Emerging Regenerative Approaches for Periodontal Reconstruction: Practical Applications From the AAP Regeneration Workshop.

Focused Clinical Question: Can emerging technologies for periodontal regeneration become clinical reality? Summary: Emerging technologies are presenting options to hopefully improve the outcomes of regeneration in challenging clinical scenarios. Cellular allografts represent a current technology in which cells and scaffolds are being delivered directly to the periodontal lesion. Recombinant human fibroblast growth factor 2 and teriparatide (parathyroid 1-34) have each been tested in controlled prospective human randomized clinical trials, and both have been shown to have potential for periodontal regeneration. These examples, as well as other emerging technologies, show promise for continued advancement in the field of periodontal regenerative therapy. Conclusions: At present, there are indications that emerging technologies can be used successfully for periodontal regeneration. Case reports and clinical trials are being conducted with a variety of emerging technologies. However, many are yet to be approved by a regulatory agency, or there is a lack of evidence-based literature to validate their expanded use.

Emerging regenerative approaches for periodontal reconstruction: a consensus report from the AAP Regeneration Workshop.

BACKGROUND: Historically, periodontal regeneration has focused predominantly on bone substitutes and/or barrier membrane application to provide for defect fill and/or selected cell repopulation of the lesion. More recently, a number of technologies have evolved that can be viewed as emerging therapeutic approaches for periodontal regeneration, and these technologies were considered in the review paper and by the consensus group. The goal of this consensus report on emerging regenerative approaches for periodontal hard and soft tissue reconstruction was to develop a consensus document based on the accompanying review paper and on additional materials submitted before and at the consensus group session. METHODS: The review paper was sent to all the consensus group participants in advance of the consensus conference. In addition and also before the conference, individual consensus group members submitted additional material for consideration by the group. At the conference, each consensus group participant introduced themselves and provided disclosure of any potential conflicts of interest. The review paper was briefly presented by two of the authors and discussed by the consensus group. A discussion of each of the following topics then occurred based on the content of the review: a general summary of the topic, implications for patient-reported outcomes, and suggested research priorities for the future. As each topic was discussed based on the review article, supplemental information was then added that the consensus group agreed on. Last, an updated reference list was created. RESULTS: The application of protein and peptide therapy, cell-based therapy, genetic therapy, application of scaffolds, bone anabolics, and lasers were found to be emerging technologies for periodontal regeneration. Other approaches included the following: 1) therapies directed at the resolution of inflammation; 2) therapies that took into account the influence of the microbiome; 3) therapies involving the local regulation of phosphate and pyrophosphate metabolism; and 4) approaches directed at harnessing current therapies used for other purposes. The results indicate that, with most emerging technologies, the specific mechanisms of action are not well understood nor are the specific target cells identified. Patient-related outcomes were typically not addressed in the literature. Numerous recommendations can be made for future research priorities for both basic science and clinical application of emerging therapies. The need to emphasize the importance of regeneration of a functional periodontal organ system was noted. The predictability and efficacy of outcomes, as well as safety concerns and the cost-to-benefit ratio were also identified as key factors for emerging technologies. CONCLUSIONS: A number of technologies appear viable as emerging regenerative approaches for periodontal hard and soft tissue regeneration and are expanding the potential of reconstructing the entire periodontal organ system. The cost-to-benefit ratio and safety issues are important considerations for any new emerging therapies. Clinical Recommendation: At this time, there is insufficient evidence on emerging periodontal regenerative technologies to warrant definitive clinical recommendations.

Accessory mandibular foramen during dental implant placement: case report and review of literature.

