The Development of Thermoresponsive Polymeric Simvastatin Prodrug for the Treatment of Experimental Periodontitis in Rats.

Periodontitis (PD) is a severe inflammatory gum pathology that damages the periodontal soft tissue and bone. It is highly prevalent in the US, affecting more than 47% of adults. Besides routine scaling and root planing, there are few effective treatments for PD. Developed as an effective treatment for hyperlipidemia, simvastatin (SIM) is also known for its well-established anti-inflammatory and osteogenic properties, suggesting its potential utility in treating PD. Its clinical translation, however, has been impeded by its poor water-solubility, lack of osteotropicity, and side effects (e.g., hepatoxicity) associated with systemic exposure. To address these challenges, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrug of SIM (ProGel-SIM) was developed as a local therapy for PD. Its aqueous solution is free-flowing at 4 °C and transitions into a hydrogel at ∼30 °C, allowing for easy local application and retention. After a thorough characterization of its physicochemical properties, ProGel-SIM was administered weekly into the periodontal pocket of an experimental rat model of PD. At 3 weeks post initiation of the treatment, the animals were euthanized with palate isolated for µ-CT and histological analyses. When compared to dose equivalent simvastatin acid (SMA, active form of SIM) treatment, the rats in the ProGel-SIM treated group showed significantly higher periodontal bone volume (0.34 mm3 vs 0.20 mm3, P = 0.0161) and less neutrophil (PMN) infiltration (P < 0.0001) and IL-1ß secretion (P = 0.0036). No measurable side effect was observed. Collectively, these results suggest that ProGel-SIM may be developed as a promising drug candidate for the effective clinical treatment of PD.

Effect of interproximal home oral hygiene on clinical parameters and inflammatory biomarkers in patients receiving periodontal maintenance.

BACKGROUND: The purpose of this 6-week, single-blinded, randomized clinical trial was to determine if the use of an interproximal brush, with or without a tracking device, is more effective than an oral irrigator in improving interproximal probing depth (PD), clinical attachment level (CAL), plaque index (PI), gingival index (GI), bleeding on probing (BOP), and inflammatory markers. METHODS: Seventy-six patients with Stages III-IV, Grade B periodontitis and a 5-7 mm posterior interproximal PD with BOP were randomized: (1) interproximal brush alone (IB; n = 26), (2) interproximal brush with tracking device (TD; n = 23), (3) oral irrigator (OI; n = 27). Participants used devices once daily for 6 weeks. Clinical measurements (PD, CAL, PI, BOP, GI) and gingival crevicular fluid (GCF) samples were collected at baseline and 6 weeks. RESULTS: All groups showed a significant reduction in PD and CAL (≥1.1 mm, p < 0.0001) and improvement in BOP (≥56%, p < 0.0001) and GI (≥82%, p < 0.001) at the experimental site with no differences among groups. The IB and IB+TD groups showed a significant reduction in PI (≥0.9, p ≤ 0.01). Interleukin (IL)-1ß was reduced in all groups (p = 0.006), but IB+TB more than OI (p ≤ 0.05). IL-10 was reduced among all groups (p = 0.01), while interferon-gamma significantly increased (p = 0.01) in all groups. CONCLUSIONS: IB and OI improved clinical parameters of PD and CAL and reduced inflammatory markers (BOP, GI, GCF IL-1ß). IB had better interproximal plaque reduction. Tracking did not significantly improve clinical parameters compared with the IB and OI groups, suggesting future modifications are needed.

Local simvastatin and inflammation during periodontal mini-flap wound healing: Exploratory results.

