Erratum: Sleeveless guided implant placement compared to conventional approaches: An in vitro study at healed sites and fresh extraction sockets.

The following amendments are made to the published article: Int J Oral Implantol (Berl) 2023;16(2): 117-132; First published 9 May 2023.

Sleeveless guided implant placement compared to conventional approaches: An in vitro study at healed sites and fresh extraction sockets.

PURPOSE: To investigate the accuracy of a novel sleeveless implant surgical guide by comparing it with a conventional closed-sleeve guide and a freehand approach. MATERIALS AND METHODS: Custom resin maxillary casts with corticocancellous compartments were used (n = 30). Seven implant sites were present per maxillary cast, corresponding to healed (right and left first premolars, left second premolar and first molar) and extraction sites (right canine and central incisors). The casts were assigned into three groups: freehand (FH), conventional closed-sleeve guide (CG) and surgical guide (SG) groups. Each group comprised 10 casts and 70 implant sites (30 extraction sites and 40 healed sites). Digital planning was used to design 3D printed conventional and surgical guide templates. The primary study outcome was implant deviation. RESULTS: At extraction sites, the largest difference between groups occurred in angular deviation, where the SG group (3.80 ± 1.67 degrees) exhibited ~1.6 times smaller deviation relative to the FH group (6.02 ± 3.44 degrees; P = 0.004). The CG group (0.69 ± 0.40 mm) exhibited smaller coronal horizontal deviation compared to the SG group (1.08 ± 0.54 mm; P = 0.005). For healed sites, the largest difference occurred for angular deviation, where the SG group (2.31 ± 1.30 degrees) exhibited 1.9 times smaller deviation relative to the CG group (4.42 ± 1.51 degrees; P < 0.001), and 1.7 times smaller deviation relative to the FH group (3.84 ± 2.14 degrees). Significant differences were found for all parameters except depth and coronal horizontal deviation. For the guided groups, there were fewer significant differences between healed and immediate sites compared to the FH group. CONCLUSION: The novel sleeveless surgical guide showed similar accuracy to the conventional closed-sleeve guide.

Living cellular constructs for keratinized tissue augmentation: A 13-year follow-up from a split-mouth randomized, controlled, clinical trial.

BACKGROUND: A 13-year follow-up was conducted of a short-term investigation of the use of living cellular construct (LCC) versus free gingival graft (FGG) for keratinized tissue width (KTW) augmentation in natural dentition, to evaluate the long-term outcomes and assess the changes occurring since the end of the original 6-month study. METHODS: Twenty-four subjects out of the original 29 enrolled participants were available at the 13-year follow-up. The primary endpoint was the number of sites demonstrating stable clinical outcomes from 6 months to 13 years (defined as KTW gain, stability, or ≤0.5 mm of KTW loss, together with reduction, stability, or increase of probing depth, and recession depth [REC] ≤0.5 mm). Secondary outcomes included the assessment of KTW, attached gingiva width (AGW), REC, clinical attachment level, esthetics, and patient-reported outcomes at the 13-year visit, assessing the changes from baseline to 6 months. RESULTS: Nine sites per group (42.9%) were found to have maintained stable (≤0.5 mm or improved) clinical outcomes from 6 months to 13 years. No significant differences were observed for the clinical parameters between LCC and FGG from 6 months to 13 years. However, the longitudinal mixed model analysis showed that FGG delivered significantly better clinical outcomes over 13 years (p < 0.01). LCC-treated sites exhibited superior esthetic outcomes compared to FGG-treated sites at 6 months and 13 years (p < 0.01). Patient-evaluated esthetics were significantly higher for LCC over FGG (p < 0.01). Patient overall treatment preference was also in favor of LCC (p < 0.01). CONCLUSIONS: A similar stability of the treatment outcomes from 6 months to 13 years was found for LCC- and FGG-treated sites, with both approaches shown to be effective in augmenting KTW and AGW. However, superior clinical outcomes were found for FGG over 13 years, while LCC was associated with better esthetics and patient-reported outcomes than FGG.

