臺灣博碩士論文加值系統

高遷移率族蛋白1（High-mobility group box-1；HMGB1）為一種前驅發炎細胞激素（proinflammatory cytokine），在發炎疾病中扮演重要的角色，牙周病為牙周組織發炎的疾病，抽菸為牙周病的危險因子之一，引導組織再生手術（guided tissue regeneration；GTR）為治療牙周病常見的手術，可促進牙周組織再生，而大範圍根尖病灶的根尖手術結果較不可預期。因此，本論文的目的包含兩部分:[1]探討抽菸與HMGB1在牙周炎表現量的相關性；[2]探討使用引導組織再生手術治療大根尖病灶合併黏膜穿孔的長期效果。
於HMGB1的研究中，共選取慢性牙周炎非抽菸與抽菸者、牙周健康非抽菸三組受試者，偵測牙齦溝液及牙齦組織中HMGB1的表現。結果顯示慢性牙周炎非抽菸者牙齦溝液的HMGB1顯著高於慢性牙周炎抽菸者，而在慢性牙周炎非抽菸者中牙齦溝液的HMGB1顯著高於牙周健康非抽菸者，且非抽菸者之HMGB1和牙周參數有顯著正相關，而慢性牙周炎抽菸者的HMGB1和牙周參數並無顯著的相關性。在牙齦組織中，牙周健康非抽菸者HMGB1表現多分佈於細胞核內，而慢性牙周炎抽菸與非抽菸者HMGB1表現分布於細胞核與細胞質內，其表現較牙周健康非抽菸者明顯。
於引導組織再生手術治療大根尖病灶合併黏膜穿孔的研究中，評估施行引導組織再生手術與引導組織再生手術合併結締組織移植二組病患的長期療效，術後引導組織再生手術合併結締組織移植處理的病例軟組織都達到完全的閉合，但只做引導組織再生手術的三例病患中有兩例術後可見不完全的癒合，需經進一步的軟組織處理，長時間的追踪結果顯示所有的病例皆達到完全的軟組織與骨癒合。
慢性牙周炎非抽菸者中相較於牙周健康非抽菸者牙齦溝液中有較高的HMGB1表現，且HMGB1與牙周炎的嚴重程度有關，而慢性牙周炎抽菸者的HMGB1表現量較低，未來需更進一步的探討以釐清HMGB1與抽菸可能的交互作用及在牙周炎致病機轉中所扮演的角色。此外，引導組織再生手術治療運用於大範圍根尖病灶合併黏膜穿孔的病灶可達到長期的穩定結果，而合併引導組織再生手術與結締組織移植的治療處理可達到較可預期的軟組織癒合與骨再生。

High-mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a role in inflammatory disorders. Periodontal disease is a periodontal tissue inflammatory disease. Smoking is a well-established risk factor for periodontal disease. Guided tissue regeneration (GTR), a common periodontal surgery, can promote periodontal tissue regeneration. The outcome of the apical surgery of large apical lesion is unpredictable. The purposes of the thesis were: [1] to evaluate the association between smoking and levels of HMGB1 in periodontitis; and [2] to evaluate the long-term outcome of using GTR to treat large apical lesions with mucosal fenestration.
Non-smokers and smokers with chronic periodontitis, and periodontally healthy non-smokers were examined in the HMGB1 study. Levels of HMGB1 in the gingival crevicular fluid (GCF) and gingival tissues were analyzed. The results showed that levels of HMGB1 in GCF were statistically significantly lower in chronic periodontitis smokers than chronic periodontitis non-smokers. Levels of HMGB1 of chronic periodontitis non-smokers were higher than periodontally healthy non-smokers. Levels of HMGB1 were positively correlated with periodontal parameters of non-smokers. However, no significant correlation was found between levels of HMGB1 and all periodontal parameters examined in chronic periodontitis smokers. In gingival tissues, HMGB1 was localized mainly in the nuclei of the epithelial cells in periodontally healthy non-smokers. HMGB1 was localized in the nuclei and cytoplasm of the epithelial cells and stained more evidently in gingival tissues of non-smokers and smokers with chronic periodontitis than periodontally healthy non-smokers.
