Michael K. McGuire

Platelet-Derived Growth Factor Promotes Periodontal Regeneration in Localized Osseous Defects: 36-Month Extension Results From a Randomized, Controlled, Double-Masked Clinical Trial

BACKGROUND Recombinant human platelet-derived growth factor (rhPDGF) is safe and effective for the treatment of periodontal defects in short-term studies up to 6 months in duration. We now provide results from a 36-month extension study of a multicenter, randomized, controlled clinical trial evaluating the effect and long-term stability of PDGF-BB treatment in patients with localized severe periodontal osseous defects. METHODS A total of 135 participants were enrolled from six clinical centers for an extension trial. Eighty-three individuals completed the study at 36 months and were included in the analysis. The study investigated the local application of β-tricalcium phosphate scaffold matrix with or without two different dose levels of PDGF (0.3 or 1.0 mg/mL PDGF-BB) in patients possessing one localized periodontal osseous defect. Composite analysis for clinical and radiographic evidence of treatment success was defined as percentage of cases with clinical attachment level (CAL) ≥2.7 mm and linear bone growth (LBG) ≥1.1 mm. RESULTS The participants exceeding this composite outcome benchmark in the 0.3 mg/mL rhPDGF-BB group went from 62.2% at 12 months, 75.9% at 24 months, to 87.0% at 36 months compared with 39.5%, 48.3%, and 53.8%, respectively, in the scaffold control group at these same time points (P <0.05). Although there were no significant increases in CAL and LBG at 36 months among all groups, there were continued increases in CAL gain, LBG, and percentage bone fill over time, suggesting overall stability of the regenerative response. CONCLUSION PDGF-BB in a synthetic scaffold matrix promotes long-term stable clinical and radiographic improvements as measured by composite outcomes for CAL gain and LBG for patients possessing localized periodontal defects ( ClinicalTrials.gov no. CT01530126).

Growth Factor–Mediated Treatment of Recession Defects: A Randomized Controlled Trial and Histologic and Microcomputed Tomography Examination

BACKGROUND The primary aims of this two-part prospective study were: 1) to compare the safety and efficacy of beta-tricalcium phosphate (beta-TCP) + 0.3 mg/ml recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with a bioabsorbable collagen wound-healing dressing and a coronally advanced flap (CAF) to a subepithelial connective tissue graft (CTG) in combination with a CAF in subjects with gingival recession defects using a randomized, controlled, split-mouth design; and 2) to compare, through histologic and microcomputed tomography (micro-CT) examination, the periodontal regenerative potential of these two therapies in surgically created gingival recession defects in restoring missing cementum, periodontal ligament (PDL), and supporting alveolar bone. METHODS In the randomized controlled trial (RCT), 30 patients with Miller Class II buccal gingival recession, > or = 3 mm deep and > or = 3 mm wide in contralateral quadrants of the same jaw were treated and followed for 6 months. Using a split-mouth design with similar bilateral recession defects, test sites were treated with 0.3 mg/ml rhPDGF-BB + beta-TCP + bioabsorbable collagen wound-healing dressing; contralateral control sites were treated with a CTG, each in combination with a CAF. In the histologic/micro-CT study segment, recession defects were created in six teeth, each requiring extraction for orthodontic therapy. These defects were created with a recession depth > or = 3 mm, the osseous crest 2 to 3 mm apical to the gingival margin, and with 2 to 3 mm of keratinized tissue. The defects were treated with a CTG (control) or rhPDGF-BB + beta-TCP + wound-healing dressing (test), plus CAF. Nine months after surgical correction, en bloc resections were obtained and examined histologically and with micro-CT. RESULTS In the RCT, test and control treatments demonstrated clinically significant improvements from baseline through month 6. Statistically significant results favoring the CTG were found in recession depth reduction (-2.9 + 0.5 mm, test; -3.3 + 0.6 mm, control; P = 0.009), root coverage (90.8%, test; 98.6%, control; P = 0.013), and -3.9 +/- 0.7 mm, control, -3.3 +/- 1.3 mm, test, recession width reduction (P = 0.035), whereas mid-buccal probing depth (PD) and PD reduction (PDR) reduction favored the test group (1.4 +/- 0.4 mm, test; 1.8 +/- 0.1 mm, control; P < 0.001 PD and -0.0 mm test; +0.4 mm control PDR). For all other parameters, the two treatments were statistically equivalent, including increases in keratinized tissue, esthetic results, and subject satisfaction. In the histologic/micro-CT portion, all four sites treated with rhPDGF-BB + beta-TCP showed evidence of regeneration of cementum, PDL with inserting connective tissue fibers, and supporting alveolar bone, whereas neither CTG-treated site exhibited any signs of periodontal regeneration. CONCLUSIONS CTG and rhPDGF-BB + beta-TCP + wound-healing dressing are effective treatment modalities for clinically correcting gingival recession defects. In addition, the current study demonstrated that regeneration of the periodontium in gingival recession defects was possible through a growth factor-mediated approach.

