Autogenous vs. Xenogeneic Peri-implant Soft Tissue Grafts Placed in Full vs. Split Thickness Flaps

Study Overview
=================
Brief Summary
-----------------
Randomized, outcome assessor and data analyst blinded, single center trial with four parallel arms and a 1:1:1:1 allocation ratio, with the aim of comparing which combination of bilaminar technique (split vs. full thickness flap) and graft type (autogenous or xenogeneic) provides better clinical, aesthetic, morphological, vascular and patients related outcomes, when augmenting the buccal peri-implant mucosa at the reopening of submerged implant fixtures

Detailed Description
-----------------
This randomized four parallel arms controlled clinical trial with blinded outcome assessment and data analysis aims to establish which combination of bilaminar technique (split vs. full thickness flap) and graft type (autogenous subepithelial connective tissue graft vs. volume stable collagen matrix) provides better clinical, aesthetic, morphological, vascular and patients related outcomes, when augmenting the buccal peri-implant mucosa at the reopening of submerged implant fixtures. The primary outcome is the gain in soft tissue thickness (standardised measurement at baseline, after surgery, at 1m and 6m). Secondary outcomes include changes in tissue volume (intraoral scans at baseline, post-op, 14d, 1m, 6m), RAL and KTW (clinical measurements at baseline, 1m, 6m), tissue color integration (∆E at 1m and 6m), and PROMS (7d, 14d, 30d). Exploratory outcomes include tissue morphology (histology at 1m,2m,4m,6m), microcirculation (Doppler flowmetry at pre-op, 7d, 14d, 1m) and revascularization (IHC at 1m,2m,4m,6m). A figure of 10 subjects per group was obtained for a 0,3mm difference in tissue thickness increase (SD 0,23mm), using 80% power, alpha 0.05, and a 10% drop-out rate. Patients will be randomly allocated to four groups: test (STF+VCM), control 1 (FTF+VCM), control 2 (SFT+CTG), control 3 (FTF+CTG). Patients will be the unit of analysis and ANOVA (normality) or Kruskall-Wallis (no normality) tests will be performed setting the significance level at p < 0.05.

Official Title
-----------------
Randomised Clinical Trial Comparing Autogenous vs. Xenogeneic Peri-implant Soft Tissue Grafts Placed in Full vs. Split Thickness Flaps: a Clinical, Histological and Vascular Analysis

Conditions
-----------------
Thin Gingiva

Intervention / Treatment
-----------------
* Procedure: Split thickness flap
* Procedure: Full thickness flap
* Procedure: Autogenous sub epithelial connective tissue graft
* Procedure: Volume stable collagen matrix


