Vol. XX • Issue X EMD Application in Intraosseous Defects 1 REVIEWS Abstract: Objective: To systematically review the literature addressing the focused question: What is the effectiveness of different surgical and nonsurgical procedures combined with enamel matrix derivative (EMD) on clinical, radiographic, and patient- centered outcomes in intraosseous defects? Methods: Electronic (Medline, Scopus, and Cochrane databases) and hand literature searches were performed for studies including at least 1 treatment arm where EMD had been applied according to 1 of the following procedures: modified Widman flap; papilla preservation variants (PPVs), including papilla preservation technique, modified papilla preservation technique, and simplified papilla preservation technique; minimally invasive variants, including minimally invasive surgical approach and minimally invasive surgical technique; single-flap variants (SFVs), including single-flap approach and modified minimally invasive surgical technique; or nonsurgical application (flapless approach). Data from 42 selected articles were used to perform a network meta-analysis, and a hierarchy of surgical and nonsurgical applications of EMD was built separately for EMD and EMD + graft based on 6- to 12-mo clinical and radiographic outcomes. Results: Among surgical approaches, EMD was associated with best regenerative outcomes when applied through SFVs, with a mean clinical attachment level gain of 3.93 mm and a reduction in the intrabony component of the defect of 3.35 mm. For EMD + graft, limited differences in regenerative outcomes were observed among surgical procedures. PPVs were associated with the highest residual probing depth for EMD (4.08 mm) and EMD + graft (4.32 mm). Conclusions: In the treatment of periodontal intraosseous defects, 1) SFVs appear to optimize the regenerative outcomes of EMD; 2) substantial regenerative outcomes can be obtained with SFVs and conservative double flaps (i.e., PPVs and minimally invasive variants) when EMD is combined with a graft; and 3) residual probing depth was higher following PPVs for EMD and EMD + graft. Knowledge Transfer Statement: The results of the present systematic review and meta-analysis can be used by clinicians to identify the most effective surgical or nonsurgical procedure to treat an intraosseous defect with EMD or EMD + graft. The main findings indicate that when EMD application is indicated, surgical access based on a single flap seems the most appropriate to optimize clinical outcomes. The application of EMD + graft can be effectively combined with single flaps and conservative double flaps. Keywords: periodontitis, surgical pro- cedures, operative, surgical flaps, enamel matrix proteins, regenerative medicine, bone substitutes JCT XX X 10.1177/2380084420934731JDR Clinical & Translational ResearchEMD Application in Intraosseous Defects research-article 2020 DOI: 10.1177/2380084420934731. 1 Research Centre for the Study of Periodontal and Peri-implant Diseases, University of Ferrara, Ferrara, Italy; 2 Operative Unit of Dentistry, Azienda Unità Sanitaria Locale, Ferrara, Italy; 3 School of Dentistry, Università Politecnica delle Marche, Ancona, Italy; 4 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 5 Department of Periodontics, West Virginia University, Morgantown, WV, USA; 6 Private practice, Qingdao, Mainland China. Corresponding author: R. Farina, Research Centre for the Study of Periodontal and Peri-implant Diseases, University of Ferrara, Corso Giovecca 203, Ferrara, 44100, Italy. Email: roberto.farina@unife.it A supplemental appendix to this article is available online. Article reuse guidelines: sagepub.com/journals-permissions © International & American Associations for Dental Research 2020 Effect of Flap Design for Enamel Matrix Derivative Application in Intraosseous Defects L. Trombelli 1,2 , A. Simonelli 1 , A. Quaranta 3 , Y.K. Tu 4 , H. Li 4 , M. Agusto 5 , X. Jiao 6 , and R. Farina 1,2