Review Article The Korean Journal of Sports Medicine 2017;35(2):77-85 pissn 1226-3729 eissn 2288-6028 https://doi.org/10.5763/kjsm.2017.35.2.77 운동선수의족관절골연골손상에서의치료 순천향대학교부천병원정형외과 1, 중앙보훈병원정형외과 2 유정우 1 ㆍ여의동 2 ㆍ이영구 1 Treatment of Osteochondral Lesions of the Talus in Athletes Jungwoo Yoo 1, Eui Dong Yeo 2, Young Koo Lee 1 1 Department of Orthopedics, Soonchunhyang University Bucheon Hospital, Bucheon, 2 Department of Orthopedics, Veterans Health Service Medical Center, Seoul, Korea The definition of osteochondral lesion of the talus (OLT) is any defect involving both the articular surface and the subchondral bone of the talus. Many of these lesions are associated with acute ankle injury. Although many classification schemes for OLT have been proposed, Berndt and Harty s 4-staging classification is most commonly used. Stage 4 lesions and symptomatic lesions under grade 3 are usually recommended to surgical treatment. The treatment approach for athletes should be more elaborate due to the need for an early return to play. Several different types of treatment are described for OLTs in athletes, including bone marrow stimulation, osteochondral autograft transfer system, and autogenous chondrocyte implantation. Osteochondral autograft transfer system shows good clinical outcome and has the advantages that could be applied to large defect and recurred lesions, however, it has some disadvantages in terms of the complications related with the donor site and the difficult approach to the medial lesions. Although autogenous chondrocyte implantation has been extensively applied for treating OLTs with successful clinical outcomes, it has some limitations that apply to athletes in terms of the 2-stage and complicated procedure and the insurance issues. Bone marrow stimulation being a simple and cost-effective procedure associated with a low complication rate and low postoperative pain has faster return to play and is recommended the first-line treatment for the OLTs of athletes. Keywords: Athletes, Microfracture, Autografts, Talus Received: July 14, 2017 Revised: August 16, 2017 Accepted: August 18, 2017 Correspondence: Young Koo Lee Department of Orthopedics, Soonchunhyang University Bucheon Hospital, 170 Jomaru-ro, Wonmi-gu, Bucheon 14584, Korea Tel: +82-32-621-6702, Fax: +82-32-621-5018 