[Scar Treatment] #3. Drugs and Topical Agents for Hypertrophic Scar and Keloid Treatment I

1. Scar treatment by pressure, humidification and occlusion

Despite lack of controlled studies, pressure therapy is empirically considered as effective for scar treatment. Generally 25-40mmHg is required, but occlusive dressing of scar area with lower pressure tape is also known to be effective. It is therefore considered useful to some extent to apply pressure with currently available DuoDerm, MediForm and common Band Aids. The mechanism of treatment is suspected diversely from reduced dermal thickness to reduced edema, and reduced fibroblast activity and collagen production due to low oxygen in the skin.

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Figure 1. Example of skin pressure.

2. Silicone gel sheets

The effect of silicone gel on scar treatment has been published a lot in the literature. It is more useful for prevention of scar formation rather than for the treatment of scars already in place. For the purpose of preventing surgical scars, continuous occlusion for at least 12 hours a day for 3-6 months from 2 weeks after surgery is required. The mechanism of action is controversial, but it has been suggested that it is either the effect of silicone itself or associated with reduced secondary scar formation due to hydration induced by occlusion.

Figure 2. Silicone gel sheet.

3. Steroids

Steroids are most commonly used for scar treatment; among others, triamcinolone injection is most representative. The main mechanism of action includes reduced inflammatory response and inhibition of fibroblast growth and collagen synthesis. Recent studies have found the presence of inhibitory function of various growth factors and genes (TGF-beta, SMAD-1, etc.) associated with scar formation. Despite such effects, steroids are frequently associated with systemic (acne, hypertension and diabetes mellitus) and local (atrophoderma and vasodilation) side effects, requiring dose and concentration control depending on the scar.



4. 5-Fluorouracil (5-FU)

5-FU is a pyrimidine analog antimetabolite. It is generally one of antitumor agents used for solid tumors. The mechanism of action is prevention of DNA synthesis and fibroblast growth, thereby reducing collagen synthesis as an inhibitory action against TGF-beta. 5-FU combined with steroid can make up for the side effects of each other, rather than when 5-FU is used alone.

Figure 3. 5-FU injection for a keloid scar.

5. Bleomycin

Bleomycin is an antitumor agent as 5-FU, but is widely used for the treatment of warts in dermatology. The mechanism of action is similar to that of 5-FU, inhibiting DNA synthesis and fibroblast growth, thereby reducing collagen synthesis as an inhibitory action against TGF-beta. Systemic side effect has not been reported, but hyperpigmentation may occur as a local side effect.

Generally, 0.5~1ml/cm² with 1.5 international unit/ml is injected.

Figure 4. Bleomycin treatment of a keloid scar.

6. Calcium channel antagonist

Verapamin or trifluoperazine are often used, which have been already in use for contracture in other medical fields. The mechanism of action is the inhibition of production and secretion of extracellular matrix, including collagen, and increasing the production of collagenase. It is also known to reduce the synthesis of IL-6 and VEGF to inhibit scar formation. The therapeutic effect is not evident for clinically established scars but has been used for prevention of surgical scars in many reports.



7. Interferon

Interferon-alpha, beta and gamma can be used for scar treatment due to its inhibitory action of collagen synthesis. However, the price is high compared to the effect and the injection may cause flu-like symptoms. Generally, 1 million unit/cm² is injected.



8. Radiation therapy

Radiation therapy is used as an adjuvant therapy for prevention of recurrence after surgery, rather than as a monotherapy. It is hardly applicable to general scars, but is considered as the most effective method until now for inhibition of radiation therapy-induced recurrence after surgery in severe keloid patients.



9. Cryotherapy

Cryotherapy can induce the most rapid reduction of scar, as with steroid injection. The accurate mechanism of action of cryotherapy on scar treatment is not known, but low oxygen condition induced by freezing seems to reduce collagen synthesis. The advantages of cryotherapy include the possibility of treating wide area within a short period of time depending on various scar sizes and lack of the risk of systemic side effect. Having said that, cryotherapy is also associated with many side effects, such as injection site pain, blistering, coloring and worsening of scar. The lack of standardization and great dependence on the operator’s experience also makes it hard to predict accurate therapeutic effect.

Figure 5. (A) Cryotherapy for hypertrophic acne scar on the chin. (B) Intralesional cryotherpay for keloid scar of the ear.

10. Other topical agents

1) Retinoic acid

2) Vitamin E

3) Onion extract

4) Heparin

5) Imiquimod: Interferon-inducing topical agent, reported as effective for prevention of surgical scars, including keloids.