BACKGROUND: The objective of this exploratory study was to evaluate inflammatory markers in periodontal maintenance patients from a randomized, double-masked, parallel intervention clinical trial comparing local simvastatin (SIM) to carrier alone following mini-flap access. METHODS: Fifty patients with a 6-9-mm inflamed pocket during periodontal maintenance therapy (PMT) were treated with papilla reflection (PR)/root planing and placement of 2.2-mg simvastatin in methylcellulose (SIM/MCL) or methylcellulose alone (MCL). A small piece of interproximal soft tissue was harvested at baseline and 2 weeks postoperatively, gingival crevicular fluid (GCF) obtained at baseline, 2 weeks and 12 months, and bleeding on probing (BOP) and clinical attachment level (CAL) were measured at baseline and 12 months. Pro-inflammatory interleukin (IL)-6 and anti-inflammatory IL-10 gene activation were determined by reverse transcriptase polymerase chain reaction (rt-PCR). GCF IL-1ß, IL-6, IL-10, and vascular endothelial growth factor (VEGF-A) were measured with multiplex technology. Comparisons between groups and over time used logistic regression and general estimating equations. Associations between inflammatory markers and 12-month outcomes used Wilcoxon rank sum tests or Pearson correlations. RESULTS: Patients in the SIM group had 4.17 greater odds (p = 0.047) of improved BOP at 12 months. Median IL-6 and VEGF were significantly increased for all patients after 2 weeks of healing (p < 0.0001 and p = 0.03, respectively), while median IL-10 gene activation was increased after 2 weeks in SIM/MCL (NS). Overall, elevated GCF IL-10 at 2 weeks was significantly correlated with improved CAL at 12 months (r = -0.32, p = 0.03). CONCLUSIONS: Local SIM/MCL may have anti-inflammatory effects that potentially are associated with improved long-term CAL outcomes.

Effect of locally applied simvastatin on clinical attachment level and alveolar bone in periodontal maintenance patients: A randomized clinical trial.

BACKGROUND: The purpose of this double-masked, randomized, controlled trial was to determine if the local application of simvastatin (SIM), combined with minimally invasive papilla reflection and root planing (PR/RP), is effective in improving clinical attachment level (CAL), probing depth (PD) reduction, and increasing interproximal bone height (IBH) in persistent 6-9 mm periodontal pockets in patients receiving periodontal maintenance therapy (PMT). METHODS: Fifty patients with Stage III, Grade B periodontitis presenting with a 6-9 mm interproximal PD with a history of bleeding on probing (BOP) were included in the study. Experimental [PR/RP+SIM/methylcellulose (MCL); n = 27] and control (PR/RP+MCL; n = 23) therapies were randomly assigned. Root surfaces were accessed via reflection of interproximal papillae, followed by RP assisted with endoscope evaluation, acid etching, and SIM/MCL or MCL application. CAL, PD, BOP, plaque presence, and IBH (using standardized vertical bitewing radiographs) were evaluated at baseline and 12 months. Measurements were compared by group and time using Chi-square, Wilcoxon rank-sum, and t-tests. RESULTS: Both PR/RP+SIM/MCL and PR/RP+MCL, respectively, resulted in improvements in clinical outcomes (CAL: -1.9 ± 0.3 mm, p < 0.0001; -1.0 ± 0.3 mm, p < 0.003; PD: -2.3 mm ± 0.3, p < 0.0001; -1.3 mm ± 0.3, p < 0.0001; BOP: -58.7%; -41.7%, p < 0.05) and stable IBH (-0.2 ± 0.12, -0.4 ± 0.2, p = 0.22) from baseline to 12 months post-therapy. PR/RP+SIM/MCL had more improvement in CAL (p = 0.03), PD (p = 0.007), and BOP (p = 0.047). CONCLUSIONS: The addition of SIM/MCL to PR/RP improved CAL, PD, and BOP compared with PR/RP alone in periodontal maintenance patients.

Association of tracking oral hygiene with dental outcomesin a general dental practice.

PURPOSE: To track plaque scores on a subset of teeth in general dental practice patients to determine if plaque scores could improve along with periodontal, restorative and extraction outcomes. METHODS: Percentage of surfaces with subgingival plaque were recorded and graphed on five teeth (#3, 8, 14, 19, 30) at each appointment, followed by focused oral hygiene instructions, in 343 patients over a 5-10-year period. Patient age, gender, prophylaxes/year, and experimental teeth periodontitis stage, % 4-5 and ≥ 6 mm pockets, % bleeding on probing, % surfaces restored and patients with extractions were recorded. Relationships among average plaque scores and the longitudinal periodontal, restorative and extraction changes were analyzed using Chi-Square, Kruskal-Wallis, and Wilcoxon Rank Sum tests. RESULTS: Plaque scores improved from median 40% to 25% (P< 0.0001) over the 5-10 years. Plaque scores and periodontitis stages were associated (P= 0.03) with few periodontally healthy patients (9%) having poor plaque scores (> 50% plaque surfaces). Furthermore, good plaque scores (≤ 25%) and periodontal health (Stage I) were linked to the need for few restorations (P< 0.0001), while prophylaxes/year had no significant relationship. Extractions were related more with Stage III/IV (advanced) periodontitis (P< 0.0001) than with plaque score (NS). CLINICAL SIGNIFICANCE: In a general dental practice, tracking plaque scores at each appointment on a subset of representative teeth can be time-efficient, and is associated with improved oral hygiene, stable periodontal status and reduced restorative needs.

