EFFICACY OF SKIN SUBSTITUTES FOR MANAGEMENT OF ...

EFFICACY OF SKIN SUBSTITUTES FOR MANAGEMENT OFACUTE BURN CASES: A SYSTEMATIC REVIEW

INTÉRÊT DES SUBSTITUTS CUTANÉS DANS LE TRAITEMENT DES BRÛ-LURES AU STADE AIGU: UNE REVUE SYSTÉMATIQUE DE LA LITTÉRATURE

Wardhana A.,* Valeria M.

Plastic Reconstructive and Aesthetic Surgery Division & Burn Unit, Department of Surgery, Cipto MangunkusumoHospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia

SUMMARY. The early management of burn cases has always been a challenging medical problem. Skinsubstitutes have been consistently studied and employed as the prospective treatment modality for burn casesworldwide. However, this treatment method remains uncommon in many developing countries. This system-atic review is designed to weigh the efficacy of skin substitutes compared to standard treatment for managingacute burn cases. A literature search was conducted using PubMed, Scopus and Cochrane database up to Feb-ruary 2020 combined with additional reference searching. Studies were restricted to randomized controlledtrials (RCTs), with no date and language restrictions. We evaluated the risk of bias with a revised risk of biastool for randomized trials (RoB2). Data were categorized based on skin substitutes with further subgroupanalysis for each skin substitute. We included 13 studies with six types of skin substitutes, Biobrane®, Tran-sCyte®, Integra®, Glyaderm®, Suprathel® and Apligraft®. Outcomes measured included wound healing time,pain, length of hospitalization and scar formation. The findings for all skin substitutes demonstrated lesssevere pain compared to the control group. Faster wound healing time, scar formation and length of hospi-talization were identified as heterogeneous depending on the type of skin substitutes used. All of the skinsubstitutes studied exhibited at least non-inferior to superior performance compared to standard treatment interms of efficacy in treating acute burn wounds, not limited to burn depth, size, location or patient age.

Keywords: skin substitutes, burns

RÉSUMÉ. Le traitement des brûlures à la phase aiguë a toujours été un sujet en quête d’amélioration. Lessubstituts cutanés ont été l’objet de nombreuses études et utilisés de façon prospective dans le traitement desbrûlures dans le monde entier. Cependant, leur utilisation reste peu fréquente dans les pays en voie d’émer-gence. Cette revue systématique de la littérature a pour but de s’interroger sur l’intérêt réel des substitutscutanés comparés au traitement standard au stade aigu de la brûlure. La recherche d’articles a été menée enutilisant les bases de données PubMed, Scopus et Cochrane jusqu’en février 2020, en y associant d’autresmoteurs de recherche. La sélection des articles n’a retenu que les essais randomisés contrôlés (RCTs) sansrestriction de dates ni de langue. Nous avons évalué le risque de biais avec un outil adapté aux essais ran-domisés (RoB2). Les données ont été classées en fonction du type de substitut cutané avec des sous-groupesd’analyse pour chacun des substituts cutanés. Nous avons retenu 13 études portant sur six substituts cutanés:Biobrane®, TransCyte®, Integra®, Glyaderm®, Suprathel® et Apligraft®. Les résultats notés portent sur le délaide cicatrisation de la plaie, la douleur, la durée d’hospitalisation et le résultat cicatriciel. Les résultats mon-trent que la douleur est moindre avec tous les substituts cutanés comparée au groupe contrôle. Les résultatsconcernant la rapidité de cicatrisation, la durée d’hospitalisation et le résultat cicatriciel sont hétérogèneset semblent dépendre du type de substitut cutané. Tous les substituts cutanés étudiés ont montré des perfor-mances au moins équivalentes voire supérieures au traitement conventionnel dans le traitement des brûluresau stade aigu, sans considération de profondeur, de surface, de localisation ou d’âge du patient.

Mots-clés : substituts cutanés, brûlure___________* Corresponding author: Aditya Wardhana, M.D., Division of Plastic Reconstructive and Aesthetic Surgery & Burn Unit, Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia.