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Any male or female adult (≥ 18 year old) patient from the University Complutense of Madrid, being able to sign an informed consent form, presenting a submerged dental implant scheduled to undergo a second stage surgery, which is bounded mesially or distally by a remaining natural tooth, and exhibits a lack of buccal soft tissue volume, will be potentially eligible for this trial. The case definition for a lack of buccal soft tissue volume will be the presence of a thin buccal mucosa (< 2mm) or a minor volumetric contraction of the alveolar process (flat or concave buccal mucosal profile at the edentulous area). Exclusion Criteria: Patients fitting to all the above inclusion criteria will be not included in the study if unable to attend to the study-related procedures (including the follow-up visits) or if one or more of the following systemic or local exclusion criteria will be found during enrolment or through the study: Systemic primary exclusion criteria: Compromised general health status contraindicating the study procedures (≥ASA IV); Drug abuse, alcohol abuse, or smoking > 10 cigarettes a day; Chronic use of corticosteroids, NSAIDs, or immune-modulators (any type, any dose); Assumption of bisphosphonates (any type, any dose, past or present); Pregnant or nursing women; Hypersensitivity to paracetamol; Local primary exclusion criteria History of previous mucogingival surgeries in the area of interest; Lack of adequate vestibule depth to perform a bilaminar procedure; Lack of osseointegration at the time of implant reopening; Need for additional bone grafting at the time of implant reopening; Intraoperative evidence of a flap thickness < 0,5mm or > 2mm. Secondary exclusion criteria: - Non compliant patients: poor oral hygiene at 2 consecutive visits.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Split thickness flap + Volume stable collagen matrix<br>A split thickness flap will be raised with a micro-blade, keeping a flap thickness >0,5mm. The healing abutment will be connected to the implant, and a 10mm wide, 6-8mm high, 6mm thick volume stable collagen matrix will be stabilised at the inner aspect of the flap. | Procedure: Split thickness flap<br>* Palatally displaced crestal incision at the edentulous site, combined with the split thickness elevation of a buccal flap, extended to the sulcus of the adjacent mesial and distal tooth. Flap elevation performed with a micro-blade, in a buccal and apical direction, for approximately 15mm apical to the crestal incision.<br>Procedure: Volume stable collagen matrix<br>* Geistlich Fibro-Gide® matrix shaped at a standardised dimension of 10mm (mesio-distally) by 6-8mm (apico-coronally) by 6mm (thickness). Matrix stabilised at the inner aspect of the buccal flap, 1mm apical to the flap margin, using one mesial and one distal horizontal mattress sutures.<br>|
| Active Comparator: Full thickness flap + Volume stable collagen matrix<br>A full thickness flap will be raised with a periosteal elevator. The healing abutment will be connected to the implant, and a 10mm wide by 6-8mm high volume stable collagen matrix will be stabilised at the inner aspect of the flap. | Procedure: Full thickness flap<br>* Palatally displaced crestal incision at the edentulous site, combined with the full thickness elevation of a buccal flap, extended to the sulcus of the adjacent mesial and distal tooth. Flap elevation performed with a fine periosteal elevator, in a buccal and apical direction, for approximately 15mm apical to the crestal incision.<br>Procedure: Volume stable collagen matrix<br>* Geistlich Fibro-Gide® matrix shaped at a standardised dimension of 10mm (mesio-distally) by 6-8mm (apico-coronally) by 6mm (thickness). Matrix stabilised at the inner aspect of the buccal flap, 1mm apical to the flap margin, using one mesial and one distal horizontal mattress sutures.<br>|
| Active Comparator: Split thickness flap + Autogenous connective tissue<br>A split thickness flap will be raised with a micro-blade, keeping a flap thickness >0,5mm. The healing abutment will be connected to the implant, and a 10mm wide, 6-8mm high, 1,5mm thick autogenous sub epithelial connective tissue graft will be stabilised at the inner aspect of the flap. | Procedure: Split thickness flap<br>* Palatally displaced crestal incision at the edentulous site, combined with the split thickness elevation of a buccal flap, extended to the sulcus of the adjacent mesial and distal tooth. Flap elevation performed with a micro-blade, in a buccal and apical direction, for approximately 15mm apical to the crestal incision.<br>Procedure: Autogenous sub epithelial connective tissue graft<br>* Harvest of a sub epithelial connective tissue graft using a double incision technique, approximately 2-3 mm apical to the palatal gingival margins of the first and second premolars. Graft dimension standardised as 10mm (mesio-distally) by 6-8mm (apico-coronally) by 1,5mm (thickness). Graft stabilised at the inner aspect of the buccal flap, 1mm apical to the flap margin, using one mesial and one distal horizontal mattress sutures.<br>|
| Active Comparator: Full thickness flap + Autogenous connective tissue<br>A full thickness flap will be raised with a periosteal elevator. The healing abutment will be connected to the implant, and a 10mm wide, 6-8mm high, 1,5mm thick autogenous sub epithelial connective tissue graft will be stabilised at the inner aspect of the flap. | Procedure: Full thickness flap<br>* Palatally displaced crestal incision at the edentulous site, combined with the full thickness elevation of a buccal flap, extended to the sulcus of the adjacent mesial and distal tooth. Flap elevation performed with a fine periosteal elevator, in a buccal and apical direction, for approximately 15mm apical to the crestal incision.<br>Procedure: Autogenous sub epithelial connective tissue graft<br>* Harvest of a sub epithelial connective tissue graft using a double incision technique, approximately 2-3 mm apical to the palatal gingival margins of the first and second premolars. Graft dimension standardised as 10mm (mesio-distally) by 6-8mm (apico-coronally) by 1,5mm (thickness). Graft stabilised at the inner aspect of the buccal flap, 1mm apical to the flap margin, using one mesial and one distal horizontal mattress sutures.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Buccal soft tissue thickness | Changes in the thickness of the buccal peri-implant mucosa, measured with trans-gingival probing. | before surgery, after surgery, 1 month after surgery, 6 months after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Volume changes | Changes in the size of the buccal peri-implant tissues and in their volume distribution, measured with a digital volumetric analysis. | before surgery, after surgery, 14 days after surgery, 1 month after surgery, 6 months after surgery | 
| Attachment level | Relative attachment level (implant) and clinical attachment level (adjacent tooth) measured with a standardised UNC-15 probe. | baseline, after surgery, 1 month after surgery, 6 months after surgery | 
| Colorimetric integration | Colorimetric integration of the augmented buccal peri-implant mucosa, relative to the buccal attached gingiva of the mesial and distal adjacent tooth, quantified throughout the ∆E score, calculated on standardised digital photographs. | 1 month after surgery, 6 months after surgery | 
| Patients related outcome measures | Patients pain and discomfort with respect to the procedure evaluated with the short form of the McGill pain questionnaire (SF-MPQ). | 7 days after surgery, 14 days after surgery, 1 month after surgery, 6 months after surgery | 
| Microcirculation of the grafted area | Microcirculation of the treated area evaluated with a laser Doppler flowmeter. | before surgery, after surgery, 7 days after surgery, 14 days after surgery, 1 month after surgery, 6 months after surgery | 
| Morphology of the grafted area | Descriptive histology performed on paraffin embedded sections from buccal gingival specimens, stained with hematoxylin-eosin. | 1 month after surgery or 2 months after surgery or 4 months after surgery or 6 months after surgery | 
| Revascularization and reinnervation of the grafted area | Immune histochemistry performed on paraffin embedded, hematoxylin-eosin stained sections using markers of tissue revascularization and reinnervation. | 1 month after surgery or 2 months after surgery or 4 months after surgery or 6 months after surgery | 
| Full mouth Plaque score | Full muouth plaque score measured with a standardised UNC-15 probe. | baseline, after surgery, 1 month after surgery, 6 months after surgery | 
| Full mouth Bleeding score | Full mouth bleeding score measured with a standardised UNC-15 probe. | baseline, after surgery, 1 month after surgery, 6 months after surgery | 
| Keratinised tissue width | Keratinised tissue width measured with a standardised UNC-15 probe. | baseline, after surgery, 1 month after surgery, 6 months after surgery | 
| Bleeding on probing | Presence/absence of bleeding on probing at the treated implant measured with a standardised UNC-15 probe. | baseline, after surgery, 1 month after surgery, 6 months after surgery | 
| Modified Plaque index | Presence/absence of plaque at the treated implant | baseline, after surgery, 1 month after surgery, 6 months after surgery | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Soft tissue management, Dental implant, Collagen matrix, Connective tissue graft, Split thickness flap, Full thickness flap