대한외상학회지 Vol. 20, No. 1, June, 2007 원 저 동종유래각질세포 (Cultured Allogenic Keratinocytes, Kaloderm ) 를이용한부분층피부결손의치료 성균관대학교의과대학강북삼성병원성형외과학교실, 테고사이언스ㄜ * 서상원 장충현 조민수 홍윤기 전세화 * Abstract Treatment of Partial Thickness Skin Defect with Cultured Allogenic Keratinocytes (Kaloderm ) Sang Won Seo, M.D., Choong Hyun Chang, M.D., Min Su Cho, M.D., Yoon Gi Hong, M.D., Sae Wha Jeon, Ph.D.* Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea, Tego Science Inc., Seoul, Korea* Purpose: Grafting with autograft skin remains the most effective method for treating skin defects. When insufficient donor sites are present or patients are afraid of the operation, a skin graft is impossible. Cultured allogenic keratinocytes speed wound healing by providing cover and by producing growth factors and extracellular matrix protein. We report an application of cultured allogenic keratinocytes (Kaloderm, Tegoscience, Seoul, Korea) in the treatment of an acute partial thickness skin defect. Methods: From March 2005 to January 2006, 20 patients with a partial thickness skin defect were treated with cultured allogenic keratinocytes. The wound was covered with a sheet of cultured allogenic keratinocytes and ointment with Bactigras gauze. The wound was inspected every two or three days. We regarded completion of epithelialization as wound healing. Results: The mean period between time of injury and time of Kaloderm application was 7.5 days. The time taken from application of Kaloderm to complete closure of the wounds was 7.2 days. Conclusion: In view of the favorable outcome, cultured allogenic keratinocytes are safe and effective biologic dressing materials for use in the treatment of open wounds. (J Korean Soc Traumatol 2007;20:1-5) Key Words: Cultured allogenic keratinocyte, Partial thickness wound Address for Correspondence : Yoon Gi Hong, M.D. Department of Plastic and Reconstructive Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-dong, Jongno-gu, Seoul 110-746, Korea Tel : 82-2-2001-2181, Fax : 82-2-2001-2177, E-mail : hipson21@dreamwiz.com 접수일 : 2006 년 11 월 17 일, 심사일 : 2007 년 2 월 20 일, 수정일 : 2007 년 3 월 14 일, 승인일 : 2007 년 3 월 21 일 본논문은 2005 년제 59 차대한성형외과학회추계학술대회에서구연발표되었음. 1
대한외상학회지제 20 권제 1 호 Ⅰ. 서론 Ⅱ. 대상및방법 피부의결손혹은찰과상등의개방창상이발생한경우창상을덮기 (close) 위해서는피부의대용물 (skin substitutes) 이필요하다. 물론이와같은개방창상은수축 (contraction), 상피화 (epitheliaization) 등의과정을거쳐이차유합 (secondary intention) 에의해치유가가능하나, 반흔을적게남기고, 기능상의문제점을최소화하기위해서는피부또는피부대용물을사용하여개방창상을덮어주는것이좋다. 결손이심한경우가장이상적인방법은자가피부를이용한피부이식술이라할수있다. 그러나피부이식술은환자가수술에대한불안감이나공여부반흔에대한거부감등으로시행하기어려운경우가있으며, 얻을수있는피부의양이한정되어있다는단점이있다. 이러한단점을보완하기위해최근자가피부를대체하기위한인공진피의사용이나상처치유를촉진하기위한배양표피세포등이개발되었다. 저자들은그중에서동종유래각질세포 (cultured allogenic keratinocytes, Kaloderm, Tego Science Inc., Seoul, Korea) 를사용하여부분층피부결손치료에적용하였다. 1. 대상 2005년 3월부터 2006년 1월까지본원성형외과를내원한부분층피부결손환자중동종유래각질세포를이용한창상치료에동의를한 20명의환자를대상으로하였다. 부분층 2도화상의경우는진피의유두층까지만화상을입은것으로써물집이발생하며핀으로긁어보거나남아있는털을뽑아보면감각이있는것이특징이다. 대개는수술적처치를요하지않고, 보통 14일이내에치유되는것으로알려져있다. 심부 2도화상은진피의그물층일부까지도화상을입은경우로써물집이있으나진피의색깔이다소흰색을띠며감각이둔하다. 저자들은부분층피부결손 (partial thickness skin defect) 을위의두경우모두를포함하는정도의병변으로임의로정하였다. 