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DIFFERENTIAL DIAGNOSIS OFHYPERTROPHIC SCARS AND KELOIDS

The pathogeneses of keloids and hypertrophicscars are not well understood.1 Many traditionaltextbooks classify hypertrophic scars and keloidsas completely different types of scars. Cliniciansdefine hypertrophic scars as scars that do not growbeyond the boundaries of the original wound,

whereas keloids grow horizontally.2

In contrast,

pathologists distinguish keloids from hypertro-phic scars histologically on the basis of thick eo-sinophilic (hyalinizing) collagen bundles that areabsent in hypertrophic scars.3 However, there arealso many cases where the scar bears the growthand histologic features of both hypertrophic scarsand keloids (Fig. 3).3 There is also the possibilitythat hypertrophic scars and keloids are manifes-

tations of the same fibroproliferative disorder of

Fig. 1. Treatment algorithms for hypertrophic scars (HSs).

Plastic and Reconstructive Surgery February 2010

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the skin that is expressed by a continuum offeatures.4 However, alleged hypertrophic scars im-prove naturally and gradually, although the fullmaturation process may take up to 2 to 5 years,2

whereas alleged keloids do not resolve naturally.Because these features shape how they should betreated, they should be defined as shown in Table1, and scars that bear features of both hypertro-phic scars and keloids should be considered and

treated as keloids.

EXCLUDING THE POSSIBILITY THATTHE LESIONS ARE ATTRIBUTABLE TO

SIMILAR-LOOKING DISEASESGulamhuseinwala et al.5 reported a pathologic

analysis of 568 scars that revealed the absence ofmalignancies or dysplasias. Therefore, they con-cluded that routine histologic analysis of scars isnot necessary. Wong and Lee6 have argued againstthis approach, saying that malignant or local de-

structive tumors can be misdiagnosed clinically as

Fig. 2. Treatment algorithms for keloids.

Volume 125, Number 2 Treatment of Hypertrophic Scars

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keloids. Indeed, malignant tumors, including der-matofibrosarcoma protuberances710 and giantcell fibroblastomas,11 have been mistaken for hy-pertrophic scars or keloids in previous reports.Furthermore, our analysis of 378 patients who hadbeen diagnosed with hypertrophic scars/keloidsand were treated in our facility revealed that 1.06percent of the lesions were actually caused byother diseases although, fortunately, all of the dis-eases were benign.12 Thus, we recommend that theparameters listed in Table 2 be reviewed beforeplanning treatment for suspected keloids/hyper-

trophic scars (Fig. 1, A, and Fig. 2, A).

PREVENTION OF HYPERTROPHICSCARS AND KELOIDS

Hypertrophic scars occur when there aremajor skin wounds, including those resultingfrom surgery, trauma, and burns. In contrast,keloids can arise from very small injuries or weakinflammation processes, including acne and in-jections. Consequently, special care should betaken when treating patients who have a historyof keloids. Risk factors that promote the devel-opment of hypertrophic scars and keloids, andthat can be limited by physicians, are mechan-ical force (stretching tension) on the wound,wound infections, and foreign body reactions

(Table 3).

Fig. 3. Hypertrophic scars and keloids can vary in their appearance. Leftand rightimages can be considered as typical

hypertrophic scar and keloid cases, respectively. (Center) However, it is difficult to determine whether this scar is a hyper-

trophic scar or a keloid, andsuchlesions shouldbe considered andtreatedclinically askeloids, although thepossibilitythat

they are actually hypertrophic scars should be kept under consideration.

Table 1. Differential Diagnosis of Hypertrophic Scarsand Keloids

Pathologists distinguish keloids from hypertrophic scars

histologically on the basis of thick eosinophilic(hyalinizing) collagen bundles that are absent inhypertrophic scars. These conditions can also be definedclinically on the basis of their growth patterns. However,clinicians and pathologists still have conflicting viewsregarding the differential diagnosis of these conditions.

Hypertrophic scar: A fibroproliferative disorder of the skinthat does not grow beyond the boundaries of theoriginal wound.

Keloid: A fibroproliferative disorder of the skin that growsbeyond the boundaries of the original wound or has anunrecognized origin.