In the study of large apical lesions with mucosal fenestrations, long-term outcomes of GTR therapy alone and GTR combined with connective tissue graft (CTG) were evaluated. The cases of GTR combined with CTG showed complete soft tissue coverage, whereas 2 of the 3 cases of GTR alone management showed incompletely healing and further soft tissue management was required. After long-term follow-up, all cases showed complete soft tissue and bone healing.
Chronic periodontitis non-smokers had elevated levels of HMGB1 in GCF than periodontally healthy non-smokers. Moreover, levels of HMGB1 were correlated with severity of periodontitis. Chronic periodontitis smokers exhibited lower levels of HMGB1 than chronic periodontitis non-smokers. Further research is needed for understanding the interaction of HMGB1 and smoking involved in the pathogenesis of periodontitis. Moreover, GTR therapy in the treatment of a large apical bony defect with mucosal fenestration could achieve long-term stable outcomes. Furthermore, GTR in combination with CTG could ensure predictable soft tissue healing and bone regeneration.

目錄
目錄……I
圖次目錄……IV
表次目錄……V
中文摘要……VI
英文摘要……VIII
第一章 緒論……1
1.1牙周病的分類與盛行率……1
1.2 牙周炎致病機轉……3
1.3 抽菸與牙周病的相關性……3
1.4 高遷移率族蛋白1 (High-mobility group box-1；HMGB1)……8
1.5 HMGB1與牙周病有關的研究……11
1.6 牙齦溝液……12
1.7 牙周-牙髓病灶……12
1.8 黏膜穿孔(mucosal fenestration)……14
1.9 引導組織再生手術運用於牙周-牙髓病灶……14
1.10 研究目的……15
第二章 材料與方法……18
2.1 抽菸與HMGB1在牙周炎表現量的相關性……18
2.1.1 受試者選擇與排除的標準……18
2.1.2 臨床檢查……19
2.1.3 牙齦溝液收集……20
2.1.4 牙齦溝液內HMGB1的偵測……20
2.1.5 牙齦溝液內總蛋白質(total proteins)的檢測……21
2.1.6 牙齦組織的取得……22
2.1.7 牙齦組織HMGB1的表現……23
2.1.8 統計分析……24
2.2 探討使用引導組織再生手術對於大範圍的根尖病灶合併黏膜穿孔的長期追踪效果……26
2.2.1 治療前臨床與根尖放射線攝影檢查……26
2.2.2 手術前之治療步驟……26
2.2.3 牙周-牙髓合併手術……27
2.2.4 術後臨床與根尖放射線攝影檢查評估……28
第三章 結果……30
3.1 抽菸與HMGB1在牙周炎表現量的相關性……30
3.1.1受試者臨床表徵……30
3.1.2 牙齦溝液內的HMGB1 與總蛋白質……30
3.1.3 牙齦溝液的HMGB1與牙周參數的相關性……31
3.1.4 牙齦組織HMGB1的表現……32
3.2 探討使用引導組織再生手術對於大範圍的根尖病灶合併黏膜穿孔的長期追踪效果……33
3.2.1 受試者臨床表徵……33
3.2.2 治療前臨床檢查結果……33
3.2.3 治療前牙髓活性測試與放射線攝影檢查結果……33
3.2.4 牙周-牙髓合併治療步驟……34
3.2.5 治療結果……35
第四章 討論……37
參考文獻……66
發表著作……84


圖次目錄
圖一、牙周健康非抽菸者、慢性牙周炎非抽菸者與慢性牙周炎抽菸者牙齦溝液內HMGB1與總蛋白質的濃度……47
圖二、HMGB1在牙齦組織的表現……48
圖三、病例1右上第一小臼齒合併引導組織再生手術與結締組織移植處理……50
圖四、病例2下顎前牙區域合併引導組織再生手術與結締組織移植處理……52
圖五、病例3左上第一大臼齒引導組織再生手術處理……54
圖六、病例4右上犬齒引導組織再生手術處理……55
圖七、病例5左上側門牙引導組織再生手術……56


表次目錄
表一、受試者臨床表徵……57
表二、受試者牙齦溝液內的HMGB1與總蛋白質的濃度……58
表三、非抽菸者牙齦溝液內HMGB1濃度與牙周參數的相關性……59
表四、慢性牙周炎抽菸者牙齦溝液內HMGB1濃度與牙周參數的相關性……60
表五、牙齦組織HMGB1的表現……61
表六、大範圍根尖病灶合併黏膜穿孔病例治療前臨床檢查結果……62
表七、大範圍根尖病灶合併黏膜穿孔病例治療前牙髓活性測試與放射線攝影檢查結果……63
表八、大範圍根尖病灶合併黏膜穿孔病例手術治療步驟說明……64
表九、大範圍根尖病灶合併黏膜穿孔病例治療長期追踪結果……65

(1) Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease. A summary of current work. Lab Invest 1976; 34: 235-249.