Figure 6. Various topical agents

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[Scar Treatment] #2. Recent Trend of Scar Treatment

Treatment of Atrophic Scars

Atrophic scars can be variously categorized depending on the reason: in therapeutic terms, atrophic scar varies from atrophy due to the lack of collagen in the dermis, as in the case of acne scars, to the lack of deep tissues under the adipose tissues due to trauma or surgery. Less invasive laser, peeling and supplements are enough to provide good outcome when dermal defect is the main problem; however, invasive methods, such as fat grafting and surgical removal, are necessary when defects of the adipose tissues and others are accompanied.



1. Treatment of acne scars

Acne scars are the most common condition among scar treatments in dermatology and plastic surgery. As acne scars present as various forms, it is very important to classify and treat them accordingly.



2. Trend of atrophic scar treatment using laser and other devices: listed in the order of development

1) Removal of the epidermis and dermis: Ablation using carbon dioxide or erbium:YAG laser

2) Stimulation of the dermis only without injury to the epidermis: Non-ablative remodeling laser, various radiofrequency devices

3) Deep dermal injury with minimal epidermal injury: Non-ablative fractional laser

4) Appropriate epidermal injury and deep dermal injury: Ablative fractional laser

5) Deep dermal injury without epidermal injury: Focused Ultrasound Devices, Fractional Microneedle Radiofrequency Devices.

Table 1. Goodman GJ,Baron JA, MDyPostacne Scarring: A Qualitative Global Scarring Grading System. DermatolSurg 2006:32:1458-1466.

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Table 2. Goodman GJ,Baron JA, MDyPostacne Scarring: A Qualitative Global Scarring Grading System. DermatolSurg 2006:32:1458-1466.

Figure 1. Treatment of atrophic scar with fractional Laser

Figure 2.Various treatments of hypertrophic scar and keloid

3. filling agents for atrophic scars

Temporary fillers using hyaluronic acid, calcium hydroxylapatite and collagen, as well as permanent fillers using polylactic acid, polyacrylamide and silicone, are commonly used. Recently, the method of correcting scars using autogenous cell has been developed. This so called ‘cell therapy’ attempts to introduce autogenous fibroblasts, adipose stem cells, adipocytes or preadipocytes.



Recent Therapies of Hypertrophic Scar and Keloid

Hypertrophic scars or keloids are not easily treated and only one method is not enough to provide a good outcome. The most traditional method is surgical excision and steroid injection, but recently various new attempts and combination therapies have been introduced. Therapies introduced at Wound forumin 2004 are summarized below.



1. Intralesional excision of keloids

Completely excised keloids tend to become bigger in size, but partial excision can reduce the size of a large lesion enough for injection therapy. Of course the surgical excision not the end of treatment; various other treatments should be combined to maintain the effect of the surgery.

Figure 3. Examples of intralesional excision

Figure 4. Hypertrophic scar treated with PDL

Figure 5. Keloid treated with fractional Laser

Recent studies reported that recurrence of a lesion can be prevented by post-operative application of imiquimod ointment (aldara).



2. Scar treatment using lasers

1) Pulsed dye Laser is known to reduce TGF-beta and to prevent collagen synthesis of fibroblasts by acting on the blood vessels in the scar and making the scar to a hypoxic state.

2) Fractional Laser has been reported recently to provide good outcomes as PDL in the treatment of keloid or hypertrophic scar.

REFERENCES

1. Kelly AP. Medical and surgicaltherapies for keloids. Dermatol Ther2004;17:212-218.

2. Al-Attar A, Mess S, ThomassenJM, Kauffman CL, Davision SP. Keloid Pathogenesis and Treatment. Plast Reconst Surg 2006;117:286-300.

3. Mustoe TA, Cooter RD, Gold M, HobbsFDR, Ramelet AA, Shakespeare PG, et al. International clinical recommendations onscar management. Plast. Reconst Surg2002; 110: 560-571.

4. Connell PG, Harland C . Treatmentof keloid scars with pulsed dye lasers and intralesional steroid. J Cutan Laser Ther2000; 2:147-150 .

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[Scar Treatment] #1. Definition and Pathological Study of Scars

Scars are treated by various methods including surgery, laser, drugs or external preparations. Recently, laser treatment becomes popular. Before laser scar treatment, general understanding about scars are absolutely necessary. This series attempts to deliver general information about scars in addition to the definition and pathological analysis of scars. The author is Professor Kim Won-serk at the Department of Dermatology of Kangbuk Samsung Hospital, Sungkyunkwan University. Prof. Kim is actively participating in clinical and academic activities of various fields including dermatology for scar treatment.