Table 2. Excluding the Possibility That the LesionsAre Caused by Similar-Looking Diseases

The following parameters should be considered before the

treatment of keloids/hypertrophic scars is planned.1. A biopsy should be conducted in anomalous cases.2. Corticosteroid injections should be performed only

after carefully excluding the possibility thatmalignancies or infections may be present.

3. It should be remembered that it is particularlychallenging to accurately differentially diagnoseAfrican Americans because the color of their skinscars and tumors is often similar.


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Mechanical Force (Skin Stretching Tension)

It is well known that hypertrophic scars/ke-loids occur frequently on particular sites, includ-ing the anterior chest, shoulder, scapular area,lower abdomen, suprapubic region, and earlobe.13

These sites all have in common the fact that theyare frequently subjected to skin stretching causedby the natural daily movements of the body. Incontrast, hypertrophic scars/keloids occur veryrarely on the scalp and the anterior lower leg,

where bones lie directly under the skin and theskin is rarely subjected to stretching tension. Thissite-specificity of hypertrophic scars/keloids sug-gests that to prevent the development of keloidsand hypertrophic scars, it would be useful to avoidsubjecting wounded skin to sustained mechanicalforce, thereby permitting the wound to rest andheal normally. Supporting this is the fact that ke-loid growth patterns can be simulated by com-puter analysis of skin-stretching tension.14 More-over, Aarabi et al.15 recently described an animalmodel of hypertrophic scars where hypertrophic

scarlike lesions developed when mechanicalforce was applied to wounds on the backs of mice.To limit skin stretching during healing and

thereby facilitating appropriate wound resting,wounds should be covered by fixable materials,including tape, bandages, garments, or siliconegel sheets. Supporting this is a study by Atkinsonet al.,16 who reported a randomized controlledtrial of the effect of tape fixation on the preventionof hypertrophic scars after cesarean section in 70subjects. They found that scar volume decreasedsignificantly when paper tape was used. The ran-

domized controlled trial of Gold et al.

17

also

showed that silicone gel sheeting significantly re-duces the incidence of hypertrophic scars or ke-loids in high-risk subjects with a history of abnor-mal scarring. The randomized controlled trial ofChan et al.18 also revealed that silicone gels may beable to prevent the development of hypertrophic

scars after sternotomy-associated wounding. How-ever, when OBrien and Pandit19 conducted ameta-analysis of 13 trials involving 559 individuals,they found that there was only weak evidence thatsilicone gel sheeting can prevent abnormal scar-ring in high-risk individuals. Further randomizedcontrolled trial studies will be necessary to eluci-date this issue fully.

Wound Infections and Foreign Body Reactions

Both infections and foreign body reactions pro-long the inflammation process associated withwound healing. It is likely that infections and foreignbody reactions induce the abnormal secretion ofproinflammatory mediators that in turn prompt ab-normal responses by fibroblasts.20 Thus, it is crucialthat wounds are kept clean by means of irrigationafter surgery and injury. Moreover, the contact ofwounded dermis (including in earlobe piercing)with foreign bodies should be avoided.

TREATMENT OF HYPERTROPHICSCARS

Hypertrophic scars become obvious withinweeks after injury, after which they rapidly in-crease in size for 3 to 6 months. Then, after a staticphase, they begin to regress. However, for thosehypertrophic scar cases with scar contractures (es-pecially joint contractures) that could result infunctional dysfunction,21 surgery is indicated.

Surgery

Releasing scar contractures improves joint func-tion and also accelerates the maturation of sur-rounding immature scars and hypertrophic scars

(Fig. 1, B). Small and linear hypertrophic scars canbe treated by complete surgical resection (Fig. 1, C)or nonsurgical multimodal therapy (Fig. 1, D). Inthese cases, a type of tension-releasing technique,which includes Z-plasty, W-plasty, and small waveincision, should be applied to prevent the recur-rence of hypertrophic scars.22 Intractable recurrenthypertrophic scars should be treated according tothe keloid treatment algorithm, where the combi-nation of surgery and adjuvant therapy is the treat-ment of choice23,24 (Fig. 1, E, and Fig. 4).

