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Gene Expression Variation and Implant Wound Healing Among Smokers and Diabetics

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by University of North Carolina, Chapel Hill
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Steven Offenbacher, DDS, PhD, MMSc, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier:
NCT01663298
First received: August 1, 2012
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

Periodontal wound healing is a complex multifactorial process that involves interactions among various cells, growth factors, hormones and extracellular matrices. Although still poorly understood, these interactions trigger a series of events that lead to new tissue formation. One growth factor that plays an important role in wound healing is fibroblast growth factor 2 (FGF2). Many animal and human studies have shown this protein is effective in periodontal regeneration. Recently, epigenetic modifications, such as DNA methylation, have been associated with changes in patterns of gene expression. Preliminary data suggests that FGF2 gene may be differentially methylated in periodontal tissues. Aberrant gene promoter methylation in smokers and diabetics has also been reported in many studies. However, the role of DNA methylation in wound healing has not yet been investigated.

The investigators hypothesize that the methylation status of FGF2 gene can affect the levels of FGF2 secreted during wound healing phase after dental implant surgery. The investigators also hypothesize there exists a difference in methylation levels of FGF2 gene in healthy, smoking and diabetic patients that can interfere with wound healing. The investigators seek to determine whether DNA methylation plays a role in wound healing and whether the methylation level of FGF2 gene varies among healthy, smoking and diabetic patients.


Condition Intervention
Smoking
Diabetes
Procedure: Dental implant surgery

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: FGF2 Promoter Hypermethylation and Implant Wound Healing Among Smokers and Diabetics

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • FGF2 methylation level [ Time Frame: On the day of implant surgery ] [ Designated as safety issue: No ]
    Genomic DNA is isolated from the collected gingival tissue samples. Methylation alterations in FGF2 are detected through differential methylation hybridization using the EpiTect® Methyl qPCR single assay.


Secondary Outcome Measures:
  • FGF2 mRNA expression level [ Time Frame: On the day of implant surgery (DAY 0) ] [ Designated as safety issue: No ]
    RNA is isolated from the collected gingival tissue samples and is then processed for gene expression analysis by quantitative real-time PCR.

  • FGF2 protein level [ Time Frame: On the day of implant surgery (DAY 0) and 2, 4 and 6 weeks following implant surgery ] [ Designated as safety issue: No ]
    Gingival crevicular fluid, obtained from the two adjacent sites closest to the implant location, is used to quantify specific FGF2 protein levels by ELISA.

  • Implant stability quotient (ISQ) [ Time Frame: 4 and 6 weeks following implant surgery ] [ Designated as safety issue: No ]
    The degree of implant stability at various time points following the surgery is measured using an Osstell ISQ instrument. An ISQ value, ranged between 1 and 100, is generated for each sample at each time point.

  • Wound healing indices (WHI) [ Time Frame: 2, 4 and 6 weeks following implant surgery ] [ Designated as safety issue: No ]
    The degree of soft tissue healing at various time points following surgery is monitored by WHI.


Biospecimen Retention:   Samples With DNA

Gingival tissues, gingival crevicular fluid, saliva


Estimated Enrollment: 44
Study Start Date: August 2010
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Control group
Subjects must have never smoked and must be non-diabetic.
Procedure: Dental implant surgery
Surgery involving placement of one dental implant, of either Astra Tech or Straumann system, is performed in all subjects within 2 weeks of screening examination. Implant placement is 1-stage, but can be either on edentulous ridges or in extraction sockets.This is not a randomized treatment arm/group design. The study is observational with regards to the analysis of tissue samples that are collected prior to the routine placement of implants. The implant choice is based upon patient needs and is not related to any outcome.
Smoking group
Subjects must have had at least 5 pack-years of self-reported smoking history, must be currently smoking and must be non-diabetic.
Procedure: Dental implant surgery
Surgery involving placement of one dental implant, of either Astra Tech or Straumann system, is performed in all subjects within 2 weeks of screening examination. Implant placement is 1-stage, but can be either on edentulous ridges or in extraction sockets.This is not a randomized treatment arm/group design. The study is observational with regards to the analysis of tissue samples that are collected prior to the routine placement of implants. The implant choice is based upon patient needs and is not related to any outcome.
Diabetic group
Subjects must have type 2 diabetes. The condition must be diagnosed subjects must be treated by medications and/or insulin. A HbA1C test result either within past 3 months or performed in the first visit must be available. They must have never smoked.
Procedure: Dental implant surgery
Surgery involving placement of one dental implant, of either Astra Tech or Straumann system, is performed in all subjects within 2 weeks of screening examination. Implant placement is 1-stage, but can be either on edentulous ridges or in extraction sockets.This is not a randomized treatment arm/group design. The study is observational with regards to the analysis of tissue samples that are collected prior to the routine placement of implants. The implant choice is based upon patient needs and is not related to any outcome.