E-mail: brain0808@hanmail.net Copyright 2017 The Korean Society of Sports Medicine CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론거골골연골병변 (osteochondral lesion of the talus) 은 1737년 Monro 1) 에의해처음소개된이래로박리성골연골염 (osteochondritis dissecans), 거골원개골절 (talar dome fracture), 골연골골절 (osteochondral fracture) 등다양한용어로불리며그발생기전이나치료방법에대해지속적으로연구되어왔다. 그리고 1959년 Berndt와 Harty 2) 에의하여이질환에대한분류가처음발표되었다. 거골골연골병변은거골의관절연골과연골하골에발생하 제 35 권제 2 호 2017 77
J Yoo, et al. Treatment of Osteochondral Lesions of the Talus in Athletes 는다양한형태의손상및결손을모두포함하여정의하고있다. 이러한손상을일으키는다양한원인이있을수있으며대부분유사한형태의병변으로나타난다. 드문원인으로는퇴행성관절질환, 관절의부정정렬, 무혈성골괴사, 말초혈관질환이나내분비대사이상등이있다 3). 하지만주된원인은급성발목손상이며많은연구를통하여거골의골연골병변은발목골절이나염좌가발생하였을경우 50% 이상에서동반된다고보고되고있다 2,4,5). 또한, 거골의연골손상의 23% 는외측만성발목불안정과연관이있어인대재건술을시행한후에도지속적인통증의원인이될수있다 6). 연골의경우치유능력이떨어지는조직이므로 7) 한번손상을입게되면불가피하게만성적인통증이나골관절염으로진행되는경우가많다 8,9). 이는운동선수에게치명적이며심한경우운동을그만두게되는하나의원인이될수있다. 또한, 발목손상은가장흔한운동손상중하나이며모든운동손상의 15% 를차지한다. 따라서발목손상이발생하였을경우충분한검사를통하여거골골연골병변의동반여부를확인하는것이중요하다. 골연골병변에대한다양한치료법이고안되었지만아직까지확립된치료가이드라인은없다 10,11). 특히운동선수의경우운동으로의빠른복귀가매우중요하기때문에치료방법선택에있어제약이있으며어떠한치료가가장좋은지에대해서는많은논란의여지가있다. 본논문의목적은현재임상에서많이사용하고있는거골골연골병변치료에대해소개하고그중운동선수에게가장효과적인치료법에대해알아보고자하는것이다. 거골체가회전하면서연골손상이발생한다. 이손상으로연골에타박상이생기고연골은점차물러지게되며심한경우금이가면서작은조각으로나누어지게된다 14). 거골체에가해진전단력 (shearing force) 은연골상층부나연골하골에전해져골조직의분리를일으킨다. 파편은발목관절내에유리체로떨어져나가거나, 혹은부분적으로연결되어남아있게된다. 이러한병변은점차치유되거나무증상으로남을수있고또는더진행하여연골하골의낭종을형성하게된다. Elias 등 16) 은거골체관절면을 9개의구역으로나누어각각구역의골연골병변의특징을연구하였고, 4구역 ( 중내측 ) 과 6구역 ( 중외측 ) 에서가장흔하게발생한다고하였다. 또한 Flick 과 Gould 12) 는 500명의환자를대상으로한연구를통하여 98% 의외측병변이발목염좌와같은외상에의해발생한다고발표하였다. 손상기전은발목이외상에의하여강제로배굴 (dorsiflexion) 되고내번 (inversion) 될때거골원개에전단력이전해지며발생한다. 이러한외측병변은내측병변에비해보통얕은경향이있으나일반적으로더심하게나타나며골편이떨어져나가는경우가더흔하다. 반면에내측병변의 70% 는발목이강제로족저굴곡 (plantar flexion) 및내전될때축하중 (axial load) 이전해지며발생한다 14). 환자초기진찰시에증상의경향을보면, 보행시불안정성이있거나, 특별한자세에서갑작스러운통증이발생한경우에는발목불안정성이동반된것을예상할수있고, 장기간보행이나발목을과하게사용한뒤에발생한관절통증이있는경우는퇴행성변화가동반되어있음을알수있다. 원 인 통증의기전 다양한원인중에서도외상은족관절의골연골질환의가장중요한원인으로알려져있다. 거골체외측의병변의경우 93% 98%, 내측의병변은 61% 70% 정도가외상으로인해발생한다고알려져있다 11,12). 그리고비외상성원인으로는허혈성손상과그로인한무혈성골괴사, 부전하방경비인대 (accessory anterior-inferior tibiofibular ligament, Bassett s ligament) 에의한연부조직충돌 (soft-tissue impingement) 이나만성발목불안정등이있다 13,14). 외상성연골손상은미세손상 (microdamage), 둔상 (blunt trauma), 연골골절과골연골골절 (chondral and osteochondral fracture) 세가지분류로나누어생각해볼수있다 15). 발목의염좌는외상성골연골병변의주된원인으로발목관절내에서 모든족관절의연골손상이통증을유발하지는않는다. 일부는무증상으로남아있기도하고또일부는연골하골낭종을형성하며체중부하시에깊은발목통증을유발하기도한다. 골연골병변에서통증을유발하는몇가지요인이있다. 첫째로골내압의증가는여러연구에서통증을일으키는요인의하나로언급되었으며관절의퇴행성변형과연관이있다 13,17,18). 관절내압력의증가도퇴행성관절질환에서통증의원인이될수있다. Goddard와 Gosling 19) 은관절내활액의압력과골관절염에서의통증사이의상관관계를발견하였다. 하지만국소적인골연골병변의경우관절내삼출이적어실제로관절내압력을높이는것으로보이지는않는다. 78 대한스포츠의학회지