Tel.: +62 878 8002 1350; email: [email protected]: submitted 23/07/2021, accepted 22/10/2021

Annals of Burns and Fire Disasters - Meditline - Pending Publications

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Introduction

The management of burn cases has always beena challenging medical problem.1,2 Treatment foracute burn wounds is highly dependent on the depthof the wounds. Superficial partial-thickness burn in-juries are generally managed nonoperatively. Dress-ings are applied and aimed to prevent additionaltrauma to the wound, wound desiccation and colo-nization of microbes. In cases with deep partial-thickness or full-thickness burn wounds, treatmentshould be done operatively with early excision andautografting.3 However, considerable limitations arepresent: major local problems confronted in acuteburn management vary from long duration onwound healing, pain, infection, and extensive scar-ring and contracture. The complexity of acute burnsmanagement warrants more studies and innovationsusing novel techniques and approaches.4

Skin substitutes present a prospective modality toaddress the limitations of the current standard treatment.It adheres to the concept of tissue engineering, whichencompasses three factors: scaffold, tissue-inducingsubstances, and isolated cells that will interact to createa skin substitute.5 Skin substitutes were initially devel-oped and studied on severe burn patients and have pri-marily been used by developed countries to treat skinloss in patients with critical health conditions andchronic wounds.6 Skin substitutes serve to cover largeburn wounds when donor sites are limited, reducing in-flammatory responses, acting as a dermal componentfor deep wounds, and reducing scarring formation.4

In developing countries, recognition and productavailability of skin substitutes are inadequate.7 We areeager to explore its potential implementation for differ-ent types of acute burn wound and its consequent supe-riority for burn treatment, hence prompting our clinicalconfidence in its future stance among the managementof acute burn cases. This systematic review is designedto weigh the efficacy of skin substitutes against standardtreatment for managing acute burn cases.

Materials and methods

Identification of relevant studiesA systematic literature search was conducted

based on the keywords: “Skin substitutes”, “Burns”,and different types of commercially available skinsubstitutes. We searched keywords on three data-bases: PubMed, Scopus and Cochrane databases, in-cluding studies up to February 2020. The search wasconducted without language and time restrictions. Wealso conducted reference searching to prevent studiesfrom being excluded from the database search.

Study selectionThe included study design is restricted to RCTs.

The treatment must be used for treating burn woundsites in humans. Uncompleted studies, treatmentother than skin substitutes and standard burn treat-ment, treatment of chronic burn wounds, and treat-ment on donor burn sites were excluded. Studyselection processes are presented in Fig. 1 based onPRISMA 2009 Flow Diagram.8

Risk of biasAssessment of risk of bias was conducted using

the revised risk of bias tool for randomized trials(RoB 2) by two independent assessors.9 Any dis-agreements were solved with discussion until a con-sensus was approved by the two assessors.

Outcome measurementData from the studies were extracted and catego-

Fig. 1 - Study selection process

rized based on types of skin substitutes. Descriptionsfor each study include study design, assigned inter-vention, number of patients, characteristic of burnwound (type, total body surface area, location) andtype of patients. Further subgroup analyses for eachskin substitute were conducted for the measurementof outcomes. Subsequently, qualitative review of se-lected literature to evaluate the efficacy of skin sub-stitutes was written based on the guidance fromPreferred Reporting Items for Systematic Reviewand Meta-Analysis Protocols (PRISMA-P) 2009.8

Results

Description of studies includedA total of 13 randomized controlled trials were in-

cluded in this review (Table I). We included all typesof burn, any location of burn wound, and burn expe-rienced by children as well as adults. Data from in-cluded studies were extracted and categorized intosix different groups. Grouping was determined based

on different skin substitutes, each with unique com-position, superiorities, and usage protocols suggestedby previous researchers and/or manufacturers.

Risk of biasAn assessment of risk of bias was conducted

using the revised risk of bias tool for randomized tri-als (RoB 2) (Fig. 2).8

Efficacy of Biobrane® for burnsBiobrane® (Bertek Pharmaceuticals, Morgan-

town, WV, US) was the first commercially availablebiosynthetic composite skin substitute (1979). It waspresented as a bilayer matrix which consists of nylonmesh with porcine-derived collagen type I as thedermal analog and a thin silicone layer as the epi-dermal analog. Biobrane® requires incorporationwith autograft using split-thickness skin grafting(STSG).23,24 Studies on Biobrane® were conductedon partial-thickness burns with the total area not ex-ceeding 30% TBSA and various age group analyses(Table II).


