Marc L. Nevins

Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration

Introduction: Achieving successful tissue regeneration following traditional therapeutic protocols, combining bone grafts and barrier membranes, may be challenging in certain clinical scenarios. A deeper understanding of periodontal and peri-implant wound healing and recent advances in the field of tissue engineering have provided clinicians with novel means to obtain predictable clinical outcomes. The use of growth factors such as recombinant human platelet-derived growth factor-BB (rhPDGF) with biocompatible matrices to promote tissue regeneration represents a promising approach in the disciplines of periodontology and implantology. Areas covered: This review covers the basic principles of bone and periodontal regeneration, and provides an overview of the biology of PDGF and its potential to predictably and reproducibly promote bone regeneration in regular clinical practice. The results of preclinical and clinical human studies evaluating the effectiveness of growth-factor-enhanced matrices are analyzed and discussed. Expert opinion: Current available evidence supports the use of rhPDGF-enhanced matrices to promote periodontal and peri-implant bone regeneration.

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).

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.

Periodontal Regeneration – Intrabony Defects: A Consensus Report From the AAP Regeneration Workshop

BACKGROUND Treatment of intrabony defects is an important therapeutic goal of periodontal therapy. The goal of this consensus report was to critically appraise the evidence for the available approaches for promoting periodontal regeneration in intrabony defects. In addition to evaluating the effectiveness of new regenerative approaches for intrabony defects, recommendations for future research were defined for this area. METHODS A systematic review was conducted using computerized searches of PubMed and Cochrane databases, supplemented with screening of references in original reports, review articles, and a hand search in selected journals. All searches were focused on regenerative approaches with histologic evidence of periodontal regeneration (proof of principle), clinical trials, and case reports. For purposes of analysis, change in intrabony defect fill was considered the primary outcome variable, with change in clinical attachment as a secondary outcome. The SORT (Strength of Recommendation Taxonomy) grade was used to evaluate the quality and strength of the evidence. During the consensus meeting, the group agreed on the outcomes of the systematic review, pertinent sources of evidence, clinical recommendations, and areas requiring future research. RESULTS The systematic review, which was conducted for the consensus conference, evaluated the effectiveness of the use of biologics for the treatment of intrabony defects. Enamel matrix derivative (EMD) and recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with β-tricalcium phosphate were shown to be efficacious in regenerating intrabony defects. The level of evidence is supported by multiple studies documenting effectiveness. The clinical application of biologics supports improvements in clinical parameters comparable with selected bone replacement grafts and guided tissue regeneration (GTR). Factors negatively affecting regeneration included smoking and excessive tooth mobility. CONCLUSIONS Periodontal regeneration in intrabony defects is possible on previously diseased root surfaces, as evidenced by a gain in clinical attachment, decreased pocket probing depth, gain in radiographic bone height, and overall improvement in periodontal health. These clinical findings are consistent with available histologic evidence. Clinical improvements can be maintained over long periods (>10 years). Although bone replacement grafts have been the most commonly investigated modality, GTR, biologics, and combination therapies have also been shown to be effective. Future research should emphasize patient-reported outcomes, individual response differences, and emerging technologies to enhance treatment results. CLINICAL RECOMMENDATIONS Early management of intrabony defects with regenerative therapies offers the greatest potential for successful periodontal regeneration. The clinical selection and application of a regenerative therapy or combination of therapies for periodontal regeneration should be based on the clinicians experiences and understanding of the regenerative biology and technology. This decision-making process should take into consideration the potential adverse influence of factors, such as smoking, poor oral hygiene, tooth mobility, and defect morphology, on regeneration. Management should be coupled with an effective maintenance program for long-term success.

