Dental Implant Placement in Adjunction With Autologous Alveolar Bone-Marrow Derived Mesenchymal Stem Cells (aBM-MSCs)
Condition: Implant Therapy
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Systemically healthy volunteers with no active periodontal disease are recruited from
      referrals to the Dept. of Preventive Dentistry, Periodontology and Biology of Implants,
      Aristotle Univ of Thessaloniki for implant therapy. After signing a consent form,
      participants will be randomized into two treatment groups. Group-A (NA=10) will receive
      crestal placement of implants following a two-stage protocol in combination with a biocomplex
      comprising autologous alveolar bone marrow mesenchymal stem cells free of animal derived
      reagents, produced in clean room facilities and seeded into collagen scaffolds enriched with
      autologous fibrin glue. In Group-B (NB=10) implants are placed on the alveolar crest
      following a two-stage protocol and the manufacturer's guidelines. Intra-surgical clinical and
      radiographic assessments are performed at the time of implant placement (T0) and at the
      two-stage surgery (T1). Changes in mucosa thickness, width of keratinized tissues, marginal
      bone and bone thickness at the surgical site will be determined at T0-T1. Groups will be
      further divided into two subgroups based on mucosal thickness of the surgical site at T0
      [thin mucosa (≤2.5mm) for Groups-AI/-BI; thick mucosa (>2.5mm) for Groups-AII/-BII]. A linear
      mixed model for repeated measures will be used for data analyses to determine changes in the
      dimensions of the peri-implant soft and hard tissues, around two stage-implants placed either
      conventionally, or in combination with the biocomplex.
    

Detailed description: 
      Aims & Objectives:

      The present study describes a novel method to preserve the crestal bone at two-stage dental
      implants using autologous aBMMSCs, free of animal derived reagents, produced in clean room
      facilities enriched with autologous fibrin glue and seeded into commercially available
      collagen scaffolds (collagen fleece) that are stabilized over the implant platform upon
      surgical implant placement.

      Primary objective:

      This study aims to assess the efficacy of a novel method based on histotechnology in crestal
      bone preservation at two-stage dental implants, as compared to conventional surgical implant
      placement following the manufacturer's guidelines with no adjunctive use of grafting
      materials.

      Secondary, changes in the peri-implant soft tissues will be also determined between implant
      placement and exposure and will be compared between the experimental and the conventional
      surgical treatment approaches.

      Study design:

      Biopsies will be derived from alveolar bone marrow of the alveolar bone under local
      anaesthesia in each patient belonging to the Experimental Group (Group-A). Briefly, after a
      thorough oral rinse with chlorhexidine 0.12% for 1min, an osteotomy using a trephine drill
      will be performed in the alveolar bone of an intraoral edentulous site other than the implant
      site and a 2x8 mm or 3cc approximately of an osseous core will be harvested. The area and the
      biopsy will be copiously irrigated with saline solution and then flaps will be sutured to
      achieve primary closure at the donor site. The bone sample will be then immediately placed in
      sterile tubes and will be transported to Biohellenika, Thessaloniki, Greece
      (http://www.biohellenika.gr) for stem cell isolation and expansion according to a strict
      clinical grade expansion protocol (Bakopoulou et al. 2013; Bakopoulou et al. in preparation).
      Since MSCs will be isolated and expanded in vitro in Good Laboratory Practice (GLP)-compliant
      clean rooms (Biohellenika facilities) meeting the quality guidelines set by the European
      Union and no animal derived reagents will be used throughout the experiments for autologous
      transplantation, the cells are considered safe for human clinical cell therapy applications.
      In Biohellenika facilities, 40ml of venous blood will be collected from each subject in
      Group-A shortly after the biopsy harvest, so that autologous serum is used for the isolation
      and culture expansion of the autologous stem cells. In addition, autologous fibrin glue will
      be used to load the BM-MSCs onto a commercially available collagen fleece. At the day of the
      surgical placement of the implants and chairside, the grafting material (BM-MSCs enriched
      with fibrin glue) will be delivered in an insulin syringe containing 10x10E6 cells/200μl
      fibrin and will be gently loaded onto the collagen fleece and activated with the addition of
      CaCl2. Subsequently, the biocomplex will be sutured onto the lingual flap using bioresorbable
      sutures (5-0 Coated VicrylTM (polyglactin 910), reverse cutting 3/8 circle - 16mm, Ethicon,
      Johnson & Johnson, New Brunswick, NJ, USA) and will be thus gently stabilized over the
      implant platform head partially covering the buccal bone. Handling of the scaffold will be
      done with care to avoid doing any harm to the viable cells.