유정우외. 운동선수의족관절골연골손상에서의치료 활액막과관절막에는신경말단들이분포하고있으며관절막과관절주변의연부조직은통각유발에중요한역할을한다. 관절의염증성변화에따른 substance P와 calcitonin gene-related peptide 양성뉴런의상향조절은퇴행성관절염에서신경펩티드와관련된통증메커니즘으로생각된다 20). 영상검사소견과실제관절경소견사이의연관성에대한여러연구가진행되었고 Pritsch 등 21) 은단순방사선사진과관절경소견사이에연관성은떨어진다고발표하였다. 반면에자기공명영상소견은관절경소견과높은상관관계를보였으며병변의중증도는실제에비해낮게보이는경향이있었다 24). 분 류 치 료 Berndt와 Harty 2) 가처음발표한 4단계의법은아직까지도가장널리사용되는분류법으로이후많은변형된형태의분류법이발표되었다. 이는단순방사선사진의형태에따라 4가지단계로구분한분류로주로연골골절에대한것이었다. 하지만단순방사선사진소견만으로는정확한진단이어려우며관절경소견과도상관관계가크지않았다 21). 최근에는다양한영상기술의발달에따라컴퓨터단층촬영, 자기공명영상과관절경소견을바탕으로한새로운분류들이발표되었다 22-25). 일부는기존의 4단계분류에낭종아류형을추가하였고또는관절연골의변화를분류에추가하였다. 지금까지다양한치료법이개발되었고각각의치료법은장단점이있으므로환자상태에맞는치료법을선택하는것이중요하다. Dragoni 등 26) 은기본적인 4단계분류체계를기반으로하여증상의유무와병변의크기에따른치료알고리즘을발표하였다 (Fig. 1). 먼저 4등급에서는수술적치료를고려하고, 1, 2, 3등급의경우에는증상의유무에따라수술을결정하게된다. 증상이없는경우는경과관찰을하고증상이있는경우라도우선적으로보존적치료를시행해보고이후에도증상이지속되는경우에는수술적치료를시행한다 26). Fig. 1. The treatment algorithm for osteochondral lesion of the talus. NSAIDs: non-steroidal anti-inflammatory drugs, OATS: osteochondral autograft transfer system, ACI: autogenous chondrocyte implantation. Reproduced from Dragoni et al. Foot Ankle Int 2011;32:910-6, with permission of SAGE Publications 26). 제 35 권제 2 호 2017 79
J Yoo, et al. Treatment of Osteochondral Lesions of the Talus in Athletes 보존적치료에는생활습관의변경, 단계적체중부하, 재활치료, 보조기, non-steroidal anti-inflammatory drugs (NSAIDs) 사용등이포함된다 27,28). 증상이적고자기공명영상에서관절연골의일부만침범한거골골연골병변환자에대한보존적치료로임상적이나방사선학적으로만족스러운결과를보였다 29). 하지만대부분증상이있는환자들에게서는만족스러운결과를얻기어려웠다. Lee 등 30) 이시행하였던연구에의하면보존적치료를통해 39% 에서증상의호전을보였으나 61% 의환자에대해서는수술적치료가필요하였다. Verhagen 등 11) 은 14개연구의메타분석을통하여 201명의보존적치료를시행받은환자중 45% 인 91명에서만만족스러운결과를보였다고발표하였다. 수술적치료로현재까지다양한치료방법이개발되었다. 소파술 (curettage) 과절편제거술 (fragment excision), 미세골절술 (microfracture) 과전향적및후향적천공술 (antergrade or retrograde drilling) 등의골수자극술 (bone marrow stimulation) 31), 골연골자가이식술 (osteochondral autograft transfer system) 과골연골동종이식술 (osteochondral allograft transplantation) 27), 그리고자가연골세포이식술 (autologous chondrocyte implantation) 과혈소판풍부혈장치료 (platelet-rich plasma therapy) 등의세포기반치료술 (cell-based repair technique) 등이현재사용되고있는대표적인치료법이다 32). 