Role of the different isoforms of cyclooxygenase and nitric oxide synthase during gastric ulcer healing in cyclooxygenase-1 and -2 knockout mice

Traditional NSAIDs, selective cyclooxygenase (COX)-2 inhibitors, and inhibitors of nitric oxide synthase (NOS) impair the healing of preexisting gastric ulcers. However, the role of COX-1 (with or without impairment of COX-2) and the interaction between COX and NOS isoforms during healing are less clear. Thus we investigated healing and regulation of COX and NOS isoforms during ulcer healing in COX-1 and COX-2 deficiency and inhibition mouse models. In this study, female wild-type COX-1(-/-) and COX-2(-/-) mice with gastric ulcers induced by cryoprobe were treated intragastrically with vehicle, selective COX-1 (SC-560), COX-2 (celecoxib, rofecoxib, and valdedoxib), and unselective COX (piroxicam) inhibitors. Ulcer healing parameters, mRNA expression, and activity of COX and NOS were quantified. Gene disruption or inhibition of COX-1 did not impair ulcer healing. In contrast, COX-2 gene disruption and COX-2 inhibitors moderately impaired wound healing. More severe healing impairment was found in dual (SC-560 + rofecoxib) and unselective (piroxicam) COX inhibition and combined COX impairment (in COX-1(-/-) mice with COX-2 inhibition and COX-2(-/-) mice with COX-1 inhibition). In the ulcerated repair tissue, COX-2 mRNA in COX-1(-/-) mice, COX-1 mRNA in COX-2(-/-) mice, and, remarkably, NOS-2 and NOS-3 mRNA in COX-impaired mice were more upregulated than in wild-type mice. This study demonstrates that COX-2 is a key mediator in gastric wound healing. In contrast, COX-1 has no significant role in healing when COX-2 is unimpaired but becomes important when COX-2 is impaired. As counterregulatory mechanisms, mRNA of COX and NOS isoforms were increased during healing in COX-impaired mice.

Bone healing and graft resorption of autograft, anorganic bovine bone and beta-tricalcium phosphate. A histologic and histomorphometric study in the mandibles of minipigs

OBJECTIVE: The purpose was to qualitatively and quantitatively compare the bone formation and graft resorption of two different bone substitutes used in both orthopedic and oral surgery, with autogenous bone as a positive control. MATERIALS AND METHODS: Three standardized bone defects were prepared in both mandibular angles of 12 adult minipigs. The defects were grafted with either autograft, anorganic bovine bone (ABB), or synthetic beta-tricalcium phosphate (beta-TCP). Sacrifice was performed after 1, 2, 4, and 8 weeks for histologic and histomorphometric analysis. RESULTS: At 2 weeks, more new bone formation was seen in defects filled with autograft than with ABB (P approximately 0.0005) and beta-TCP (P approximately 0.002). After 4 weeks, there was no significant difference between beta-TCP and the two other materials. Defects grafted with ABB still exhibited less bone formation as compared with autograft (P approximately 0.004). At 8 weeks, more bone formation was observed in defects grafted with autograft (P approximately 0.003) and beta-TCP (P approximately 0.00004) than with ABB. No difference could be demonstrated between beta-TCP and autograft. beta-TCP resorbed almost completely over 8 weeks, whereas ABB remained stable. CONCLUSION: Both bone substitutes seemed to decelerate bone regeneration in the early healing phase as compared with autograft. All defects ultimately regenerated with newly formed bone and a developing bone marrow. The grafting materials showed complete osseous integration. Both bone substitutes may have a place in reconstructive surgery where different clinical indications require differences in biodegradability.

Resonance frequency analysis in relation to jawbone characteristics and during early healing of implant installation

OBJECTIVES: To monitor resonance frequency analysis (RFA) in relation to the jawbone characteristics and during the early phases of healing and incorporation of Straumann dental implants with an SLA surface. MATERIAL AND METHODS: 17 Straumann 4.1 mm implants (10 mm) and 7 Straumann 4.8 mm implants (10 mm) were installed and ISQ determined at baseline and after 1, 2, 3, 4, 5, 6, 8 and 12 weeks. Central bone cores were analyzed from the 4.1 mm implants using micro CT for bone volume density (BVD) and bone trabecular connectivity (BTC). RESULTS: Pocket probing depths ranged from 2-4 mm and bleeding on probing from 5-20%. At baseline, BVD varied between 24% and 65% and BTC between 4.9 and 25.4 for the 4.1 mm implants. Baseline ISQ varied between 55 and 74 with a mean of 61.4. No significant correlations were found between BVD or BTC and ISQ Values. For the 4.8 mm diameter implants baseline ISQ values ranged from 57-70 with a mean of 63.3. Over the healing period ISQ values increased at 1 week and decreased after 2-3 weeks. After 4 weeks ISQ values, again increased slightly, no significant differences were noted over time. One implant (4.1 mm) lost stability at 3 weeks. Its ISQ value had dropped from 68 to 45. However the latter value was determined after the clinical diagnosis of instability. CONCLUSION: ISQ values of 57-70 represented homeostasis and implant stability. However no predictive value for loosing implant stability can be attributed to RFA since the decrease occurred after the fact.

