. Chemical biology for understanding matrix metalloproteinase function. Chembiochem (2012) 13:2002–20.10.1002/cbic.201200298
19
GillSEParksWC. Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol (2008) 40:1334–47.10.1016/j.biocel.2007.10.024
20
NiessenFBSpauwenPHSchalkwijkJKonM. On the nature of hypertrophic scars and keloids: a review. Plast Reconstr Surg (1999) 104:1435–58.10.1097/00006534-199910000-00031
21
GhaharyAShenYJNedelecBWangRScottPGTredgetEE. Collagenase production is lower in post-burn hypertrophic scar fibroblasts than in normal fibroblasts and is reduced by insulin-like growth factor-1. J Invest Dermatol (1996) 106:476–81.10.1111/1523-1747.ep12343658
22
Gutierrez-FernandezAInadaMBalbinMFueyoAPitiotASAstudilloAet alIncreased inflammation delays wound healing in mice deficient in collagenase-2 (MMP-8). FASEB J (2007) 21:2580–91.10.1096/fj.06-7860com
23
HopkinsDRKelesSGreenspanDS. The bone morphogenetic protein 1/Tolloid-like metalloproteinases. Matrix Biol (2007) 26:508–23.10.1016/j.matbio.2007.05.004
24
Vadon-Le GoffSHulmesDJMoaliC. BMP-1/tolloid-like proteinases synchronize matrix assembly with growth factor activation to promote morphogenesis and tissue remodeling. Matrix Biol (2015) 4(4–46):14–23.10.1016/j.matbio.2015.02.006
25
KesslerETakaharaKBiniaminovLBruselMGreenspanDS. Bone morphogenetic protein-1: the type I procollagen C-proteinase. Science (1996) 271:360–2.10.1126/science.271.5247.360
26
GeGGreenspanDS. Developmental roles of the BMP1/TLD metalloproteinases. Birth Defects Res C Embryo Today (2006) 78:47–68.10.1002/bdrc.20060
27
SuzukiNLaboskyPAFurutaYHargettLDunnRFogoABet alFailure of ventral body wall closure in mouse embryos lacking a procollagen C-proteinase encoded by Bmp1, a mammalian gene related to Drosophila tolloid. Development (1996) 122:3587–95.
28
MuirAMMassoudiDNguyenNKeeneDRLeeS-JBirkDEet alBMP1-like proteinases are essential to the structure and wound healing of skin. Matrix Biol (2016) 56:114–31.10.1016/j.matbio.2016.06.004
29
GrgurevicLMacekBHealyDRBraultALErjavecICipcicAet alCirculating bone morphogenetic protein 1-3 isoform increases renal fibrosis. J Am Soc Nephrol (2011) 22:681–92.10.1681/asn.2010070722
30
GrgurevicLMacekBMercepMJelicMSmoljanovicTErjavecIet alBone morphogenetic protein (BMP)1-3 enhances bone repair. Biochem Biophys Res Commun (2011) 408:25–31.10.1016/j.bbrc.2011.03.109
31
ZhangZLiXJLiuYZhangXLiYYXuWS. Recombinant human decorin inhibits cell proliferation and downregulates TGF-beta1 production in hypertrophic scar fibroblasts. Burns (2007) 33:634–41.10.1016/j.burns.2006.08.018
32
ZhangZGarronTMLiXJLiuYZhangXLiYYet alRecombinant human decorin inhibits TGF-beta1-induced contraction of collagen lattice by hypertrophic scar fibroblasts. Burns (2009) 35:527–37.10.1016/j.burns.2008.08.021
33
WangPLiuXXuPLuJWangRMuW. Decorin reduces hypertrophic scarring through inhibition of the TGF-beta1/Smad signaling pathway in a rat osteomyelitis model. Exp Ther Med (2016) 12:2102–8.10.3892/etm.2016.3591
34
ZoppiNGardellaRDe PaepeABarlatiSColombiM. Human fibroblasts with mutations in COL5A1 and COL3A1 genes do not organize collagens and fibronectin in the extracellular matrix, down-regulate alpha2beta1 integrin, and recruit alphavbeta3 instead of alpha5beta1 integrin. J Biol Chem (2004) 279:18157–68.10.1074/jbc.M312609200
35
ToWSMidwoodKS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair (2011) 4:21.10.1186/1755-1536-4-21
36
PlikusMVGuerrero-JuarezCFItoMLiYRDedhiaPHZhengYet alRegeneration of fat cells from myofibroblasts during wound healing. Science (2017) 355:748–52.10.1126/science.aai8792
37
SunQGuoSWangCCSunXWangDXuNet alCross-talk between TGF-beta/Smad pathway and Wnt/beta-catenin pathway in pathological scar formation. Int J Clin Exp Pathol (2015) 8(6):7631–9.