Accurate knowledge of vital anatomical structures, such as the inferior alveolar nerve, mental nerve, and mental foramen, is critical to achieve favorable results during oral surgical procedures and dental implant placement. Although uncommon, variations in mandibular foramina have been reported and if unnoticed and, as a result, injured, may lead to patient morbidity, neurosensory disturbances, and other undesired complications. We present a case report of identification of an accessory mandibular foramen (AMF) encountered during placement of 2 dental implants for a mandibular implant-retained overdenture and demonstrate appropriate management. In addition, we propose a more reasonable terminology for such accessory foramina so as to facilitate communication through common terminology among health care providers. As conventional radiography (periapical and panoramic films) may not allow for proper identification of such anatomical variations, cone-beam computed tomography may be useful in the diagnosis of AMF during treatment planning of dental implants in the mandible.

The role of factors associated with apoptosis in assessing periodontal disease status.

BACKGROUND: Little is known about the release of apoptotic proteins during periodontal breakdown. This pilot study investigates the presence of factors associated with apoptosis in serum, saliva, and gingival crevicular fluid (GCF) and their association with periodontal disease severity and activity. METHODS: GCF, whole saliva, and serum were obtained from 47 adult patients with chronic periodontitis (CP) and 10 healthy controls. Clinical measurements, including probing depth (PD), clinical attachment level (CAL), and radiographs, were used to classify patients into healthy, mild, and moderate/severe CP groups. Enzyme-linked immunosorbent assays were used to measure apoptosis or DNA fragmentation in GCF and active caspase-3, soluble Fas (sFas), and sFas ligand (sFasL) in saliva and serum. Western immunoblotting was used to detect Fas, FasL, sFasL, and caspase-3 expression in GCF. RESULTS: DNA fragmentation was positively correlated with PD and CAL regardless of patient disease status (P <0.001). sFas and sFasL were present in saliva and serum, but there were no differences between groups. In GCF, the greater odds of detecting Fas, sFasL, and caspase-3 increased with increasing PD and CAL (P <0.05). In addition, sites with inflammation and PD ≥5 mm had significantly greater odds of exhibiting Fas, sFasL, and caspase-3 expression compared with sites without inflammation and PD <5 mm (P <0.05). Caspase-3 was not detected in saliva or serum. At the patient level, only FasL and disease status were significantly correlated (P <0.05). CONCLUSION: Factors associated with apoptosis were detected in GCF in patients with CP.

The effect of flapless surgery on implant survival and marginal bone level: a systematic review and meta-analysis.

BACKGROUND: The clinical outcomes of implants placed using the flapless approach have not yet been systematically investigated. Hence, the present systematic review and meta-analysis aims to study the effect of the flapless technique on implant survival rates (SRs) and marginal bone levels (MBLs) compared with the conventional flap approach. METHODS: An electronic search of five databases (from 1990 to March 2013), including PubMed, Ovid (MEDLINE), EMBASE, Web of Science, and Cochrane Central, and a hand search of peer-reviewed journals for relevant articles were performed. Human clinical trials with data on comparison of SR and changes in MBL between the flapless and conventional flap procedures, with at least five implants in each study group and a follow-up period of at least 6 months, were included. RESULTS: Twelve studies, including seven randomized controlled trials (RCTs), one cohort study, one pilot study, and three retrospective case-controlled trials (CCTs), were included. The SR of each study was recorded, weighted mean difference (WMD) and confidence interval (CI) were calculated, and meta-analyses were performed for changes in MBL. The average SR is 97.0% (range, 90% to 100%) for the flapless procedure and 98.6% (range, 91.67% to 100%) for the flap procedure. Meta-analysis for the comparison of SR among selected studies presented a similar outcome (risk ratio = 0.99, 95% CI = 0.97 to 1.01, P = 0.30) for both interventions. Mean differences of MBL were retrieved from five RCTs and two retrospective CCTs and subsequently pooled into meta-analyses; however, none of the comparisons showed statistical significance. For RCTs, the WMD was 0.07, with a 95% CI of -0.05 to 0.20 (P = 0.26). For retrospective CCTs, the WMD was 0.23, with a 95% CI of -0.58 to 1.05 (P = 0.58). For the combined analysis, the WMD was 0.03, with a 95% CI of -0.11 to 0.18 (P = 0.67). The comparison of SR presented a low to moderate heterogeneity, but MBL presented a considerable heterogeneity among studies. CONCLUSION: This systematic review revealed that the SRs and radiographic marginal bone loss of flapless intervention were comparable with the flap surgery approach.