Thermoresponsive Hydrogel-Based Local Delivery of Simvastatin for the Treatment of Periodontitis.

Except for routine scaling and root planing, there are few effective nonsurgical therapeutic interventions for periodontitis and associated alveolar bone loss. Simvastatin (SIM), one of the 3-hydroxy-3-methylglutaryl-cosenzyme A reductase inhibitors, which is known for its capacity as a lipid-lowering medication, has been proven to be an effective anti-inflammatory and bone anabolic agent that has shown promising benefits in mitigating periodontal bone loss. The local delivery of SIM into the periodontal pocket, however, has been challenging due to SIM's poor water solubility and its lack of osteotropicity. To overcome these issues, we report a novel SIM formulation of a thermoresponsive, osteotropic, injectable hydrogel (PF127) based on pyrophosphorolated pluronic F127 (F127-PPi). After mixing F127-PPi with F127 at a 1:1 ratio, the resulting PF127 was used to dissolve free SIM to generate the SIM-loaded formulation. The thermoresponsive hydrogel's rheologic behavior, erosion and SIM release kinetics, osteotropic property, and biocompatibility were evaluated in vitro. The therapeutic efficacy of SIM-loaded PF127 hydrogel on periodontal bone preservation and inflammation resolution was validated in a ligature-induced periodontitis rat model. Given that SIM is already an approved medication for hyperlipidemia, the data presented here support the translational potential of the SIM-loaded PF127 hydrogel for better clinical management of periodontitis and associated pathologies.

GSK3 inhibitor-loaded osteotropic Pluronic hydrogel effectively mitigates periodontal tissue damage associated with experimental periodontitis.

Periodontitis is a chronic inflammatory disease caused by complex interactions between the host immune system and pathogens that affect the integrity of periodontium. To prevent disease progression and thus preserve alveolar bone structure, simultaneous anti-inflammatory and osteogenic intervention are essential. Hence, a glycogen synthase kinase 3 beta inhibitor (BIO) was selected as a potent inflammation modulator and osteogenic agent to achieve this treatment objective. BIO's lack of osteotropicity, poor water solubility, and potential long-term systemic side effects, however, have hampered its clinical applications. To address these limitations, pyrophosphorylated Pluronic F127 (F127-PPi) was synthesized and mixed with regular F127 to prepare an injectable and thermoresponsive hydrogel formulation (PF127) of BIO, which could adhere to hard tissue and gradually release BIO to exert its therapeutic effects locally. Comparing to F127 hydrogel, PF127 hydrogels exhibited stronger binding to hydroxyapatite (HA). Additionally, BIO's solubility in PF127 solution was dramatically improved over F127 solution and the improvement was proportional to the polymer concentration. When evaluated on a rat model of periodontitis, PF127-BIO hydrogel treatment was found to be very effective in preserving alveolar bone and ligament, and preventing periodontal inflammation, as shown by the micro-CT and histological data, respectively. Altogether, these findings suggested that the thermoresponsive PF127 hydrogel is an effective local drug delivery system for better clinical management of periodontitis and associated pathologies.

Effects of enamel matrix derivative on clinical and inflammatory outcomes in periodontal maintenance patients: Randomized controlled clinical trial.