(2) Armitage GC. Development of a classification system for periodontal diseases and conditions. Ann Periodontol 1999; 4: 1-6.
(3) Lang N, Bartold PM, Cullinam M, et al. Consensus report: Aggressive periodontitis. Ann Periodontol 1999; 4: 53.
(4) Lindhe J, Ranney R, Lamster I, et al. Consensus report: Chronic periodontitis. Ann Periodontol 1999; 4: 38.
(5) Albandar JM, Brunelle JA, Kingman A. Destructive periodontal disease in adults 30 years of age and older in the United States, 1988-1994. J Periodontol 1999; 70: 13-29.
(6) Holtfreter B, Kocher T, Hoffmann T, Desvarieux M, Micheelis W. Prevalence of periodontal disease and treatment demands based on a German dental survey (DMS IV). J Clin Periodontol 2010; 37: 211-219.
(7) Lai H, Lo MT, Wang PE, Wang TT, Chen TH, Wu GH. A community-based epidemiological study of periodontal disease in Keelung, Taiwan: a model from Keelung community-based integrated screening programme (KCIS No. 18). J Clin Periodontol 2007; 34: 851-859.
(8) Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000 1997; 14: 9-11.
(9) Albandar JM, Streckfus CF, Adesanya MR, Winn DM. Cigar, pipe, and cigarette smoking as risk factors for periodontal disease and tooth loss. J Periodontol 2000; 71: 1874-1881.
(10) Moimaz SA, Zina LG, Saliba O, Garbin CA. Smoking and periodontal disease: clinical evidence for an association. Oral Health Prev Dent 2009; 7: 369-376.
(11) Zimmermann H, Hagenfeld D, Diercke K, et al. Pocket depth and bleeding on probing and their associations with dental, lifestyle, socioeconomic and blood variables: a cross-sectional, multicenter feasibility study of the German National Cohort. BMC Oral Health 2015; 15: 1-9.
(12) Preber H, Bergstrom J. The effect of non-surgical treatment on periodontal pockets in smokers and non-smokers. J Clin Periodontol 1986; 13: 319-323.
(13) Hughes FJ, Syed M, Koshy B, et al. Prognostic factors in the treatment of generalized aggressive periodontitis: II. Effects of smoking on initial outcome. J Clin Periodontol 2006; 33: 671-676.
(14) Grossi SG, Zambon J, Machtei EE, Schifferle R, Andreana S, Genco RJ, Cummins D, Harrap G. Effects of smoking and smoking cessation on healing after mechanical periodontal therapy. J Am Dent Assoc 1997; 128: 599-607.
(15) Kotsakis GA, Javed F, Hinrichs JE, Karoussis IK, Romanos GE. Impact of cigarette smoking on clinical outcomes of periodontal flap surgical procedures: a systematic review and meta-analysis. J Periodontol 2015; 86: 254-263.
(16) Tonetti MS, Pini-Prato G, Cortellini P. Effect of cigarette smoking on periodontal healing following GTR in infrabony defects. A preliminary retrospective study. J Clin Periodontol 1995; 22: 229-234.
(17) Trombelli L, Kim CK, Zimmerman GJ, Wikesjo UM. Retrospective analysis of factors related to clinical outcome of guided tissue regeneration procedures in intrabony defects. J Clin Periodontol 1997; 24: 366-371.