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Table I - Description of studies included

Study Design Intervention N (patients) Types of burn TBSA Location Types of patient Biobrane

[10] RCT Biobrane Silver Sulfadiazine

10 10

Partial-thickness 2-29% NS Pediatrics

[11] RCT Biobrane Silver Sulfadiazine

30 wounds 26 wounds

Partial-thickness <10% NS Pediatrics and adults

[12] RCT Biobrane Duoderm

35 37

Superficial and mid-dermal partial

<10% NS Pediatrics

[13] RCT Biobrane Intrasite+Acticoat+Duoderm

4 4

Partial-thickness >2% NS Pediatrics

[14] RCT (pp) Biobrane Silver Sulfadiazine

17 wounds 21 wounds

Partial-thickness ±5% NS Pediatrics

[15] RCT (pp) Biobrane Silver Sulfadiazine

41 48

Superficial partial-thickness

5-25% NS Pediatrics

TransCyte [14] RCT (pp) TransCyte

Silver Sulfadiazine 20 wounds 21 wounds

Partial-thickness ±5% NS Pediatrics

[16] RCT TransCyte Silver Sulfadiazine

14 Moderate or deep partial-thickness

2-30% Excluding face, hands, feet, buttocks, genitalia

Pediatrics and adults

[17] RCT TransCyte Bacitracin

10 11

Partial-thickness 50% of facial surface

Facial Adults

Integra [18] RCT (pp) Integra + autograft

Allograft + autograft 10 10

No limitations 50%; full-thickness ( 40%)

NS Pediatrics

[19] RCT Integra + autograft Autograft

10a

Full-thickness >20% Anterior side of the body Adults

Glyaderm [20] RCT Glyaderm + autograft

Autograft 32 wounds/ 28 patientsb

Full-thickness NS Pediatrics and adults

Suprathel [21] RCT (pp) Suprathel

Autograft 18 18

Deep partial-thickness NS NS Adults

Apligraf [22] RCT Apligraf + autograft

Allograft + autograft 80 wounds/ 40 patients

Partial to full-thickness 2-97% NS Pediatrics and adults

RCT = randomized controlled trial. TBSA = total body surface area. NS = not stated on the study. (a) experimental and standard interventions are done simultaneously in each subject to enable intra-individual comparison between treatments. (b) burn wound: n=13 sites (9 pts); other: n=19 sites (19 pts). Pp = per-protocol analysis.


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The Biobrane® treated group was statistically sig-nificant in shortening the wound healing time com-pared to silver sulfadiazine-treated groups in fourstudies (Barret et al.10 p<0.001, Gerding et al.11

p<0.01, Kumar et al.13 p<0.001, and Lal et al.14

p=0.025 and 0.026).10,11,13,14 Three studies (Barret etal.10 p<0.01, Gerding et al.11 p<0.001, and Kumar etal.14 p=0.0001) reported a lower pain score in theBiobrane®-treated group when compared with thesilver sulfadiazine-treated group.

Two studies reported a shorter length of hospitaliza-tion in the Biobrane®-treated group compared to the sil-ver sulfadiazine treated group (Barret et al.10 p=0.017,Lal et al.15 p=0.02 and p=0.026). The number of dress-ing changes was lower in the Biobrane®-treated groupcompared to the silver sulfadiazine-treated group(Kumar et al.14 p=0.0001).

A comparison of Biobrane® with modern dress-ings (Duoderm® and Duoderm®+Intrasite™+Acti-

coat™ respectively) was performed in two studiesby Cassidy et al.12 and Wood et al.13 These studiesdemonstrated Biobrane® and modern dressinggroups yielding equal results in wound healing time,pain, number of dressing change and VSS.