38
ArnoAIGauglitzGGBarretJPJeschkeMG. Up-to-date approach to manage keloids and hypertrophic scars: a useful guide. Burns (2014) 40:1255–66.10.1016/j.burns.2014.02.011
39
PakyariMFarrokhiAMaharlooeiMKGhaharyA. Critical role of transforming growth factor beta in different phases of wound healing. Adv Wound Care (New Rochelle) (2013) 2:215–24.10.1089/wound.2012.0406
40
ShahMForemanDMFergusonMW. Neutralisation of TGF-beta 1 and TGF-beta 2 or exogenous addition of TGF-beta 3 to cutaneous rat wounds reduces scarring. J Cell Sci (1995) 108:985–1002.
41
LiNKongMMaTGaoWMaS. Uighur medicine abnormal savda munzip (ASMq) suppresses expression of collagen and TGF-beta1 with concomitant induce Smad7 in human hypertrophic scar fibroblasts. Int J Clin Exp Med (2015) 8:8551–60.
42
RobertsABRussoAFeliciAFlandersKC. Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta. Ann N Y Acad Sci (2003) 995:1–10.10.1111/j.1749-6632.2003.tb03205.x
43
BaiXHeTLiuJWangYFanLTaoKet alLoureirin B inhibits fibroblast proliferation and extracellular matrix deposition in hypertrophic scar via TGF-beta/Smad pathway. Exp Dermatol (2015) 24:355–60.10.1111/exd.12665
44
BaiXZLiuJQYangLLFanLHeTSuLLet alIdentification of sirtuin 1 as a promising therapeutic target for hypertrophic scars. Br J Pharmacol (2016) 173:1589–601.10.1111/bph.13460
45
ZhaoJShuBChenLTangJZhangLXieJet alProstaglandin E2 inhibits collagen synthesis in dermal fibroblasts and prevents hypertrophic scar formation in vivo. Exp Dermatol (2016) 25:604–10.10.1111/exd.13014
46
ArmourAScottPGTredgetEE. Cellular and molecular pathology of HTS: basis for treatment. Wound Repair Regen (2007) 15:S6–17.10.1111/j.1524-475X.2007.00219.x
47
ProfyrisCTziotziosCDo ValeI. Cutaneous scarring: pathophysiology, molecular mechanisms, and scar reduction therapeutics Part I. The molecular basis of scar formation. J Am Acad Dermatol (2012) 66:1–10; quiz 1–2.10.1016/j.jaad.2011.05.055
48
SidgwickGPBayatA. Extracellular matrix molecules implicated in hypertrophic and keloid scarring. J Eur Acad Dermatol Venereol (2012) 26:141–52.10.1111/j.1468-3083.2011.04200.x
49
WolframDTzankovAPülzlPPiza-KatzerH. Hypertrophic scars and keloids—a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg (2009) 35:171–81.10.1111/j.1524-4725.2008.34406.x
50
EnglishRSShenefeltPD. Keloids and hypertrophic scars. Dermatol Surg (1999) 25:631–8.10.1046/j.1524-4725.1999.98257.x
51
OgawaRAkaishiS. Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis – keloids and hypertrophic scars may be vascular disorders. Med Hypotheses (2016) 96:51–60.10.1016/j.mehy.2016.09.024
52
ButzelaarLUlrichMMMink van der MolenABNiessenFBBeelenRH. Currently known risk factors for hypertrophic skin scarring: a review. J Plast Reconstr Aesthet Surg (2016) 69:163–9.10.1016/j.bjps.2015.11.015
53
MustoeTACooterRDGoldMHHobbsFRameletA-AShakespearePGet alInternational clinical recommendations on scar management. Plast Reconstr Surg (2002) 110:560–71.10.1097/00006534-200208000-00031
54