Application of modified bony lid technique to remove or replace compromised implants: case series.

PURPOSE: The original bony lid technique involves removing window of cortical bone using a microsaw, removing a failing implant through the window, and then replacing the bone into its original position. The purpose of this case series was to present modifications to the bony lid technique to improve outcomes. MATERIALS AND METHODS: Ten patients (9 men and 1 woman) aged between 47 and 89 years were treated during a 5-year period with modifications to the bony lid technique. Modifications to the bony lid technique included restricting the size of the bony lid, use of a long shank drill, performing guided bone regeneration, immediate implant placement, and providing rigid fixation. RESULTS: No complications occurred in the 10 cases presented in this case series. An immediate implant placement procedure was performed in 3 of the 10 patients treated. Fixation screws and a microplate were used to fix the bony lid in 1 patient. Allogenic bone was used in another case. Additional trephine and thin drills were used in 2 cases in the mandibular molar area. CONCLUSIONS: Replacing failing dental implants can be successfully accomplished by removing cortical bone on the buccal aspect of the implant and then replacing this bone after the implant is removed or replaced. Using allogenic bone, fixation screws, microplates, and thin drills can help facilitate the success of this procedure.

Effect of flapless surgery on single-tooth implants in the esthetic zone: a randomized clinical trial.

BACKGROUND: Implant therapy is a highly predictable treatment option; however, insufficient data exist to show whether flapless implant surgery provides better esthetic outcomes and less bone loss than implant surgery with a flap approach. METHODS: In this randomized, controlled study comparing the flapless and traditional flap protocol for implant placement, 24 patients received a single implant in the anterior maxillary region. A cone beam computed tomography-aided surgical guide was used for implant placement surgery for both groups. Implants were restored using a one-piece, screw-retained ceramic crown at 3 months. Radiographic and clinical measurements were assessed at baseline (implant placement) and at 3 (crown placement), 6, 9, and 15 months. Clinical parameters evaluated were plaque index, gingival index, papillary index (PPI) (0 = no papilla, 1 = less than half, 2 = more than half but not complete, 3 = complete fill, and 4 = overfill), marginal tissue levels, biotype, width of keratinized tissue, and soft tissue thickness. RESULTS: Implant success rate was 92% in both groups. Mean PPI values for the flap control group and flapless test group were 2.38 ± 0.51 versus 2.31 ± 0.48 at crown placement (P = 0.68) and 2.52 ± 0.52 versus 2.64 ± 0.54 at 15 months (P = 0.42), respectively. PPI increased over time in both groups, although the flapless group had a significantly larger change in PPI from crown placement to 6 and 9 months (P <0.01). Crestal bone levels in the flap group were more apical in relation to the implant platform than those in the flapless group for the duration of the study. No differences among groups were noted for all other measurements. CONCLUSIONS: Both flapless and flap implant placement protocols resulted in high success rates. A flapless protocol may provide a better short-term esthetic result, although there appears to be no long-term advantage.

Statins, glucocorticoids, and nonsteroidal anti-inflammatory drugs: their influence on implant healing.

This article aimed at exploring the effects of common systemic medications used in the United States and their effects on periimplant bone healing. An electronic search for articles evaluating the influence of systemic medications on periimplant bone healing was conducted using the PubMed (MEDLINE) database. Statins, when administered locally or systemically, were found to increase bone formation and density. A reduction in bone turnover and bone-to-implant contact was observed in animal models examining the effect of glucocorticoids on periimplant bone healing. Continued use of nonsteroidal anti-inflammatory drugs (NSAIDs) during or after implant placement was associated with reduced bone-to-implant contact, bone area, and bone density. Evidence seems to suggest that statins improve implant osseointegration. However, glucocorticoids and NSAIDs showed conflicting results. Therefore, more randomized clinical trials are needed to validate the effect of glucocorticoids and NSAIDs on periimplant bone healing.