각각의치료법은연구마다어느정도의편차는있지만대부분만족스러운결과를보였다. Zengerink 등 33) 의메타분석연구에서는보존적치료를포함한많은수술적치료법중에서절제술및소파술은 77%, 절제술및소파술과골수자극술은 85%, 골연골자가이식술은 87%, 자가연골세포이식술은 76% 의치료성공률을보였다. 하지만아직까지거골골연골병변치료에대한충분한장기추시결과나정립된치료방법은없다 10,11). 또한, 각각의치료법은수술전준비기간과수술후재활기간, 술기의난이도, 수술비용등많은부분에서차이가있기때문에단순한치료성공률만으로수술방법의우위를결정할수는없다. 따라서수술적치료방법을결정하기전환자의전신적상태, 급성또는만성의경과여부, 치료시기, 재발여부, 빠른복귀의필요성, 환자의경제적상태등다양한인자들을고려하여치료법을선택해야한다. 운동선수의족관절골연골병변은일반인들과는다르게접근해야한다. 치열한경쟁이필요한스포츠선수들에게초기치료의기간이길어진다면운동으로의복귀가늦어지고그로인해꾸준한경기력의유지가어려워지게되며결국에는조기 은퇴를해야할상황에처할수있다. 그렇기때문에운동선수에게치료의성공은일반인들의기준보다더엄격하게판단되어야하고초기치료법의선택에있어서단순히성공률이가장높은치료보다는빠른운동으로의복귀가가능한최소침습수술 (minimal invasive surgery) 을선택해야할것이다 34). 골수자극술미세골절술로대표되는골수자극술은관절경시술시간단하게시행할수있어골연골병변치료시널리시행되는치료법이다. 골수자극술은천공술이나미세골절술을통하여연골하골에작은구멍을만들어줌으로써중간엽줄기세포 (mesenchymal stem cell) 를연골결손부위로이동시켜치유하는방법으로연골하골에구멍이만들어지면섬유성응괴가결손부위를채우게되며염증반응이시작되고이어서사이토카인 (cytokine) 과성장인자들이분비되어치유를촉진하게된다 31). 이때중간엽줄기세포가섬유성응괴속으로이동하여분화및증식하여주로제1형콜라겐을함유한섬유연골성치유조직으로변화하게된다 (Fig. 2) 35). 골수자극술은관절경수술과함께빠르고간단하게시행할수있다는장점이있다. 또한, 최소침습적이며수술후합병증이나통증도적어서초기치료로선호되고있다 31). 무엇보다도골수자극술은다른치료법에비하여빠른운동으로의복귀가가능하다는점에서운동선수의치료에있어서큰장점이있다. 슬관절의골연골병변에대한한연구 36) 에서미세골절술은골연골자가이식술에비해 1개월정도운동복귀가늦은반면에발목관절의골연골병변환자를대상으로한 Saxena와 Eakin 6) 의연구에서미세골절술은골연골자가이식술과유사한임상적증상호전을보였으나운동으로의복귀는미세골절술이약 4개월, 골연골자가이식술이약 5개월로미세골절술이 1개월정도더빨랐다. 또한, 미세골절술을시행한환자를대상으로체중부하시기를달리하여비교한연구에서수술후 2주째부터부분체중부하를시작한환자군은수술후 6주동안체중부하를하지않은환자군과임상적, 방사선학적결과에서차이를보이지않았다. 이는미세골절술후조기체중부하및재활치료를시작할수있다는점에서미세골절술후빠른운동으로의복귀를지지해주고있다 37). 다만미세골절술은병변의크기가 1.5 cm 2 이상이거나장경이 15 mm 이상인경우치료성공률이높지않았다 38). Chuckpaiwong 등 39) 은 105명의환자를대상으로한연구에서병변의크기가 15 mm 이하의경우모든환자에서좋은결과를 80 대한스포츠의학회지
유정우외. 운동선수의족관절골연골손상에서의치료 Fig. 2. Arthroscopic microfracture technique. (A) Arthroscopic view of the medial talar dome lesion. (B) The same lesion after curettage and (C) microfracture. (D) The healed lesion filling with fibrous cartilage after 2 years. 얻었지만 15 mm 이상의병변의가진 32명의환자에서는단 1명만이성공적인치료를하였다고보고하였다. 골연골이식술일반적으로골연골이식술은큰골연골결손부위에사용되는수술방법이다. 이식되는골연골의종류에따라골연골자가이식술과골연골동종이식술등으로불리며동종골이식의경우과거에는동결과신선동결동종골 (frozen and fresh-frozen allograft) 을사용한이식도시행하였지만, 연골세포의활성도저하에따른높은실패율때문에현재는신선동종골을이용한수술법이주로사용되고있다 40-42). 골연골이식술의큰장점중의하나는섬유연골로치유되는골수자극술과달리원래의관절연골성분인초자연골의복원이가능하다는점이다 28). 