Efficacy of TransCyte® for burnsTransCyte® (Advanced BioHealing, Inc., US),

previously known as DermagraftTC, is a bilayer ma-trix consisting of porcine dermal collagen-coatednylon mesh acting as dermal analog with siliconelayer seeded with neonatal human foreskin fibrob-last. It was approved by FDA in 1997 and 2001.TransCyte® requires a secondary procedure acquir-ing STSG and has a higher risk of immune rejectionoriginating from the presence of allogenic cellsseeded.23,24

TransCyte® was compared with silver sulfadiazineand bacitracin in three different studies (Table III). Allstudies (Kumar et al.14, Noordenbos et al.15, Dem-ling et al.16) suggested TransCyte® was statisticallymore effective in decreasing wound healing time,pain management, lowering the number of dressingchanges, and managing scar formation, regardless ofthe location of burn wounds.

Efficacy of Integra for burnsIntegra® (Integra Life Sciences, Plainsboro, NJ,

US) was first designed in 1980 and FDA-approvedin 1996. The bilayer skin substitute consists of bovinecollagen and shark chondroitin-6-sulfate GAG actingas a dermal analog and semipermeable silicone poly-mer polysiloxane as an epidermal analog. Integraalso requires a two-step procedure with STSG place-ment replacing the silicon layer. Integra has been re-ported to successfully form dermal components witha minimal scar but a higher chance of infection.19,24,25

A comparison between Integra®, allograft, andcombination between autograft and allograft wasconducted in two different studies (Table IV). Theeffect of Integra in scar formation has varied be-tween studies. Integra® was found to yield a betterscar result compared to allograft based on the Hamil-ton burn-scar scoring system on month 12 andmonth 18-24 in the study by Branski et al.18 Theother study by Lagus et al.19 concluded a non-signif-icant difference in scar formation measured on

Fig. 2 - Risk of bias assessment of individual studies


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Table II - Efficacy of Biobrane® for burns

Outcome and Study Biobrane® Silver sulfadiazine Modern dressings* p-value

Wound healing time Number of days [10] 0.5 [0.1] (10) 1.9 [0.4] (10) - <0.001 [11] 10.6 [0.8] (30) 15.0 [1.2] (26) <0.01

[12] 12.24 [6.5] (35) - 11.21 [6.5] (37) 0.47 [13] 17.75 [4.99] (4) - 34.25 [14.39] (4) NP

[14] 9.5 (17) 11.2 (21) - <0.001 Days/%TBSA burned-percent [15] a - 0.025 (age <3)

0.026 (age 3-17) Pain

Faces scale 1 to 4 [10] 2.6 [0.3] (10) 3.8 [0.4] (10) - <0.001 Oucher scale or VAS 1 to 10 [12] 2.36 [2.62] (35) - 2.37 [2.77] (37) 0.993 Pain scale 1 to 5 [11] 1,6 [0.8] (30) 3.6 [1.3] (26) - <0.001 Median difference pain score [13] -2.0 (4) - +1.0 (4) insignificant Fewer pain medication [14] a - 0.0001

Number of dressing change [13] 11.5 [4.79] (4) - 7.5 [2.64] (4) NP [14] 2.4 (17) 9.2 (21) - 0.0001

Length of hospitalization

Number of days[10] 1.5 [0.2] (10) 3.6 [0.2] (10) 0.017 Days/%TBSA burned percent[15] b b - Age <3; p=0.002

Age 3-17; p=0.026

VSS [13] 4.25 [3.2] (4) - 4.25 [2.87] (4) NP

Values expressed as mean [standard deviation] (sample size). NP = statistical analysis not performed. VSS = Vancouver scar scale. a: Not stated, but analyzed as Biobrane® with shorter wound healing time compared to silver sulfadiazine. b: Not stated, but analyzed as Biobrane® with shorter length of hospitalization compared to silver sulfadiazine. *Modern dressings (Duoderm® or Duoderm®+Intrasite™+Acticoat™)

Table III - Efficacy of TransCyte® for burns

Outcome and Study Transcyte® Silver Sulfadiazine Bacitracin p-value

Wound healing time Number of days [14] 7.5 (20) 11.2 (21) - <0.001

[16] 11.14 [4.37] (14) 18.14 [6.05] (14) - 0.002 [17] Major: 8 [2] (5)