연령은생후 1개월에서 69세까지였고, 창상의원인은화상 7명, 교통사고 5명, 자상 3명, 넘어짐 2명, 부분층피부이식술공여부 2명, 고삼투액의혈관외유출 1명이었다. 대상환자중 1명 (Patient No. 14) 에서제2형당뇨병이있어혈액투석을받는상태였다 (Table 1). Table 1. Clinical data for the 20 patients No. Sex/Age Cause A (days) B (days) C 01 F/28 Knife injury 01 09 1 02 M/24 TA 10 06 1 03 F/1mo Extravasation 22 07 1 04 M/21mo Burn 10 10 2 05 F/26 Burn 05 04 1 06 M/45 Slip down 00 05 1 07 M/3 Burn 03 09 1 08 M/4 TA 12 10 1 09 F/14 TA 04 06 1 10 F/21 Knife injury 02 07 1 11 F/11mo TA 01 05 1 12 F/19mo Burn 04 07 2 13 M/26 Slip down 06 05 1 14 M/69 Burn 23 07 1 15 F/31 Knife injury 15 14 2 16 F/10 TA 22 09 1 17 F/15mo Burn 04 06 1 18 M/53 Burn 03 06 1 19 M/42 STSG donor site 00 07 1 20 M/5 STSG donor site 00 05 1 No.: number, mo: months, TA: traffic accident, STSG: split thickness skin graft A: period between time of injury and time of Kaloderm application, B: time taken from application of Kaloderm to complete closure of wounds, C: the number of Kaloderm used 2
서상원외 : 동종유래각질세포를이용한피부결손치료 2. 방법부분층피부결손환자의내원시동일한담당의사가환부를소독하였다. 삼출물의양이과도하거나염증이있는경우는삼출물이나염증이감소될때까지고식적인습윤소독을시행하여, 궤사조직및삼출물등을충분히제 거한후동종유래각질세포를적용하였다. 동종유래각질세포위에연고를도포하고, 올이굵은거즈 (Bactigras, Smith & Nephew, London, England) 및식염수거즈혹은바셀린거즈및식염수거즈를이용하여습윤한환경을유지하였다. 병변이사지 (extremities) 에있는경우에는부목 (splint) 을대주었다. 동종유래각질세포를적용한후 2~3 A B C Fig. 1. A 26-year-old man with deep abrasion and traumatic tattoos on his face. Preoperative view (A). Intraoperative view. Kaloderm applied on wound (B). Postoperative view at 5 days. Wound completely healed (C). A B C D Fig. 2. A 19-month-old girl with contact burn. Preoperative view (A). Postoperative view at 7 days. Wound completely healed (B). Postoperative view at 2 months (C). Postoperative view at 9 months (D). 3
대한외상학회지제 20 권제 1 호 일간격으로식염수거즈를교환하였고, 동종유래각질세포 1회적용시안면부는 5일, 기타부위는 7일동안유지하는것을원칙으로하였다. 필요시동종유래각질세포를재적용하였으며, 창상치유가완료된경우에는소독재료를개방하였다. 창상치유의완료는상피화가완성된경우를기준으로삼았다. 소독재료의개방후에는보습제 (Atoderm, Bioderma, Lyon, France) 와자외선차단제 (Photoderm, Bioderma, Lyon, France) 를적용하였고, 소아수부의경우에는 2개월간고탄력압박복 (compressive garment) 을착용하도록권장하였다. Ⅲ. 결과환자들의평균연령은 20.3세 (1개월 ~69세 ) 였으며, 그중남자가 10명, 여자가 10명이었다. 수상후동종유래각질세포를적용할때까지의기간은평균 7.5±7.7일 (0일 ~23일 ) 이었으며, 동종유래각질세포적용후창상치유가완료될때까지걸린기간은평균 7.2±2.4일 (4일 ~14일 ) 이었다. 수상후부터창상치유완료까지걸린기간은평균 14.6±8.9 일 (5일 ~31일 ) 이었다. 총 20명의환자들중 17명은동종유래각질세포 1회적용에창상치유가완료되었다. 생후 21 개월남자환아 (Patient No. 4) 와 19개월여자환아 (Patient No. 12) 가수부에발생한심부 2도화상으로동종유래각질세포 2 회적용후에창상치유가완료되었으며, 수상후 창상치유까지는각각 20일과 11일이소요되었다. 또한 31 세여자환자 (Patient No. 15) 가칼에의한수지의피부결손으로내원하여동종유래각질세포 2 회적용후에창상치유가완료되었으며, 소요기간은 29일이었다 (Table 1)(Fig. 1-3). Ⅳ. 고찰창상에대한소독방법은개방소독, 폐쇄소독, 습윤환경소독, 생물학적소독등이있다. 최근창상처치의목표로는창상치유촉진, 통증감소, 피부보호기능의회복, 미용적으로만족할만한결과, 더욱깊은손상으로의진행방지등을들수있으며, 이러한목표에가장부합하는것으로는생물학적소독을들수있다.(1) 생물학적소독재료의종류에는사체피부, 양막등의동종이식과돼지, 개의피부, 소의양막과같은이종피부등이있고, 인공제작된 Kaloderm, Biobrane (Bertek Pharmaceuticals Inc., Morgan town, WV) TransCyte (Advanced Tissue Sciences, La Jolla, CA) 등이있다.(2) 동종이식또는이종피부등은항원성 (antigenicity) 이있으며, 내인성 (durability), 무균성 (sterility) 의결여와항상사용할수없다는점에서임상적사용에제한이있다.(3) 따라서최근에는인공제작된생물학적소독재료를많이사용하는추세다. 1975년 Rheinwald와 Green이각질세포배양기술을발 A B C D Fig. 3. A 69-year-old man with deep 2nd degree burn and type II DM. Preoperative view (A). Postoperative view at 14 days. The wound was healed completely (B). Postoperative view at 4 months (C). Postoperative view at 9 months (D). 4
