Versican Promotes Cardiomyocyte Proliferation and Cardiac Repair.

BACKGROUND: The adult mammalian heart is incapable of regeneration, whereas a transient regenerative capacity is maintained in the neonatal heart, primarily through the proliferation of preexisting cardiomyocytes. Neonatal heart regeneration after myocardial injury is accompanied by an expansion of cardiac fibroblasts and compositional changes in the extracellular matrix. Whether and how these changes influence cardiomyocyte proliferation and heart regeneration remains to be investigated. METHODS: We used apical resection and myocardial infarction surgical models in neonatal and adult mice to investigate extracellular matrix components involved in heart regeneration after injury. Single-cell RNA sequencing and liquid chromatography-mass spectrometry analyses were used for versican identification. Cardiac fibroblast-specific Vcan deletion was achieved using the mouse strains Col1a2-2A-CreER and Vcanfl/fl. Molecular signaling pathways related to the effects of versican were assessed through Western blot, immunostaining, and quantitative reverse transcription polymerase chain reaction. Cardiac fibrosis and heart function were evaluated by Masson trichrome staining and echocardiography, respectively. RESULTS: Versican, a cardiac fibroblast-derived extracellular matrix component, was upregulated after neonatal myocardial injury and promoted cardiomyocyte proliferation. Conditional knockout of Vcan in cardiac fibroblasts decreased cardiomyocyte proliferation and impaired neonatal heart regeneration. In adult mice, intramyocardial injection of versican after myocardial infarction enhanced cardiomyocyte proliferation, reduced fibrosis, and improved cardiac function. Furthermore, versican augmented the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. Mechanistically, versican activated integrin ß1 and downstream signaling molecules, including ERK1/2 and Akt, thereby promoting cardiomyocyte proliferation and cardiac repair. CONCLUSIONS: Our study identifies versican as a cardiac fibroblast-derived pro-proliferative proteoglycan and clarifies the role of versican in promoting adult cardiac repair. These findings highlight its potential as a therapeutic factor for ischemic heart diseases.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Polycomb Group Protein CBX7 Represses Cardiomyocyte Proliferation Through Modulation of the TARDBP/RBM38 Axis.

BACKGROUND: Shortly after birth, cardiomyocytes exit the cell cycle and cease proliferation. At present, the regulatory mechanisms for this loss of proliferative capacity are poorly understood. CBX7 (chromobox 7), a polycomb group (PcG) protein, regulates the cell cycle, but its role in cardiomyocyte proliferation is unknown. METHODS: We profiled CBX7 expression in the mouse hearts through quantitative real-time polymerase chain reaction, Western blotting, and immunohistochemistry. We overexpressed CBX7 in neonatal mouse cardiomyocytes through adenoviral transduction. We knocked down CBX7 by using constitutive and inducible conditional knockout mice (Tnnt2-Cre;Cbx7fl/+ and Myh6-MCM;Cbx7fl/fl, respectively). We measured cardiomyocyte proliferation by immunostaining of proliferation markers such as Ki67, phospho-histone 3, and cyclin B1. To examine the role of CBX7 in cardiac regeneration, we used neonatal cardiac apical resection and adult myocardial infarction models. We examined the mechanism of CBX7-mediated repression of cardiomyocyte proliferation through coimmunoprecipitation, mass spectrometry, and other molecular techniques. RESULTS: We explored Cbx7 expression in the heart and found that mRNA expression abruptly increased after birth and was sustained throughout adulthood. Overexpression of CBX7 through adenoviral transduction reduced proliferation of neonatal cardiomyocytes and promoted their multinucleation. On the other hand, genetic inactivation of Cbx7 increased proliferation of cardiomyocytes and impeded cardiac maturation during postnatal heart growth. Genetic ablation of Cbx7 promoted regeneration of neonatal and adult injured hearts. Mechanistically, CBX7 interacted with TARDBP (TAR DNA-binding protein 43) and positively regulated its downstream target, RBM38 (RNA Binding Motif Protein 38), in a TARDBP-dependent manner. Overexpression of RBM38 inhibited the proliferation of CBX7-depleted neonatal cardiomyocytes. CONCLUSIONS: Our results demonstrate that CBX7 directs the cell cycle exit of cardiomyocytes during the postnatal period by regulating its downstream targets TARDBP and RBM38. This is the first study to demonstrate the role of CBX7 in regulation of cardiomyocyte proliferation, and CBX7 could be an important target for cardiac regeneration.