Periodontal soft tissue root coverage procedures: a consensus report from the AAP Regeneration Workshop.

BACKGROUND Management of gingival recession defects, a common periodontal condition, using root coverage procedures is an important aspect of periodontal regenerative therapy. The goal of the periodontal soft tissue root coverage procedures group was to develop a consensus report based on the accompanying systematic review of root coverage procedures, including priorities for future research and identification of the best evidence available to manage different clinical scenarios. METHODS The group reviewed and discussed the accompanying systematic review, which covered treatment of single-tooth recession defects, multiple-tooth recession defects, and additional focused questions on relevant clinical topics. The consensus group members submitted additional material for consideration by the group in advance and at the time of the meeting. The group also identified priorities for future research. RESULTS All reviewed root coverage procedures provide significant reduction in recession depth, especially for Miller Class I and II recession defects. Subepithelial connective tissue graft (SCTG) procedures provide the best root coverage outcomes. Acellular dermal matrix graft (ADMG) or enamel matrix derivative (EMD) in conjunction with a coronally advanced flap (CAF) can serve as alternatives to autogenous donor tissue. Additional research is needed to do the following: 1) assess the treatment outcomes for multiple-tooth recession defects, oral sites other than maxillary canine and premolar teeth, and Miller Class III and IV defects; 2) assess the role of patient- and site-specific factors on procedure outcomes; and 3) obtain evidence on patient-reported outcomes. CONCLUSIONS Predictable root coverage is possible for single-tooth and multiple-tooth recession defects, with SCTG procedures providing the best root coverage outcomes. Alternatives to SCTG are supported by evidence of varying strength. Additional research is needed on treatment outcomes for specific oral sites. Clinical Recommendation: For Miller Class I and II single-tooth recession defects, SCTG procedures provide the best outcomes, whereas ADMG or EMD in conjunction with CAF may be used as an alternative.

Angiogenic Biomarkers and Healing of Living Cellular Constructs

The use of intra-oral soft-tissue-engineered devices has demonstrated potential for oral mucosa regeneration. The aim of this study was to investigate the temporal expression of angiogenic biomarkers during wound healing of soft tissue reconstructive procedures comparing living cellular constructs (LCC) with autogenous free gingival grafts. Forty-four human participants bilaterally lacking sufficient zones of attached keratinized gingiva were randomly assigned to soft tissue surgery plus either LCC or autograft. Wound fluid samples were collected at baseline and weeks 1, 2, 3, and 4 post-operatively and analyzed for a panel of angiogenic biomarkers: angiogenin (ANG), angiostatin (ANT), PDGF-BB, VEGF, FGF-2, IL-8, TIMP-1, TIMP-2, GM-CSF, and IP-10. Results demonstrated a significant increase in expression of ANT, PDGF-BB, VEGF, FGF-2, and IL-8 for the LCC group over the autograft group at the early stages of wound repair. Although angiogenic biomarkers were modestly elevated for the LCC group, no clinical correlation with wound healing was found. This human investigation demonstrates that, during early wound-healing events, expression of angiogenic-related biomarkers is up-regulated in sites treated with LCC compared with autogenous free gingival grafts, which may provide a safe and effective alternative for regenerating intra-oral soft tissues (ClinicalTrials.gov number, NCT01134081).

Evaluation of Human Recession Defects Treated With Coronally Advanced Flaps and Either Enamel Matrix Derivative or Connective Tissue: Comparison of Clinical Parameters at 10 Years

