Twenty Years Of Enamel Matrix Derivative The Past The Present And The Future

[Charise Zelnick]

Thesite is secure.

The ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Bacground: On June 5th, 2015 at Europerio 8, a group of leading experts were gathered to discuss what has now been 20 years of documented evidence supporting the clinical use of enamel matrix derivative (EMD). Original experiments led by Lars Hammarstrm demonstrated that enamel matrix proteins could serve as key regenerative proteins capable of promoting periodontal regeneration including new cementum, with functionally oriented inserting new periodontal ligament fibres, and new alveolar bone formation. This pioneering work and vision by Lars Hammarstrm has paved the way to an enormous amount of publications related to its biological basis and clinical use. Twenty years later, it is clear that all these studies have greatly contributed to our understanding of how biologics can act as mediators for periodontal regeneration and have provided additional clinical means to support tissue regeneration of the periodontium.

Aims: This review article aims to: (1) provide the biological background necessary to understand the rational for the use of EMD for periodontal regeneration, (2) present animal and human histological evidence of periodontal regeneration following EMD application, (3) provide clinically relevant indications for the use of EMD and (4) discuss future avenues of research including key early findings leading to the development of Osteogain, a new carrier system for EMD specifically developed with better protein adsorption to bone grafting materials.

This study aimed to evaluate the impact of enamel matrix derivative (EMD) application following subgingival instrumentation of residual pockets in periodontitis patients on inflammatory host response, microbiological composition, and clinical outcome.

Application of EMD as an adjunct to subgingival instrumentation of residual pockets yielded benefits regarding CAL gain; however, effects on PPD reduction, inflammatory cytokines, and bacterial count were negligible.

Based on the obtained results, additional non-surgical EMD application compared to subgingival instrumentation alone showed no clinically relevant effects on treatment outcome and underlying biological mechanisms.

Periodontitis is a biofilm-driven inflammatory disease characterized by progressive destruction of the periodontal structures, thereby leading to tooth loss if left untreated [1]. Nonsurgical periodontal therapy (NSPT) aims to eliminate the subgingival bacterial load and to improve clinical parameters such as probing pocket depths (PPD), bleeding on probing (BoP), and clinical attachment levels (CAL) [2, 3]. However, residual pockets with persisting inflammation might still remain at re-evaluation after initial therapy, thereby possibly influencing further disease progression and jeopardizing tooth survival [4]. One treatment approach for residual pockets is to perform resective or regenerative periodontal surgery to achieve resolution of inflammation and, if possible, to restore physiologic anatomy. In this context, it has been shown that periodontal surgery is associated with high dental anxiety scores in patients [5], emphasizing the need for effective non-surgical alternatives. Thus, therapies have been developed to selectively target diseased sites, such as local delivery of antibiotics or antiseptics, the use of laser irradiation, as well as other strategies [6, 7].

For more than 25 years, enamel matrix derivatives (EMD) have been in use as an adjunctive agent during surgical therapy to promote periodontal soft and hard tissue regeneration and have shown beneficial effects such as PPD reduction and CAL gain [8,9,10,11]. Studies on nonsurgical (flapless) EMD application as an adjunct to NSPT have so far shown inconsistencies regarding the clinical efficacy, either reporting benefits [12,13,14,15,16] or no additional value [17,18,19,20,21]. Although two recent meta-analyses revealed no significant improvements on PPD and CAL after 3 to 12 months when EMD was used as adjunctive therapy to NSPT, the included studies were of high heterogeneity and authors suggested performing additional RCTs for further assessment [22, 23].

While clinical parameters can be used to assess periodontal disease progression, the underlying inflammatory host immune response is one key aspect promoting tissue destruction [24]. With regard to anti-inflammatory effects, EMD have been demonstrated to reduce interleukin (IL)-1β and receptor activator of NF-κB ligand (RANKL) expression, but also to increase prostaglandin E2 and osteoprotegerin (OPG) expression in vitro [25]. However, clinical data on inflammatory response following non-surgical EMD application in periodontal therapy is scarce and inconsistent. Giannopoulou et al. did not observe statistically significant effects on IL-1β, and myeloid-related protein (MRP) 8/14 levels in GCF when EMD was used as an adjunct to subgingival instrumentation [17]. In contrast, Jentsch et al. suggested that additional EMD application following subgingival instrumentation of residual pockets yielded a significant reduction of IL-1β expression in GCF within 12 months [26].