With regard to suture materials, the random-

ized controlled trial performed by Luck et al.25

Table 3. Key Points for Preventing Hypertrophic Scarand Keloid Development

Key Points

1. Avoid excessive movements that stretch the wound, anduse bandages and appropriate garments.

2. Avoid subjecting the wound to direct mechanical force

(e.g., friction, scratching) and use gel sheeting andtaping.3. For patients with earlobe wounds, minimize contact

with pillows when lying down to avoid friction.4. For female patients with chest wounds, tight brassieres

and underwear should be worn to avoid the skin-stretching tension caused by the weight of the breasts.

5. For patients with suprapubic wounds, a belly-warmer tieor garment is recommended.

6. After surgery and injury, the wound should be keptclean by means of irrigation and application ofantibacterial/antimycotic agents.

7. After surgery and injury, contact of the woundeddermis (including earlobe pierce holes) with foreignbodies should be avoided.


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revealed that absorbable and nonabsorbable su-tures do not differ significantly in terms of therates at which facial hypertrophic scars form. How-ever, when Durkaya et al.26 performed a similar

randomized controlled trial, this time on hypertro-phic scars that develop after midline sternotomy in-cision, they found that the use of nonabsorbablesutures diminished the risk of hypertrophic scars.Thus, the choice of suture materials depends on thesite of application, withnonabsorbablesutures beingmore suitable for high-skin-tension sites such as theanterior chest wall.

Nonsurgical Therapies

Hypertrophic scars without scar contracturesimprove naturally during the process of scar mat-

uration (Fig. 5). However, various nonsurgicaltherapies can accelerate this process and improvethe subjective symptoms. Thus, it is recommendedthat hypertrophic scars without scar contracturesshould be treated by one or more of the multiplenonsurgical therapies available, especially thenoninvasive therapies, which include compressiontherapy and gel sheeting (Fig. 1, D).

Compression TherapyThe randomized controlled trial of Chang

et al.27 that examined the effectiveness of pressuretherapy in 122 cases found that when pressure

garmenttreated and untreated groups were com-

pared in terms of their average age, surface areaof the burn on the body, length of hospital stay, ortime to wound maturation, significant differencesbetween the groups were not observed. However,

when Van den Kerckhove et al.28

performed asimilar randomized controlled trial, but more pre-cisely measured the pressure applied, they foundthat pressure garments that deliver a pressure ofat least 15 mmHg tend to accelerate scar matura-tion. The mechanisms by which pressure can ac-celerate scar maturation should be elucidated. Inthe meantime, it seems that applying appropriateamounts of pressure on hypertrophic scars couldbe a useful therapeutic technique.

Gel SheetingGel sheeting therapy can be used in two set-

tings, namely, to prevent hypertrophic scars aftersurgery and to treat hypertrophic scars.19 Regard-ing the latter application, Majan29 reported a ran-domized controlled trial that revealed that pa-tients treated with soft silicone dressings showedgreater and more rapid improvement in hyper-trophic scar maturation than untreated patients.Moreover, the randomized controlled trial con-ducted by Li-Tsang et al.30 indicated that siliconegel sheeting helps to reduce the thickness, pain,itchiness, and rigidity of severe hypertrophic scars.

Regarding the materials from which gel sheets

are made, de Oliveira et al.31

examined the effec-

Fig. 4. Treatment of hypertrophic scars by surgery:(left) 2 years after burninjury and (right)1year

afterskingrafting.Thehypertrophicscarsinthiscasehadnotimprovedinthe2yearssincetheburns

weresustained.Indeed,mildscarcontracturesdeveloped,especiallyonthefirstweb.Consequently,

all scars wereremoved and reconstructedby full-thickness skingrafts harvested from the inguinal

region. Surgery is sometimeseffective for suchintractable hypertrophic scar cases.


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tiveness of nonsilicone gel sheeting in their ran-domized controlled trial and concluded that sili-cone and nonsilicone gel dressings are equallyeffective. Akaishi et al.32 used a computer analysisto show that silicone gel sheeting reduces the ten-sion on the hypertrophic scar. They concluded

that it is vital that gel sheets are soft and elastic.However, So et al.33 reported that improvedpatient education increases their compliance insilicone gel sheeting therapy, as patients partici-pating in an improved education program hadsignificantly better ratings regarding scar borderheight and thickness at 6 months than the con-ventionally educated patients. These observationssuggest that hypertrophic scars are most effectivelytreated with gel sheets if the patients are properlyeducated, whereas the type of material used toconstruct gel sheets may be a less important factor.