Histological analysis of soft and hard tissues in a periimplantitis lesion: a human case report.

BACKGROUND: Little is known regarding the histologic hard and soft tissue changes that occur in chronic periimplantitis situations in humans. It is critical to gain an understanding of all aspects of periimplantitis to develop appropriate therapeutic approaches. METHODS: An 83-year-old African American man presented with a fractured implant affected by severe, chronic periimplantitis and surrounded by keratinized gingiva. A trephine biopsy of the implant and surrounding tissues was analyzed histologically. RESULTS: Histological analysis of the periimplantitis specimen revealed significant inflammatory infiltrate consisting predominantly of lymphocytes and plasma cells. In addition, epithelial migration and bone loss to the apical vent were noted. CONCLUSION: This case report documents a single case of periimplantitis that was left untreated for 7 years. The presence of significant keratinized tissue and a smooth surface implant failed to prevent fibrous encapsulation of the implant.

Systemic Teriparatide Administration Promotes Osseous Regeneration of an Intrabony Defect: A Case Report.

INTRODUCTION: Teriparatide comprises the first 34 amino acids of parathyroid hormone and is a systemic anabolic agent that is Food and Drug Administration approved for the treatment of osteoporosis but not for periodontitis. To our knowledge, this is the first clinical case report to document the treatment of a patient with severe periodontitis using an open-flap debridement procedure in conjunction with teriparatide. CASE PRESENTATION: A 45-year-old female patient was diagnosed with severe chronic periodontitis, including the presence of an intrabony defect on tooth #6. She received open-flap debridement surgery in conjunction with daily systemic administration of 20 µg teriparatide, oral vitamin D, and calcium supplements for 6 weeks. Radiographic, clinical, gingival crevicular fluid (pyridinoline cross-linked carboxy-terminal propeptide of type I procollagen, procollagen type 1 N-propeptide, and osteocalcin), and serum parameters (parathyroid hormone, bone alkaline phosphatase, calcium, and 25-hydroxyvitamin D) were assessed. Treatment outcomes were evaluated over 4 years, with successful radiographic and clinical results throughout the follow-up period. CONCLUSION: Teriparatide administration in conjunction with traditional open-flap debridement surgery offers potential for the treatment of severe intrabony defects resulting from chronic periodontitis.

Retrograde peri-implantitis: a case report introducing an approach to its management.

BACKGROUND: Although several potential etiologic factors associated with retrograde peri-implantitis (RPI) and potential treatment options have been discussed in the literature, the etiology has not been fully investigated and the definitive management methods remain undefined. We propose a decision-making protocol for the treatment of RPI and provide new insight into the etiology of this process based on the findings from two clinical cases. METHODS: The medical and dental histories of two patients who developed RPI were thoroughly reviewed. Both patients were treated according to the treatment guidelines proposed in this manuscript. Fluid from the lesions was collected to examine the presence of 11 bacterial species by molecular-based microbial testing. Biopsies were also obtained for histopathologic examination. RESULTS: Patient 1, previously diagnosed with human immunodeficiency virus infection, developed RPI 3 months after implant placement. Histopathologic examination revealed a predominantly fibrous connective tissue response with minimal inflammatory infiltrate and bone formation. Patient 2 presented histopathologically with an intense acute inflammatory response. Eikenella corrodens was detected by microbial testing. Three months after surgical intervention, both cases healed uneventfully, and the radiodensity in the lesions significantly increased. The two implants are now functional and free of further complications. CONCLUSIONS: The possible role of bacterial infection from an adjacent tooth may be a potential etiologic factor in the development of RPI. In addition, HIV infection may be associated with RPI and deserves further investigation. A decision-making flowchart was proposed after critically evaluating the currently available relevant literature. Both cases presented in this manuscript were successfully treated by following this protocol.

Biologic Agents to Promote Periodontal Regeneration and Bone Augmentation.