BACKGROUND: Efficient methods to treat persistent pockets during periodontal maintenance therapy (PMT) require further investigation. The hypothesis of this randomized controlled clinical trial was that local application of enamel matrix derivative (EMD) added to papilla reflection/root preparation (PR/RP) could enhance clinical and inflammatory outcomes, primarily clinical attachment level (CAL). METHODS: Fifty PMT patients with generalized stage III-IV, grade B periodontitis presenting with a 6- to 9-mm interproximal PD were randomly allocated to (PR/RP+EMD; n = 24) and control (PR/RP+saline; n = 26) therapies by sex and smoking status. Roots were treated with reflection of interproximal papillae, root planing assisted with endoscope evaluation, and acid etching, followed by EMD or saline application. Probing depth (PD), CAL, plaque index (PI), and interproximal bone height were evaluated at baseline and 12-months post-therapy. Gingival crevicular fluid, bleeding on probing (BOP), and interleukin-1ß were tested (ELISA) at baseline, 2 weeks, and 6 and 12 months. Groups were compared over time and between groups with Wilcoxon Rank Sum and t-tests. RESULTS: Both PR/RP+ EMD and PR/RP+S resulted in significant improvements in clinical outcomes (PD and CAL, BOP) from baseline to 12 months. No significant differences were found in clinical or inflammatory outcomes between the experimental and control groups. CONCLUSIONS: The addition of EMD to PR/RP does not significantly improve clinical or inflammatory outcomes compared with PR/RP alone during periodontal maintenance therapy.

Engineering Biomimetic Nanofiber Microspheres with Tailored Size, Predesigned Structure, and Desired Composition via Gas Bubble-Mediated Coaxial Electrospray.

Minimally invasive therapies avoiding surgical complexities evoke great interest in developing injectable biomedical devices. Herein, a versatile approach is reported for engineering injectable and biomimetic nanofiber microspheres (NMs) with tunable sizes, predesigned structures, and desired compositions via gas bubble-mediated coaxial electrospraying. The sizes and structures of NMs are controlled by adjusting processing parameters including air flow rate, applied voltage, distance, and spinneret configuration in the coaxial setup. Importantly, unlike the self-assembly method, this technique can be used to fabricate NMs from any material feasible for electrospinning or other nanofiber fabrication techniques. To demonstrate the versatility, open porous NMs are successfully fabricated that consist of various short nanofibers made of poly(ε-caprolactone), poly(lactic-co-glycolic acid), gelatin, methacrylated gelatin, bioglass, and magneto-responsive polymer composites. Open porous NMs support human neural progenitor cell growth in 3D with a larger number and more neurites than nonporous NMs. Additionally, highly open porous NMs show faster cell infiltration and host tissue integration than nonporous NMs after subcutaneous injection to rats. Such a novel class of NMs holds great potential for many biomedical applications such as tissue filling, cell and drug delivery, and minimally invasive tissue regeneration.

Dual Delivery of Alendronate and E7-BMP-2 Peptide via Calcium Chelation to Mineralized Nanofiber Fragments for Alveolar Bone Regeneration.

The fixation and stability of dental implants is governed by the quality of the underlying alveolar bone. The current study investigates if the dual delivery of calcium chelating bone therapeutics from mineralized nanofiber fragments can help regenerate alveolar bone in vivo. Alendronate (ALN) or/and bone morphogenetic protein-2-mimicking peptide conjugated to a heptaglutamate moiety (E7-BMP-2) were incorporated onto mineralized nanofiber fragments of polylactide-co-glycolide-collagen-gelatin (PCG in 2:1:1 weight ratios) via calcium coupling/chelation. Two mg of the single-loaded (ALN) and coloaded (ALN + E7-BMP-2) mineralized nanofiber PCG grafts was filled into critical-sized (2 mm diameter × 2 mm depth) alveolar bone defects in rat maxillae and let heal for 4 weeks. X-ray microcomputed tomography analysis of the retrieved maxillae revealed significantly elevated new bone formation parameters for the ALN and ALN + E7-BMP-2 groups compared with the unfilled defect controls. However, no significant differences between the single and coloaded nanofiber grafts were noted. Furthermore, the histopathological analysis of the tissue sections divulged islands of new bone tissue in the ALN and ALN + E7-BMP-2 groups, whereas the control defect was covered with gingival tissue. Together, the presented strategy using mineralized nanofiber fragments in the sustained delivery of dual calcium chelating therapeutics could have potential applications in enhancing bone regeneration.

Tethering peptides onto biomimetic and injectable nanofiber microspheres to direct cellular response.

