Biological Responses Affecting Early-stage Dental Implant Placement in Patients With History of Periodontitis

Study Overview
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Brief Summary
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This prospective parallel, double-blind, four-arm randomised controlled clinical study is planned to assess the difference in the level of the inflammatory biomarkers expressed following the placement of the first dental implant in patients with history of periodontitis (successfully treated) and healthy controls without the disease, during implant osseointegration period. The subjects in both groups will also be randomised to receive one of the two types of implants provided which have different surface treatment.

Detailed Description
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This is a prospective, parallel, double-blind, four-arm randomised clinical control study, aims to investigate the changes of clinical parameters and pro-inflammatory biomarkers expression and the shift following the first dental implant placement in patients who have been successfully treated for periodontitis, compared with healthy control without the disease. The main questions to answer are: Why do patients with history of periodontitis are at a greater risk to develop peri-implantitis than patients without history of periodontitis? Is there any difference in the microbial composition, histological and immunological reaction of the host's dental plaque, peri-implant soft tissue, gingival crevicular fluids (GCF) of adjacent teeth and peri-implant sulcular fluids (PISF) following implant placement in patients with and without a history of periodontitis? The test group will consist of subjects with stabilised periodontitis, whilst the control group will consist of healthy patients with no history of periodontitis, as identified via history taking and clinical screening. Periodontal condition will be determined based on the new 2017 periodontal classification. All participants in both groups will be randomised to receive one of two types of implants with different surface treatment. Clinical measurement, GCF and PISF will be collected around the single implant and adjacent teeth, at the following stages (time-point): Baseline (pre-operative) After implant placement (prior to the second stage surgery) After implant exposure (prior to the crown restoration) 3-month after the implant is restored Soft tissue will be obtained during the first stage (baseline) and second stage implant surgery (post-operative) and analysed.

Official Title
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Identification of Biological Responses as a Causal Link for the Increased Peri-implantitis in Patients With History of Periodontitis

Conditions
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Periodontitis, Peri-implant Mucositis, Peri-Implantitis

Intervention / Treatment
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* Other: Megagen implant placement
* Other: Biomate-Swiss implant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Specific inclusion criteria for test group: History of periodontitis but currently stable Must have successfully completed active periodontal treatment at least 4 months prior to the commencement of study Specific inclusion criteria for control group: No history of periodontitis, with minimal age-related radiographic bone loss Reason for losing the tooth/teeth was not due to periodontal problem General inclusion criteria: Medically healthy Aged between 30 to 65 years old Non-smoker, or quit smoking at least 12 months before study commencement Good oral hygiene (full mouth plaque score (FMPS)<20%, full mouth bleeding score (FMBS)<15%) Indicated for a single implant placement in the posterior region, with adjacent and contralateral natural tooth Intact inter-cuspal position Exclusion Criteria: Previous history of dental implant placement Currently pregnant or intend to be pregnant, and/or lactating mothers Taking long-term medicines which may affect gingival tissue and oral microbiome, e.g. antibiotics, anticoagulants, anticonvulsants, immunosuppressants and calcium channel blockers.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Test group: Patient with history of periodontitis Control group: Patient without history of periodontitis Patients in both groups will be randomised to receive one of two type of implants with different surface characteristics.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group T-A<br>7 patients with history of periodontitis | Other: Megagen implant placement<br>* Megagen implant with sand-blasted, large-grit, acid-etched (SLA) and nano-calcium ions incorporated surface<br>|
| Experimental: Group T-B<br>7 patients with history of periodontitis | Other: Biomate-Swiss implant<br>* Biomate-Swiss implant with precision dimension laser (PDL) surface<br>|
| Active Comparator: Group C-A<br>7 patients without history of periodontitis | Other: Megagen implant placement<br>* Megagen implant with sand-blasted, large-grit, acid-etched (SLA) and nano-calcium ions incorporated surface<br>|
| Active Comparator: Group C-B<br>8 patients without history of periodontitis | Other: Biomate-Swiss implant<br>* Biomate-Swiss implant with precision dimension laser (PDL) surface<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of matrix metalloproteinase (MMP)-8 expressed in the gingival crevicular and peri-implant sulcular fluids during the early-stage of dental implant placement | To measure the absolute quantification of MMP-8 level expressed during the implant osseointegration period in all study groups via ELISA method. | From baseline (1st time-point (TP1)) to 1st stage surgery (implant placement - TP2), after 2nd stage surgery (implant exposure (TP3) and 3-months after implant crown restoration (final visit- TP4) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Shift of the microbial composition in the supragingival dental plaque, identified via 16S rRNA next generation sequencing | Identification and comparison of supragingival dental plaque bacteria species/genus and the shift of the bacterial composition during the early-stage of dental implant placement between study groups | From baseline (1st time-point (TP1)) to 1st stage surgery (implant placement - TP2), after 2nd stage surgery (implant exposure (TP3) approximately 3 months after the 1st stage surgery) and 3-months after implant crown restoration (final visit- TP4) | 
| Shift of proteome profiles in the gingival crevicular and peri-implant sulcular fluids during the early-stage of dental implant placement | To assess the protein profile and levels of expression of the pro-inflammatory cytokines in GCF and gingival tissue via liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS) proteomic analysis following osseointegration. | From baseline (1st time-point (TP1)) to 1st stage surgery (implant placement - TP2), after 2nd stage surgery (implant exposure (TP3) approximately 3 months after the 1st stage surgery) and 3-months after implant crown restoration (final visit- TP4) | 
| Histological changes in the peri-implant soft tissue before and after implant placement | Number and co-localisation of cells with MMP-8, pro-inflammatory (M1)- and anti-inflammatory (M2)-related cytokines via hematoxylin and eosin staining, immunohistochemistry and immunofluorescence analysis | Between first stage (baseline/pre) and second stage implant surgery (post-operative) at 3 months after the first surgery | 
| Changes in the clinical parameters during the early-stage implant placement | To assess intra-oral clinical parameters changes (i.e. patient-level and tooth-level mean periodontal pocket depth (mm) and clinical attachment level (mm); full mouth plaque score (%) and bleeding score (%)) following the first dental implant placement, each time-point (TP). The deeper the depth/higher the level or percentage means the worse the condition is. | From baseline (1st time-point (TP1)) to 1st stage surgery (implant placement - TP2), after 2nd stage surgery (implant exposure (TP3) approximately 3 months after the 1st stage surgery) and 3-months after implant crown restoration (final visit- TP4) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dental implant, history of periodontitis, matrix metalloproteinase (MMP)-8, histological analysis, next generation sequencing, dental plaque, gingival crevicular fluids, peri-implant sulcular fluids, peri-implant soft tissue, proteomic analysis