BACKGROUND The effective treatment of gingival recession (GR) defects is crucial for predictable outcomes. The most common treatment is the subepithelial connective tissue graft (CTG), but good outcomes have also been obtained using enamel matrix derivative (EMD). A split-mouth, randomized controlled trial was previously performed during a 12-month period to evaluate primary and secondary outcomes in Miller Class I and II GR defects treated with CTG or EMD, both in combination with coronally advanced flap (CAF). The purpose of the current study is to examine the major qualitative and quantitative parameters of this study after a 10-year follow-up. METHODS Nine of 17 original patients were available for follow-up evaluation 10 years after the original surgery. The parameters measured were: (1) GR depth; (2) probing depth (PD); (3) clinical attachment level; (4) width of keratinized tissue (wKT); (5) percentage of root coverage; (6) root dentin hypersensitivity; (7) color, texture, and contour of treatment sites; and (8) patient satisfaction at 10 years. Results at 1 and 10 years of these nine patients (nine test and nine control teeth) were compared to original baseline values. In addition, results within treatment groups between 1 and 10 years and between treatment groups (i.e., EMD versus CTG) at the same time points were examined. RESULTS At 10 years, all quantitative parameters except PD for both treatment protocols showed statistically significant improvements from baseline values, including wKT in the EMD group, which at 1 year was not significantly improved compared with baseline wKT. In addition, at 10 years, there were no statistically significant differences between EMD + CAF and CTG + CAF for any measured parameter. The only statistically significant finding in this study was the difference in wKT found at 1 year (EMD, 3.00 mm; CTG, 3.89 mm; P = 0.031). Qualitative parameters at 10 years demonstrated similar stability. The only major qualitative difference was the marginal tissue contour, which was similar to adjacent tissues at EMD-treated sites but greater than adjacent tissues at all CTG sites except one. Esthetically, both EMD- and CTG-mediated treatments were similar at 10 years. However, given the choice, six of nine patients would choose EMD over CTG treatment to avoid a secondary harvesting procedure. CONCLUSIONS This paper highlights the importance of long-term data as it relates to procedural effectiveness in selecting optimally effective protocols to treat gingival recession. Based on the results of this 10-year follow-up investigation, treatment with either EMD + CAF or CTG + CAF for Miller Class I and II GR defects appears stable, clinically effective, and similar to each other on all measured parameters.

Living Cellular Construct for Increasing the Width of Keratinized Gingiva: Results From a Randomized, Within-Patient, Controlled Trial

BACKGROUND The standard of care for increasing keratinized gingiva adjacent to teeth that do not require root coverage is the free gingival graft (FGG). A pilot study indicated that the use of a living cellular construct (LCC) could be effective in this clinical scenario. METHODS A pivotal, multicenter, randomized, within-patient, controlled, open-label trial was conducted (N = 96 patients). After removing the mucosa and keratinized gingiva from the test site, either an LCC or FGG was applied. The primary efficacy endpoint was the ability of the LCC to regenerate ≥2 mm keratinized gingiva at 6 months. Secondary measures were the same color and texture as the adjacent tissue, a 1-mm width of keratinized gingiva at 6 months, patient treatment preference, surgical site sensitivity at 1 week, and patient-reported pain after 3 days. Safety was assessed by reports of adverse events. RESULTS At 6 months, the LCC regenerated ≥2 mm of keratinized gingiva in 95.3% of patients (81 of 85 patients; P <0.001 versus a 50% predefined standard). As expected, the FGG generated more keratinized gingiva than the LCC (4.57 ± 1.0 mm versus 3.2 ± 1.1 mm, respectively). The gingiva regenerated with the LCC matched the color and texture of the adjacent gingiva. All patients achieved ≥1 mm keratinized gingiva with the LCC treatment by 6 months, and more patients preferred treatment with the LCC than with the FGG. No difference in sensitivity or pain was noted between the treatments. The treatments were well tolerated, and reported adverse events were typical for this type of periodontal surgery. CONCLUSION The use of an LCC may provide a safe and effective therapy for augmenting the zone of keratinized gingiva.

Randomized, Controlled Clinical Trial to Evaluate a Xenogeneic Collagen Matrix as an Alternative to Free Gingival Grafting for Oral Soft Tissue Augmentation

BACKGROUND The standard of care for increasing keratinized tissue (KT) and vestibular area is an autogenous free gingival graft (FGG) and vestibuloplasty; however, there is morbidity associated with the harvest of autogenous tissue, and supply is limited. The purpose of this study is to determine if a xenogeneic collagen matrix (CM) might be as effective as FGG. METHODS This study is a single-masked, randomized, controlled, split-mouth study of 30 patients with insufficient zones of KT (<2 mm). It uses a within-patient treatment-comparison design to establish non-inferiority of the test (CM) versus control (FGG) therapy. The primary efficacy endpoint was change in KT width (∆KT) from surgery to 6 months post-surgery. Secondary endpoints included traditional periodontal measures, such as clinical attachment level, recession, and bleeding on probing. Patient-reported pain, discomfort, and esthetic satisfaction were also recorded. Biopsies were obtained at 6 months. RESULTS Surgery and postoperative sequelae were uneventful, with normal healing observed at both test and control sites. The primary outcome, ∆KT width at 6 months, did not establish non-inferiority of CM compared to FGG (P = 0.9992), with the FGG sites averaging 1.5 mm more KT width than CM sites. However, the amount of new KT generated for both therapies averaged ≥2 mm. Secondary outcomes were not significantly different between test and control sites. All site biopsies appeared as normal mucoperiosteum with keratinized epithelium. CM sites achieved better texture and color matches, and more than two-thirds of patients preferred the appearance of their CM sites. CONCLUSION With the proviso of sufficient KT (≈2 mm in width) and study goals of lower morbidity, unlimited supply, and patient satisfaction, CM appears to be a suitable substitute for FGG in vestibuloplasty procedures designed to increase KT around teeth.