Periodontal regeneration is preferred over tissue repair and is accomplished through the exclusion of epithelial tissues, which allows cementum, bone, and connective tissue to repopulate the wound. Recently, biologic materials have emerged as adjuncts to aid in regeneration by augmenting the events of wound healing in the area. A review of biologic agents was conducted using the following MeSH terms: guided tissue regeneration, intercellular signaling peptides and proteins, and biologic factors. Enamel matrix derivative (EMD), platelet-derived growth factor (PDGF), platelet-rich plasma, bone morphogenetic proteins (BMPs), fibroblast growth factor (FGF), and parathyroid hormone (PTH) have all shown promise in promoting hard- or soft-tissue regeneration. No biologic agent is ideal for all clinical situations so the clinician must evaluate each situation to identify the best indication for its usage. Currently, EMD and PDGF have Food and Drug Administration approval for periodontal regeneration, whereas BMP-2 is approved for bone augmentation. FGF and PTH do not have Food and Drug Administration approval for periodontal applications and so their clinical usage is not indicated.

Teriparatide and osseous regeneration in the oral cavity.

BACKGROUND: Intermittent administration of teriparatide, a drug composed of the first 34 amino acids of parathyroid hormone, has anabolic effects on bone. Although teriparatide has been evaluated for the treatment of osteoporosis and for the healing of fractures, clinical trials evaluating it for the treatment of osseous conditions of the oral cavity in humans are lacking. METHODS: A total of 40 patients with severe, chronic periodontitis underwent periodontal surgery and received daily injections of teriparatide (20 µg) or placebo, along with oral calcium (1000 mg) and vitamin D (800 IU) supplementation, for 6 weeks. The patients were followed for 1 year. The primary outcome was a radiographic linear measurement of alveolar bone level. Secondary outcomes included clinical variables, bone turnover markers in serum and oral fluid, systemic bone mineral density, and quality of life. RESULTS: Radiographic linear resolution of osseous defects was significantly greater after teriparatide therapy than after placebo beginning at 6 months, with a mean linear gain in bone at 1 year of 29% as compared with 3% (P<0.001). Clinical improvement was greater in patients taking teriparatide than in those taking placebo, with a reduction in periodontal probing depth of 33% versus 20% (2.42 mm vs. 1.32 mm) and a gain in clinical attachment level of 22% versus 7% (1.58 mm vs. 0.42 mm) in target lesions at 1 year (P = 0.02 for both comparisons). No serious adverse events were reported; however, the number of patients in the study was small. No significant differences were noted with respect to the other variables that were assessed. CONCLUSIONS: Teriparatide, as compared with placebo, was associated with improved clinical outcomes, greater resolution of alveolar bone defects, and accelerated osseous wound healing in the oral cavity. Teriparatide may offer therapeutic potential for localized bone defects in the jaw. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00277706 .).

Implant compression necrosis: current understanding and case report.

BACKGROUND: Implants fail for a variety of reasons; it can be difficult to determine the exact cause of failure, especially if there are multiple contributing factors. Overcompression of the adjacent bone during implant placement is a potential contributing factor to implant failure that is not well documented in the literature. METHODS: This case report reviews the concept of bone loss induced by overcompression and presents a case of implant failure with overcompression as a potential etiology. Histology, radiographs, and clinical data are presented that document the failure of four implants placed in the posterior mandible of a 48-year-old female patient. RESULTS: After uneventful implant placement, one implant exfoliated 3 weeks postoperatively. The other three implants were removed because of severe bone loss up to 2 months later. Histology of the area revealed non-viable bony sequestra with bacterial colonization. CONCLUSIONS: This case highlights unusual implant failures that likely occurred as a result of overcompression of the bone during placement. Areas involving dense bone seem to be at increased risk for compression necrosis.

Periodontal and endodontic regeneration.