Biomimetic and injectable nanofiber microspheres (NMs) could be ideal candidate for minimally invasive tissue repair. Herein, we report a facile approach to fabricate peptide-tethered NMs by combining electrospinning, electrospraying, and surface conjugation techniques. The composition and size of NMs can be tuned by varying the processing parameters during the fabrication. Further, bone morphogenic protein-2 (BMP-2) and vascular endothelial growth factor (VEGF) mimicking peptides have been successfully tethered onto poly(ε-caprolactone) (PCL):gelatin:(gelatin-methacryloyl) (GelMA)(1:0.5:0.5) NMs through photocrosslinking of the methacrylic group in GelMA and octenyl alanine (OCTAL) in the modified peptides. The BMP-2-OCTAL peptide-tethered NMs significantly promote osteogenic differentiation of bone marrow-derived stem cells (BMSCs). Moreover, human umbilical vein endothelial cells (HUVECs) seeded on VEGF mimicking peptide QK-OCTAL-tethered NMs significantly up-regulated vascular-specific proteins, leading to microvascularization. The strategy developed in this work holds great potential in developing a biomimetic and injectable carrier to efficiently direct cellular response (Osteogenesis and Angiogenesis) for tissue repair.

Mineralized nanofiber segments coupled with calcium-binding BMP-2 peptides for alveolar bone regeneration.

Bone loss around tooth extraction sites can occur, thus making future placement of dental implants difficult. Alveolar bone regeneration can be guided by the application of a nanofibrous bone graft coupled with osteoinductive proteins/peptides, following tooth loss or tooth extraction. In the present study, we demonstrate the potential of mineralized nanofiber segments coupled with calcium-binding bone morphogenetic protein 2 (BMP-2) mimicking peptides for periodontal bone regeneration. Thin electrospun nanofiber membranes of PLGA-collagen-gelatin (2:1:1 wt ratios) were mineralized in 10× modified simulated body fluid (10× mSBF) and cryocut to segments of 20 µm. For predetermined weights of the mineralized nanofiber segments, it was possible to load various amounts of heptaglutamate E7-domain-conjugated BMP-2 peptide. Mineralized short fiber grafts (2 mg), with and without E7-BMP-2 peptides, were implanted into 2 mm × 2 mm (diameter × depth) critical-sized socket defects created in rat maxillae, following extraction of the first molar teeth. A sustained release profile of E7-BMP-2 from the mineralized nanofiber segments was recorded over 4 weeks. X-ray microcomputed tomography (µ-CT) analysis of peptide-loaded nanofiber graft filled defects revealed ∼3 times greater new bone volume and bone mineral density over 4 weeks in comparison to unfilled control defects. Further, histopathology data confirmed the formation of greater new osseous tissue in the BMP2 peptide-loaded, mineralized nanofiber segment group than that of fibrous connective tissue in the unfilled defect group. Altogether, the mineralized nanofiber segments coupled with E7-BMP-2 peptides may be an effective treatment option for alveolar bone loss and defects. STATEMENT OF SIGNIFICANCE: With the high incidence of dental implants/fixtures for missing teeth, the success of the surgical procedures in restorative dentistry is dictated by the quality and quantity of the supporting alveolar bone. To address the problem of alveolar bone loss and defects due to tumor, periodontitis, or even postextraction remodeling, the present study is the first report on the application of mineralized nanofiber fragments coupled with calcium-binding osteoinductive BMP-2 peptides as a synthetic graft material for oral bone regeneration. The ease of fabrication and application of cryocut mineralized nanofiber fragments as maxillofacial bone defect fillers present a promising alternative to the current dental bone graft formulations. Furthermore, the nanofiber segments may also be utilized for several biomedical applications including hemostasis, soft tissue engineering, and wound healing.

Two-Year Randomized Clinical Trial of Adjunctive Minocycline Microspheres in Periodontal Maintenance.