Minor: 8 [1] (5) - -

Major: 14 [4] (6) Minor: 12 [3] (5)

<0.05 <0.05

Pain

VAS 1 to 10 [17] - During dressing change Major: 2 [1] (5)

Minor: 2 [1] (5) - Major: 5 [1] (6)

Minor: 5 [1] (5) <0.05 <0.05

- Between dressing change Major: 2 [1] (5) Minor: 1 [0.5] (5)

- Major: 4 [2] (6) Minor: 3 [2] (5)

<0.05 <0.05

Fewer pain medications [14] a - 0.0001

Number of dressing changes [14] 1.5 (20) 9.2 (21) - 0.0001

Scar formation Vancouver car cale [16] - Month 3 1,39 [1,14] 4,82 [1,27] - <0,001 - Month 6 0,8 [1,31] 3,7 [1,37] - <0,001 - Month 12 0,375 [0,74] 2,125 [1,46] - 0,006

Values expressed as mean [standard deviation] (sample size). Major burns are defined as burns requiring at least seven days of hospitalization. Minor burns are defined as burns with potential outpatient care by American Burn Association (ABA) and established critical pathways. a: Not stated


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months 3 and 12. Adding Integra® to the treatmentplan also did not shorten the length of hospitalizationcompared to autograft alone.18

Efficacy of Glyaderm® for burnsGlyaderm® (Euro Skin Bank, Beverwijk, The

Netherlands) is an acellular dermal substitute de-rived from preserved glycerol of human allogeneicskin. It consists of collagen and elastin fiber net-works bonded with native collagen. It further re-quires STSG to restore the bilayer skin function.Application of Glyaderm® has been reported to bedependent on preliminary wound bed preparationwith allograft before application of Glyaderm® andtopped with the autograft.20

An evaluation of scar quality was executed in onestudy by Pirayesh et al.20 using the Vancouver ScarScale (VSS). The overall VSS evaluation was simi-lar in Glyaderm® combined with the STSG groupand STSG alone group (p=0.682). However, a sub-group analysis showed a significantly improvedelasticity of the skin in patients treated with Glya-derm® and STSG (p=0.003).20

Efficacy of Suprathel® for burnsSuprathel® (PolyMedics Innovations GmbH,

Denkendorf, Germany) is a cellular, biodegradable,synthetic polylactide-based copolymer that can beutilized as an epidermis analog.21,25

Suprathel® was compared directly to STSG as thestandard wound coverage for full thickness burnwounds in a study by Selig et al.21 An efficacy onscar assessment was done using two instruments:

VSS and patient and observer scar assessment scale(POSAS).21 Most features on VSS (pigmentation,pliability, height) yielded equally effective results onboth the Suprathel® group and STS group, except onvascularity. Meanwhile, three subgroup analysesfrom POSAS (elasticity, relief and pliability)showed a significantly superior result in theSuprathel® treated group compared to STSG(p=0.024, p=0.036, p=0.019, respectively).21

Efficacy of Apligraft® for burnsApligraf® (Organogenesis/Novartis, Canton MA

US) consists of a bovine collagen matrix bonded andseeded with live fibroblast and keratinocytes from theneonatal foreskin. Its commercial use was approvedby FDA in 1998. This skin substitute causes temporaryclosure and requires subsequent STSG;22,23 it was re-ported to be placed after STSG in the included study.21

Evidence from one study by Waymack et al.22

showed that Apligraf® combined with autograft pro-duced superior results in scar evaluation when com-pared to standard STSG treatment. Scar evaluation onmonth 24 with VSS yielded a better median score inApligraf® compared to allograft (p<0,0001). Addi-tionally, the number of days needed for adequate graftuptake and exudate presence was lower in theApligraf® group.22

Discussion

We included 13 studies with six types of skin sub-stitutes: Biobrane®, TransCyte®, Integra®, Glya-

Table IV - Efficacy of Integra® for burns

Outcome and Study Integra® + Autograft Autograft + Allograft Autograft p-value

Length of hospitalization [18] 41 [4] (10) 39 [4] (10) - NS

Scar formation

5,4 [1,7] (10) 7,7 [2,6] (10) - 0,003 4,3 [2,2] (10) 6,6 [3,1] (10) - 0,02

Hamilton burn-scar scoring system [18] Month 12 Month 18-24

Vancouver car cale [19] Month 3 2,5 (10)* - 2,5 (10)* >0,05 Month 12 1,3 (10)* - 0,8 (10)* >0,05

Values expressed as mean [standard deviation] (sample size). NS = not stated. (*) experimental and standard intervention is done simultaneously in each subject to enable intra-individual comparison between treatments.