Commentary: Incorporating Patient-Reported Outcomes in Periodontal Clinical Trials

The authors review patient-reported outcome (PRO) metrics for dentistry, and in particular, periodontics. The PRO commentary for periodontics includes a review of split-mouth, randomized, controlled clinical trial results that specifically tracked pain at different sites over time after intervention and provided guidelines for peak pain time points and evidence for referred pain assessment when studying soft tissue augmentation procedures. Both the questions that are asked of patients and the timing of those questions are important study design considerations. The authors suggest PRO methodology for periodontal clinical trials that can be used to identify information important to patients and clinicians.

A Randomized Clinical Trial Evaluating rh-FGF-2/β-TCP in Periodontal Defects

Biological mediators have been used to enhance periodontal regeneration. The aim of this prospective randomized controlled study was to evaluate the safety and effectiveness of 3 doses of fibroblast growth factor 2 (FGF-2) when combined with a β-tricalcium phosphate (β-TCP) scaffold carrier placed in vertical infrabony periodontal defects in adult patients. In this double-blinded, dose-verification, externally monitored clinical study, 88 patients who required surgical intervention to treat a qualifying infrabony periodontal defect were randomized to 1 of 4 treatment groups—β-TCP alone (control) and 0.1% recombinant human FGF-2 (rh-FGF-2), 0.3% rh-FGF-2, and 0.4% rh-FGF-2 with β-TCP—following scaling and root planing of the tooth prior to a surgical appointment. Flap surgery was performed with EDTA conditioning of the root prior to device implantation. There were no statistically significant differences in patient demographics and baseline characteristics among the 4 treatment groups. When a composite outcome of gain in clinical attachment of 1.5 mm was used with a linear bone growth of 2.5 mm, a dose response pattern detected a plateau in the 0.3% and 0.4% rh-FGF-2/β-TCP groups with significant improvements over control and 0.1% rh-FGF-2/β-TCP groups. The success rate at 6 mo was 71% in the 2 higher-concentration groups, as compared with 45% in the control and lowest treatment groups. Percentage bone fill in the 2 higher-concentration groups was 75% and 71%, compared with 63% and 61% in the control and lowest treatment group. No increases in specific antibody to rh-FGF-2 were detected, and no serious adverse events related to the products were reported. The results from this multicenter trial demonstrated that the treatment of infrabony vertical periodontal defects can be enhanced with the addition of rh-FGF-2/β-TCP (ClinicalTrials.gov NCT01728844).

Periodontal Soft Tissue Root Coverage Procedures: Practical Applications From the AAP Regeneration Workshop

Focused Clinical Question: How should gingival recession (GR) defects be managed based on current evidence? Summary: The purpose of this practical application is to illustrate the management of GR defects with a primary outcome goal of complete root coverage. The consensus in dental literature and among expert clinicians is that root coverage may be attained through the application of different procedures and that outcomes are generally measured by reduced defect depth, gain in clinical attachment, and an increase in keratinized tissue (KT). These procedures may include the use of: 1) subepithelial connective tissue graft (SCTG); 2) coronally advanced flap; 3) free gingival graft; and 4) soft tissue graft substitutes (acellular dermal matrix and xenogeneic collagen matrix materials) and biologics (recombinant human platelet-derived growth factor and enamel matrix derivative). The variability in these techniques revolves around the inclusion or avoidance of a palatal donor graft. The decision as to how to approach a specific clinical GR-type defect should be a combination of considerations relative to the clinicians surgical goals and the patients understanding of the anticipated outcome. The associated systematic review (Chambrone and Tatakis, J Periodontol 2015;86(Suppl.):S8-S51) provides clear evidence that SCTG-based procedures provide the best outcome for mean and complete root coverage, as well as an increase in KT. Patient-reported outcomes, a topic that needs additional research, should be considered in the decision-making process. Conclusion: Based on the available evidence and the illustrated cases included in this practical application, root coverage can be predictably achieved and a successful clinical outcome can be maintained long term.