Guided tissue regeneration (GTR) is effective in halting tissue and bone destruction and promoting new tissue and bone formation. Although the goal of complete and predictable regeneration still remains elusive, many techniques and materials have been developed that show good clinical and histologic outcomes. The most commonly used materials in GTR include bone replacement grafts from numerous sources, nonresorbable and bioabsorbable membranes, and recently growth hormones/cytokines and other host modulating factors. This article reviews the biologic rationale behind current techniques used for tissue/bone regeneration, reviews the most common materials and techniques, and attempts to explain the factors that influence the outcomes of these therapies.

Role of platelet-rich plasma in soft tissue root-coverage procedures: a review.

The aim of this article was to review the current evidence on the role of platelet-rich plasma (PRP) in enhancing root-coverage techniques and discuss the rationale for its use in these applications. Sound biologic rationale and a multitude of basic science research support the use of PRP to promote soft tissue healing, although evidence of its role in enhancing periodontal applications, especially root coverage, is limited. Current scientific research has yet to elucidate all of the mechanisms by which PRP can affect soft tissue healing and assess its capacity to stimulate regeneration. Furthermore, clinical evidence on the use of PRP in root-coverage procedures is extremely limited, with only 2 randomized controlled trials published as of May 2007. A pertinent review of medical and dental literature relating to PRP and its role in wound healing and enhancement of root-coverage procedures was performed. Preliminary reports in this area suggest that the potential benefits of PRP in root-coverage procedures may be improved esthetics, decreased patient morbidity, and accelerated wound healing. An appropriate assessment of the effects of PRP and its possible use in enhancing root-coverage procedures cannot be made at this time because of inadequate clinical evidence.

Common implant esthetic complications.

Today, osseointegration of implants is readily attainable with high long-term survival rates. Consequently, clinicians are now focusing on improving implant esthetics and are starting to incorporate this parameter into their definition of implant success. However, studies measuring factors that affect implant esthetics and implant esthetic outcomes are lacking in the literature. A satisfactory esthetic outcome requires the clinician to be aware of the different factors affecting esthetics during the preplanning, surgical, and prosthetic phases of implant placement. This article addresses the etiologies of esthetic complications during each of these 3 phases and provides preventive and corrective treatment suggestions for these situations.

Effects of Vitaxin, a novel therapeutic in trial for metastatic bone tumors, on osteoclast functions in vitro.

The integrin alphavbeta3 mediates cell-matrix interactions. Vitaxin(R), a humanized monoclonal antibody that blocks human and rabbit alphavbeta3 integrins, is in clinical trials for metastatic melanoma and prostate cancer. alphavbeta3 is the predominant integrin on osteoclasts, the cells responsible for bone resorption in health and disease. Here, we report the first investigation of Vitaxin's effects on osteoclast activity. Vitaxin (100-300 ng/ml) decreased total resorption by 50%, but did not alter resorptive activity per osteoclast. Vitaxin (300 ng/ml) decreased osteoclast numbers on plastic by 35% after 48 h. Similarly, attachment after 2 h was reduced by 30% when osteoclasts were incubated with Vitaxin (300 ng/ml) for 25 min prior to plating; however, the rate of fusion of osteoclast precursors in Vitaxin-treated and control groups was equal. Using time-lapse microscopy, we evaluated the effect of Vitaxin on osteoclast morphology and found a significant reduction in osteoclast planar area only when cells were pretreated with macrophage colony stimulating factor (M-CSF). Extracellular Ca(2+) and M-CSF have opposite effects on alphavbeta3 conformation. Elevation of extracellular Ca(2+) eliminated the inhibitory effect of Vitaxin on osteoclast attachment. In contrast, the effect of Vitaxin was enhanced in cells pretreated with M-CSF. This action of M-CSF was suppressed by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor wortmannin, suggesting that M-CSF increases Vitaxin's inhibitory effect by inside-out activation of alphavbeta3. In conclusion, Vitaxin decreases resorption by impairing osteoclast attachment, without affecting osteoclast formation and multinucleation. Our data also show that Vitaxin's inhibitory effects on osteoclasts can be modulated by factors known to alter the conformation of alphavbeta3.