Recombinant human platelet-derived growth factor improves root coverage of a collagen matrix for multiple adjacent gingival recessions: A triple-blinded, randomized, placebo-controlled trial.

AIM: To evaluate the efficacy of recombinant human platelet-derived growth factor (rhPDGF)-BB combined with a cross-linked collagen matrix (CCM) for the treatment of multiple adjacent gingival recession type 1 defects (MAGRs) in combination with the coronally advanced flap (CAF). MATERIALS AND METHODS: Thirty patients were enrolled in this triple-blind, randomized, placebo-controlled trial and treated with either CAF + CCM + rhPDGF, or CAF + CCM + saline. The primary outcome was mean root coverage (mRC) at 6 months. Complete root coverage, gain in gingival thickness (GT), keratinized tissue width, volumetric and ultrasonographic changes, and patient-reported outcome measures were also assessed. Mixed-modelling regression analyses were used for statistical comparisons. RESULTS: At 6 months, the mRC of the CCM + rhPDGF and CCM alone groups were 88.25% and 77.72%, respectively (p = .02). A significant gain in GT was consistently observed for both treatment arms, and more so for the patients receiving the matrix containing rhPDGF through time (0.51 vs. 0.80 mm, on average, p = .01). The rhPDGF + CCM treated patients presented greater volume gain, higher soft tissue thickness, and a superior aesthetic score. CONCLUSION: rhPDGF enhances the clinical, volumetric, and aesthetic outcomes of MAGRs above the results achieved with CAF + CCM alone (ClinicalTrials.gov NCT04462237).

Agreement among international periodontal experts using the 2017 World Workshop classification of periodontitis.

BACKGROUND: A new periodontitis classification was recently introduced involving multidimensional staging and grading. The aim of the study was to assess if individuals well-trained in periodontics consistently used the new classification for patients with severe periodontitis. The secondary goal was to identify "gray zones" related to classifications. METHODS: Participants (raters) individually classified 10 pre-selected severe periodontitis cases using the 2017 World Workshop classification. An internet case-based study was conducted after inviting members from American Academy of Periodontology and European Federation of Periodontology. Gold-standard diagnoses were determined by five experts who developed the new periodontitis classification. Inter-reliability agreement among raters was assessed using Fleiss Kappa index with the jackknife method for linearly weighted kappa calculations. McNemar test was used to determine symmetry between raters and gold-standard panel. RESULTS: A total of 103 raters participated and classified nine clinical cases. Fleiss Kappa values showed moderate inter-examiner consistency among raters for stage (K value: 0.49; 95% CI, 0.19 to 0.79), grade (K value: 0.50; 95% CI, 0.30 to 0.70) and extent (K value: 0.51; 95% CI, 0.23 to 0.77). When analyzed as composite (stage, grade, extent) a moderate inter-reliability was present among raters, k = 0.479 (K value: 0.47; 95% CI, 0.442 to 0.515). Agreement between raters and gold-standard panel was staging 76.6%; grading 82%; and extent 84.8%. In six of nine cases 77% to 99% of raters consistently agreed with gold-standard panel, and the other three cases had gray zone factors that reduced rater consistency. CONCLUSIONS: Clinicians trained in the 2017 World Workshop periodontitis classification demonstrated moderate concordance in classifying nine severe periodontitis cases, and in six of nine cases raters consistently agreed with the gold-standard panel.

Association between metabolic syndrome and periodontitis: The role of lipids, inflammatory cytokines, altered host response, and the microbiome.