Corticosteroid InjectionIt has been suggested that synthetic cortico-steroids decrease the production of inflammatorycytokines, chemokines, adhesion molecules, lyso-somal enzymes, and tissue inhibitor of metallo-proteinase, and inhibit fibroblast proliferation.34

However, the disadvantages of corticosteroidtreatment include severe pain caused by the in-jection and systemic side effects that include men-strual dysfunction in women, the suppression ofadrenal cortical function, and the development ofcataracts or glaucoma. The local side effects in-

clude thinning and atrophy of the skin and sub-

cutaneous tissues, development of steroid acne,capillary dilatation, and hypopigmentation. Thesecomplications can hamper the use of corticoste-roids in combination treatments. Indeed, cortico-steroid-based treatment of hypertrophic scars re-quires careful planning with the patient. An

international panel of experts that reviewed theavailable clinical literature has recommended thatcorticosteroid doses of 2.5 to 40 mg per site shouldbe used,2 but additional randomized controlledstudies are needed to determine the appropriatesite-specific dose.

LaserWittenberg et al.35 and Alster36 reported ran-

domized controlled trials examining the efficacyof pulsed dye laser therapy combined with siliconegel sheeting and steroid injection, respectively,but found that these combination therapies did

not yield significant effects. However, pulsed dyelaser irradiation alone effected a substantial clin-ical and histologic improvement. The randomizedcontrolled trial performed by Allison et al.37 alsosuggested that pulsed dye laser is an effective treat-ment for the intense pruritus that is often expe-rienced during the healing process after a burninjury. However, this study did not reveal othersignificant benefits, including reductions in scarredness or improvements in the height and textureof the scar. Manuskiatti and Fitzpatrick38 reportedthat pulsed dye laser applied at a pulse width of 0.45

msec was more effective in decreasing scar size and

Fig. 5. Naturallyhealing hypertrophic scars. (Left) Granulation tissues immediatelyafter the burnwounds weresustained. (Center)

Hypertrophicscars2yearsaftertheburnwoundsweresustained.(Right)Maturescars5yearsaftertheburnwoundsweresustained;

hypertrophicscars withoutscar contractures improvegradually during theprocessof scarmaturation,despiteminimalnoninvasive

treatment being applied. However, textural improvements take longer to manifest.


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improving scar pliability than a pulse of 40 msec. Inconclusion, pulsed dye laser on itsown may be usefulfor treating hypertrophic scars.

OthersInvasive treatments, including cryotherapy and

5-fluorouracil injections, should not be used to treat

hypertrophic scars, although they may be effectivewith keloids (see below). However, noninvasive ex-ternal and internal agents such as ointments andgels, tape, and nonsteroidal antiinflammatory drugsare useful for treating hypertrophic scars, althoughtheir effects are limited because they mainly reducesubjective symptoms (e.g., itching and pain).

Corticosteroid ointments, tape, and nonste-roidal anti-inflammatory drugs have been shownto be effective in reducing symptoms, but furtherrandomized controlled trials are required to fullyelucidate the therapeutic potential of these agents.

Several randomized controlled trials have been per-formed to test the benefits of onion extract gels39,40

and mugwort lotion,41 but these agents do not seemto improve objective symptoms.

Oral administration of another internal agent,namely, the antiallergic drug tranilast,42 appears toreduce the symptoms of hypertrophic scars. It is wellknown that tranilast also effectively reduces the rateof restenosis of coronary arteries (which is a type offibrosis similar to hypertrophic scars) after percuta-neous transluminal coronary angioplasty.43 Thus,this drug is promising as a hypertrophic scar therapy.

Finally, to manage the psychological stress ofpatients, makeup or camouflage therapy44 shouldbe considered, as these therapies improve not onlythe cosmetic appearance of the scars, but alsoreportedly promote physiologic changes.45 Thisissue warrants scientific study.