서상원외 : 동종유래각질세포를이용한피부결손치료 전시킨이후광범위화상환자의치료에적용되었으며, 1983년동종유래각질세포가광범위화상환자의피부대용물로사용되기시작하였다.(4) 다른동종장기이식 (solid-organ allograft) 과는달리동종유래각질세포는 passenger leukocyte를포함하지않으며, MHC class II 항원 (antigen) 을표현하지않는다. 그러나생체내에서는 interferon-γ와여러가지사이토카인등이존재하여결국면역학적활성을가지게된다.(4,5) 따라서동종유래각질세포는급성면역반응은없으나궁극적으로는거부되거나숙주 (host) 의각질세포로대체되게된다. 동종유래각질세포를화상이나부분층피부이식공여부창상에적용할경우창상치유가촉진된다는보고가있다.(6) 동종유래각질세포는 GM-CSF, TGF-β1, TGF-α, β FGF, VEGF, IL-1α, IL-8 등의성장인자를분비하며, 상피의부착과이동에관여하는 fibronectin, laminin, thrombospondin, 세포외기질단백질 (extracellular matrix proteins) 등을합성및분비하여창상치유를촉진한다.(6) 따라서, 창상부위의가장자리에서창상중심부위를향해이동하는각질세포와창상부의모근 (hair follicle) 등에일부남아있는각질세포들이동종유래각질세포와접촉 (contact) 함으로써보다더빠르게상피화를할수있다. 실제로각질세포 (keratinocyte) 는표피의주요세포로서외부의자극을받으면여러가지사이토카인 (cytokine) 을분비하며, 화학주성수용체 (chemokine receptors) 를가지고있다.(7) 특히각질세포에서분비하는 GM-CSF, TGFβ1, TGF-α등은창상치유를촉진시키는것으로알려져있다.(7,8) 이상적인생물학적소독재료는부착성 (adherence), 세균증식억제, 수분및전해질손실방지, 내인성 (durability), 저장성 (availability), 안정성, 경제성, 지혈성 (hemostatic) 및사용의간편성등의특성을가져야한다.(8) 동종유래각질세포는미리준비되어있어필요시즉시사용할수있으며, 화상환자에서는면역기능의저하로이식물이장기간생착가능하며, 각종성장인자등의분비로재상피화를촉진시킨다는장점이있다. 또한통증이적고잦은소독재료의교환이필요없어특히소아의경우에적용할만하다.(9) 그러나가격이비싸며, 감염에약하다는단점이있다. 저자들의경우동종유래각질세포를이 용하여다양한부위와다양한손상정도의병변을치료하였으나대조군이없어객관적인결과를알기힘든한계가있었다. Ⅴ. 결론 동종유래각질세포는고가이며감염에약한단점에도불구하고, 창상치유를촉진하며쉽게적용가능하고, 필요한양을필요한시기에사용할수있어부분층창상을가진환자의보존적치료에도움을줄수있어보고하는바이다. REFERENCES 01) Kim SH, Lee JH, Lee DE: Dressing materials in the STSG donor site management: a comparative study. J Korean Soc Plast Reconstr Surg 2004;31:71-5. 02) Jeon JW, Kim DH, Hur J, Chun W, Jang WY, Kim JH: Clinical practice of glycerol preserved xenograft. J Korean Soc Burn 2004;7:73-8. 03) Tark KC, Rah DK, Lee YH: Clinical study on the effect of Biobrane in burn wounds. J Korean Soc Plast Reconstr Surg 1987;14:201-10. 04) Scott CH, John PH, Hiromasa Y, Athina G, Suzan D, Jeffrey AF, Anthony AM: Immunogenicity of cultured keratinocyte allografts deficient in major histocompatibility complex antigens. J Trauma 1998;45:25-34. 05) Nigel C, Harshad AN, Colin JG, Irene ML: Acute rejection of cultured keratinocyte allografts in nonimmunosuppressed pigs. Transplantation 1991;52:918-21. 06) Richard F, Frances P, Ihsan H, Cindy L, Irwin AS: Keratinocyte allografts accelerate healing of split-thickness donor sites: applications for improved treatment of burns. J Burn Care Rehabil 1993;14:148-54. 07) Hiroshi U, Hiroshi T, Tetsuya K, Masutaka F: Cytokines and chemokines in the epidermis. J Dermatol Sci 2000;24:S29-S38. 08) Koji H: Regulation of keratinocyte function by growth factors. J Dermatol Sci 2000;24:S46-S50. 09) Whang KK, Kim MJ, Song WK, Cho S: Comparative treatment of giant congenital melanocytic nevi with curettage or Er: YAG laser ablation alone versus with cultured epithelial autografts. Dermatol Surg 2005; 31:1660-7. 5