GoldMHBermanBClementoniMTGauglitzGGNahaiFMurciaC. Updated international clinical recommendations on scar management: part 1 – evaluating the evidence. Dermatol Surg (2014) 40:817–24.10.1111/dsu.0000000000000049
55
BurdAHuangL. Hypertrophic response and keloid diathesis: two very different forms of scar. Plast Reconstr Surg (2005) 116:150e–7e.10.1097/01.prs.0000191977.51206.43
56
VerhaegenPDVan ZuijlenPPPenningsNMVan MarleJNiessenFBVan Der HorstCMet alDifferences in collagen architecture between keloid, hypertrophic scar, normotrophic scar, and normal skin: an objective histopathological analysis. Wound Repair Regen (2009) 17:649–56.10.1111/j.1524-475X.2009.00533.x
57
SlempAEKirschnerRE. Keloids and scars: a review of keloids and scars, their pathogenesis, risk factors, and management. Curr Opin Pediatr (2006) 18:396–402.10.1097/01.mop.0000236389.41462.ef
58
LeeJYYangCCChaoSCWongTW. Histopathological differential diagnosis of keloid and hypertrophic scar. Am J Dermatopathol (2004) 26:379–84.10.1097/00000372-200410000-00006
59
EhrlichHPDesmouliereADiegelmannRFCohenIKComptonCCGarnerWLet alMorphological and immunochemical differences between keloid and hypertrophic scar. Am J Pathol (1994) 145:105–13.
60
KhansaIHarrisonBJanisJE. Evidence-based scar management: how to improve results with technique and technology. Plast Reconstr Surg (2016) 138:165s–78s.10.1097/prs.0000000000002647
61
VieraMHAminiSValinsWBermanB. Innovative therapies in the treatment of keloids and hypertrophic scars. J Clin Aesthet Dermatol (2010) 3:20–6.
62
CarmichaelSW. The tangled web of Langer’s lines. Clin Anat (2014) 27:162–8.10.1002/ca.22278
63
BurkeM. Scars. Can they be minimised?Aust Fam Physician (1998) 27:275–8.
64
BloemenMCvan der VeerWMUlrichMMvan ZuijlenPPNiessenFBMiddelkoopE. Prevention and curative management of hypertrophic scar formation. Burns (2009) 35:463–75.10.1016/j.burns.2008.07.016
65
OgawaR. The most current algorithms for the treatment and prevention of hypertrophic scars and keloids. Plast Reconstr Surg (2010) 125:557–68.10.1097/PRS.0b013e3181c82dd5
66
BleasdaleBFinneganSMurrayKKellySPercivalSL. The use of silicone adhesives for scar reduction. Adv Wound Care (New Rochelle) (2015) 4:422–30.10.1089/wound.2015.0625
67
ChernoffWGCramerHSu-HuangS. The efficacy of topical silicone gel elastomers in the treatment of hypertrophic scars, keloid scars, and post-laser exfoliation erythema. Aesthetic Plast Surg (2007) 31:495–500.10.1007/s00266-006-0218-1
68
MacintyreLBairdM. Pressure garments for use in the treatment of hypertrophic scars – a review of the problems associated with their use. Burns (2006) 32:10–5.10.1016/j.burns.2004.06.018
69
Del ToroDDedhiaRTollefsonTT. Advances in scar management: prevention and management of hypertrophic scars and keloids. Curr Opin Otolaryngol Head Neck Surg (2016) 24:322–9.10.1097/moo.0000000000000268
70
PoetschkeJGauglitzGG. Current options for the treatment of pathological scarring. J Dtsch Dermatol Ges (2016) 14:467–77.10.1111/ddg.13027
71
MeaumeSLe Pillouer-ProstARichertBRoseeuwDVadoudJ. Management of scars: updated practical guidelines and use of silicones. Eur J Dermatol (2014) 24:435–43.10.1684/ejd.2014.2356
72
