Delayed osteoblast differentiation and altered inflammatory response around implants placed in incisor sockets of type 2 diabetic rats

Objective: Central to the process of osseointegration is the recruitment of mesenchymal progenitor cells to the healing site, their proliferation and differentiation to bone synthesising osteoblasts. The process is under the control of pro-inflammatory cytokines and growth factors. The aim of this study was to monitor these key stages of osseointegration and the signalling milieu during bone healing around implants placed in healthy and diabetic bone. Methods: Implants were placed into the sockets of incisors extracted from the mandibles of normal Wistar and diabetic Goto-Kakizaki rats. Mandibles 1-12 weeks post-insertion of the implant were examined by histochemistry and immunocytochemistry to localise the presence of Stro-1- positive mesenchymal progenitor cells, proliferating cellular nuclear antigen proliferative cells, osteopontin and osteocalcin, macrophages, pro-inflammatory cytokines interleukin (IL)-1 , IL-6, tumour necrosis factor (TNF)- and tumour growth factor (TGF)- 1. Image analysis provided a semi-quantification of positively expressing cells. Results: Histological staining identified a delay in the formation of mineralised bone around implants placed in diabetic animals. Within the diabetic bone, the migration of Stro-1 mesenchymal cells in the healing tissue appeared to be unaffected. However, in the diabetic healing bone, the onset of cell proliferation and osteoblast differentiation were delayed and subsequently prolonged compared with normal bone. Similar patterns of change were observed in diabetic bone for the presence of IL-1 , TNF- , macrophages and TGF- 1. Conclusion: The observed alterations in the extracellular presence of pro-inflammatory cytokines, macrophages and growth factors within diabetic tissues that correlate to changes in the signalling milieu, may affect the proliferation and differentiation of mesenchymal progenitor cells in the osseointegration process. To cite this article: Colombo JS, Balani D, Sloan AJ, St Crean J, Okazaki J, Waddington RJ. Delayed osteoblast differentiation and altered inflammatory response around implants placed in incisor sockets of type 2 diabetic rats Clin. Oral Impl. Res22, 2011; 578-586 doi: 10.1111/j.1600-0501.2010.01992.x.

Osseointegration: the slow delivery of BMP-2 enhances osteoinductivity

Although the placement of dental and orthopedic implants is now generally a safe, reliable and successful undertaking, the functional outcome is less assured in patients whose bone-healing capacity is compromised. To enhance peri-implant osteogenesis in these individuals, BMP-2 could be locally administered. However, neither a free suspension nor an implant-adsorbed depot of the agent is capable of triggering sustained bone formation. We hypothesize that this end could be achieved by incorporating BMP-2 into the three-dimensional crystalline latticework of a bone-mineral like, calcium-phosphate implant coating, where from it would be liberated gradually - as the inorganic layer undergoes osteoclast-mediated degradation - not rapidly, as from an implant-adsorbed (two-dimensional) depot. To test this postulate, we compared the osteoinductive efficacies of implant coatings bearing either an incorporated, an adorbed, or an incorporated and an adsorbed depot of BMP-2 at a maxillary site in miniature pigs. The implants were retrieved 1, 2 and 3 weeks after surgery for the histomorphometric analysis of bone formation within a defined 'osteoinductive' space. At each juncture, the volume of newly-formed bone within the osteoinductive space was greatest around implants that bore a coating-incorporated depot of BMP-2, peak osteogenic activity being attained during the first week and sustained thereafter. In the other groups, the temporal course of bone formation was variable, and the peak levels were not sustained. The findings of this study confirm our hypothesis: they demonstrate that we now have at our disposal a means of efficaciously augmenting and expediting peri-implant bone formation. Clinically, this possibility would render the process of implant placement a safer and a more reliable undertaking in patients whose bone-healing capacity is compromised, and would also permit a curtailment of the postoperative recovery period by a forestallment of the mechanical-loading phase.