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derm®, Suprathel® and Apligraft®. A total of 431 pa-tients, including adult and pediatric patients, had su-perficial to full-thickness burn depth, and theirTBSA ranged from 2-97%.

Conventional dressing options to surgical woundexcision and skin grafting are the current mainstaytreatments with recognizable efficacy in treatingacute burn patients.2,4 Topical antimicrobials are thestandard of care for all burn wounds that lose theirepidermal layers. In this review, two antimicrobialswere used (silver sulfadiazine and bacitracin).Deeper burn wounds should be treated operativelywith early excision and autografting. Therefore, skinsubstitute treatment for deeper burn wounds in thisreview were compared to autograft with/without al-lograft depending on each center’s preferences.

All skin plays a unique role, whether it is as anepidermal or dermal or both epidermal and dermalanalog. All but one type of skin substitute can be ap-plied directly to the wound site as temporary dress-ing waiting for spontaneous re-epithelialization ofburn wounds. In cases treated with Glyaderm®,wound bed preparation using allograft for five daysshould be done in advance to allow a successfulGlyaderm® and autograft take.

Evidences on Biobrane®Out of the six skin substitutes, Biobrane® is the

most frequently analyzed (reported in six studies)with the most extensive total number of samples(206 patients and 114 wounds). Since partial-thick-ness burns act as target treatment in all instances, itis appropriate to use topical antibiotics as the controlgroup. Compared to silver sulfadiazine, Biobrane®

excels in shortening the wound healing time, man-aging pain, minimizing dressing changes and short-ening the length of hospitalization.10,11,14,15

Wound healing time has been analyzed in sixstudies using two parameters: the total number ofdays required for healing10-13 and days required forhealing per percentage TBSA of burn patients15. Awound is considered healed when epithelializationin 90% of the wound area is present. Collagen,which is the biological component of the matrix inBiobrane,® has long been proven to promote attach-ment and proliferation of keratinocytes and fibrob-last.26 It is the most significant part of dermis and it

has a proper structure that ensures adequate adher-ence and supports the silicon layer to maintain thephysical barrier for the burn site.14 This barrier prop-erty perchance acts as the basis for decreasing thedressing change requirements in this review. Lessfrequent dressing changes identified in the study byKumar et al.14 correlates with better pain manage-ment as pain is the most excruciating factor in dress-ing change. Infrequent dressing changeaccompanied with less pain and rapid wound healingresulted in earlier discharge from hospital. De-creased exposure to the external environment al-lowed us to reduce nosocomial infection and furtherunnecessary additional costs.

Additionally, in line with the increased healingrate, decreased risk of scarring follows. A woundthat does not heal within ten days has a higher riskof scar formation.14 Even so, Biobrane® exhibitedsimilar scar prevention performance when comparedwith modern dressing (Duoderm® or Duoderm®+In-trasite™+Acticoat™) in the study by Wood et al.13

Two other studies involved research comparingBiobrane® against modern dressings, which both in-clude Duoderm.®12,13 Duoderm® is a hydrocolloid-based occlusive dressing with the advantage ofcreating physical barriers to provide a conducive en-vironment for wound healing. Wood et al.13 used In-trasite™ and Acticoat™ in addition to Duoderm®

which may help in decreasing bacterial colonizationincidence and assist in wound healing. These twostudies demonstrated that treatment using Biobrane®

and modern dressing provided equally effective treat-ment for partial-thickness burns.12,13 However, previ-ous literature searches were conducted by Cassidy etal. before the study; they showed that both Biobrane®

and Duoderm® are more effective in treating acuteburn wounds compared to silver sulfadiazine.12