Instructions for the use of L-PRF in different clinical indications.

Autologous platelet concentrates (APCs) have demonstrated clear benefits across various clinical applications, including alveolar ridge preservation, guided tissue regeneration, guided bone regeneration, sinus floor elevation (both lateral window approach and transcrestal technique), endodontic surgery, the treatment of medication-related osteonecrosis of the jaw bones, and periodontal plastic surgery. To ensure an optimal clinical outcome, clinicians must adhere strictly to the protocol to prepare the APCs and, especially follow evidence-based surgical guidelines, often simple but crucial, to minimize the likelihood of errors. The majority of clinical trials reported on second-generation APCs [the leukocyte- and platelet-rich fibrin (L-PRF) family, including its modifications (A-PRF, A-PRF+, CGF, T-PRF, H-PRF, etc.)]. These second-generation APCs offer additional benefits compared to the first-generation APCs, making them the preferred choice for the development of clinical recommendations. These recommendations have been formulated through a meticulous examination of the available clinical data and the clinical experience of the authors of this paper.

Native vs. ribosome-crosslinked collagen membranes for periodontal regeneration: A randomized clinical trial.

AIM: To evaluate whether the ribosome-crosslinked collagen membrane (RCCM) is non-inferior to the natural collagen membrane (NCM) used in regeneration surgery in terms of clinical attachment level (CAL) gain at 6 months. METHODS: Eighty patients diagnosed as generalized periodontitis presenting with isolated infrabony defect (≥4 mm deep) were enrolled and randomized to receive regenerative surgery, either with NCM or RCCM, both combined with deproteinized bovine bone mineral (DBBM). CAL, pocket probing depth (PPD), and gingival recession (GR) were recorded at baseline, 3, and 6 months postoperatively. Periapical radiographs were taken at baseline, immediately, and 6 months after surgery. Early wound healing index (EHI) and patients' responses were recorded at 2 weeks postoperatively. RESULTS: At 6 months post-surgery, the mean CAL gain was 3.1 ± 1.5 mm in the NCM group and 2.9 ± 1.5 mm in the RCCM group, while the mean PPD was 4.3 ± 1.1 mm in the NCM group and 4.2 ± 1.0 mm in the RCCM group. Both groups demonstrated a statistically significant improvement from the baseline (p < .01). RCCM was non-inferior to NCM concerning the primary outcome (CAL gain at 6 months). The GR at 6 months postoperatively was 1.3 ± 1.2 and 1.2 ± 1.1 mm, which showed no difference compared with baseline. At 6 months follow-up, the radiographic linear bone fill (RLBF) was 6.5 ± 2.8 and 5.5 ± 2.6 mm (p > .05), while the bone fill percentage (BF%) was 102.3 ± 53.5% and 92.3 ± 40.1% (p > .05), in the NCM and RCCM groups, respectively. There was no significant difference in EHI and postoperative responses between two groups. CONCLUSION: RCCM + DBBM resulted in no-inferior clinical and radiographic outcomes to NCM + DBBM for the treatment of isolated infrabony defect in 6 months.

The impact of bone grafting with/without barrier membrane placement on the outcome of apical surgery: A systematic review and meta-analysis.