Detailed Description:

Periodontal wound healing is a complex multifactorial process that involves interactions among various cells, growth factors, hormones and extracellular matrices. Although still poorly understood, these interactions trigger a series of events that lead to new tissue formation. One growth factor that plays an important role in wound healing is fibroblast growth factor 2 (FGF2). FGF2 is a member of the heparin-binding growth factor family, secreted by macrophages and endothelial cells. During the proliferative healing phase, it stimulates fibroblast proliferation & ECM synthesis, and increases chemotaxis, proliferation and differentiation of endothelial cells. During the bone remodeling phase, FGF2 also stimulates mesenchymal progenitor cell migration. Many animal and human studies have shown FGF2 are effective in periodontal regeneration. In 1999, Murakami showed surgically treated 3-wall intrabony defect in dogs grafted with FGF2 was able to demonstrate significantly greater cementum and bone formation. Four years later, his group again found that topical application of rhbFGF in surgically treated class 2 furcation defects in dogs also showed increase in formation of PDL, cementum and bone. In 2008, Kitamura performed a randomized controlled study in humans with 2- or 3-wall intrabony periodontal defects and found that rhbFGF was able to stimulate alveolar bone growth and PDL regeneration.

Recently, epigenetic modifications, such as DNA methylation, have been associated with changes in patterns of gene expression that do not involve changes in DNA sequence. DNA methylation is characterized by the addition of the methyl group onto cytokines within CpG regions. Methylated CpG regions interfere with the access of transcription factors to the promoter region, thereby silencing the gene. This DNA methylation phenomenon has important regulatory functions in normal and pathological cellular processes. It was recognized that alteration in the methylation states at the promoter regions of tumor suppressor genes are implicated with cancer. A persistent inflammation was also observed to cause DNA methylation, which inactivates suppressors of cytokine signaling and results in exaggerated cytokine production. This makes an individual susceptible to periodontal disease. In our laboratory, the investigators have discovered that periodontal disease is associated with increased DNA methylation of the COX-2 promotor, especially the locus immediately adjacent to the NF-kB in the promoter region. Preliminary data (not shown) suggests that FGF2 may be differentially methylated in periodontal tissues. Aberrant gene promoter methylation in smokers and diabetics has also been reported in many studies. However, the role of DNA methylation in wound healing has not yet been investigated.

We hypothesize that the methylation status of FGF2 can affect the levels of FGF2 secreted during wound healing phase after dental implant surgery. We also hypothesize there exists a difference in methylation levels of FGF2 in healthy, smoking and diabetic patients that can interfere with wound healing. We seek to determine whether DNA methylation plays a role in wound healing and whether the methylation level of FGF2 varies among healthy, smoking and diabetic patients.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Patients in the graduate periodontal clinic in the school of dentistry at the University of North Carolina

Criteria

Inclusion Criteria:

  • Adult males or females between the age of 18 and 70 years (inclusive)
  • Able and willing to follow study procedures and instructions
  • Have read, understood and signed an informed consent form
  • In good general health
  • Have one or more implant placements as their future treatment needs. The implant placement can be either as one-stage or two-stage, and can be either in an edentulous ridge or an extraction socket
  • Qualify for enrollment into one of the three study groups
  • Have probing depth ≤ 4 mm for all teeth at the same quadrant of implant placement. Sites with probing depth 5 mm will also be included if bleeding on probing in these sites are absent.

Exclusion Criteria:

  • Have a chronic disease with oral manifestations
  • Exhibit gross oral pathology
  • Use of either antibiotics or NSAIDs within 1 month prior to screening examination
  • Chronic treatment (i.e. two weeks or more) with any medication known to affect periodontal status (e.g. phenytoin, calcium, antagonists, cyclosporin, Coumadin) within 1 month prior to screening examination
  • Systemic conditions, except smoking and diabetes, that are known to affect the periodontal status
  • With active infectious diseases such as hepatitis, HIV or tuberculosis
  • Known to be pregnant or breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01663298

Contacts
Contact: Sherrill T Phillips, RDH 919-537-3422 sherrill_phillips@unc.edu
Contact: Wendy Lamm, DA 919-537-3424 wendy_lamm@unc.edu

Locations
United States, North Carolina
Department of Periodontology, UNC School of Dentistry Recruiting
Chapel Hill, North Carolina, United States, 27514
Contact: Sherrill Phillips, RDH    919-966-5271    Sherrill_phillips@dentistry.unc.edu   
Principal Investigator: Steven Offenbacher, DDS,PhD,MMSc         
Sub-Investigator: Silvana Barros, DDS,MS,PhD         
Sub-Investigator: Ping Seung Alice Wu, DDS,MSc         
Sub-Investigator: Sherrill Phillips, RDH         
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Investigators
Principal Investigator: Steven Offenbacher, DDS,PhD,MMSc Center for Oral and Systemic Diseases
  More Information

Publications:

Responsible Party: Steven Offenbacher, DDS, PhD, MMSc, Distinguished Professor and Department Chair, University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT01663298     History of Changes
Other Study ID Numbers: AWU, 1R01DE021052-01, 1UL1RR025747
Study First Received: August 1, 2012
Last Updated: July 8, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of North Carolina, Chapel Hill:
DNA methylation
FGF2
Wound healing
Smoking
Diabetes
Implant

ClinicalTrials.gov processed this record on November 27, 2014