Periodontitis has been associated with many systemic diseases and conditions, including metabolic syndrome. Metabolic syndrome is a cluster of conditions that occur concomitantly and together they increase the risk of cardiovascular disease and double the risk of type 2 diabetes. In this review, we focus on the association between metabolic syndrome and periodontitis; however, we also include information on diabetes mellitus and cardiovascular disease, since these two conditions are significantly intertwined with metabolic syndrome. With regard to periodontitis and metabolic syndrome, to date, the vast majority of studies point to an association between these two conditions and also demonstrate that periodontitis can contribute to the development of, or can worsen, metabolic syndrome. Evaluating the effect of metabolic syndrome on the salivary microbiome, data presented herein support the hypothesis that the salivary bacterial profile is altered in metabolic syndrome patients compared with healthy patients. Considering periodontitis and these three conditions, the vast majority of human and animal studies point to an association between periodontitis and metabolic syndrome, diabetes, and cardiovascular disease. Moreover, there is evidence to suggest that metabolic syndrome and diabetes can alter the oral microbiome. However, more studies are needed to fully understand the influence these conditions have on each other.

Repeated delivery of chlorhexidine chips for the treatment of peri-implantitis: A multicenter, randomized, comparative clinical trial.

BACKGROUND: Peri-implantitis is a challenging condition to manage and is frequently treated using non-surgical debridement. The local delivery of antimicrobial agents has demonstrated benefit in mild to moderate cases of peri-implantitis. This study compared the safety and efficacy of chlorhexidine gluconate 2.5 mg chip (CHX chips) as an adjunctive treatment to subgingival debridement in patients afflicted with peri-implantitis. METHODS: A multicenter, randomized, single-blind, two-arm, parallel Phase-3 study was conducted. Peri-implantitis patients with implant pocket depths (IPD) of 5-8 mm underwent subgingival implant surface debridement followed by repeated bi-weekly supragingival plaque removal and chlorhexidine chips application (ChxC group) for 12 weeks, or similar therapy but without application of ChxC (control group). All patients were followed for 24 weeks. Plaque and gingival indices were measured at every visit whereas IPD, recession, and bleeding on probing were assessed at 8, 12, 16, 24 week. RESULTS: A total of 290 patients were included: 146 in the ChxC group and 144 in the control. At 24 weeks, a significant reduction in IPD (P = 0.01) was measured in the ChxC group (1.76 ± 1.13 mm) compared with the control group (1.54 ± 1.13 mm). IPD reduction of ≥2 mm was found in 59% and 47.2% of the implants in the ChxC and control groups, respectively (P = 0.03). Changes in gingival recession (0.29 ± 0.68 mm versus 0.15 ± 0.55 mm, P = 0.015) and relative attachment gain (1.47 ± 1.32 mm and 1.39 ± 1.27 mm, P = 0.0017) were significantly larger in the ChxC group. Patients in the ChxC group that were < 65 years exhibited significantly better responses (P < 0.02); likewise, non-smokers had similarly better response (P < 0.02). Both protocols were well tolerated, and no severe treatment-related adverse events were recorded throughout the study. CONCLUSIONS: Patients with peri-implantitis that were treated with an intensive treatment protocol of bi-weekly supragingival plaque removal and local application of chlorhexidine chips had greater mean IPD reduction and greater percentile of sites with IPD reduction of ≥2 mm as compared with bi-weekly supra-gingival plaque removal.

Incidence of retrograde peri-implantitis in sites with previous apical surgeries: A retrospective study.

BACKGROUND: Retrograde peri-implantitis (RPI) is a rapidly progressing periapical infection that forms around the implant apex. It is usually associated with sites adjacent to teeth with apical lesions; previous endodontic failures, retained root fragments, etc. This study aimed to study the incidence of RPI in sites with a history of apical surgeries. METHODS: Patients with sites treated for both apicoectomy and implant placement presenting to the University of Michigan School of Dentistry from 2001 to 2016 were screened. A total of 502 apicoectomies were performed, only 25 of these fit the predetermined eligibility criteria and were thus included in this retrospective analysis. RESULTS: Implants that were placed in sites with a previous apical surgery had a cumulative survival rate of 92%. The incidence of peri-implantitis was 8%, while the incidence of RPI was 20%. There was an increased trend for RPI in cases where the cause of extraction was persistent apical periodontitis (35.7%), but this increase didn't reach the level of statistical significance (P = 0.061). CONCLUSION: Implants placed in sites with previous apical surgery are not at an increased risk of implant failure or RPI.