BACKGROUND: Regenerative techniques are increasingly being advocated in endodontic apical surgery (AS) to enhance the healing of periapical lesions. Various grafting and membrane materials are employed as adjuncts to modern AS. OBJECTIVES: This systematic review aimed to answer the following PICO question: In patients with apical periodontitis (P) what is the impact of bone grafting with/without barrier membrane materials (I) compared with surgery without grafting materials (C) on the outcome of AS evaluated clinically and radiographically (O). METHODS: A systematic search was conducted in four databases (Embase, Web of Science, PubMed and Cochrane Central Register of Controlled Trials) until 1 August 2023. Google Scholar was also manually searched. Studies with a prospective randomized design were included. Cochrane risk-of-bias (RoB) tool 2.0 assessed bias. Two independent reviewers performed the study selection, data extraction and appraisal of studies. Meta-analysis was performed using R3.5.1 software. RESULTS: From the identified 2582 studies, eight randomized clinical trials were included for meta-analysis. Two studies had low RoB, while six had some concerns. Analysis revealed significantly better outcomes when surgery involved bone regeneration techniques than conventional surgery (OR = 2.18, 95% CI: 1.32-4.31, p = .004). Subgroup analyses on individual grafts (OR = 0.22, 95% CI: -0.99 to 1.44, p = .720) (OR = -0.09, 95% CI: -1.42 to 1.23, p = .885) and membranes (OR = -1.09, 95% CI: -2.94 to 0.76, p = .247) and their combinations (OR = 0.03, 95% CI: -1.50 to 1.55, p = .970) did not yield any significant results. The type of membrane used did not significantly impact the outcome (OR = -1.09, 95% CI: -2.94 to 0.76, p = .247) nor did altering the combination of graft/membrane. DISCUSSION: This systematic review examined the effects of bone grafting with/without membrane placement on the outcome of AS. It highlights the potential advantages of regenerative techniques and the need for further research in this area. CONCLUSIONS: Based on current evidence, bone grafting with/without barrier membrane placement significantly improves healing after AS. Subgroup analysis of resorbable membranes or grafting did not significantly influence the outcome. The combination of membrane and graft was also not significant. Future well-designed, randomized controlled trials in this area are essential before these materials can be recommended for routine use to enhance healing outcomes in AS. REGISTRATION: PROSPERO (CRD42021255171).

The adjunctive use of antimicrobial photodynamic therapy, light-emitting-diode photobiomodulation and ozone therapy in regenerative treatment of stage III/IV grade C periodontitis: a randomized controlled clinical trial.

OBJECTIVES: To assess the short-term efficacy of multiple sessions of antimicrobial photodynamic therapy (aPDT), light-emitting-diode (LED) photobiomodulation, and topical ozone therapy applications following surgical regenerative treatments on clinical parameters, patient-centered outcomes, and mRNA expression levels of VEGF, IL-6, RunX2, Nell-1, and osterix in gingival crevicular fluid samples in patients with stage III/IV, grade C periodontitis. MATERIALS AND METHODS: Forty-eight systemically healthy patients were assigned into four groups to receive adjunctive modalities with regenerative periodontal surgical treatment. A 970 ± 15 nm diode laser plus indocyanine-green for aPDT group, a 626 nm LED for photobiomodulation group, and topical gaseous ozone were applied at 0, 1, 3, and 7 postoperative days and compared to control group. The clinical periodontal parameters, early wound healing index (EHI), and postoperative patients' morbidity were evaluated. The mRNA levels of biomarkers were assessed by real-time polymerase chain reaction. RESULTS: No significant difference in the clinical parameters except gingival recession (GR) was identified among the groups. For group-by-time interactions, plaque index (PI) and probing pocket depths (PD) showed significant differences (p = 0.034; p = 0.022). In sites with initial PD > 7 mm, significant differences were observed between control and photobiomodulation groups in PD (p = 0.011), between control and aPDT, and control and photobiomodulation groups in CAL at 6-month follow-up (p = 0.007; p = 0.022). The relative osterix mRNA levels showed a statistically significant difference among the treatment groups (p = 0.014). CONCLUSIONS: The additional applications of aPDT and LED after regenerative treatment of stage III/IV grade C periodontitis exhibited a more pronounced beneficial effect on clinical outcomes in deep periodontal pockets.

Developments in Alloplastic Bone Grafts and Barrier Membrane Biomaterials for Periodontal Guided Tissue and Bone Regeneration Therapy.

Periodontitis is a serious form of oral gum inflammation with recession of gingival soft tissue, destruction of the periodontal ligament, and absorption of alveolar bone. Management of periodontal tissue and bone destruction, along with the restoration of functionality and structural integrity, is not possible with conventional clinical therapy alone. Guided bone and tissue regeneration therapy employs an occlusive biodegradable barrier membrane and graft biomaterials to guide the formation of alveolar bone and tissues for periodontal restoration and regeneration. Amongst several grafting approaches, alloplastic grafts/biomaterials, either derived from natural sources, synthesization, or a combination of both, offer a wide variety of resources tailored to multiple needs. Examining several pertinent scientific databases (Web of Science, Scopus, PubMed, MEDLINE, and Cochrane Library) provided the foundation to cover the literature on synthetic graft materials and membranes, devoted to achieving periodontal tissue and bone regeneration. This discussion proceeds by highlighting potential grafting and barrier biomaterials, their characteristics, efficiency, regenerative ability, therapy outcomes, and advancements in periodontal guided regeneration therapy. Marketed and standardized quality products made of grafts and membrane biomaterials have been documented in this work. Conclusively, this paper illustrates the challenges, risk factors, and combination of biomaterials and drug delivery systems with which to reconstruct the hierarchical periodontium.