A Prospective, Randomized Controlled Preclinical Trial to Evaluate Different Formulations of Biphasic Calcium Phosphate in Combination With a Hydroxyapatite Collagen Membrane to Reconstruct Deficient Alveolar Ridges

Many patients and clinicians would prefer a synthetic particulate bone replacement graft, but most available alloplastic biomaterials have limited osteogenic potential. An alloplast with increased regenerative capacity would be advantageous for the treatment of localized alveolar ridge defects. This prospective, randomized controlled preclinical trial utilized 6 female foxhounds to analyze the osteogenic impact of different formulations of biphasic calcium phosphate (BCP) in combination with an hydroxyapatite-collagen membrane and their ability to reconstruct deficient alveolar ridges for future implant placement. The grafted sites were allowed to heal 3 months, and then trephine biopsies were obtained to perform light microscopic and histomorphometric analyses. All treated sites healed well with no early membrane exposure or adverse soft tissue responses during the healing period. The grafted sites exhibited greater radiopacity than the surrounding native bone with BCP particles seen as radiopaque granules. The graft particles appeared to be well-integrated and no areas of loose particles were observed. Histologic evaluation demonstrated BCP particles embedded in woven bone with dense connective tissue/marrow space. New bone growth was observed around the graft particles as well as within the structure of the graft particulate. There was intimate contact between the graft particles and newly formed bone, and graft particles were bridged by the newly formed bone in all biopsies from the tested groups. The present study results support the potential of these BCP graft particulates to stimulate new bone formation. Clinical studies are recommended to confirm these preclinical findings.

Generation of Site-Appropriate Tissue by a Living Cellular Sheet in the Treatment of Mucogingival Defects

BACKGROUND Generation of site-appropriate tissue in the oral cavity includes the restoration of the correct anatomic type, amount, and distribution of the tissue. This study is a post hoc analysis of data collected during previously published results from two randomized clinical trials of a living cellular sheet (LCS; allogenic cultured keratinocytes and fibroblasts in bovine collagen) versus a free gingival graft (FGG), evaluating their ability to augment keratinized tissue or gingiva. METHODS Post hoc histologic and clinical (photographic) comparisons of the outcomes of treatment were performed on histologic and photographic data gathered in the two randomized clinical trials. RESULTS Histologic findings showed that LCS-treated sites resembled gingiva rather than alveolar mucosa. Photographic analysis indicated that LCS treatment resulted in more site-appropriate tissue than FGG in terms of tissue color, with adjacent untreated tissue, absence of scar formation or keloid-like appearance, and mucogingival junction alignment. CONCLUSION Treatment of mucogingival defects with LCS resulted in the generation of tissue that is more site appropriate than tissue transplanted from the palate.

The Combination of Purified Recombinant Human Platelet-Derived Growth Factor-BB and Equine Particulate Bone Graft for Periodontal Regeneration

BACKGROUND The objective of this study is to evaluate the potential for periodontal regeneration of a critical-sized defect with the application of recombinant human platelet-derived growth factor (rhPDGF-BB) combined with either a particulate equine or a β-tricalcium phosphate (β-TCP) matrix. METHODS Critical-sized intrabony 2-wall defects were created bilaterally on the distal surface of the second premolar and the mesial surface of the first molar in nine hounds. Twelve defects received rhPDGF-BB/equine treatment, 12 defects received rhPDGF-BB/β-TCP treatment, and the remaining 12 sites served as sham-surgery controls. The animals were sacrificed after a 10-week healing period. RESULTS Clinical healing was uneventful without obvious signs of overt gingival inflammation. Histologic and histomorphometric analyses revealed statistically that there were differences among the three groups in terms of new bone formation (P <0.001). The amount of test material for both rhPDGF-BB/equine and rhPDGF-BB/β-TCP groups was comparable, but the amount of newly formed bone was significantly higher (P <0.01) in favor of the rhPDGF-BB/equine group. The amount of new cementum formed for the rhPDGF-BB/equine group (4.8 ± 1.3 mm) was significantly higher (P =0.001) than the sham-surgery control group (1.7 ± 1.9 mm). CONCLUSION Both rhPDGF-BB/equine and rhPDGF-BB/β-TCP have the potential to support the regeneration of the periodontal attachment apparatus.