Biosensor and Lab-on-a-chip Biomarker-identifying Technologies for Oral and Periodontal Diseases.

Periodontitis is a complex multifactorial disease that can lead to destruction of tooth supporting tissues and subsequent tooth loss. The most recent global burden of disease studies highlight that severe periodontitis is one of the most prevalent chronic inflammatory conditions affecting humans. Periodontitis risk is attributed to genetics, host-microbiome and environmental factors. Empirical diagnostic and prognostic systems have yet to be validated in the field of periodontics. Early diagnosis and intervention prevents periodontitis progression in most patients. Increased susceptibility and suboptimal control of modifiable risk factors can result in poor response to therapy, and relapse. The chronic immune-inflammatory response to microbial biofilms at the tooth or dental implant surface is associated with systemic conditions such as cardiovascular disease, diabetes or gastrointestinal diseases. Oral fluid-based biomarkers have demonstrated easy accessibility and potential as diagnostics for oral and systemic diseases, including the identification of SARS-CoV-2 in saliva. Advances in biotechnology have led to innovations in lab-on-a-chip and biosensors to interface with oral-based biomarker assessment. This review highlights new developments in oral biomarker discovery and their validation for clinical application to advance precision oral medicine through improved diagnosis, prognosis and patient stratification. Their potential to improve clinical outcomes of periodontitis and associated chronic conditions will benefit the dental and overall public health.

Long-term Clinical Outcomes and Cost-Effectiveness of Full-Arch Implant-Supported Zirconia-Based and Metal-Acrylic Fixed Dental Prostheses: A Retrospective Analysis.

PURPOSE: To provide a long-term comparison of metal-acrylic and zirconia implant-supported fixed complete dental prostheses. MATERIALS AND METHODS: Patients treated with a metal-acrylic or zirconia fixed implant prosthesis with a minimum 5-year follow-up were included. All complications were registered, along with events such as peri-implantitis and implant failure. Survival and all costs associated with the prostheses were assessed to provide an overall evaluation of each type of fixed implant prosthesis protocol. RESULTS: Seventy-four rehabilitated arches (43 metal-acrylic, 31 zirconia, mean follow-up: 8.7 ± 3.37 years) were included. Delayed complications accompanied the metal-acrylic prostheses more frequently. In both groups, single tooth chipping/fracture was the most prominent minor complication, and incidence of multiple teeth and framework fracture was the most frequent major complication. Zirconia fixed implant prostheses demonstrated higher prosthetic survival rates than the metal-acrylic prostheses (93.7% ± 5.5% at 5 years vs 83.0% ± 11.1%). No difference was observed for peri-implantitis or implant failure. The initial cost for zirconia prosthesis fabrication was significantly higher than metal-acrylic hybrids (an estimated difference of $7,829 [P < .001]); however, due to reduced complication rates for the zirconia fixed implant prosthesis, maintenance and treatment for complications did not greatly differ between groups. CONCLUSION: Within the limitations, zirconia fixed implant prostheses presented higher initial costs than metal-acrylic hybrids, however, with satisfactory outcomes, reduction of overall complications, and superior survival rates.

Treatment effect of guided tissue regeneration on the horizontal and vertical components of furcation defects: A retrospective study.