In addition to an overactivated inflammatory response, periodontitis is characterized by a dysbiotic overgrowing subgingival biofilm with increased prevalence of potential periodontal pathogens, dysregulated immune response, and tissue destruction [27]. Spahr et al. have shown in vitro that EMD combined with propylene glycol alginate exert an inhibitory effect on the growth of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia [28]. In line with these findings, Wyganowska-Świątkowska et al. demonstrated an inhibition of Porphyromonas gingivalis and Prevotella development when EMD was applied as an adjunct to NSPT in patients undergoing initial periodontal therapy [20].

To the best of our knowledge, the impact of EMD application in the nonsurgical retreatment of remaining periodontal pockets on inflammatory response and subgingival biofilm has so far not been investigated in depth. Thus, the aim of the present study was to assess EMD effects on a broad range of host inflammation biomarkers and bacterial count of periodontitis associated bacteria in addition to clinical outcome in periodontitis patients presenting with residual pockets at re-evaluation. The null-hypothesis of the present study was that the use of EMD in addition to subgingival instrumentation would have no beneficial effects on the clinical outcome, inflammation, and bacterial count when compared to subgingival instrumentation alone.

CONSORT flow chart of the study design. Evaluation of clinical parameters (PD, CAL, PI, BOP), oral hygiene indices (API, PBI), cytokine analysis, and microbial assessments were performed at baseline and at 6-month follow-up

All patients were instructed to apply chlorhexidine gel (Chlorhexamed 1% Gel, GlaxoSmithKline, Brentfort, UK) at the treated sites for 2 weeks and to refrain from brushing and flossing at the respective areas. At weeks 3 and 4, patients were told to use a soft toothbrush for the treatment sites. Afterwards, oral hygiene was performed as usual. Treatment procedures were performed by two certified examiners with a specialization in periodontology (CW, GD). Re-assessment was performed 6 months post-treatment by a third examiner who was blinded to the treatment method (DT).

According to our results, no essential reduction of bacterial count in residual pockets was observed following subgingival instrumentation combined with flapless EMD application compared to subgingival instrumentation alone. This is in contrast to Wyganowska-Świątkowska who found that the use of EMD as an adjunct to subgingival instrumentation during initial periodontal therapy inhibited the growth of Gram-negative bacteria including Porphyromonas gingivalis and Prevotella intermedia [20]. However, the respective investigation again represents an earlier treatment stage than the current study setting. Although mechanical debridement of the root surface has shown high efficacy in biofilm elimination and reduction of subgingival microflora during initial periodontal therapy [34], this effect might be less present in residual pockets that have recently been treated. Also, in the current study setting, 6 months between treatment and re-evaluation might be too long to detect significant differences on bacteria count. In this context, it might be worth evaluating possible effects of EMD application on bacterial reduction at earlier time points. Moreover, another reason for our results might be that participants had to apply chlorhexidine gel at the treatment sites, which could have reduced bacterial count in both groups.

The present findings also indicate no substantial influence of non-surgical EMD application on inflammatory markers in GCF. These results confirm findings by Giannopoulou et al. who assessed IL-1 expression at protein level in GCF 2 months after nonsurgical periodontal treatment with and without adjunctive EMD application [17]. Although several tendencies for a reduction in pro-inflammatory cytokines were observed in the present study, they did not meet the level of significance. While EMD has been shown downregulate the expression of genes associated with early inflammation in PDL cells in vitro [35], this potential anti-inflammatory effect did not translate into clinical conditions under the current treatment setting.

The present clinical investigation had some limitations. The limited sample size might have prevented further findings on clinical parameters, as well as on cytokine or bacterial levels. Focus on retreatment of periodontal sites that have already undergone initial periodontal therapy without sufficient site-specific success might have resulted in less improvement of clinical parameters when compared to first phase interventions. The inclusion of groups with application of PGA and/or 24% EDTA solution only might also provide further information, as PGA has also antimicrobial properties. Moreover, measurements of the assessed inflammatory and bacterial parameters at different time points might also elucidate effects of EMD application. Further research is needed to determine whether clinical benefit of nonsurgical EMD application might be influenced by site-specific conditions or treatment settings. Also, direct comparison of treatment outcome of surgical and nonsurgical application of EMD should be encouraged.

3a8082e126