Resonance Frequency Analysis (RFA) during early healing

Objectives: - to monitor resonance frequency analysis (RFA) in relation to the jawbone characteristics during the early phases of healing and incorporation of Straumann® dental implants with an SLA surface. Material and methods: 17 Straumann 4.1mm implants (10mm) and 7 Straumann 4.8mm implants (10mm) were installed and ISQ determined at baseline and after 1, 2, 3, 4, 5, 6, 8 and 12 weeks. Central bone cores were analyzed from the 4.1mm implants using micro CT for bone volume density (BVD) and bone trabecular connectivity (BTC). Results: Pocket probing depths ranged between 2-4mm and bleeding on probing between 5-20%. At baseline, BVD varied between 24 and 65% and BTC between 4.9 and 25.4 for the 4.1mm implants. Baseline ISQ varied between 55 and 74 with a mean of 61.4. No significant correlations were found between BVD or BTC and ISQ Values. For the 4.8mm diameter implants baseline ISQ values ranged from 57 – 70 with a mean of 63.3. Over the healing period ISQ values increased at 1 week and decreased after 2-3 weeks. After 4 weeks ISQ values, again increased slightly, no significant differences were noted over time. One implant (4.1mm) lost stability at 3 weeks. Its ISQ value had dropped from 68 to 45. However the latter value was determined after the clinical diagnosis of instability. Conclusion: ISQ values of 57 – 70 represented homeostasis and implant stability. However no predictive value for loosing implant stability can be attributed to RFA since decease occurred after the fact.

Correlation of bone defect dimensions with healing outcome one year after apical surgery

This clinical study prospectively evaluated the healing outcome 1 year after apical surgery in relation to bony crypt dimensions measured intraoperatively. The study cohort included 183 teeth in an equal number of patients. For statistical analysis, results were dichotomized (healed versus non-healed cases). The overall success rate was 83% (healed cases). Healing outcome was not significantly related to the level and height of the facial bone plate. In contrast, a significant difference was found for the mean size of the bony crypt when healed cases (395 mm(3)) were compared with non-healed cases (554 mm(3)). In addition, healed cases had a significantly shorter mean distance (4.30 mm) from the facial bone surface to the root canal (horizontal access) compared with non-healed cases (5.13 mm). With logistic regression, however, the only parameter found to be significantly related to healing outcome was the length of the access window to the bony crypt.

Clinical and radiographic assessment of various predictors for healing outcome 1 year after periapical surgery

This clinical study prospectively evaluated the influence of various predictors on healing outcome 1 year after periapical surgery. The study cohort included 194 teeth in an equal number of patients. Three teeth were lost for the follow-up (1.5% drop-out rate). Clinical and radiographic measures were used to determine the healing outcome. For statistical analysis, results were dichotomized (healed versus nonhealed). The overall success rate was 83.8% (healed cases). The only individual predictors to prove significant for the outcome were pain at initial examination (p=0.030) and other clinical signs or symptoms at initial examination (p=0.042), meaning that such teeth had lower healing rates 1 year after periapical surgery compared with teeth without such signs or symptoms. Logistic regression revealed that pain at initial examination (odds ratio=2.59, confidence interval=1.2-5.6, p=0.04) was the only predictor reaching significance. Several predictors almost reached statistical significance: lesion size (p=0.06), retrofilling material (p=0.06), and postoperative healing course (p=0.06).

Immediate implant placement with transmucosal healing in areas of aesthetic priority. A multicentre randomized-controlled clinical trial I. Surgical outcomes

OBJECTIVES: To compare the clinical outcomes of standard, cylindrical, screw-shaped to novel tapered, transmucosal (Straumann Dental implants immediately placed into extraction sockets. Material and methods: In this randomized-controlled clinical trial, outcomes were evaluated over a 3-year observation period. This report deals with the need for bone augmentation, healing events, implant stability and patient-centred outcomes up to 3 months only. Nine centres contributed a total of 208 immediate implant placements. All surgical and post-surgical procedures and the evaluation parameters were discussed with representatives of all centres during a calibration meeting. Following careful luxation of the designated tooth, allocation of the devices was randomly performed by a central study registrar. The allocated SLA titanium implant was installed at the bottom or in the palatal wall of the extraction socket until primary stability was reached. If the extraction socket was >or=1 mm larger than the implant, guided bone regeneration was performed simultaneously (Bio Oss and BioGide. The flaps were then sutured. During non-submerged transmucosal healing, everything was done to prevent infection. At surgery, the need for augmentation and the degree of wound closure was verified. Implant stability was assessed clinically and by means of resonance frequency analysis (RFA) at surgery and after 3 months. Wound healing was evaluated after 1, 2, 6 and 12 weeks post-operatively. RESULTS: The demographic data did not show any differences between the patients receiving either standard cylindrical or tapered implants. All implants yielded uneventful healing with 15% wound dehiscences after 1 week. After 2 weeks, 93%, after 6 weeks 96%, and after 12 weeks 100% of the flaps were closed. Ninety percent of both implant designs required bone augmentation. Immediately after implantation, RFA values were 55.8 and 56.7 and at 3 months 59.4 and 61.1 for cylindrical and tapered implants, respectively. Patient-centred outcomes did not differ between the two implant designs. However, a clear preference of the surgeon's perception for the appropriateness of the novel-tapered implant was evident. CONCLUSIONS: This RCT has demonstrated that tapered or standard cylindrical implants yielded clinically equivalent short-term outcomes after immediate implant placement into the extraction socket.