DueERossenKSorensenLTKliemAKarlsmarkTHaedersdalM. Effect of UV irradiation on cutaneous cicatrices: a randomized, controlled trial with clinical, skin reflectance, histological, immunohistochemical and biochemical evaluations. Acta Derm Venereol (2007) 87:27–32.10.2340/00015555-0154
73
PowersPSSarkarSGoldgofDBCruseCWTsapLV. Scar assessment: current problems and future solutions. J Burn Care Rehabil (1999) 20:54–60; discussion 53.10.1097/00004630-199901001-00011
74
CollinsLKKnackstedtTJGangerPSchererESamieFH. Applying a visual assessment tool to facial linear scars. Facial Plast Surg (2017) 33:97–101.10.1055/s-0036-1597684
75
IdrissNMaibachHI. Scar assessment scales: a dermatologic overview. Skin Res Technol (2009) 15:1–5.10.1111/j.1600-0846.2008.00327.x
76
SeoSRKangNOYoonMSLeeHJKimDH. Measurements of scar properties by SkinFibroMeter(R), SkinGlossMeter(R), and Mexameter(R) and comparison with Vancouver Scar Scale. Skin Res Technol (2016) 66:251–9.10.1111/srt.12334
77
ReinholzMSchwaigerHPoetschkeJEppleARuzickaTVon BraunmuhlTet alObjective and subjective treatment evaluation of scars using optical coherence tomography, sonography, photography, and standardised questionnaires. Eur J Dermatol (2016) 26:599–608.10.1684/ejd.2016.2873
78
PoetschkeJSchwaigerHGauglitzGG. Current and emerging options for documenting scars and evaluating therapeutic progress. Dermatol Surg (2017) 43:25–36.10.1097/dss.0000000000000698
79
RenYZhouXWeiZLinWFanBFengS. Efficacy and safety of triamcinolone acetonide alone and in combination with 5-fluorouracil for treating hypertrophic scars and keloids: a systematic review and meta-analysis. Int Wound J (2017) 14:480–7.10.1111/iwj.12629
80
AtiyehBS. Nonsurgical management of hypertrophic scars: evidence-based therapies, standard practices, and emerging methods. Aesthetic Plast Surg (2007) 31:468–92.10.1007/s00266-006-0253-y
81
BermanBPerezOAKondaSKohutBEVieraMHDelgadoSet alA review of the biologic effects, clinical efficacy, and safety of silicone elastomer sheeting for hypertrophic and keloid scar treatment and management. Dermatol Surg (2007) 33:1291–302; discussion 302–3.10.1111/j.1524-4725.2007.33280.x
82
MustoeTA. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic Plast Surg (2008) 32:82–92.10.1007/s00266-007-9030-9
83
SignoriniMClementoniMT. Clinical evaluation of a new self-drying silicone gel in the treatment of scars: a preliminary report. Aesthetic Plast Surg (2007) 31:183–7.10.1007/s00266-005-0122-0
84
HosnuterMPayasliCIsikdemirATekerekogluB. The effects of onion extract on hypertrophic and keloid scars. J Wound Care (2007) 16:251–4.10.12968/jowc.2007.16.6.27070
85
Ocampo-CandianiJVazquez-MartinezOTIglesias BenavidesJLBuskeKLehnAAckerC. The prophylactic use of a topical scar gel containing extract of Allium cepae, allantoin, and heparin improves symptoms and appearance of cesarean-section scars compared with untreated scars. J Drugs Dermatol (2014) 13:176–82.
86
ChoJWChoSYLeeSRLeeKS. Onion extract and quercetin induce matrix metalloproteinase-1 in vitro and in vivo. Int J Mol Med (2010) 25:347–52.