Purpose: The purpose of this study was to evaluate the effects of repeated scaling and root planing (SRP), with or without locally-delivered minocycline microspheres (MM) on residual pockets in patients undergoing periodontal maintenance (PMT).Methods: Patients on PMT were randomized into two groups for treatment of one posterior interproximal inflamed pocket (≥5 mm) with a history of bleeding on probing every 6 months: SRP plus MM (n=30) or exclusively SRP (n=30). Baseline and 24-month measurements included radiographic interproximal alveolar bone height, probing depths (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival crevicular fluid (GCF), and salivary interleukin (IL) - 1ß, (24 month only). Results were analyzed for baseline data or change in measurements after 24 months of treatment between different treatment groups, as well as whether significant changes occurred after 24 months of treatment for each treatment group individually.Results: Alveolar bone height and GCF IL-1ß remained stable over the 24 months. The SRP + MM and SRP groups each demonstrated reduced PD (0.8 ± 0.9 mm and 1.1 ±0.6 mm, respectively, p < 0.001 each), CAL (0.8 ± 0.9 mm and 1.0 ± 0.6 mm, respectively, p < 0.001 each) and BOP (55% and 48%, respectively, p = 0.001 each). However, there were no differences between groups over the 24-month study period.Conclusion: Scaling and root planning alone, of moderately inflamed periodontal pockets at 6-month intervals, produced stable interproximal alveolar bone height as well as sustained improvements in probing depths, clinical attachment level, bleeding on probing over 24 months; minocycline microspheres were not shown to enhance these results.

Local Application of Pyrophosphorylated Simvastatin Prevents Experimental Periodontitis.

PURPOSE: Simvastatin (SIM), a HMG-CoA reductase inhibitor widely prescribed for hypercholesterolemia, has been reported to ameliorate inflammation and promote osteogenesis. Its clinical applications on these potential secondary indications, however, have been hampered by its lack of osteotropicity and poor water solubility. To address this challenge, we propose to design and evaluate the therapeutic efficacy of a novel simvastatin prodrug with better water solubility and bone affinity. METHOD: The prodrug (SIM-PPi) was synthesized by directly conjugating a SIM trimer to a pyrophosphate (PPi). It was characterized and evaluated in vitro for its water solubility, osteotropicity, toxicity, anti-inflammatory and osteoinductive properties. It was then tested for anti-inflammatory and osteoinductive properties in vivo by three weekly injections into gingiva of a ligature-induced experimental periodontitis rat model. RESULTS: In vitro studies showed that SIM-PPi has greatly improved water-solubility of SIM and shows strong binding to hydroxyapatite (HA). In macrophage culture, SIM-PPi inhibited LPS-induced pro-inflammatory cytokines (IL-1ß, IL-6). In osteoblast culture, it was found to significantly increase alkaline phosphatase (ALP) activity with accelerated mineral deposition, confirming the osteogenic potential of SIM-PPi. When tested in vivo on an experimental periodontal bone-loss model, SIM-PPi exhibited a superior prophylactic effect compared to dose equivalent SIM in reducing inflammatory cells and in preserving alveolar bone structure, as shown in the histological and micro-CT data. CONCLUSION: SIM-PPi may have the potential to be further developed for better clinical management of bone loss associated with periodontitis.

Standardized Rat Model Testing Effects of Inflammation and Grafting on Extraction Healing.

BACKGROUND: Loss of alveolar ridge width and height after tooth extraction is well documented, but models to evaluate ridge preservation are neither standardized nor cost-effective. This rat model characterizes the pattern of bone turnover and inflammation after extraction and bone grafting with or without local simvastatin (SIM). METHODS: Fifty retired-breeder rats underwent extraction of the maxillary right first molar and standard surgical defect creation under inhalation/local anesthesia. The left side of each animal served as unmanipulated control. Untreated groups (n = 8 to 9 per group) were compared (analysis of variance, t test) at days 0, 7, 14, and 28 for alveolar ridge height and width and for markers of inflammation and bone turnover by microcomputed tomography, histology, and enzyme-linked immunosorbent assay. Seventeen additional specimens had defects grafted with either bone mineralized matrix (BMM) or a BMM+SIM conjugate. RESULTS: Extraction-induced bone loss (BL) was noted on buccal, palatal, and interproximal height (P <0.05) and ridge width (P <0.01). Week 1 inflammation positively correlated with ridge height; thereafter, a more intense inflammatory reaction corresponded to reduction in alveolar bone height and density (r = 0.74; P <0.05; Spearman). BMM+SIM preserved the most interproximal bone height (P <0.01), increased ridge width and bone density (P <0.01), enhanced 7-day prostaglandin E2 (P <0.01), and reduced 28-day inflammation density (P <0.05). CONCLUSIONS: The standard defect used in the current study paralleled human postextraction alveolar BL. Defect grafting, especially BMM+SIM, reduced inflammation and preserved bone.

Local Minocycline Effect on Inflammation and Clinical Attachment During Periodontal Maintenance: Randomized Clinical Trial.