Systemic response of the GH/IGF-I axis in timely versus delayed fracture healing

The GH-IGF axis has profound effects on the local and systemic regulation of bone metabolism and may be important for quality of fracture healing. To test the hypothesis that deficiency of the GH/IGF axis may play a role in the pathogenesis of fracture non-union we investigated whether alterations of serum concentrations of the GH-IGF axis could be related to failed fracture healing compared to timely fracture healing in trauma patients. Serum probes were prospectively collected from 186 patients with surgical treatment of long bone fractures up to 6 months after surgery. Samples from 14 patients with atrophic type of non-union have been compared to 14 matched patients with normal bone healing. Postoperative time courses of serum concentrations have been analyzed using commercially available chemiluminescence sandwich assays (GH), fully automated assay systems (IGF-I, IGFBP-3) or sandwich immunometric assays (ALS). Comparison between both collectives revealed significantly lower serum concentrations of GH dependent ALS during early (1st week after surgery) and of both IGFBP-3 and ALS during late stages of fracture healing (6 and 8 weeks after surgery) in non-union patients, coinciding clinically with failed fracture healing. Tendentially lower serum levels of IGF-I in the non-union group over the entire investigation period were statistically not significant. We have been able to show time courses of serum concentrations of the GH/IGF-I axis during normal and failed fracture healing in humans. An impairment of the GH/IGF-I axis might be involved in the biochemical mechanisms determining delayed or failed fracture healing.

[TGF-beta1 as a pathophysiological factor in fracture healing]

AIM: TGF-beta1 is an important local and systemic regulatory molecule during fracture healing. Various authors have shown differences in the systemic levels of TGF-beta1 over the time taken for bone healing in distraction osteogenesis and osteotomies. Previous studies have shown characteristic differences in the physiological levels of growth factors between normal fracture healing and delayed fracture union. The aim of the present study was to evaluate possible differences in sera levels of patients with normal and delayed union fracture healing. METHODS: Patients with long bone shaft fractures were recruited prospectively. Peripheral blood samples were collected over a period of 1 year using a standardized time schedule. At the end of the individual's investigation period, TGF-beta1 levels were determined. To achieve a homogeneous collective of patients, only those with a maximum of two fractures were included in the study. After matching for four criteria, we compared patients with normal fracture healing to patients with delayed unions. The fact of delayed union was accepted in case of failed consolidation 4 months after trauma. RESULTS: During a prospective study period of 1 year, 15 patients with normal fracture healing could be compared to 15 patients suffering from delayed union. By determining the absolute sera levels we found a typical increase of TGF-beta1 up to 2 weeks after fracture in both groups, with a subsequent decrease up to the sixth week after fracture. However, a decline in serum concentration occurred earlier in patients with delayed union, causing significantly lower TGF-beta1 levels in the non-union group 4 weeks after trauma (P=0.00006). CONCLUSION: Even with a relatively small number of patients, we could show a significant difference in serum concentrations of TGF-beta1 between the investigated groups. If these results can be verified within a larger collective, TGF-beta1 could be used as a predictive cytokine for delayed fracture healing.

Evaluation of healing criteria for success after periapical surgery

INTRODUCTION: In periapical surgery, the absence of standardization between different studies makes it difficult to compare the outcomes. OBJECTIVE: To compare the healing classification of different authors and evaluate the prognostic criteria of periapical surgery at 12 months. MATERIAL AND METHODS: 278 patients (101 men and 177 women) with a mean age of 38.1 years (range 11 to 77) treated with periapical surgery using the ultrasound technique and a 2.6x magnifying glass, and silver amalgam as root-end filling material were included in the study. Evolution was analyzed using the clinical criteria of Mikkonen et al., 1983; radiographic criteria of Rud et al., 1972; the overall combined clinical and radiographic criteria of von Arx and Kurt, 1999; and the Friedman (2005) concept of functional tooth at 12 months of surgery. RESULTS: After 12 months, 87.2% clinical success was obtained according to the Mikkonen et al., 1983 criteria; 73.9% complete radiographic healing using Rud et al. criteria; 62.1% overall success, following the clinical and radiographic parameters of von Arx and Kurt, and 91.9% of teeth were functional. The von Arx and Kurt criteria was found to be the most reliable. CONCLUSION: Overall evolution according to von Arx and Kurt agreed most closely with the other scales.