(18) Mayfield L, Soderholm G, Hallstrom H, et al. Guided tissue regeneration for the treatment of intraosseous defects using a biabsorbable membrane. A controlled clinical study. J Clin Periodontol 1998; 25: 585-595.
(19) Parashis AO, Polychronopoulou A, Tsiklakis K, Tatakis DN. Enamel matrix derivative in intrabony defects: prognostic parameters of clinical and radiographic treatment outcomes. J Periodontol 2012; 83: 1346-1352.
(20) Bowers GM, Schallhorn RG, McClain PK, Morrison GM, Morgan R, Reynolds MA. Factors influencing the outcome of regenerative therapy in mandibular Class II furcations: Part I. J Periodontol 2003; 74: 1255-1268.
(21) Patel RA, Wilson RF, Palmer RM. The effect of smoking on periodontal bone regeneration: a systematic review and meta-analysis. J Periodontol 2012; 83: 143-155.
(22) Luepke PG, Mellonig JT, Brunsvold MA. A clinical evaluation of a bioresorbable barrier with and without decalcified freeze-dried bone allograft in the treatment of molar furcations. J Clin Periodontol 1997; 24: 440-446.
(23) Ah MK, Johnson GK, Kaldahl WB, Patil KD, Kalkwarf KL. The effect of smoking on the response to periodontal therapy. J Clin Periodontol 1994; 21: 91-97.
(24) Bostrom L, Linder LE, Bergstrom J. Influence of smoking on the outcome of periodontal surgery. A 5-year follow-up. J Clin Periodontol 1998; 25: 194-201.
(25) Silvestri M, Rasperini G, Milani S. 120 infrabony defects treated with regenerative therapy: long-term results. J Periodontol 2011; 82: 668-675.
(26) Cortellini P, Tonetti MS. Long-term tooth survival following regenerative treatment of intrabony defects. J Periodontol 2004; 75: 672-678.
(27) Zambon JJ, Grossi SG, Machtei EE, Ho AW, Dunford R, Genco RJ. Cigarette smoking increases the risk for subgingival infection with periodontal pathogens. J Periodontol 1996; 67: 1050-1054.
(28) Haffajee AD, Socransky SS. Relationship of cigarette smoking to the subgingival microbiota. J Clin Periodontol 2001; 28: 377-388.
(29) Dietrich T, Bernimoulin JP, Glynn RJ. The effect of cigarette smoking on gingival bleeding. J Periodontol 2004; 75: 16-22.
(30) Morozumi T, Kubota T, Sato T, Okuda K, Yoshie H. Smoking cessation increases gingival blood flow and gingival crevicular fluid. J Clin Periodontol 2004; 31: 267-272.
(31) Kenney EB, Kraal JH, Saxe SR, Jones J. The effect of cigarette smoke on human oral polymorphonuclear leukocytes. J Periodontal Res 1977; 12: 227-234.
(32) MacFarlane GD, Herzberg MC, Wolff LF, Hardie NA. Refractory periodontitis associated with abnormal polymorphonuclear leukocyte phagocytosis and cigarette smoking. J Periodontol 1992; 63: 908-913.
(33) Kraal JH, Chancellor MB, Bridges RB, Bemis KG, Hawke JE. Variations in the gingival polymorphonuclear leukocyte migration rate in dogs induced by chemotactic autologous serum and migration inhibitor from tobacco smoke. J Periodontal Res 1977; 12: 242-249.
(34) Bostrom L, Linder LE, Bergstrom J. Smoking and crevicular fluid levels of IL-6 and TNF-alpha in periodontal disease. J Clin Periodontol 1999; 26: 352-357.
(35) Tymkiw KD, Thunell DH, Johnson GK, et al. Influence of smoking on gingival crevicular fluid cytokines in severe chronic periodontitis. J Clin Periodontol 2011; 38: 219-228.
(36) Petropoulos G, McKay IJ, Hughes FJ. The association between neutrophil numbers and interleukin-1alpha concentrations in gingival crevicular fluid of smokers and non-smokers with periodontal disease. J Clin Periodontol 2004; 31: 390-395.