Development of a PVA/PCL/CS-Based Nanofibrous Membrane for Guided Tissue Regeneration and Controlled Delivery of Doxycycline Hydrochloride in Management of Periodontitis: In Vivo Evaluation in Rats.

Antibiotic administration is an adjacent therapy to guided tissue regeneration (GTR) in the management of periodontitis. This is due to the major role of pathogen biofilm in aggravating periodontal defects. This study aimed to fabricate a GTR membrane for sustained delivery of doxycycline hydrochloride (DOX) while having a space-maintaining function. The membranes were prepared using a polymeric blend of polycaprolactone/polyvinyl alcohol/chitosan by the electrospinning technique. The obtained membranes were characterized in terms of physicochemical and biological properties. Nanofibers showed a mean diameter in the submicron range of < 450 nm while having uniform randomly aligned morphology. The obtained membranes showed high strength and flexibility. A prolonged in vitro release profile during 68 h was observed for manufactured formulations. The prepared membranes showed a cell viability of > 70% at different DOX concentrations. The formulations possessed antimicrobial efficacy against common pathogens responsible for periodontitis. In vivo evaluation also showed prolonged release of DOX for 14 days. The histopathological evaluation confirmed the biocompatibility of the GTR membrane. In conclusion, the developed nanofibrous DOX-loaded GTR membranes may have beneficial characteristics in favour of both sustained antibiotic delivery and periodontal regeneration by space-maintaining function without causing any irritation and tissue damage.

Comparison of immediate vs. delayed guided tissue regeneration in Infrabony defect of second molars after adjacent third molar extraction: a retrospective study.

BACKGROUND: The distal aspect of the second molar (d-M2) often exhibits infrabony defects due to the adjacent third molar. Although the defects can be treated by guided tissue regeneration (GTR) after removing the third molar, the optimal timing remains uncertain following third molar removal in clinical decision-making. This study aimed to compare delayed and immediate GTR treatments to assist in clinical decision-making. METHODS: D-M2 infrabony defects with a minimum 1-year follow-up were collected and divided into three groups: Immediate GTR group, which underwent third molar extraction and received GTR simultaneously; Delayed GTR group, which underwent delayed GTR at least 3 months after third molar extraction; and Control group, which underwent only scaling and root planing during third molar extraction. The clinical and radiographic parameters related to the infrabony defect before GTR and post-surgery were evaluated using the Kruskal-Wallis test or one-way ANOVA, followed by post-hoc Dunn's test or the Bonferroni test for pairwise comparisons. RESULTS: A total of 109 d-M2 infrabony defects were assessed. No significant differences were found between the two GTR groups, although both of them showed significant reductions in infrabony defect depth: the immediate GTR group (2.77 ± 1.97 mm vs. 0.68 ± 1.03 mm, p < 0.001) and the delayed GTR group (2.98 ± 1.08 mm vs. 0.68 ± 1.03 mm, p < 0.001) compared to the control group. CONCLUSION: GTR can effectively improve d-M2 infrabony defects when the third molar is removed, whether simultaneously or delayed. Patients may experience less discomfort with immediate GTR treatment as it requires only one surgery.

Comparative evaluation of treatment of angular bone defect related to over-erupted tooth using guided tissue regeneration (GTR) followed by orthodontic intrusion (OI) versus OI followed by GTR: a controlled clinical trial.