골연골자가이식술은많은연구에서좋은결과를얻었다. Imhoff 등 43) 은골연골자가이식술을시행한 26명의환자를장기추시하여 22명에서 American Orthopedic Foot and Ankle Score (AOFAS), visual analogue scale 점수면에서만족스러운결과를얻었다. Scranton 등 44) 도 50명의낭종성거골결손환자에게골연골자가이식술을시행후 36개월이상추시하여 45명에서 Karlsson-Peter 점수등을평가하여만족스러운결과를얻었다. 또한골연골자가이식술은이전치료에실패하였을경우구제치료로써시행할수있다. Kreuz 등 45) 은이전치료에 실패하였던 35명의거골골연골병변환자에게골연골자가이식술을시행하여평균 4년간추시하였고 35명모두에서의미있는 AOFAS의향상을얻었다. 이처럼골연골자가이식술은많은장점을가진치료법이지만운동선수에게적용하는데에는몇가지단점을가지고있다. 우선골연골공여부와연관된합병증을들수있다. 자가골연골이식술의경우공여골연골은주로동측슬관절의대퇴외과 (lateral femoral condyle) 나대퇴과간절흔 (intercondylar notch) 그리고동측거골골연골등에서채취하게된다 32,46). 그러나채취후공여부슬관절에지속적인통증이나내반슬변형과같은합병증이보고되기도하였다 47). 또다른단점으로는수술시거골의골연골결손부위로의접근이어렵다는점이다. Peters 등 48) 이시행한연구에서제한적경골천장성형술을이용한연부조직접근방법으로절골술없이거골의많은부분을노출시킬수있었지만거골의중간후방부의 10% 정도는접근이불가능하다고하였으며, Young 등 49) 이시행한연구에서거골의내측에발생한골연골병변의경우대부분시상면에서가운데또는후측에있기때문에관절경과관절절개술 (arthrotomy) 등만으로는접근이쉽지않았다. 이런경우족관절내과골절제술을시행해야하고골절제술을시행한경우수술후수술부위로장기간통증이남을수있고오랜기간의관절고정이필요하다 (Fig. 3). 그리고골연골이식술을시행한환자들은수술후에수술 제 35 권제 2 호 2017 81
J Yoo, et al. Treatment of Osteochondral Lesions of the Talus in Athletes Fig. 3. The fluoroscopic images of osteochondral autograft transfer system. (A) The resection of the lateral malleolus was done during the approach to the lateral talar dome lesion. (B) The image shows plating of the lateral malleolus after the procedure. Fig. 4. These pictures show second look arthroscopy after autologous chondrocyte implantation of osteochondral lesion of the talus. (A, B) Complete degree of defect repair and filling of the defect, (C, D) <50% incomplete degree of defect repair and filling of the defect. Reproduced from Lee et al. Scand J Med Sci Sports 2012;22:510-550). 전과 같은 정도의 운동량으로 회복되지 않는 경향이 있다는 51) 세포 기반 치료술 점이다. Paul 등 이 시행한 연구에서 골연골 이식술이 임상적 으로 좋은 결과를 보이더라도 환자들은 수술 후 스포츠 활동에 가장 최근에 연구되고 있는 치료 방법으로는 세포 기반 덜 적극적이며 컨택트 스포츠(contact sport)의 참여 빈도가 치료술인 자가 연골세포 이식술이 대표적이다32,54). 자가 연골 52) 53) 감소하였다. 또 Tegner와 Lysholm 과 Marx 등 이 시행한 세포 이식술은 자신의 연골세포를 골연골 결손부에 이식함으 연구에서도 골연골 이식술을 시행 받은 환자의 평균 활동 로써 골연골 자가이식술과 같이 원래의 관절연골과 생화학적, 수준은 유의하게 감소하였다. 생체역학적으로 유사한 초자연골 조직으로 골연골의 결손을 치유하는 치료법이다(Fig. 4). 자가 연골세포 이식술은 2가지 82 대한스포츠의학회지