TREATMENT OF KELOIDSUnlike when hypertrophic scars are treated, the

size and number of keloid lesions should be deter-mined before planning the treatment. In otherwords, are thekeloidlesions small and single or large

and multiple? This categorization is necessary be-cause small (early) and single keloids can be treatedradically (Fig. 2, B), which is an approach that hasbeen facilitated by the improvement in our under-standing of adjuvant therapies after primary surgery(Fig. 2, D).23,24,34,4648 Several therapeutic approaches,including laser treatment,38,49 are also effective asmonotherapies in the radical treatment of early ke-loids (Fig. 2, E). Nonsurgical conservative therapiesalone do not seem to be effective for treatingkeloids.2 In particular, careful discussions and goal-setting with patients are essential steps in the man-

agement of large and multiple keloids (Figs. 2 and

6, below, left). Patients with such keloids usually havemajor problems, including infections (e.g., inclu-sion cysts) and pain. Consequently, mass reductionsurgery (Fig. 2, F) andsymptomatic multimodalther-apies (Fig. 2, G) can be considered on a case-by-casebasis.

Surgery

Surgery can be used to treat keloids in twoways: first, radically resecting keloids (Fig. 2, D);and second, reducing keloid mass (Fig. 2, F). Rad-ical resection should be combined with adjuvanttherapy because keloid excision alone is associatedwith a high rate of recurrence (45 to 100 percent).2

With regard to the mass reduction approach, itshould be used only to remove infected regions andto reduce enough of the keloid(s) to effect symp-tomatic improvement. Adjuvant therapy after massreduction surgery is not recommended because thiscould lead to excessive exposure to radiation or theside effects of corticosteroids.

Corticosteroid Injections

Corticosteroid injections can be used to treatkeloids in three ways: first, as an adjuvant therapythat is to be combined with surgery (Fig. 2, D);second, as a monotherapy for the radical treat-ment of keloids (Fig. 2, E); and third, as a com-ponent of multimodal therapy for the treatment

of symptoms (Fig. 2, G). In a prospective trialperformed by Kiil,50 52 patients were treated withtriamcinolone injections alone, whereas 15 pa-tients received the steroid therapy together withkeloid excision. The combined treatment and in-jection therapy alone were similarly effective.However, partial recurrence was observed in one-third of the cases after 1 year, regardless of thetreatment that had been applied, whereas after 5years, the recurrence rate was 50 percent. Muneu-chi et al.51 reported that corticosteroid injectionmonotherapy had beneficial long-term outcomes,with 82 percent of 63 patients experiencing animprovement in subjective symptoms. Combiningcorticosteroid injections with 5-fluorouracil,38,52

pulsed dye laser,52 and cryotherapy5355 has beenreported to be more beneficial than corticosteroidinjection monotherapy, although there are toofew randomized controlled trials testing these is-sues to be able to draw solid conclusions.

Cryotherapy

Cryotherapy has been used to treat keloids ei-ther as a monotherapy or in combination with in-

tralesional triamcinolone injection. Cryotherapy de-


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livery methods include contact,56 sprays,5557 andintralesional needles.58,59 Layton et al.60 found fromtheir randomized controlled trial that early, vascularlesions responded to cryosurgery significantly betterthan larger lesions. It should be noted that cryother-

apy should be limited to small regions, as it inducessevere pain and hypopigmentation.The mechanism by which cryotherapy reduces

keloids is very interesting. It is well known thathypertrophic scars and keloids occur on burnedskin areas but not on frostbitten areas. It appearsthat although burning and frostbite both induceapparent tissue necrosis, they induce the secretionof quite different proinflammatory mediators; theresponse to these inflammatory signals by the fi-broblasts may also differ. Further basic researchshould be performed to elucidate these mecha-

nistic discrepancies.

RadiationCombining surgery with postoperative radiation

therapy has been suggested to more effectively treatkeloids than radiation monotherapy.61 The successrate of this combined approach varies between 67

and 98 percent,62

although few randomized con-trolled trials have been performed to test the effec-tiveness of this technique. In many institutions, radia-tion is initiated right after surgery, and the total dose islimited to 20 Gy over several administrations.23,24,47

Guix et al.46 described keloid treatment using high-dose-rate brachytherapy and concluded that it treatskeloids more effectively than superficial x-ray or low-energy electron beam administration.