BACKGROUND: Prematurity resulted from pathological migration of periodontally involved teeth with the loss of vertical stopping points between teeth, which can lead to teeth over eruption with dimensional changes favoring occlusal discrepancies. Therefore, evaluating and comparing the effect of guided tissue regeneration followed by orthodontic intrusion as opposed to orthodontic intrusion tracked by guided tissue regeneration in the treatment of an over-erupted tooth with angular bone loss. METHODS: Twenty teeth in ten cases were selected with at least two teeth with vertical over-eruption and angular bone loss with the presence of their opposing. In group one, ten teeth over-erupted were treated by guided tissue regeneration followed by orthodontic intrusion, whereas, in group two, ten teeth over-erupted were treated by orthodontic intrusion followed by guided tissue regeneration. They were evaluated clinically for pocket depth, bleeding on probing, and tooth mobility. Radiographical evaluation assessed by cone beam computed tomography. RESULTS: Clinically, there existed a statistically significant difference (P value ≤ 0.05) in favor of group one at six months post and in favor of group two at one year from re-evaluation regarding pocket depth and tooth mobility. Radiographically, in group one, there was a statistically significant improvement (P value ≤ 0.05) at six months post-guided tissue regeneration or orthodontic intrusion regarding defect depth and dimensional changes of the defect area, with a statistically significant difference (P value ≤ 0.05) in favor of group two at one year from re-evaluation phase regarding defect depth and defect area dimensional changes. CONCLUSION: There was a short-term improvement in group one, which deteriorated over a long period compared with group two, so it is preferable to start orthodontic intrusion before guided tissue regeneration.

Minimal invasiveness in the surgical treatment of intraosseous defects: A systematic review.

The modern approach to regenerative treatment of periodontal intraosseous defects should aim at maximizing the clinical outcomes while minimizing the invasiveness (pain, complications, aesthetic impairment, chair time, and costs) of the procedure. The present systematic review evaluated the effect of flap design, regenerative technology, and perioperative and postoperative adjunctive protocols on invasiveness. Overall, the results of the 13 included trials indicate that: (a) the elevation of a single (buccal or lingual) flap positively influences the intensity of postoperative pain and improves the quality of early wound healing compared with double flaps; (b) while the adjunctive use of a membrane is associated with significantly longer surgery-related chair time and higher postoperative pain, the adjunctive use of enamel matrix derivative at sites receiving a graft significantly reduces postoperative pain; also, graft materials showed no significant impact on invasiveness; (c) open flap debridement performed through the elevation of a single flap may lead to substantial clinical improvements of the lesion with reduced surgery-related chair time and costs, thus representing a promising alternative to regenerative treatment. However, for such an approach, a histological evaluation of the nature of the reconstructed tissues is still lacking, and the presurgery conditions (eg, probing depth, defect severity, and defect morphology), which may benefit in terms of invasiveness, have not yet been defined; and (d) intraoperative and postoperative low-level laser biostimulation of the defect site may favorably modulate the postoperative course.

Do autologous platelet concentrates (APCs) have a role in intra-oral bone regeneration? A critical review of clinical guidelines on decision-making process.

In the past decades, personalized regenerative medicine has gained increased attention. Autologous platelet concentrates (APCs) such as PRP, PRGF, and L-PRF, all serving as a source of a large variety of cells and growth factors that participate in hard and soft tissue healing and regeneration, could play a significant role in regenerative periodontal procedures. This narrative review evaluated the relative impact of APCs in alveolar ridge preservation, sinus floor augmentation, and the regeneration of bony craters around teeth, both as a single substitute or in combination with a xenograft. L-PRF has a significant beneficial effect on alveolar ridge preservation (bone quality). The data for PRGF are less convincing, and PRP is controversial. L-PRF can successfully be used as a single substitute during transcrestal (≥3.5 mm bone gain) as well as 1-stage lateral window sinus floor elevation (>5 mm bone gain). For PRGF and especially PRP the data are very scarce. In the treatment of bony craters around teeth, during open flap debridement, L-PRF as a single substitute showed significant adjunctive benefits (e.g., >PPD reduction, >CAL gain, >crater depth reduction). The data for PRP and PRGF were non-conclusive. Adding PRP or L-PRF to a xenograft during OFD resulted in additional improvements (>PPD reduction, >CAL gain, >bone fill), for PRGF no data were found. Autologous platelet concentrates demonstrated to enhance bone and soft tissue healing in periodontal regenerative procedures. The data for L-PRF were most convincing. L-PRF also has the advantage of a greater simplicity of production, and its 100% autologous character.

Network meta-analysis of platelet-rich fibrin in periodontal intrabony defects.