87
PhanTTLimIJChanSYTanEKLeeSTLongakerMT. Suppression of transforming growth factor beta/Smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma (2004) 57:1032–7.10.1097/01.TA.0000114087.46566.EB
88
PradoAAndradesPBenitezSUmanaM. Scar management after breast surgery: preliminary results of a prospective, randomized, and double-blind clinical study with aldara cream 5% (imiquimod). Plast Reconstr Surg (2005) 115:966–72.10.1097/01.PRS.0000153823.52784.7E
89
FooCWTristani-FirouziP. Topical modalities for treatment and prevention of postsurgical hypertrophic scars. Facial Plast Surg Clin North Am (2011) 19:551–7.10.1016/j.fsc.2011.06.008
90
JuckettGHartman-AdamsH. Management of keloids and hypertrophic scars. Am Fam Physician (2009) 80:253–60.
91
HuangLCaiYJLungILeungBCBurdA. A study of the combination of triamcinolone and 5-fluorouracil in modulating keloid fibroblasts in vitro. J Plast Reconstr Aesthet Surg (2013) 66:e251–9.10.1016/j.bjps.2013.06.004
92
Boutli-KasapidouFTsakiriAAnagnostouEMourellouO. Hypertrophic and keloidal scars: an approach to polytherapy. Int J Dermatol (2005) 44:324–7.10.1111/j.1365-4632.2004.02570.x
93
FitzpatrickRE. Treatment of inflamed hypertrophic scars using intralesional 5-FU. Dermatol Surg (1999) 25:224–32.10.1046/j.1524-4725.1999.08165.x
94
AsilianADaroughehAShariatiF. New combination of triamcinolone, 5-fluorouracil, and pulsed-dye laser for treatment of keloid and hypertrophic scars. Dermatol Surg (2006) 32:907–15.10.1111/j.1524-4725.2006.32195.x
95
LedonJASavasJFrancaKChaconANouriK. Intralesional treatment for keloids and hypertrophic scars: a review. Dermatol Surg (2013) 39:1745–57.10.1111/dsu.12346
96
LarrabeeWFJrEastCAJaffeHSStephensonCPetersonKE. Intralesional interferon gamma treatment for keloids and hypertrophic scars. Arch Otolaryngol Head Neck Surg (1990) 116:1159–62.10.1001/archotol.1990.01870100053011
97
TakeuchiMTredgetEEScottPGKilaniRTGhaharyA. The antifibrogenic effects of liposome-encapsulated IFN-alpha2b cream on skin wounds. J Interferon Cytokine Res (1999) 19:1413–9.10.1089/107999099312876
98
GauglitzGG. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol (2013) 6:103–14.10.2147/CCID.S35252
99
NaeiniFFNajafianJAhmadpourK. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg (2006) 32:1023–9; discussion 9–30.10.1111/j.1524-4725.2006.32225.x
100
AggarwalHSaxenaALubanaPSMathurRKJainDK. Treatment of keloids and hypertrophic scars using bleom. J Cosmet Dermatol (2008) 7:43–9.10.1111/j.1473-2165.2008.00360.x
101
AhujaRBChatterjeeP. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2014) 40:583–8.10.1016/j.burns.2013.09.029
102
Margaret ShanthiFXErnestKDhanrajP. Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian J Dermatol Venereol Leprol (2008) 74:343–8.10.4103/0378-6323.42899
103
ZiadeMDomergueSBatifolDJreigeRSebbaneMGoudotPet alUse of botulinum toxin type A to improve treatment of facial wounds: a prospective randomised study. J Plast Reconstr Aesthet Surg (2013) 66:209–14.10.1016/j.bjps.2012.09.012
104
XiaoZZhangMLiuYRenL. Botulinum toxin type a inhibits connective tissue growth factor expression in fibroblasts derived from hypertrophic scar. Aesthetic Plast Surg (2011) 35:802–7.10.1007/s00266-011-9690-3
105
XiaoZZhangFCuiZ. Treatment of hypertrophic scars with intralesional botulinum toxin type A injections: a preliminary report. Aesthetic Plast Surg (2009) 33:409–12.10.1007/s00266-009-9334-z
106
DuraniPOcclestonNO’KaneSFergusonMW. Avotermin: a novel antiscarring agent. Int J Low Extrem Wounds (2008) 7:160–8.10.1177/1534734608322983