(37) Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev 1999; 20: 345-357.
(38) Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93: 165-176.
(39) Tang TH, Fitzsimmons TR, Bartold PM. Effect of smoking on concentrations of receptor activator of nuclear factor kappa B ligand and osteoprotegerin in human gingival crevicular fluid. J Clin Periodontol 2009; 36: 713-718.
(40) Ozcaka O, Nalbantsoy A, Kose T, Buduneli N. Plasma osteoprotegerin levels are decreased in smoker chronic periodontitis patients. Aust Dent J 2010; 55: 405-410.
(41) Baker C, Isenberg I, Goodwin GH, Johns EW. Physical studies of the nonhistone chromosomal proteins HMG-U and HMG-2. Biochemistry 1976; 15: 1645-1649.
(42) Bustin M. Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol 1999; 19: 5237-5246.
(43) Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 2013; 93: 865-873.
(44) Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 2003; 22: 5551-5560.
(45) Ito I, Fukazawa J, Yoshida M. Post-translational methylation of high mobility group box 1 (HMGB1) causes its cytoplasmic localization in neutrophils. J Biol Chem 2007; 282: 16336-16344.
(46) Oh YJ, Youn JH, Ji Y, et al. HMGB1 is phosphorylated by classical protein kinase C and is secreted by a calcium-dependent mechanism. J Immunol 2009; 182: 5800-5809.
(47) Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science 1999; 285: 248-251.
(48) Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 2002; 418: 191-195.
(49) Park JS, Svetkauskaite D, He Q, et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279: 7370-7377.
(50) Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 2007; 8: 487-496.
(51) Wahamaa H, Schierbeck H, Hreggvidsdottir HS, et al. High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis Res Ther 2011; 13: R136.
(52) Taniguchi N, Kawahara K, Yone K, et al. High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum 2003; 48: 971-981.
(53) Zhou Z, Han JY, Xi CX, et al. HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res 2008; 23: 1084-1096.
(54) Park SY, Lee SW, Kim HY, Lee WS, Hong KW, Kim CD. HMGB1 induces angiogenesis in rheumatoid arthritis via HIF-1alpha activation. Eur J Immunol 2015; 45: 1216-1227.
(55) Lu M, Yu S, Xu W, Gao B, Xiong S. HMGB1 promotes systemic lupus erythematosus by enhancing macrophage inflammatory response. J Immunol Res 2015; 2015: 946748. http://dx.doi.org/10.1155/2015/946748.
(56) Gibot S, Massin F, Cravoisy A, et al. High-mobility group box 1 protein plasma concentrations during septic shock. Intensive Care Med 2007; 33: 1347-1353.
(57) Min HJ, Kim SJ, Kim TH, Chung HJ, Yoon JH, Kim CH. Level of secreted HMGB1 correlates with severity of inflammation in chronic rhinosinusitis. Laryngoscope 2015; 125: e225-230.
(58) Morimoto Y, Kawahara KI, Tancharoen S, et al. Tumor necrosis factor-alpha stimulates gingival epithelial cells to release high mobility-group box 1. J Periodontal Res 2008; 43: 76-83.
(59) Ebe N, Hara-Yokoyama M, Iwasaki K, et al. Pocket epithelium in the pathological setting for HMGB1 release. J Dent Res 2011; 90: 235-240.
(60) Ito Y, Bhawal UK, Sasahira T, et al. Involvement of HMGB1 and RAGE in IL-1beta-induced gingival inflammation. Arch Oral Biol 2012; 57: 73-80.
(61) Taubman MA, Valverde P, Han X, Kawai T. Immune response: the key to bone resorption in periodontal disease. J Periodontol 2005; 76: 2033-2041.
(62) Armitage GC. Periodontal diseases: diagnosis. Ann Periodontol 1996; 1: 37-215.
(63) Buduneli N, Kinane DF. Host-derived diagnostic markers related to soft tissue destruction and bone degradation in periodontitis. J Clin Periodontol 2011; 38 Suppl 11: 85-105.