OBJECTIVES: To evaluate the effect of platelet-rich fibrin alone or in combination with different biomaterials for the treatment of periodontal intra-bony defect. METHODS: Up to April 2022, Cochrane library, Medline, EMBASE, and Web of Science databases were searched for randomized clinical trials. The outcomes of interest were probing pocket depth reduction, clinical attachment level gain, bone gain, and bone defect depth reduction. Bayesian network meta-analysis with 95% credible intervals was calculated. RESULTS: Thirty-eight studies with 1157 participants were included. Platelet-rich fibrin alone or platelet-rich fibrin +biomaterials showed a statistically significant difference when compared with open flap debridement (p < 0.05, low to high certainty evidence). Neither biomaterials alone nor platelet-rich fibrin +biomaterials showed a statistically significant difference when compared to platelet-rich fibrin alone (p > 0.05, very low to high certainty evidence). Platelet-rich fibrin +biomaterials showed insignificant differences as compared to biomaterials alone (p > 0.05, very low to high certainty evidence). Allograft +collagen membrane ranked the best in probing pocket depth reduction while platelet-rich fibrin +hydroxyapatite ranked the best in bone gain. CONCLUSION: It seems that (1) platelet-rich fibrin with/without biomaterials were more effective than open flap debridement. (2) Platelet-rich fibrin alone provides a comparable effect to biomaterials alone and platelet-rich fibrin +biomaterials. (3) Platelet-rich fibrin +biomaterials provide a comparable effect to biomaterials alone. Although allograft +collagen membrane and platelet-rich fibrin +hydroxyapatite ranked the best in terms of probing pocket depth reduction and bone gain respectively, the difference between different regenerative therapies remains insignificant, and therefore, further studies are still needed to confirm these results.

Long-term stability of infrabony defects treated with enamel matrix derivative alone: A retrospective two-centre cohort study.

AIM: To assess the long-term stability of attachment gain in infrabony defects (IBDs) 10 years after regenerative treatment with an enamel matrix derivative (EMD) alone. MATERIALS AND METHODS: Two centres (Frankfurt [F] and Heidelberg [HD]) invited patients for re-examination 120 ± 12 months after regenerative therapy. Re-examination included clinical examination (periodontal probing depths (PPD), vertical clinical attachment level (CAL), plaque index (PlI), gingival index (GI), plaque control record, gingival bleeding index and periodontal risk assessment) and review of patient charts (number of supportive periodontal care [SPC] visits). RESULTS: Both centres included 52 patients (29 female; median baseline age: 52.0 years; lower/upper quartile: 45.0/58.8 years; eight smokers), each contributing one IBD. Nine teeth were lost. For the remaining 43 teeth, regenerative therapy showed significant CAL gain after 1 year (3.0; 2.0/4.4 mm; p < .001) and 10 years (3.0; 1.5/4.1 mm; p < .001) during which CAL remained stable (-0.5; -1.0/1.0 mm; p = 1.000) after an average SPC of 9 years. Mixed-model regression analyses revealed a positive association of CAL gain from 1 to 10 years with CAL 12 months post operation (logistic: p = .01) as well as a higher probability for CAL loss with an increasing vertical extent of a three-walled defect component (linear: p = .008). Cox proportional hazard analysis showed a positive association between PlI after 12 months and tooth loss (p = .046). CONCLUSION: Regenerative therapy of IBDs showed stable results over 9 years. CAL gain is associated with CAL after 12 months and decreasing initial defect depth in a three-walled defect morphology. Tooth loss is associated with PlI 12 months post operation. CLINICAL TRIAL NUMBER: DRKS00021148 (URL: https://drks.de).

Clinical, radiographic, and histological/histomorphometric analysis of maxillary sinus grafting with deproteinized porcine or bovine bone mineral: A randomized clinical trial.

OBJECTIVE: The present study aimed to compare histomorphometrically evaluated new bone formation, radiographically measured graft stability, and clinical implant outcome between maxillary sinus grafting with either deproteinized porcine bone mineral (DPBM) or deproteinized bovine bone mineral (DBBM). MATERIALS AND METHODS: Thirty maxillary sinuses were initially included and randomly assigned to the test group (TG; DPBM, n = 15) or control group (CG; DBBM, n = 15). After a healing period (6 months), axially retrieved bone biopsies of the molar region were used for histological/histomorphometric analysis of new bone formations. Additionally, radiographically measured graft stability and clinical implant outcome were assessed. RESULTS: Twenty-three sinus sites with 10 sinuses of the TG and 13 of the CG were ultimately available for data and statistical analysis. In the TG, a slightly, but yet significantly (p = .040) higher proportion of new bone formation (TG: 27.7 ± 5.6% vs. CG: 22.9 ± 5.1%) and a lesser (p = .019) amount of connective (non-mineralized) tissue (TG: 47.5 ± 9.5% vs. CG: 56.1 ± 9.5%) was found than in the CG. However, both xenografts showed comparable (n.s.) residual bone graft (TG: 23.7 ± 7.2% vs. CG: 21.1 ± 9.85.6%), bone-to-graft contacts (TG: 26.2 ± 9.8% vs. CG: 30.8 ± 13.8%), similar graft height reduction over time (TG: 12.9 ± 6.7% CG: 12.4 ± 5.8%) and implant survival/success rate (100%). At the 3-year post-loading evaluation, the peri-implant marginal bone loss (TG: 0.52 ± 0.19 mm; CG: 0.48 ± 0.15 mm) and the peri-implant health conditions (TG: 87.5%/CG: 81.2%) did not differ between implants inserted in both xenografts used. CONCLUSIONS: The use of DPBM or DBBM for maxillary sinus augmentation is associated with comparable bone formation providing stable graft dimension combined with healthy peri-implant conditions.