An important concern associated with keloid ra-diation therapy is the risk of inducing malignanttumors. However, in the reported cases where

malignant tumors arose after keloid radiation

Fig. 6. Typical severe keloids: (above, left) 9 years ago, (above, right) 5 years ago, (below, left) 2 years ago, and

(below, right)intheircurrentstate.Keloidsgrownotonlyverticallybutalsohorizontally.Inthecasepresentedhere,

thevarious keloids grew over 9 years to the point they hadmerged. However, the central area of thekeloidmass

has become depressed and become mature scar.


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therapy,6367 it remains unclear whether the radia-tion therapy involved appropriate radiation dosesand adequate protection of the surrounding tissues,especially the mammary glands and thyroid. To ad-dress this issue, Leer et al.68 performed a question-naire-based study in which radiation oncologists in

508 facilities throughout theworld were askedaboutthe indications of radiation therapy for keloids. Theradiation oncologists in 78 percent of the facilitiesreplied that keloids are an accepted indication forradiation therapy. Moreover, of the 77 facilities lo-cated in the United States and Canada, over 90 per-cent found that radiation therapy for keloids is ac-ceptable. It should be noted that plastic surgeonsgenerally avoid radiation therapy for benign tumors,including keloids, for fear of inducing malignanttumors. The latter study suggests that surgeonsshould perhaps liaise more closely with radiation

oncologists before excluding the possibility of radi-ation therapy for keloids.69

Antitumor/Immunosuppressive Agents

Uppal et al.70 and Nanda and Reddy71 havereported randomized controlled trials that testedthe efficacy of 5-fluorouracil for treating keloids.The keloid scar scores of the majority of patientsimproved by more than 50 percent after 5-flu-orouracil treatment. Haurani et al.72 found fromstudying a prospective case series (n 32) thatintralesional 5-fluorouracil treatment after sur-gery prevented recurrence, as the recurrence ratewas 19 percent at the 1-year follow-up. The authorsrecommended the use of 50 mg per session, witha total exposure of 500 mg. However, Fitzpatric73

and Gupta and Kalra74 have reported using up to150 mg per session, with total doses being between1200 and 2400 mg. Further work to determine theappropriate dose should be initiated.

Naeini et al.75 have reported that bleomycin iseffective in treating keloids, and the randomizedcontrolled trial of Broker et al.76 revealed that inter-feron therapy is also effective. However, Davison etal.77 reported that their randomized controlled trialof interferon -2b showed it was not effective intreating the 39 keloids examined and they con-cluded that it is not useful for the clinical manage-ment of keloids. These therapies should be studiedby additional randomized controlled trials.

LONG-TERM FOLLOW-UP OFHYPERTROPHIC SCARS AND KELOIDS

AFTER TREATMENTIt is important that sequentially treated hyper-

trophic scar and keloid patients are followed up

over the long-term and are appropriately edu-cated about managing their scars (Fig. 1, FandFig. 2, H). With regard to hypertrophic scars, it isimportant that wounds are not subjected to me-chanical force (skin-stretching tension) and areallowed to rest by using gel sheeting or tape fix-

ation, and that these measures be sustained untilthe hypertrophic scars become mature scars. Withregard to massage therapy for hypertrophic scars,Patino et al.78 reported that it did not appreciablyimprove the vascularity, pliability, or height of hy-pertrophic scars, although a decrease in prurituswas observed in some patients. Thus, there is littleevidence that suggests massage accelerates hyper-trophic scar maturation.

CONCLUSIONSMany plastic surgeons, especially those in non-

Caucasian societies, avoid treating abnormal scarsbecause of their high frequency of recurrence.However, over the past decade, many more ran-domized controlled trials addressing abnormalscar management and treatment have been per-formed. This means there is now sufficient evi-dence-based information for us to start devisingstandard international algorithms of abnormalscar treatment. Here, algorithms for the treatmentof hypertrophic scars and keloids have been pro-posed. However, these algorithms should be opti-mized for each human race. They are also likely to

improve significantly as our knowledge of scar biol-ogy progresses, higher quality clinical trials are per-formed, and new agents to treat scars are developed.

Rei Ogawa, M.D., Ph.D.Division of Plastic Surgery

Department of SurgeryBrigham and Womens Hospital

Harvard Medical School75 Francis Street

Boston, Mass. [email protected]

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