(64) Luo L, Xie P, Gong P, Tang XH, Ding Y, Deng LX. Expression of HMGB1 and HMGN2 in gingival tissues, GCF and PICF of periodontitis patients and peri-implantitis. Arch Oral Biol 2011; 56: 1106-1111.
(65) Seltzer S, Bender IB, Ziontz M. The interrelationship of pulp and periodontal disease. Oral Surg Oral Med Oral Pathol 1963; 16: 1474-1490.
(66) Simon JH, Glick DH, Frank AL. The relationship of endodontic-periodontic lesions. J Periodontol 1972; 43: 202-208.
(67) De Deus QD. Frequency, location, and direction of the lateral, secondary, and accessory canals. J Endod 1975; 1: 361-366.
(68) Hirsch JM, Ahlstrom U, Henrikson PA, Heyden G, Peterson LE. Periapical surgery. Int J Oral Surg 1979; 8: 173-185.
(69) Skoglund A, Persson G. A follow-up study of apicoectomized teeth with total loss of the buccal bone plate. Oral Surg Oral Med Oral Pathol 1985; 59: 78-81.
(70) Kim E, Song JS, Jung IY, Lee SJ, Kim S. Prospective clinical study evaluating endodontic microsurgery outcomes for cases with lesions of endodontic origin compared with cases with lesions of combined periodontal-endodontic origin. J Endod 2008; 34: 546-551.
(71) Lin YC, Lee YY, Ho YC, Hsieh YC, Lai YL, Lee SY. Treatment of large apical lesions with mucosal fenestration: a clinical study with long-term evaluation. J Endod 2015; 41: 563-567.
(72) Rawlinson A. Treatment of a labial fenestration of a lower incisor tooth apex. Br Dent J 1984; 156: 448-449.
(73) Ju YR, Tsai AH, Wu YJ, Pan WL. Surgical intervention of mucosal fenestration in a maxillary premolar: a case report. Quintessence Int 2004; 35: 125-128.
(74) Chen G, Fang CT, Tong C. The management of mucosal fenestration: a report of two cases. Int Endod J 2009; 42: 156-164.
(75) Jhaveri HM, Amberkar S, Galav L, Deshmukh VL, Aggarwal S. Management of mucosal fenestrations by interdisciplinary approach: a report of three cases. J Endod 2010; 36: 164-168.
(76) Yang ZP. Treatment of labial fenestration of maxillary central incisor. Endod Dent Traumatol 1996; 12: 104-108.
(77) Lehman J, 3rd, Meister F, Jr., Gerstein H. Use of a pedicle flap to correct an endodontic problem: a case report. J Endod 1979; 5: 317-320.
(78) Tseng CC, Chen YH, Huang CC, Bowers GM. Correction of a large periradicular lesion and mucosal defect using combined endodontic and periodontal therapy: a case report. Int J Periodontics Restorative Dent 1995; 15: 377-383.
(79) Nyman S, Lindhe J, Karring T, Rylander H. New attachment following surgical treatment of human periodontal disease. J Clin Periodontol 1982; 9: 290-296.
(80) Caton JG, DeFuria EL, Polson AM, Nyman S. Periodontal regeneration via selective cell repopulation. J Periodontol 1987; 58: 546-552.
(81) Gottlow J, Nyman S, Karring T, Lindhe J. New attachment formation as the result of controlled tissue regeneration. J Clin Periodontol 1984; 11: 494-503.
(82) Gottlow J, Nyman S, Lindhe J, Karring T, Wennstrom J. New attachment formation in the human periodontium by guided tissue regeneration. Case reports. J Clin Periodontol 1986; 13: 604-616.
(83) Polimeni G, Susin C, Wikesjo UM. Regenerative potential and healing dynamics of the periodontium: a critical-size supra-alveolar periodontal defect study. J Clin Periodontol 2009; 36: 258-264.
(84) Kao RT, Nares S, Reynolds MA. Periodontal regeneration - intrabony defects: a systematic review from the AAP Regeneration Workshop. J Periodontol 2015; 86: S77-104.