BACKGROUND: Minocycline microspheres (MMs) are being used to treat residual inflamed periodontal pockets during periodontal maintenance therapy (PMT), but evidence for efficacy from randomized clinical trials is lacking. The purpose of this study is to evaluate the effect of MMs plus scaling and root planing (SRP) on these sites. METHODS: Sixty patients with chronic periodontitis on 6-month PMT intervals to be followed for 1 year were randomized (51 completed the study) into two statistically similar groups, SRP + MM (aged 66.8 years) and SRP alone (aged 67 years), to treat a ≥5 mm posterior interproximal pocket during PMT with a history of bleeding on probing (BOP). Group treatments were applied to the site at baseline and 6 months. Clinical attachment levels (CALs; primary outcome), probing depths (PDs), plaque, and BOP also were recorded at baseline and 6 and 12 months. In addition, gingival crevicular fluid was analyzed for an inflammation index ratio of interleukin (IL)-1ß/IL-1 receptor antagonist (ra) using enzyme-linked immunosorbent assays. RESULTS: All clinical parameters improved significantly (P <0.005) from baseline in both groups with no differences between groups at any time point. CAL decreased 17% (0.9 ± 0.8 mm) and 13% (0.7 ± 0.9 mm) in SRP + MM and 11% (0.7 ± 1.1 mm) and 21% (1.2 ± 0.9 mm) in SRP at 6 and 12 months, respectively. The odds of having BOP decreased 90% (down to 38% of patients) and 95% (26%) in SRP + MM and 82% (42%) and 82% (41%) in SRP at 6 and 12 months, respectively. IL-1ß/IL-1ra decreased a significant 61% (P = 0.009) only in SRP + MM at 6 months. CONCLUSIONS: SRP of inflamed moderate pockets during 6-month PMT, with or without MMs, improves CALs, along with PDs and BOP over a 1-year period. The use of MMs did not result in an additional benefit over SRP alone.

Effect of Simvastatin Prodrug on Experimental Periodontitis.

BACKGROUND: Local application of statins has shown potential in preventing and regenerating bone loss associated with experimental periodontitis. This study evaluates the effect of a novel simvastatin (SIM) prodrug (capable of delivering high doses to periodontitis inflammatory lesion and cells) on experimental periodontitis bone loss and inflammation. METHODS: Forty mature female Sprague Dawley rats were subjected to ligature-induced experimental periodontitis between maxillary first and second molars (M1-M2). Equal groups were treated with three weekly doses of: 1) prodrug carrier alone (mPEG); 2) 0.5 mg SIM dose equivalent in carrier (SIM/SIM-mPEG); 3) 1.0 mg SIM/SIM-mPEG; 4) 1.5 mg SIM/SIM-mPEG; or 5) ligature alone. Contralateral molars served as unmanipulated controls. Four weeks after initiation of periodontitis, animals were euthanized, the M1-M2 interproximal was evaluated with microcomputed tomography and histology, and data were analyzed with one-way analysis of variance. RESULTS: Ligature alone caused a mean bone loss of 1.01 ± 0.06 mm from the cemento-enamel junction, whereas all doses of SIM/SIM-mPEG reduced bone loss, especially 1.5 mg SIM/SIM-mPEG (0.68 ± 0.05 mm, P <0.001), which was not statistically different from contralateral control (0.47 ± 0.06 mm). A dose of 1.5 mg SIM/SIM-mPEG also reduced percentage of neutrophils compared with carrier alone (2.0% ± 1.0% versus 5.7% ± 1.1%; P <0.05), and increased amount of uninflamed connective tissue in the M1-M2 interproximal area (65.2% ± 3.3% versus 46.3% ± 3.3%; P <0.001). The mPEG carrier alone did not have bone-sparing or anti-inflammatory properties. CONCLUSION: Multiple local 1.5-mg doses of a macromolecular SIM prodrug decreases amount of experimental periodontitis bone loss and inflammation in rats.

Do Mobility and Occlusal Trauma Impact Periodontal Longevity?

The impact of tooth mobility and occlusal trauma (OT) on periodontal bone loss and need for therapy has been debated for many years. This paper summarizes the relevant literature reported in three Dental Clinics of North America articles in the late 1990s, and adds newer information from the 2000s. Principle findings indicate that strong evidence of mobility and OT impacting tooth longevity is lacking, but reducing inflammation in the surrounding periodontium remains a critical treatment. Occlusal therapy when mobility is increasing, comfort or function are compromised, or periodontal regeneration procedures are planned should be considered.