107
OcclestonNLO’kaneSLavertyHGCooperMFairlambDMasonTet alDiscovery and development of avotermin (recombinant human transforming growth factor beta 3): a new class of prophylactic therapeutic for the improvement of scarring. Wound Repair Regen (2011) 19(s1):s38–48.10.1111/j.1524-475X.2011.00711.x
108
TziotziosCProfyrisCSterlingJ. Cutaneous scarring: pathophysiology, molecular mechanisms, and scar reduction therapeutics Part II. Strategies to reduce scar formation after dermatologic procedures. J Am Acad Dermatol (2012) 66:13–24.10.1016/j.jaad.2011.08.035
109
EngravLHHeimbachDMRivaraFPMooreMLWangJCarrougherGJet al12-Year within-wound study of the effectiveness of custom pressure garment therapy. Burns (2010) 36:975–83.10.1016/j.burns.2010.04.014
110
AnzarutAOlsonJSinghPRoweBHTredgetEE. The effectiveness of pressure garment therapy for the prevention of abnormal scarring after burn injury: a meta-analysis. J Plast Reconstr Aesthet Surg (2009) 62:77–84.10.1016/j.bjps.2007.10.052
111
Li-TsangCWZhengYPLauJC. A randomized clinical trial to study the effect of silicone gel dressing and pressure therapy on posttraumatic hypertrophic scars. J Burn Care Res (2010) 31:448–57.10.1097/BCR.0b013e3181db52a7
112
RenoFGrazianettiPStellaMMagliacaniGPezzutoCCannasM. Release and activation of matrix metalloproteinase-9 during in vitro mechanical compression in hypertrophic scars. Arch Dermatol (2002) 138:475–8.10.1001/archderm.138.4.475
113
RenoFGrazianettiPCannasM. Effects of mechanical compression on hypertrophic scars: prostaglandin E2 release. Burns (2001) 27:215–8.10.1016/S0305-4179(00)00101-7
114
WeshahyAHAbdel HayR. Intralesional cryosurgery and intralesional steroid injection: a good combination therapy for treatment of keloids and hypertrophic scars. Dermatol Ther (2012) 25:273–6.10.1111/j.1529-8019.2012.01456.x
115
OgawaRAkaishiSHuangCDohiTAokiMOmoriYet alClinical 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 (2011) 78:68–76.10.1272/jnms.78.68
116
KoikeSAkaishiSNagashimaYDohiTHyakusokuHOgawaR. Nd:YAG laser treatment for keloids and hypertrophic scars: an analysis of 102 cases. Plast Reconstr Surg Glob Open (2014) 2:e272.10.1097/gox.0000000000000231
117
VrijmanCvan DroogeAMLimpensJBosJDvan der VeenJPSpulsPIet alLaser and intense pulsed light therapy for the treatment of hypertrophic scars: a systematic review. Br J Dermatol (2011) 165:934–42.10.1111/j.1365-2133.2011.10492.x
118
AllisonKPKiernanMNWatersRAClementRM. Pulsed dye laser treatment of burn scars. Alleviation or irritation?Burns (2003) 29:207–13.
Summary
Keywords
wound healing, skin scarring, hypertrophic scar, scar management, topical therapy, prevention, treatment
Citation
Mokos ZB, Jović A, Grgurević L, Dumić-Čule I, Kostović K, Čeović R and Marinović B (2017) Current Therapeutic Approach to Hypertrophic Scars. Front. Med. 4:83. doi: 10.3389/fmed.2017.00083
Received
17 March 2017
Accepted
06 June 2017
Published
20 June 2017
Volume
4 - 2017
Edited by
Gregor Jemec, University of Copenhagen, Denmark
Reviewed by
Cristina Has, Albert Ludwig University of Freiburg, Germany; Elisabetta Palazzo, Universita’ di Modena, Italy
Updates
Copyright
© 2017 Mokos, Jović, Grgurević, Dumić-Čule, Kostović, Čeović and Marinović.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zrinka Bukvić Mokos, zrinka.bukvic@zg.t-com.hr
Specialty section: This article was submitted to Dermatology, a section of the journal Frontiers in Medicine
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