      In the Control Group (Group-B), the implants will be placed crestally following the
      manufacturer's guidelines with no adjunctive use of grafting materials. One system of
      implants will be consistently used throughout the study in both groups (Osseotite, Certain,
      parallel wall, Biomet 3i, Palm Beach Gardens, USA).

      Post-operative care Post-operative pain will be controlled with Ibuprofen (600mg) at the end
      of the surgical procedure and 12h later if in pain. Amoxicillin (500mg / 8 hours for 5 days)
      will be prescribed to both Groups. All patients will be instructed to use 0.12% chlorhexidine
      twice daily and avoid brushing and chewing hard in the treated area for two weeks. During
      this 2-week period, patients will be followed on a weekly basis to record uneventful healing,
      and after that patients will discontinue rinsing with chlorhexidine solution and resume oral
      hygiene. Thereafter, subjects will be seen at three to four months to have their implants
      exposed.

      Subjects will be assessed at baseline (T0: surgical implant placement) and T1 (implant
      exposure at 3-4 months). Clinical recordings will be determined by a single calibrated
      examiner using a manual periodontal probe (Hu-Friedy XP-23/QW, Hu-Friedy, Chicago, IL, USA)
      with an endo-stop attached on it and all measurements will be digitalised using an electronic
      caliper. A customised metallic caliper will measure the thickness of the bone at the
      buccal/lingual aspects of the implant. At T0 and T1, clinical recordings will assess:

        1. Thickness of mucosa at the top of the alveolar ridge and 2- and 4mm apically, on the
           buccal and the lingual aspects of the ridge.

        2. Width of keratinized mucosa buccally and lingually of the implantation site.

        3. Thickness of buccal and lingual bone at 0, 3- and 6mm from the implant shoulder.

        4. Level of of the buccal and lingual marginal bone, in relation to the implant shoulder.

      Standardised digital radiographs will be collected at T0 and T1 to linearly determine changes
      (in mm) in the height of the alveolar bone between the implant shoulder and teh alveolar
      crest using the VixWin™ Platinum|Gendex software.

      Groups will be further divided into two subgroups based on mucosal thickness of the surgical
      site at T0 [thin mucosa (≤2.5mm) for Groups-AI/-BI; thick mucosa (>2.5mm) for
      Groups-AII/-BII] and all the parameters will be determined and compared on the basis of the
      surgical approach and mucosa thickness at the surgical site.

      A linear mixed model for repeated measures will be used for data analyses to determine
      changes in the dimensions of the peri-implant soft and hard tissues, around two
      stage-implants placed either conventionally, or in combination with the biocomplex.
    

Intervention name(s): Biocomplex: aBM-MSCs/fibrin glue/collagen fleece; Two-stage surgical implant placement
Intervention type(s): Biological; Procedure
Intervention description(s): Xeno-free, clinical-grade, autologous alveolar bone marrow mesenchymal stem cells enriched with autologous fibrin glue and loaded into a commercially available collagen fleece.; Implants are surgically placed on the alveolar crest following a two-stage protocol and the manufacture's guidelines with no adjunctives.
Intervention MeSH terms: Fibrin Tissue Adhesive
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Prospective, randomised, single blind, control clinical trial
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: surgical implant placement; crestal bone; mucosa thickness; stem cells; fibrin glue; collagen fleece