Table 2.

Treatment options for hypertrophic scars.

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

↑, 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.