BACKGROUND: Identifying factors affecting the treatment outcomes of guided tissue regeneration (GTR) in furcation defects is imperative in order to obtain predictable regeneration outcomes. The aims of this study were to evaluate the clinical outcomes and survival of furcation-involved teeth treated with GTR, and potential factors affecting the results. METHODS: Furcation defects treated with GTR using an allogeneic cancellous bone graft and covered by an absorbable membrane with at least 1-year follow-up were selected. All data relative to the clinical outcomes were recorded. Analyses were conducted to evaluate the immediate (1-year post-op) clinical outcomes and the long-term (the last assessment time) survival of the treated teeth. The effect of variables on the 1-year post-op clinical attachment level (CAL) changes and the tooth survival were assessed via multi-level regression analyses and Cox Proportional-Hazards Models. RESULTS: Ninety-eight treated defects were selected. The average follow-up was 5.3 ± 4.3 years. At the 1-year post-surgical recall, 1.23 ± 1.48 mm CAL gain was observed (P < 0.05). The 5- and 10-year survival rates of the treated teeth were 86.5% and 74.3%, respectively. The vertical component of the defect and the location of the furcation were significantly related to the post-surgical 1-year CAL gain, whereas membrane exposure significantly affected tooth survival. CONCLUSION: Within the limitations of this study, data suggests GTR using allogeneic cancellous bone graft and absorbable collagen membrane to be a viable option for treating furcation-involved teeth if the defect morphology and the location of the defect are favorable.

Stem cell therapy for reconstruction of alveolar cleft and trauma defects in adults: A randomized controlled, clinical trial.

BACKGROUND: Stem cell therapy with bone marrow-derived mesenchymal stem cells is a promising tissue engineering strategy to promote regeneration of craniofacial bone. PURPOSE: To determine whether cell therapy with ex vivo expanded stem cell populations would be safe and efficacious in the regeneration of large alveolar defects in patients with a history of cleft palate or craniofacial trauma. MATERIALS AND METHODS: Eighteen patients (10 patients with traumatic injury and 8 patients with cleft palate) presenting with missing teeth associated with horizontal alveolar bone deficiencies were included in this randomized controlled clinical trial. Patients were randomized to receive either conventional autogenous block grafts or stem cell therapy. After a healing period of 4 months the treated sites were re-entered and the bone width re-assessed prior to implant placement. Implant stability was evaluated through torque testing of the implant upon insertion and at 6 months postloading. RESULTS: The mean gain in bone width was 1.5 ± 1.5 mm in the stem cell therapy group and 3.3 ± 1.4 mm in the control group. Overall, bone gain was higher in trauma patients as compared to patients with cleft palate, for both the control and the stem cell therapy groups. Most postoperative complications were wound dehiscences and incision line openings. Implants were placed successfully in 5 out of 10 patients in the stem cell therapy group and in all 8 patients in the control group. One implant from the control/cleft palate group failed before loading, while the rest of the implants were loaded successfully and remained stable at 6 months. The patients who did not receive implants were re-treated with autogenous block bone graft. CONCLUSION: The ability of stem cells to treat large alveolar defects is safe, yet, their ability to completely reconstitute large alveolar defects is limited. This approach requires further optimization to meet the outcomes seen using current methods to treat large defects, particularly those resultant of cleft palate.

Dental implants and grafting success remain high despite large variations in maxillary sinus mucosal thickening.

BACKGROUND: Although mucosal thickening is the most common radiographic finding observed regarding sinus pathology, the knowledge regarding its clinical significance on the outcomes of dental implants and grafting in the maxillary sinuses is still limited. We hypothesized that mucosal thickening would not alter the predictability for sinus floor augmentation and dental implant placement. The purpose of this retrospective study was to evaluate the outcomes of dental implant placement in sinus-augmented areas with preexisting sinus mucosal thickening. METHODS: This study involved the review of cone-beam computed tomographic (CBCT) scans taken on patients that underwent both maxillary sinus elevation with grafting and implant placement at the University of Michigan School of Dentistry from 2004 to 2014. Cases with documented radiographic and clinical follow-up were included. The data analyses revealed the following. RESULTS: A total of 29 CBCT scans met the inclusion criteria for evaluation, and 93.1% of them had maxillary sinus mucosal/tissue thickening. Specifically, 6.9% of cases exhibited no thickening, 6.9% had minimal thickening (1-2 mm), 20.7% of cases had moderate thickening (2-5 mm), and 65.5% had severe thickening (>5 mm). We propose these categorical measurements of tissue thickening as a new "mucosal thickening index." The tissue thickening did not vary based on gender, age, or smoking status, nor did it relate to the underlying alveolar ridge height. However, patients with a history of periodontal diseases demonstrated a significant association with mucosal thickening (p = 0.0043). These data indicate that there is high implant and grafting success rate (100%) in the maxillary sinus despite large and varied physiologic sinus mucosal/tissue thickening. CONCLUSIONS: Based on study findings, this research will help guide dental practitioners regarding cases that exhibit mucosal thickening. These data support the concept that physiologic mucosal thickening in varied ranges is not associated with implant or grafting failure in the maxillary sinus.