L51P - A BMP2 variant with osteoinductive activity via inhibition of Noggin

Bone morphogenetic proteins (BMP) have to be applied at high concentrations to stimulate bone healing. The limited therapeutic efficacy may be due to the local presence of BMP antagonists such as Noggin. Thus, inhibiting BMP antagonists is an attractive therapeutic option. We hypothesized that the engineered BMP2 variant L51P stimulates osteoinduction by antagonizing Noggin-mediated inhibition of BMP2. Primary murine osteoblasts (OB) were treated with L51P, BMP2, and Noggin. OB proliferation and differentiation were quantified with XTT and alkaline phosphatase (ALP) assays. BMP receptor dependent intracellular signaling in OB was evaluated with Smad and p38 MAPK phosphorylation assays. BMP2, Noggin, BMP receptor Ia/Ib/II, osteocalcin, and ALP mRNA expressions were analyzed with real-time PCR. L51P stimulated OB differentiation by blocking Noggin mediated inhibition of BMP2. L51P did not induce OB differentiation directly and did not activate BMP receptor dependent intracellular signaling via the Smad pathway. Treatment of OB cultures with BMP2 but not with L51P resulted in an increased expression of ALP, BMP2, and Noggin mRNA. By inhibiting the BMP antagonist Noggin, L51P enhances BMP2 activity and stimulates osteoinduction without exhibiting direct osteoinductive function. Indirect osteoinduction with L51P seems to be advantageous to osteoinduction with BMP2 as BMP2 stimulates the expression of Noggin thereby self-limiting its own osteoinductive activity. Treatment with L51P is the first protein-based approach available to augment BMP2 induced bone regeneration through inhibition of BMP antagonists. The described strategy may help to decrease the amounts of exogenous BMPs currently required to stimulate bone healing.

Biomechanical evaluation of the interfacial strength of a chemically modified sandblasted and acid-etched titanium surface

The functional capacity of osseointegrated dental implants to bear load is largely dependent on the quality of the interface between the bone and implant. Sandblasted and acid-etched (SLA) surfaces have been previously shown to enhance bone apposition. In this study, the SLA has been compared with a chemically modified SLA (modSLA) surface. The increased wettability of the modSLA surface in a protein solution was verified by dynamic contact angle analysis. Using a well-established animal model with a split-mouth experimental design, implant removal torque testing was performed to determine the biomechanical properties of the bone-implant interface. All implants had an identical cylindrical shape with a standard thread configuration. Removal torque testing was performed after 2, 4, and 8 weeks of bone healing (n = 9 animals per healing period, three implants per surface type per animal) to evaluate the interfacial shear strength of each surface type. Results showed that the modSLA surface was more effective in enhancing the interfacial shear strength of implants in comparison with the conventional SLA surface during early stages of bone healing. Removal torque values of the modSLA-surfaced implants were 8-21% higher than those of the SLA implants (p = 0.003). The mean removal torque values for the modSLA implants were 1.485 N m at 2 weeks, 1.709 N m at 4 weeks, and 1.345 N m at 8 weeks; and correspondingly, 1.231 N m, 1.585 N m, and 1.143 N m for the SLA implants. The bone-implant interfacial stiffness calculated from the torque-rotation curve was on average 9-14% higher for the modSLA implants when compared with the SLA implants (p = 0.038). It can be concluded that the modSLA surface achieves a better bone anchorage during early stages of bone healing than the SLA surface; chemical modification of the standard SLA surface likely enhances bone apposition and this has a beneficial effect on the interfacial shear strength.