Adjunctive Non-Surgical Therapy of Inflamed Periodontal Pockets During Maintenance Therapy Using Diode Laser: A Randomized Clinical Trial.

BACKGROUND: Numerous studies have documented the clinical outcomes of laser therapy for untreated periodontitis, but very few have reported on lasers treating inflamed pockets during maintenance therapy. The aim of this study is to compare the effectiveness of scaling and root planing (SRP) plus the adjunctive use of diode laser therapy to SRP alone on changes in the clinical parameters of disease and on the gingival crevicular fluid (GCF) inflammatory mediator interleukin-1ß (IL-1ß) in patients receiving regular periodontal maintenance therapy. METHODS: This single-masked and randomized, controlled, prospective study includes 22 patients receiving regular periodontal maintenance therapy who had one or more periodontal sites with a probing depth (PD) ≥ 5 mm with bleeding on probing (BOP). Fifty-six sites were treated with SRP and adjunctive laser therapy (SRP + L). Fifty-eight sites were treated with SRP alone. Clinical parameters, including PD, clinical attachment level (CAL), and BOP, and GCF IL-1ß levels were measured immediately before treatment (baseline) and 3 months after treatment. RESULTS: Sites treated with SRP + L and SRP alone resulted in statistically significant reductions in PD and BOP and gains in CAL. These changes were not significantly different between the two therapies. Similarly, differences in GCF IL-1ß levels between SRP + L and SRP alone were not statistically significant. CONCLUSION: In periodontal maintenance patients, SRP + L did not enhance clinical outcomes compared to SRP alone in the treatment of inflamed sites with ≥ 5 mm PD.

Effect of dexamethasone prodrug on inflamed temporomandibular joints in juvenile rats.

INTRODUCTION: Juvenile idiopathic arthritis (JIA) often causes inflammation of the temporomandibular joint (TMJ) and has been treated with both systemic and intra-articular steroids, with concerns about effects on growing bones. In this study, we evaluated the impact of a macromolecular prodrug of dexamethasone (P-DEX) with inflammation-targeting potential applied systemically or directly to the TMJ. METHODS: Joint inflammation was initiated by injecting two doses of complete Freund's adjuvant (CFA) at 1-month intervals into the right TMJs of 24 growing Sprague-Dawley male rats (controls on left side). Four additional rats were not manipulated. With the second CFA injection, animals received (1) 5 mg of P-DEX intra-articularly (n = 9), (2) 15 mg of P-DEX into the tail vein (n = 7), or (3) nothing in addition to CFA (n = 8). The rats were killed 28 days later and measured by radiography for ramus height (condylar superior to gonion inferior [CsGoInf]), by micro-computed tomography for condylar width (CW) and bone volume/standardized condylar volume (BV/CV), and by histology for retrodiscal inflammatory cells. Inflammation targeting of systemic P-DEX was confirmed by IVIS infrared dye imaging. Inflammation and bone growth were compared between groups using analysis of variance and Pearson's correlations. RESULTS: CFA caused a significant reduction in CsGoInf (p < 0.05), but neither route of P-DEX administration had an effect on CsGoInf or CW at CFA injection sites. BV/CV was significantly reduced in both inflamed and control condyles as a result of either steroid application (p < 0.05). The inflammatory infiltrate was overwhelmingly lymphocytic, comprising 16.4 ± 1.3 % of the field in CFA alone vs. <0.01 % lymphocytes in contralateral controls (p < 0.0001). Both P-DEX TMJ (10.1 ± 1.2 %) and systemic P-DEX (8.9 ± 1.7 %) reduced lymphocytes (p < 0.002). The total area of inflammatory infiltrate was significantly less in the systemic injection group than in the group that received CFA injections alone (2.6 ± 1.5 mm(2) vs. 8.0 ± 1.3 mm(2); p = 0.009), but not in the group that received intra-articular P-DEX (8.8 ± 1.2 mm(2)). CONCLUSIONS: High-dose systemic administration of inflammation-targeting P-DEX is more effective than an intra-articular injection in reducing TMJ inflammation, but both routes may affect TMJ bone density.