유정우외. 운동선수의족관절골연골손상에서의치료 단계로진행되는데첫단계에서는본인의연골세포를슬관절이나족관절등에서채취한뒤배양, 증식시키는과정이며두번째단계는결손부위에증식된세포를이식하는과정이다. 임상적으로여러연구가이치료법을이용하여좋은결과를얻었다. Giannini 등 55) 은 8명의비교적큰결손부위 ( 평균 3.3 cm 2 ) 환자를대상으로한 26개월간의추시에서 AOFAS의의미있는증가를얻었다. 그리고육안검사에서도이식부위가연골로모두덮여있었으며조직검사에서도제 2형콜라겐과프로테오글리칸 (proteoglycan) 을모든조직에서확인할수있었다. Lee 등 50,56,57) 은족관절골연골병변에대한자가연골세포이식에대해세차례연구를시행하였다. 먼저종골의전방돌기에서연골세포를채취하여 6주간배양을한뒤수술적치료를진행하였으며분석은변형된 magnetic resonance observation of cartilage repair tissue 체계를이용하여치유연골형성에영향을줄수있는여러요인을분석하였다. 결과적으로나이와병변의크기가자가연골세포이식술후치유연골형성에영향을주는요인으로생각되며병변의위치나깊이, 수술전 AOFAS 등은영향을주지못했다. 세포기반치료술은많은연구를통하여임상적유용성이입증되고있으나아직까지충분한수의장기추시연구가진행되지않았으며현재국내에서보험적용과관련한비용문제로실제로임상에서사용하기는어렵다. 또한, 치료를위하여두번의수술이필요하고수술후운동으로의복귀기간도길기때문에운동선수의초기치료로는적절하지않을것으로생각된다. 결론족관절의골연골병변치료에있어서운동선수는수술후재활기간이나수술후합병증의발생여부가선수생명에지대한영향을미칠수있다는점에서일반인들과는다른관점으로접근해야한다. 보존적치료에실패한경우수술적치료를고려해야하는데이때초기치료로써우선적으로고려되어야할점은빠른운동으로의복귀이다. 그러기위해서는시술이간단해야하며수술후발생할수있는합병증이적어야하고재활기간이짧아야한다. 미세골절술, 골연골자가이식술, 자가연골세포이식술등은현재골연골병변에대해널리사용되는치료법들이다. 하지만자가연골세포이식술의경우치료기간이길고보험적용문제와 International Olympic Committee 성명서관련한문제등으로현재적용하는데는어려움이있다. 미세골절술은관절경과함께시술이간단하고다른수술적방법과비교하였을때빠른체중부하및재활이가능하다는점그리고수술과관련한합병증이적다는점에서운동선수의초기치료로가장적절한방법으로생각된다. 골연골자가이식술은수술후임상적으로나생역학적으로우수한결과를보이는수술법이지만수술후운동으로의복귀가미세골절술에비해조금늦고수술과관련하여공여부합병증및일부병변으로의수술적접근이쉽지않다는점에서초기치료로사용하는데적절하지않아보인다. 다만 1.5 cm 2 이상의큰병변에서미세골절술에비해우수한결과를보이며수술후생역학적으로우수한방법이기때문에골연골자가이식술이나자가연골세포이식술은자가연골세포이식과함께 1.5 cm 2 이상의큰병변이나초기치료에실패하였을경우이차적인수술방법으로적절할것으로생각된다. Conflict of Interest No potential conflict of interest relevant to this article was reported. References 1. Monro A. Part of the cartilage of the joint separated and ossified. Medical essays and observations. 2nd ed. Edinburgh: T and W Ruddimans; 1737. 2. Berndt AL, Harty M. Transchondral fractures (osteochondritis dissecans) of the talus. J Bone Joint Surg Am 1959;41: 988-1020. 3. O'Loughlin PF, Heyworth BE, Kennedy JG. Current concepts in the diagnosis and treatment of osteochondral lesions of the ankle. Am J Sports Med 2010;38:392-404. 4. Draper SD, Fallat LM. Autogenous bone grafting for the treatment of talar dome lesions. J Foot Ankle Surg 2000;39: 15-23. 5. Leontaritis N, Hinojosa L, Panchbhavi VK. Arthroscopically detected intra-articular lesions associated with acute ankle fractures. J Bone Joint Surg Am 2009;91:333-9. 6. Saxena A, Eakin C. Articular talar injuries in athletes: results of microfracture and autogenous bone graft. Am J Sports Med 2007;35:1680-7. 7. Aigner J, Tegeler J, Hutzler P, et al. Cartilage tissue engineering with novel nonwoven structured biomaterial based on hyaluronic acid benzyl ester. J Biomed Mater Res 1998;42:172-81. 제 35 권제 2 호 2017 83
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