Evidence on TransCyte®The biological significance of TransCyte® may

be affected by its composition. TransCyte® presentsto wound bed as formed bilayer with collagens,tenascin, and fibronectin composed dermal matrixand silicon seeded with fibroblast as a superficiallayer. As dermal component adheres to the wound,fibroblast stimulates growth factors and facilitatesrelease of other biological active human proteins


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(collagens, fibronectin, tenascin). All these factorswill promote migration, replication and spread ofepidermal cells and accelerate epithelialization.14,16,17

The properties of skin substitutes offer adherenceto the wound bed as well as a physical barrier thatmay enhance wound healing, decrease the need fordressing changes, and protect the wound from infec-tion or physical trauma simultaneously. Tran-sCyte®’s superiority was identified in all studies onthe skin substitute reviewed in this paper, which con-sisted of all age groups, types, and sizes of burns,strengthening the conclusion that its efficacy hasbeen proven for burn patients.14,16,17

Evidence on Integra®, Glyaderm®, Suprathel®,Apligraft®

The analysis regarding Integra® and Suprathel®

did not yield sufficient evidence of their superior ef-ficacy compared with standard treatment. Glya-derm® also did not show significant scarringprevention but has potential efficacy in promotingthe elasticity of the wound. Apligraft® combinedwith autografts was proven to produce better cos-metic outcomes up to month 24 compared to auto-grafts only through intrapatient evaluation.

Integra® is built with acellular collagen and gly-cosaminoglycan component, which is deemed to re-semble a normal dermis. It does not require a propervascularized wound bed for its adherence, thus re-vealing its potency in covering deeper burn sites. Asthere are no living cells in its composition, Integra®

does not have metabolic demand nor does it requireearly revascularization. The dermal template of Inte-gra® allows infiltration of fibroblast, macrophages,lymphocytes, and a neovascular network for the newdermal replacement. The vascularization processmay take 2 to 4 weeks and even 6 to 8 weeks in graftsand other non-graftable areas of the wound. The ex-tended vascularization time may explain the longerwound healing time that was experienced with Inte-gra.®18 Other studies on Integra® also suggested thatIntegra® is the most appropriate choice to achievepreferable skin color and matching skin texture.5,19

Glyaderm® is a relatively new line and least stud-ied among the available skin substitutes. The differ-ence between Glyaderm® and other skin substituteslies in the effort to combine elastin into collagen der-

mal matrix that potentially optimizes skin texture, re-silience and cellular responses in epithelialization.The presence of elastin in the matrix has shown a de-crease in stiffness, and reduced wound contractionand scar formation by suppressing the proliferationof contracting myofibroblast. Normally, elastin willnot be self-regenerated until 4-5 years after a burntrauma. Therefore, an external source of elastin isneeded to promote wound elasticity in the acute set-ting. A study by Pirayesh et al.20 successfully showedGlyaderm’s® role in promoting elasticity in burnwounds. Even so, the overall scar quality was not im-proved when compared to the control. Other aspectsof scar formation including pigmentation and vascu-larization might not be enhanced with Glyaderm.®20

A study by Selig et al.21 stressed the importanceof measuring the long-term outcome of Suprathel®

in deeper burn wounds. Previously, Suprathel® hasbeen shown to be successfully used in partial-thick-ness burn sites and donor sites. Its cellular qualityrequires a properly vascularized wound bed to opti-mize its growth. In deeper wounds where vascularityis not always present, Suprathel® applicability wasquestioned.21 One preliminary study showed longerwound healing and less preferable scar formationcompared to skin grafting by three months of treat-ment.26 Selig et al. conducted a scar evaluation 12months post-treatment and showed slightly favor-able results for Suprathel® compared to autologousskin grafts, but this was not supported through sta-tistical analysis. The reasoning behind its scar for-mation was initially sought by correlating scarformation with its late wound-healing process. How-ever, Selig et al. demonstrated that a properly epithe-lialized wound by day 15 may still be accompaniedby an ongoing scar formation.21 This possibility cre-ated some room for further research regarding whatother contributing factors of scar formation mayarise in deep dermal wounds. Up until now, evidenceon Suprathel® can only justify its use on partial-thickness burn wounds.