(85) Murphy KG, Gunsolley JC. Guided tissue regeneration for the treatment of periodontal intrabony and furcation defects. A systematic review. Ann Periodontol 2003; 8: 266-302.
(86) Cortellini P, Carnevale G, Sanz M, Tonetti MS. Treatment of deep and shallow intrabony defects. A multicenter randomized controlled clinical trial. J Clin Periodontol 1998; 25: 981-987.
(87) Cortellini P, Pini Prato G, Tonetti MS. Periodontal regeneration of human intrabony defects with bioresorbable membranes. A controlled clinical trial. J Periodontol 1996; 67: 217-223.
(88) Pecora G, Kim S, Celletti R, Davarpanah M. The guided tissue regeneration principle in endodontic surgery: one-year postoperative results of large periapical lesions. Int Endod J 1995; 28: 41-46.
(89) Brugnami F, Mellonig JT. Treatment of a large periapical lesion with loss of labial cortical plate using GTR: a case report. Int J Periodontics Restorative Dent 1999; 19: 243-249.
(90) Taschieri S, Del Fabbro M, Testori T, Saita M, Weinstein R. Efficacy of guided tissue regeneration in the management of through-and-through lesions following surgical endodontics: a preliminary study. Int J Periodontics Restorative Dent 2008; 28: 265-271.
(91) Taschieri S, Corbella S, Tsesis I, Bortolin M, Del Fabbro M. Effect of guided tissue regeneration on the outcome of surgical endodontic treatment of through-and-through lesions: a retrospective study at 4-year follow-up. Oral Maxillofac Surg 2011; 15: 153-159.
(92) Lin GH, Chang LY, Lin WC, Lee SY, Lai YL. Interdisciplinary approach for treating a large through-and-through periapical defect using guided tissue regeneration: a case report. Int J Periodontics Restorative Dent 2014; 34: e1-8.
(93) Abramowitz PN, Rankow H, Trope M. Multidisciplinary approach to apical surgery in conjunction with the loss of buccal cortical plate. Oral Surg Oral Med Oral Pathol 1994; 77: 502-506.
(94) Pompa DG. Guided tissue repair of complete buccal dehiscences associated with periapical defects: a clinical retrospective study. J Am Dent Assoc 1997; 128: 989-997.
(95) Blank BS, Levy AR. Combined treatment of a large periodontal defect using GTR and DFDBA. Int J Periodontics Restorative Dent 1999; 19: 481-487.
(96) Tsesis I, Rosen E, Tamse A, Taschieri S, Del Fabbro M. Effect of guided tissue regeneration on the outcome of surgical endodontic treatment: a systematic review and meta-analysis. J Endod 2011; 37: 1039-1045.
(97) Silness J, Loe H. Periodontal disease in pregnancy. II. Correlation between oral hygiene and periodontal condition. Acta Odontol Scand 1964; 22: 121-135.
(98) Loe H, Silness J. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol Scand 1963; 21: 533-551.
(99) Ainamo J, Bay I. Problems and proposals for recording gingivitis and plaque. Int Dent J 1975; 25: 229-235.
(100) Smith PK, Krohn RI, Hermanson GT, et al. Measurement of protein using bicinchoninic acid. Anal Biochem 1985; 150: 76-85.
(101) McDonald JW, Pilgram TK. Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma. Histopathology 1999; 34: 439-446.
(102) Miller SC. Textbook of periodontia. Philadelphia: Blakiston, 1938.
(103) Rud J, Andreasen JO, Jensen JE. Radiographic criteria for the assessment of healing after endodontic surgery. Int J Oral Surg 1972; 1: 195-214.
(104) Wang H, Liao H, Ochani M, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004; 10: 1216-1221.
(105) Feghali K, Iwasaki K, Tanaka K, et al. Human gingival fibroblasts release high-mobility group box-1 protein through active and passive pathways. Oral Microbiol Immunol 2009; 24: 292-298.
(106) Nogueira AV, de Souza JA, de Molon RS, et al. HMGB1 localization during experimental periodontitis. Mediators Inflamm 2014; 2014: 816320. http://dx.doi.org/10.1155/2014/816320.