Lesser tuberosity osteotomy for total shoulder arthroplasty. Surgical technique

BACKGROUND: Recent studies have suggested that tenotomy and repair of the subscapularis tendon carried out for anterior approaches to the shoulder can be followed by failure of the tendon repair and by changes resulting in permanent loss of subscapularis function. We hypothesized that release of the subscapularis with use of a superficial osteotomy of the lesser tuberosity followed by repair of the two opposing bone surfaces would lead to consistent bone-to-bone healing, which would be possible to monitor radiographically, and would lead to satisfactory clinical and structural outcomes. METHODS: Thirty-nine shoulders in thirty-six consecutive patients who, at an average age of fifty-seven years, had undergone total shoulder replacement through an anterior approach involving an osteotomy of the lesser tuberosity were evaluated at an average of thirty-nine months. Assessment included a standardized interview and physical examination, scoring according to the system described by Constant and Murley, and imaging with conventional radiography and computed tomography to assess healing of the osteotomy site and changes in the subscapularis. RESULTS: The osteotomized tuberosity fragment healed in an anatomical position in all shoulders, and no cuff tendon ruptures were observed. At the time of follow-up, thirty-three (89%) of thirty-seven shoulders evaluated with a belly-press test had a negative result and twenty-seven (75%) of thirty-six shoulders evaluated with a lift-off test had an unequivocally normal result. Fatty infiltration of the subscapularis muscle increased after the operation (p < 0.0001) and was at least stage two in eleven (32%) of thirty-four shoulders. The fatty infiltration had progressed by one stage in eight (24%) of the thirty-four shoulders, by two stages in five shoulders (15%), and by three stages in two shoulders (6%). CONCLUSIONS: Osteotomy of the lesser tuberosity provides an easy anterior approach for total shoulder replacement and is followed by consistent bone-to-bone healing, which can be monitored, and good subscapularis function. In the presence of documented anatomical healing of the osteotomy site, postoperative fatty infiltration of the subscapularis muscle remains unexplained and needs to be investigated further as it is associated with a poorer clinical outcome.

The effect of rhBMP-2 around endosseous implants with and without membranes in the canine model

BACKGROUND: Bone morphogenetic protein (BMP) is a potent differentiating agent for cells of the osteoblastic lineage. It has been used in the oral cavity under a variety of indications and with different carriers. However, the optimal carrier for each indication is not known. This study examined a synthetic bioabsorbable carrier for BMP used in osseous defects around dental implants in the canine mandible. METHODS: Twelve canines had their mandibular four premolars and first molar teeth extracted bilaterally. After 5 months, four implants were placed with standardized circumferential defects around the coronal 4 mm of each implant. One-half of the defects received a polylactide/glycolide (PLGA) polymer carrier with or without recombinant human BMP-2 (rhBMP-2), and the other half received a collagen carrier with or without rhBMP-2. Additionally, one-half of the implants were covered with a non-resorbable (expanded polytetrafluoroethylene [ePTFE]) membrane to exclude soft tissues. Animals were sacrificed either 4 or 12 weeks later. Histomorphometric analysis included the percentage of new bone contact with the implant, the area of new bone, and the percentage of defect fill. This article describes results with the PLGA carrier. RESULTS: All implants demonstrated clinical and radiographic success with the amount of new bone formed dependent on the time and presence/absence of rhBMP-2 and presence/absence of a membrane. The percentage of bone-to-implant contact was greater with rhBMP-2, and after 12 weeks of healing, there was approximately one-third of the implant contacting bone in the defect site. After 4 weeks, the presence of a membrane appeared to slow new bone area formation. The percentage of fill in membrane-treated sites with rhBMP-2 rose from 24% fill to 42% after 4 and 12 weeks, respectively. Without rhBMP-2, the percentage of fill was 14% rising to 36% fill, respectively. CONCLUSIONS: After 4 weeks, the rhBMP-2-treated sites had a significantly higher percentage of contact, more new bone area, and higher percentage of defect fill than the sites without rhBMP-2. After 12 weeks, there was no significant difference in sites with or without rhBMP-2 regarding percentage of contact, new bone area, or percentage of defect fill. In regard to these three outcomes, comparing the results with this carrier to the results reported earlier with a collagen carrier in this study, only the area of new bone was significantly different with the collagen carrier resulting in greater bone than the PLGA carrier. Thus, the PLGA carrier for rhBMP-2 significantly stimulated bone formation around dental implants in this model after 1 month but not after 3 months of healing. The use of this growth factor and carrier combination appears to stimulate early bone healing events around the implants but not quite to the same degree as a collagen carrier.