Apligraft’s® superiority in long-term cosmeticoutcome measured by the Vancouver scar scale wasproven in a study by Waymack et al.22 Apligraft® isrich in human fibroblast derived from neonates andspeculated to create similar properties to human skin.Apligraft,® which is identical to other dermal substi-


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tutes, creates volume in between wound bed and au-tograft, thus it provides amiable contour for regener-ated skin. In the reviewed study, Apligraft® was solelycompared with the standard STSG treatment, whileno previous comparative study of Apligraft® withother skin substitutes has ever existed.22

Skin substitutes also act as a mechanical barrierthat may prevent microbes from entering woundsites. We found no studies that pointed to any in-creased risk of infection with skin substitute appli-cations. Branski et al. performed a statistical analysiscomparing the infection rate of the Integra® groupwith the allograft group and concluded that therewas a nonsignificant difference in infection rate be-tween the two groups.17 Lal et al. also compared theuse of oral antibiotics between Biobrane® and silversulfadiazine and found no significant difference be-tween the two groups.14 There were also no adversereactions, such as allergies or foreign body rejectionexperienced in any studies included in this review.Skin substitute take was adequate in all studies.

Analyses of cost-efficiency of treatment usuallyincludes length of hospitalization, number of proce-dures, and frequency of wound care in both groups.In burn cases, this typically relates well to deepburns, infected wounds, and need for daily woundcare by health personnel. On one hand, the applica-tion of skin substitutes will directly shorten the lengthof hospitalization and frequency of wound care.However, skin substitutes are generally expensive,especially in large burn areas. A cost-efficiencyanalysis was conducted by Branski et al. comparingIntegra® to allograft. It was found that there were nosignificant differences between the two treatments inlong-term and short-term cost-efficiency indicators.18

Faster wound healing time, enhanced skin qual-ity, and scar formation were identified to be hetero-geneous depending on type of skin substitute usedand comparison groups. Consistent excellent find-ings for burn wounds treated with skin substitutesincluded minimal disruption for dressing changes,which correlates with diminished pain experiences,comfort, and wound exposure to infection.

Study limitationsHeterogeneity was an obvious shortcoming in this

review. Pooling data from studies with a small num-

ber of samples to increase statistical power was im-possible for a significant portion of this review, re-sulting from the diversity of outcome measurementinstruments and characteristics of the studies.

Most of the studies lack the reporting process ofrandomization, including sequence generation andallocation concealment, sparking some concerns re-garding the randomization process. This resulted in10 studies with some bias. Only four RCTs showeda good randomization process. Hardly possible blind-ing on participants, care providers and observers canbe implemented due to grossly visible treatment dif-ferences. However, this reason is less likely to causeany outcome deviations. Most previous studies onskin substitutes and similar interventions also re-ported similar blinding difficulties. Patients’ nonad-herence to treatment is usually due to other factorsaside from therapy. In one study, patients’ nonadher-ence was caused by patient denial in both groupsequally (skin substitutes group and control group),thereby not affecting the outcome directly. Outcomemeasurement in all studies appears to be objective,using standard measurement tools and professionalassessors for other clinical-based measures with noavailable tool. The selection of reported outcomeswas proper with most RCT data supported with sta-tistical analysis, except in one study by Wood et al.13

where the outcome was consequently considered tohave less significance in this trial.

Conclusion

Implications for practiceAll of the skin substitutes studied exhibited at

least non-inferior to superior performance comparedto standard treatment in terms of efficacy in treatingvarious burn wounds, not limited to burn depth, size,or patients’ age and wound location.

Implications for researchFuture trials should consider and report in detail

on the randomization process, possibly blinding theoutcome assessor (as blinding of patient or careprovider is formidable), and proper outcome analy-sis to minimize risk of bias to improve the quality ofevidence. A minimum number of samples should be


10

calculated to strengthen statistical power. The out-come assessed can also be expanded to encompassthe safety of treatment. Cost issues are another ex-citing aspect to evaluate in the future as it is a com-

mon barrier preventing a treatment shift from con-ventional standard treatment, especially in develop-ing countries.

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