Bone Engineering of Maxillary Sinus Bone Deficiencies Using Enriched CD90+ Stem Cell Therapy: A Randomized Clinical Trial.

Bone engineering of localized craniofacial osseous defects or deficiencies by stem cell therapy offers strong prospects to improve treatment predictability for patient care. The aim of this phase 1/2 randomized, controlled clinical trial was to evaluate reconstruction of bone deficiencies of the maxillary sinus with transplantation of autologous cells enriched with CD90+ stem cells and CD14+ monocytes. Thirty human participants requiring bone augmentation of the maxillary sinus were enrolled. Patients presenting with 50% to 80% bone deficiencies of the maxillary sinus were randomized to receive either stem cells delivered onto a ß-tricalcium phosphate scaffold or scaffold alone. Four months after treatment, clinical, radiographic, and histologic analyses were performed to evaluate de novo engineered bone. At the time of alveolar bone core harvest, oral implants were installed in the engineered bone and later functionally restored with dental tooth prostheses. Radiographic analyses showed no difference in the total bone volume gained between treatment groups; however, density of the engineered bone was higher in patients receiving stem cells. Bone core biopsies showed that stem cell therapy provided the greatest benefit in the most severe deficiencies, yielding better bone quality than control patients, as evidenced by higher bone volume fraction (BVF; 0.5 versus 0.4; p = 0.04). Assessment of the relation between degree of CD90+ stem cell enrichment and BVF showed that the higher the CD90 composition of transplanted cells, the greater the BVF of regenerated bone (r = 0.56; p = 0.05). Oral implants were placed and restored with functionally loaded dental restorations in all patients and no treatment-related adverse events were reported at the 1-year follow-up. These results provide evidence that cell-based therapy using enriched CD90+ stem cell populations is safe for maxillary sinus floor reconstruction and offers potential to accelerate and enhance tissue engineered bone quality in other craniofacial bone defects and deficiencies (Clinicaltrials.gov NCT00980278).

Optimized cell survival and seeding efficiency for craniofacial tissue engineering using clinical stem cell therapy.

Traumatic injuries involving the face are very common, yet the clinical management of the resulting craniofacial deficiencies is challenging. These injuries are commonly associated with missing teeth, for which replacement is compromised due to inadequate jawbone support. Using cell therapy, we report the upper jaw reconstruction of a patient who lost teeth and 75% of the supporting jawbone following injury. A mixed population of bone marrow-derived autologous stem and progenitor cells was seeded onto ß-tricalcium phosphate (ß-TCP), which served as a scaffold to deliver cells directly to the defect. Conditions (temperature, incubation time) to achieve the highest cell survival and seeding efficiency were optimized. Four months after cell therapy, cone beam computed tomography and a bone biopsy were performed, and oral implants were placed to support an engineered dental prosthesis. Cell seeding efficiency (>81%) of the ß-TCP and survival during the seeding process (94%) were highest when cells were incubated with ß-TCP for 30 minutes, regardless of incubation temperature; however, at 1 hour, cell survival was highest when incubated at 4°C. Clinical, radiographic, and histological analyses confirmed that by 4 months, the cell therapy regenerated 80% of the original jawbone deficiency with vascularized, mineralized bone sufficient to stably place oral implants. Functional and aesthetic rehabilitation of the patient was successfully completed with installation of a dental prosthesis 6 months following implant placement. This proof-of-concept clinical report used an evidence-based approach for the cell transplantation protocol used and is the first to describe a cell therapy for craniofacial trauma reconstruction.