Influence of buccal bone wall thickness on the peri-implant hard and soft tissue dimensional changes: A systematic review

BACKGROUND: The significance on the association between the peri-implant bucco-lingual dimension (BLD) at the stage of implant placement and the occurrence of biological and esthetic complications is yet unknown. MATERIAL AND METHODSS: Systematic screening of electronic sources was carried out to identify clinical and preclinical studies reporting on the baseline BLD and/or buccal bone thickness (BBT) values. A secondary objective was to assess the effect of simultaneous grafting at sites with deficient or no buccal bone wall (BBW) at baseline. The primary outcome variables were BBT, BLD, and buccal vertical bone loss (VBL) at re-evaluation. Moreover, radiographic, clinical, and patient-reported outcome measures (PROMs) were evaluated. RESULTS: Overall, 12 clinical and four preclinical studies met the inclusion criteria. Inconsistencies were found in defining the critical BBT across the clinical and preclinical data evaluated. The clinical evidence demonstrated that during healing, dimensional changes occur in the alveolar bone and in the BBW that may compromise the integrity of the peri-implant bone, leading to VBL and mucosal recession (MR), particularly in scenarios exhibiting a thin BBW. The preclinical evidence validated the fact that implants placed in the presence of a thin BBW, are more prone to exhibit major dimensional changes and VBL. Moreover, the clinical data supported that, in scenarios where dehiscence-type defects occur and are left for spontaneous healing, greater VBL and MR together with the occurrence of biologic complications are expected. Furthermore, the augmentation of dehiscence-type defects is associated with hard and soft tissue stability. PROMs were not reported. CONCLUSIONS: Dimensional changes occur as result of implant placement in healed ridges that may lead to instability of the peri-implant hard and soft tissues. Sites presenting a thin BBW are more prone to exhibit major changes that may compromise the integrity of the buccal bone and may lead to biologic and esthetic complications.

Effect of laser-assisted reconstructive surgical therapy of peri-implantitis on protein biomarkers and bacterial load.

OBJECTIVES: This randomized clinical trial assessed changes in protein biomarker levels and bacterial profiles after surgical reconstructive therapy of peri-implantitis and investigated whether the adjunctive use of Er:YAG laser impacts protein biomarker and microbial outcomes. MATERIALS AND METHODS: Twenty-four patients received surgical reconstructive therapy for peri-implantitis with guided bone regeneration following mechanical debridement with (test) or without (control) the adjunctive irradiation of Er:YAG laser. Bacterial and peri-implant crevicular fluid (PICF) samples were collected over 6 months and analyzed with bacterial qPCR and luminex multiplex assays. RESULTS: Surgical reconstructive treatment significantly affected the concentration of PICF protein biomarkers, including a 50% reduction in IL-1ß between 2 and 4 weeks (p < .0001). Both MMP-9 (p < .001) and VEGF (p < .05) levels steadily decreased after treatment. In the laser group, the peak increase in IL-1ß was attenuated at 2 weeks, followed by significant reduction in MMP-9 (p < .01) and VEGF (p < .05) across all follow-up appointments compared with the control nonlaser group. The total bacterial load was reduced 2 weeks after treatment, especially in the laser group, but recolonized to presurgical levels after 4 weeks in both groups (p < .01). The composition of selective pathogens varied significantly over the follow-up, but recolonization patterns did not differ between groups. CONCLUSIONS: Reconstructive therapy of peri-implantitis significantly altered PICF protein biomarker and microbial levels during the healing process. The adjunctive use of Er:YAG laser significantly modulated the inflammatory response through reduced levels of MMP-9 and VEGF during the postsurgical period. The bacterial load was reduced immediately after therapy, but recolonization was observed by 4 weeks in both groups.