1. Definition of scar

Scar is considered as a wrong process of wound healing, which occurs mainly in human and some mammals. Scars are visibly distinct from the surrounding skin by their contour, color and texture and may accompany volume changes, such as in case of atrophy and protrusion. A scar, in a broad sense, includes depressing scar made by acne or trauma, scars accompanying difference only in the color or texture as stretch marks, hypertrophic scar made by protuberance of postoperative suture site or burned site, and keloid which grows continuous like a tumor.

[Figure 1. Classification of scar]

2. Epidemiological study of scars

1) Keloid: Keloid is known to develop only in humans, but there have been reports of keloid cases in some mammals, including horse, cow, dog, etc. Keloid is most frequent in black people, followed by Asians and white people. The incidence is not different between men and women, and occurs often in younger people. Postmenopausal reduction of lesions has been observed in women.



2) Hypertrophic scar: Accurate incidence is not known, but hypertrophic scar is generally more common than keloids and are mostly recovered spontaneously unlike keloids. As with keloids, hypertrophic scar is frequent in the order of black people, Asians and then white people.

[Figure 2. Clinical patterns of various scars (keloid/mature scare/atrophic scar/immature scare/hypertrophic scar)]

3. Causes of scarring

1) Genetic: Generic factors are considered to be involved mostly with keloids. Genetic factors, such as HLA-B14 and 21, have been studied for their involvement.



2) Trauma: A variety of skin stimulus, including surgery, injection, piercing and burn, may be important causes of scarring.



3) Surface tension: In addition to natural surface tension arising from skin defect, difference in body parts also makes some parts more easily affected than other body parts. For example, scars or keloids are bigger and more frequent at sites with major muscle movements (arms and legs) and sites where breathing occurs (front chest).



4) Hormonal effect: Considering the fact that scarring occurs less frequently before puberty and after menopause, it is suspected that sex hormone might have some association with scarring, although the exact association has not been studied a lot.



5) Immunologic cause: Immunology is not considered as an important cause of scarring, but there have been reports that higher serum level of immunoglobulin E was associated with higher frequency of scarring and that allergic people are more likely to develop keloids.



6) Melanin pigment cells: This hypothesis comes from frequent scarring in black people and less frequent scarring in areas without melanin pigment cells.



7) Association of collagen diseases: Patients with a congenital abnormality in collagen metabolism may have excess or lack of scarring.

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4. Pathological study of scars

1) Scars are mostly confined to the dermis but may extend to the subcutaneous layer in rare cases. The most significant histopathological characteristic of a scar, compared to normal tissues, is the absence of skin appendages (hair and glands)



2) Pathological differences may be observed between an early lesion and an advanced lesion; early lesions show infiltration of inflammatory cells, vasodilation and vascularization, while advanced scars show reduced cell density, deposition of firm and thick collagens, and loss of blood vessels. These pathological features well matched with red color of early scars and white color of mature scars.



3) Scar tissues have thick epidermis and flattening of epidermal ridge.



4) Collagens in scar tissues have increased collagen synthesis than in normal dermis; among others type 1 and type 3 collagens are increased, while type 4 and type 5 are decreased. It has been reported that type 1 collagen increases by 95% in keloids.

5) In the course of wound healing, the most important growth factors for collagen synthesis and contraction in fibroblast are TGF-beta and PDGF, which are increased in scar tissues.



6) Hypoxic condition within tissues is thought as an important triggering factor of scarring. This might be associated with frequent vascular occlusion in scar tissues.



7) Accumulation of immunoglobulin G, A and M is observed often in scar tissues, and there have been reports of autoimmune anti-fibroblast antibodies detected in keloids.



8) A lot of mast cells are detected in scar tissues and, as mentioned earlier, keloid patients often have allergic symptoms. Mast cells distributed between collagen fibers stimulate immunoglobulin E and releases a large number of growth factors, histamine and serotonin, which affects the synthesis of components in the dermis.

[Figure 3. Pathological finding of a keloid]

[Figure 4. Pathological finding of a hypertrophic scar]

References

1. Berman B, Zell D. The Medical Treatment of Scarring, In: Arndt KA, editors. Scar Revision. 1st ED. Philadelphia: Elsevier Saunders, 2006:17-43

2. Decker RH, Wilson LD. Effect of Radiation on Wound Healing and the Treatment of Scarring, In: Arndt KA, editors. Scar Revision. 1st ED. Philadelphia: Elsevier Saunders, 2006:89-103

3. Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davision SP. Keloid Pathogenesis and Treatment. Plast Reconstr Surg 2006; 117:286-300

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