The search for an all-rounder “magic potion” to assist our body in healing and regeneration has driven alchemists and scientists for centuries. Our body has an amazing ability to heal, but in cases of critical size defects or wounds it will always need an exogenous source of help in the form of anti-microbials, enzymes or proteins that are either human, animals or even plant derived. By way of understanding how human and animal teeth develop, particularly in relation to the development of the tooth’s attachment apparatus, the group of Lindskog, Slavkin and Hammarstrom in the 1980s and 1990s were inspired by the role of enamel matrix proteins (EMPs) and amelogenin (AMEL) in particular, in cementogenesis and the formation of the periodontal attachment apparatus (Lindksog S 1981, Hammarstrom et al 1991, 1992, 1995). EMPs are proteins secreted by Hertwig’s epithelial root sheath (HERS) capable of promoting complete or partial periodontal regeneration (Gestrelius et al 1997, Heijl et al 1997). The commercial formulation of these enamel proteins, Emdogain® (EMD), is derived from the enamel layer of developing porcine teeth, with Propylene Glycol Alginate (PGA) as the carrier. The product is packaged in a syringe container to be injected directly into the defect or site where it is needed. Since the development of this product in the mid 1990s, hundreds of animal and human studies and clinical trials have been performed with varying results. The majority of the results are positive, showing that EMD that can assist in periodontal regeneration, recession coverage and possibly general wound healing and new bone formation. Among the hundreds of available studies already, why did I then choose to investigate this protein as the subject of my research? I believe that there is still a big gap in the knowledge of how EMD works and that we are only scratching the surface of the potential of this enamel-derived protein, which when added to an environment with inflammatory cells is capable of inciting numerous proinflammatory reactions that can lead to repair, healing or even regeneration. Chapter one of this thesis is a review of the relevant literature in the field, leading to the identification of the limitations of the existing published clinical researches on EMD, which are:

1. Most clinical trials available on recession coverage have a small sample size and of short duration (2 years or less).
2. There are very few clinical studies on recession coverage that include patientcentred outcomes such as their perception of pain and the patient’s opinion on the success of the procedure.
3. There is no randomized clinical trial available on recession coverage with or without EMD on Class III-Class IV Miller recession, particularly on the lower anterior teeth.
4. Only a handful of clinical trials are available that look at the regenerative role of EMD on peri-implantitis management.
5. There is a gap in the knowledge about the osteogenic potential of EMD in healing extraction sockets and its possible ability in helping to reduce ridge dimensional shrinkage. Chapter two of this thesis examines the degree of recession coverage of multiple adjacent non-molar recessions using sub-epithelial connective tissue graft (SCTG) with or without the adjunctive use of EMD. The patients were reviewed every 6 months for 3 years and the clinical data at 12th, 24th and 36th months are reported. The clinical parameters (probing depth (PD), keratinised tissue (KT) and recession measurement showed no statistically significant difference between the two groups at the 24th month of the clinical trial. However, following 36th months, the EMD group showed less residual gingival recession, more percentage of teeth with complete root coverage and more keratinised tissue. This difference on the test and control groups observed only after 3 years provides important data about the potential long-term benefits of using EMD, especially since most clinical trials on EMD are of short duration (less than 2 years) and report no statistical significance between the two groups. It is possible that the adjunctive benefit of EMD, either by inducing periodontal regeneration or inducing more keratinised tissue, may only be relevant after years of function of the treated teeth. Chapter two of this thesis also showed that less pain was experienced by the patients in the EMD group on the 2nd day, 7th day and 14th day after the recession coverage surgery. Chapter three of this thesis investigated the benefits of using EMD in more advanced recession defects (Miller Class III-IV recession). To the best of my knowledge, it is the only randomised clinical trial available on Miller Class III-IV recession of the lower anterior teeth. The 3-year data showed more recession stability, less residual recession and more keratinised tissue on the EMD-Sub-epithelial Connective Tissue Graft (SCTG) treated group versus the SCTG alone. The EMD-SCTG group also experienced less pain on the first and 2nd week after the recession coverage procedures. Whether or not the improvement in clinical parameters of these severely affected lower anterior teeth can prolong their life-span needs to be monitored longterm. Chapter four of the thesis investigated the use of EMD for regenerative therapy in a cohort of peri-implantitis affected patients. After non-surgical treatment, implants affected by peri-implantitis was debrided using a highly irrigated ultrasonic machine, decontaminated with PrefgelÒ (24% ethylenediamine tetra-acetic acid, EDTA) and the crater-like defect filled with deproteinised bovine bone mineral with 10% collagen (DBBMC, Bio-Oss CollagenÒ) mixed with EMD. Primary closure was achieved and the implants monitored for 3 years. Although no 100% bone fill was observed, significant bone fill (on average 50-60%) was noted on all the implants and this was maintained in most cases for the 3-year duration of the study. Another notable finding in this study was the need for more regular supportive periodontal therapy (SPT) (every 3-4) months) to achieve stability as evaluated by lack of pocketing and the absence of bleeding on probing. The final experimental chapter (five) investigated the potential benefit of EMD as an adjunct to DBBMC in anterior ridge preservation or management and evaluated the potential osteogenic potential of EMD in the extraction socket. Two groups, one using DBBMC only (control) and a test group with DBBMC-EMD, were closed by free gingival graft harvested from the palate. Radiographs were taken before extraction and 4 months after the ridge management surgical procedures. A core trephine biopsy was also taken in the center of the ridge prior to implant placement. The results showed that the addition of EMD did not contribute to reduction of the ridge dimension, although all the ridge reduction measurement parameters compared favourably to published studies where no ridge management was performed, suggesting that anterior ridge management (ARM) worked in minimizing ridge resorption after extraction, regardless of the use of EMD. However, the histomorphometric analysis of the trephined cores showed superior new bone formation in the DBBMC-EMD group, which may create more favourable conditions for osseointegration of implants inserted in these sites. Another interesting finding of this study was that when the data were re-analyzed according to buccal wall thickness of the extraction socket (BT), instead of the treatment performed (DBBMC with or without EMD), the following results were observed:
6. Teeth with buccal wall thickness (BT) thickness ³1mm showed less statistically significant ridge reduction, suggesting the importance of thick BT in ridge stability.
7. Teeth with BT <1mm still showed some degree of ridge reduction (10-14%) which is still significantly less than if a thin-buccal walled socket is allowed to heal spontaneously (50-60% reduction). Although there is already a plethora of research work done on EMD, the novel aspects of the research reported in this thesis are:
8. The first RCT on Class III-IV Miller Recession on lower anterior teeth.
9. The largest 3-year data set on Class I-II Miller multiple adjacent recession.
10. One of the few clinical recession studies that considered patientcentred outcomes data
11. One of the few studies that assess the possible osteogenic potential of EMD using peri-implantitis and anterior ridge management models.
12. The only available human histology of bone core of DBBMC with EMD trephined from an extraction socket, showing the significant osteogenic potential of EMD.
13. One of the few papers that highlights the important role of buccal wall thickness on the degree of ridge reduction after extraction.