A randomized, controlled, multicentre clinical trial of post-extraction alveolar ridge preservation.

Abstract Aim To compare the effectiveness of two‐ridge preservation treatments. Materials and Methods Forty subjects with extraction sockets exhibiting substantial buccal dehiscences were enrolled and randomized across 10 standardized centres. Treatments were demineralized allograft plus reconstituted and cross‐linked collagen membrane (DFDBA + RECXC) or deproteinized bovine bone mineral with collagen plus native, bilayer collagen membrane (DBBMC + NBCM). Socket dimensions were recorded at baseline and 6 months. Wound closure and soft tissue inflammation were followed post‐operatively, and biopsies were retrieved for histomorphometric analysis at 6 months. Results Primary endpoint: at 6 months, extraction socket horizontal measures were significantly greater for DBBMC + NBCM (average 1.76 mm greater, p = 0.0256). Secondary and Exploratory endpoints: (1) lingual and buccal vertical bone changes were not significantly different between the two treatment modalities, (2) histomorphometric % new bone and % new bone + graft were not significantly different, but significantly more graft remnants remained for DBBMC; (3) at 1 month, incision line gaps were significantly greater and more incision lines remained open for DFDBA + RECXC; (4) higher inflammation at 1 week tended to correlate with lower ridge preservation results; and (5) deeper socket morphologies with thinner bony walls correlated with better ridge preservation. Thirty‐seven of 40 sites had sufficient ridge dimension for implant placement at 6 months; the remainder were DFDBA + RECXC sites. Conclusion DBBMC + NBCM provided better soft tissue healing and ridge preservation for implant placement. Deeper extraction sockets with higher and more intact bony walls responded more favourably to ridge preservation therapy.

Recombinant human platelet-derived growth factor BB for reconstruction of human large extraction site defects.

This study investigated the ability of growth factor-enhanced matrices combined with a tenting screw scaffolding system and resorbable membrane to regenerate large alveolar extraction site defects. Eight patients were randomized to treatment either with a bovine or equine matrix mixed in a ratio of 1.0 mL (0.3 mg/mL) recombinant human platelet-derived growth factor BB (rh-PDGF-BB) per gram of xenograft and allowed to absorb for 10 minutes. Tenting screws were used to provide additional support, and the growth factor-enhanced particulate matrix was incrementally placed and condensed into the defect and covered by a resorbable membrane. Reentry surgery after 5 months allowed for trephine core biopsies and implant placement. All sites healed well with evidence of bonelike hard tissue that was confirmed histologically as vital bone around the remaining graft particulate in both treatment groups. The results of this study demonstrate the capability of growth factor-enhanced matrices combined with tenting screws and a resorbable membrane to support the reconstruction of large extraction site defects.

Use of Er: YAG laser to decontaminate infected dental implant surface in preparation for reestablishment of bone-to-implant contact

The prevalence of peri-implantitis is of concern to all clinicians participating in implant dentistry. Peri-implant inflammation results in the loss of supporting bone for the implant that may or may not be accompanied by bleeding on probing and suppuration. Early diagnosis and intervention are mandated, but there is a paucity of evidence leading to the most effective therapy. There is agreement that one of the challenges in surgically treating peri-implant defects is the process of cleaning and decontaminating the implant surface, which may be contaminated by bacterial aggregates. This preclinical canine study investigates the erbium:yttrium-aluminum-garnet laser to decontaminate the complex rough surface of the implant by stripping the contaminated oxide layer for induction of hard and soft tissue adaptation to a compromised or failing implant. The results provide evidence of new bone-to-implant contact established at a level representative of the size of the defects. The soft tissues contain little or no evidence of inflammation, which can be interpreted as an arrest of the disease progression process. The results can be translated to a treatment goal of stabilizing the prognosis of an implant that has been compromised.