Influence of buccal bone wall thickness on the peri-implant hard and soft tissue dimensional changes: A systematic review.

BACKGROUND: The significance on the association between the peri-implant bucco-lingual dimension (BLD) at the stage of implant placement and the occurrence of biological and esthetic complications is yet unknown. MATERIAL AND METHODS: Systematic screening of electronic sources was carried out to identify clinical and preclinical studies reporting on the baseline BLD and/or buccal bone thickness (BBT) values. A secondary objective was to assess the effect of simultaneous grafting at sites with deficient or no buccal bone wall (BBW) at baseline. The primary outcome variables were BBT, BLD, and buccal vertical bone loss (VBL) at re-evaluation. Moreover, radiographic, clinical, and patient-reported outcome measures (PROMs) were evaluated. RESULTS: Overall, 12 clinical and four preclinical studies met the inclusion criteria. Inconsistencies were found in defining the critical BBT across the clinical and preclinical data evaluated. The clinical evidence demonstrated that during healing, dimensional changes occur in the alveolar bone and in the BBW that may compromise the integrity of the peri-implant bone, leading to VBL and mucosal recession (MR), particularly in scenarios exhibiting a thin BBW. The preclinical evidence validated the fact that implants placed in the presence of a thin BBW, are more prone to exhibit major dimensional changes and VBL. Moreover, the clinical data supported that, in scenarios where dehiscence-type defects occur and are left for spontaneous healing, greater VBL and MR together with the occurrence of biologic complications are expected. Furthermore, the augmentation of dehiscence-type defects is associated with hard and soft tissue stability. PROMs were not reported. CONCLUSIONS: Dimensional changes occur as result of implant placement in healed ridges that may lead to instability of the peri-implant hard and soft tissues. Sites presenting a thin BBW are more prone to exhibit major changes that may compromise the integrity of the buccal bone and may lead to biologic and esthetic complications.

Influence of ethylenediaminetetraacetic acid irrigation on the regenerative endodontic procedure in an immature rat molar model.

AIM: To analyse the influence of ethylenediaminetetraacetic acid (EDTA) on the repair process in immature rat molars after a regenerative endodontic procedure (REP). METHODOLOGY: The lower first molars of 12 4-week-old Wistar rats underwent pulpectomy in the mesial root and were divided into the following groups: sodium hypochlorite (NaOCl; n = 6) - the mesial canals were irrigated with 2.5% NaOCl for 5 min, and NaOCl-EDTA (n = 6) - the canals were irrigated with 2.5% NaOCl, followed by 17% EDTA for 5 min each. After evoking bleeding using a size 10 K-file, the cavities were sealed. Three molars on the untreated side were randomly used as control (control-15 d; n = 3), and three molars from the other three rats untreated were used as immediate control (n = 3). After 15 days (NaOCl, NaOCl-EDTA and control-15 d groups) or immediately (control-immediate), the animals were euthanized, and the teeth were subjected to histologic evaluation of tissue regeneration and presence of collagen fibres. Mann-Whitney U-test was used (p < .05). RESULTS: The experimental groups had newly formed cementum-like tissue and increased root length and thickness. Half of the specimens in NaOCl-EDTA group showed apical foramen closure, whilst the NaOCl group had partial apical closure. The experimental groups showed inflammatory infiltrate extending mainly to the medium third of the root canal. These parameters were similar between experimental groups (p > .05). Newly formed connective tissue in the pulp space was significantly higher in the NaOCl-EDTA group than in NaOCl group (p < .05). Regarding the collagen fibres, the NaOCl-EDTA group had more collagen fibres in the root tip, but there was no significant difference compared to NaOCl group, and both groups showed greater amount of immature fibres in this area; in the centre of the apical third of root canal, there was equivalence between mature and immature fibres from both groups (p > .05). CONCLUSIONS: Ethylenediaminetetraacetic acid irrigation improved newly formed intracanal connective tissue after REP in immature molars of rats; however, EDTA did not influence cementum-like tissue formation, apical closure, inflammatory infiltrate and maturation of collagen fibres.