Differential expression of mitogen activating protein kinases in periodontitis.

AIM: Following toll-like receptor (TLR) engagement, lipopolysaccharide (LPS) can stimulate the expression of pro-inflammatory cytokines thus activating the innate immune response. The production of inflammatory cytokines results, in part, from the activation of kinase-induced signalling cascades and transcriptional factors. Of the four distinct classes of mitogen-activated protein kinases (MAPK) described in mammals, p38, c-Jun N-terminal activated kinases (JNK1-3) and extracellular activated kinases (ERK1,2) are the best studied. Previous data have established that p38 MAPK signalling is required for inflammation and bone loss in periodontal disease pre-clinical animal models. MATERIALS & METHODS: In this study, we obtained healthy and diseased periodontal tissues along with clinical parameters and microbiological parameters. Excised fixed tissues were immunostained with total and phospho-specific antibodies against p38, JNK and ERK kinases. RESULTS: Intensity scoring from immunostained tissues was correlated with clinical periodontal parameters. Rank correlations with clinical indices were statistically significantly positive (p-value < 0.05) for total p38 (correlations ranging 0.49-0.68), phospho-p38 (range 0.44-0.56), and total ERK (range 0.52-0.59) levels, and correlations with JNK levels also supported association (range 0.42-0.59). Phospho-JNK and phospho-ERK showed no significant positive correlation with clinical parameters of disease. CONCLUSION: These data strongly implicate p38 MAPK as a major MAPK involved in human periodontal inflammation and severity.

Effect of adjunctive systemic azithromycin with periodontal surgery in the treatment of chronic periodontitis in smokers: a pilot study.

BACKGROUND: Along with conventional surgical therapy, systemic antibiotics may provide more effective treatment in smokers by targeting tissue-invasive bacteria. The aim of this randomized, placebo-controlled, double-masked clinical trial was to evaluate the adjunctive effects of systemic azithromycin (AZM) in combination with periodontal pocket reduction surgery in the treatment of chronic periodontitis in smokers. METHODS: Thirty patients with a greater than one pack/day smoking habit and generalized moderate to severe chronic periodontitis were randomized to the test (surgery plus 3 days of AZM, 500 mg) or control group (surgery plus 3 days of placebo). Full-mouth probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival index (GI), plaque index, and wound healing indices (WHI) were assessed at baseline and at 2 weeks and 1, 3, and 6 months following surgical intervention. Plaque and gingival crevicular fluid were collected for trypsin-like enzyme activity (benzoyl-dl-arginine naphthylamine) and bone biomarker (crosslinked telopeptide of type I collagen [ICTP]) analyses, respectively, at baseline, 2 weeks, and 1, 3, and 6 months. RESULTS: Surgical treatment of moderate (PD = 4 to 6 mm) and deep (PD > 6 mm) pockets significantly improved clinical parameters of treated and untreated teeth (CAL gain, PD reduction, and reduction of BOP). The additional use of AZM did not enhance this improvement nor did it promote reduction of ICTP levels. Compared to the control group, the test group had significantly better WHI scores at 1 month, significantly less GI at 2 weeks, and sustained reductions of red-complex bacteria with trypsin-like enzyme activity at 3 months. For non-surgery teeth, only the test group showed significant gains in overall CAL compared to baseline. CONCLUSIONS: The findings of this pilot study demonstrated that in heavy smokers, adjunctive systemic AZM in combination with pocket reduction surgery did not significantly enhance PD reduction or CAL gain. However, the clinical value of adjunctive AZM may be appreciated by more rapid wound healing, less short-term gingival inflammation, and sustained reductions of periopathogenic bacteria. More expanded studies are recommended to better determine the clinical effects of adjunctive AZM in patients who smoke.