(107) Wang N, Knight K, Dao T, Friedman S. Treatment outcome in endodontics-The Toronto Study. Phases I and II: apical surgery. J Endod 2004; 30: 751-761.
(108) von Arx T, Penarrocha M, Jensen S. Prognostic factors in apical surgery with root-end filling: a meta-analysis. J Endod 2010; 36: 957-973.
(109) Pinto VS, Zuolo ML, Mellonig JT. Guided bone regeneration in the treatment of a large periapical lesion: a case report. Pract Periodontics Aesthet Dent 1995; 7: 76-81; quiz 82.
(110) Douthitt JC, Gutmann JL, Witherspoon DE. Histologic assessment of healing after the use of a bioresorbable membrane in the management of buccal bone loss concomitant with periradicular surgery. J Endod 2001; 27: 404-410.
(111) Britain SK, Arx T, Schenk RK, Buser D, Nummikoski P, Cochran DL. The use of guided tissue regeneration principles in endodontic surgery for induced chronic periodontic-endodontic lesions: a clinical, radiographic, and histologic evaluation. J Periodontol 2005; 76: 450-460.
(112) Bittencourt S, Ribeiro Edel P, Sallum EA, Sallum AW, Nociti FH, Casati MZ. Semilunar coronally positioned flap or subepithelial connective tissue graft for the treatment of gingival recession: a 30-month follow-up study. J Periodontol 2009; 80: 1076-1082.
(113) Cairo F, Cortellini P, Pilloni A, et al. Clinical efficacy of coronally advanced flap with or without connective tissue graft for the treatment of multiple adjacent gingival recessions in the aesthetic area: a randomized controlled clinical trial. J Clin Periodontol 2016; 43: 849-856.
(114) da Silva RC, Joly JC, de Lima AF, Tatakis DN. Root coverage using the coronally positioned flap with or without a subepithelial connective tissue graft. J Periodontol 2004; 75: 413-419.
(115) Paolantonio M. Treatment of gingival recessions by combined periodontal regenerative technique, guided tissue regeneration, and subpedicle connective tissue graft. A comparative clinical study. J Periodontol 2002; 73: 53-62.
(116) Zucchelli G, Clauser C, De Sanctis M, Calandriello M. Mucogingival versus guided tissue regeneration procedures in the treatment of deep recession type defects. J Periodontol 1998; 69: 138-145.
(117) Tsesis I, Faivishevsky V, Kfir A, Rosen E. Outcome of surgical endodontic treatment performed by a modern technique: a meta-analysis of literature. J Endod 2009; 35: 1505-1511.
(118) Tsesis I, Rosen E, Schwartz-Arad D, Fuss Z. Retrospective evaluation of surgical endodontic treatment: traditional versus modern technique. J Endod 2006; 32: 412-416.
(119) Rud J, Andreasen JO, Jensen JE. A follow-up study of 1,000 cases treated by endodontic surgery. Int J Oral Surg 1972; 1: 215-228.
(120) Rubinstein RA, Kim S. Short-term observation of the results of endodontic surgery with the use of a surgical operation microscope and Super-EBA as root-end filling material. J Endod 1999; 25: 43-48.
(121) Rubinstein RA, Kim S. Long-term follow-up of cases considered healed one year after apical microsurgery. J Endod 2002; 28: 378-383.
(122) von Arx T, Jensen SS, Hanni S. Clinical and radiographic assessment of various predictors for healing outcome 1 year after periapical surgery. J Endod 2007; 33: 123-128.
(123) Torabinejad M, Smith PW, Kettering JD, Pitt Ford TR. Comparative investigation of marginal adaptation of mineral trioxide aggregate and other commonly used root-end filling materials. J Endod 1995; 21: 295-299.
(124) Torabinejad M, Rastegar AF, Kettering JD, Pitt Ford TR. Bacterial leakage of mineral trioxide aggregate as a root-end filling material. J Endod 1995; 21: 109-112.
(125) Dorn SO, Gartner AH. Retrograde filling materials: a retrospective success-failure study of amalgam, EBA, and IRM. J Endod 1990; 16: 391-393.