Delivery mode and efficacy of BMP-2 in association with implants

Bone healing may be improved in implant patients by the administration of osteogenic agents, such as bone morphogenetic protein 2 (BMP-2). But the efficacy of BMP-2 depends upon its mode of application. We hypothesized that BMP-2 is capable of a higher osteogenic efficacy when delivered physiologically, viz., when incorporated into a calcium-phosphate carrier that mimics mineralized bone matrix, than when administered via simple pharmacological modes, such as by adsorption onto a carrier surface. Using an ectopic rat model, we compared the osteoinductive efficacies of calcium-phosphate implant-coatings bearing either incorporated, adsorbed, or incorporated and adsorbed BMP-2. When adsorbed directly onto the naked implant surface, BMP-2 was not osteogenic. When adsorbed onto a calcium-phosphate coating, it was osteoinductive, but not highly efficacious. When BMP-2 was incorporated into calcium-phosphate coatings, it was a potent bone-inducer, whose efficacy was compromised, not potentiated, by the additional deposition of an adsorbed pool.

Spinal Instrumentation

Spinal instrumentation basically means the implantation of more or less rigid metallic or non-metallic devices which are attached to the spine. These devices function to provide spinal stability and thus facilitate bone healing leading to spinal fusion (spondylodesis). Fundamental biomechanical knowledge and its application serves to improve the performance of the individual spine surgeon with respect to the rate of bony fusion, implant failure or degree of deformity correction. However, biomechanics is inherently linked with (mechano-)biology. And there is still an incomplete understanding of spinal biomechanics and even more so of the underlying biology. Moreover, apparently advantageous biomechanical concepts do not necessarily lead to a better patient outcome.

Interventions for the management of mandibular fractures

BACKGROUND Fractures of the mandible (lower jaw) are a common occurrence and usually related to interpersonal violence or road traffic accidents. Mandibular fractures may be treated using open (surgical) and closed (non-surgical) techniques. Fracture sites are immobilized with intermaxillary fixation (IMF) or other external or internal devices (i.e. plates and screws) to allow bone healing. Various techniques have been used, however uncertainty exists with respect to the specific indications for each approach. OBJECTIVES The objective of this review is to provide reliable evidence of the effects of any interventions either open (surgical) or closed (non-surgical) that can be used in the management of mandibular fractures, excluding the condyles, in adult patients. SEARCH METHODS We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 28 February 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1), MEDLINE via OVID (1950 to 28 February 2013), EMBASE via OVID (1980 to 28 February 2013), metaRegister of Controlled Trials (to 7 April 2013), ClinicalTrials.gov (to 7 April 2013) and the WHO International Clinical Trials Registry Platform (to 7 April 2013). The reference lists of all trials identified were checked for further studies. There were no restrictions regarding language or date of publication. SELECTION CRITERIA Randomised controlled trials evaluating the management of mandibular fractures without condylar involvement. Any studies that compared different treatment approaches were included. DATA COLLECTION AND ANALYSIS At least two review authors independently assessed trial quality and extracted data. Results were to be expressed as random-effects models using mean differences for continuous outcomes and risk ratios for dichotomous outcomes with 95% confidence intervals. Heterogeneity was to be investigated to include both clinical and methodological factors. MAIN RESULTS Twelve studies, assessed as high (six) and unclear (six) risk of bias, comprising 689 participants (830 fractures), were included. Interventions examined different plate materials and morphology; use of one or two lag screws; microplate versus miniplate; early and delayed mobilization; eyelet wires versus Rapid IMF™ and the management of angle fractures with intraoral access alone or combined with a transbuccal approach. Patient-oriented outcomes were largely ignored and post-operative pain scores were inadequately reported. Unfortunately, only one or two trials with small sample sizes were conducted for each comparison and outcome. Our results and conclusions should therefore be interpreted with caution. We were able to pool the results for two comparisons assessing one outcome. Pooled data from two studies comparing two miniplates versus one miniplate revealed no significant difference in the risk of post-operative infection of surgical site (risk ratio (RR) 1.32, 95% CI 0.41 to 4.22, P = 0.64, I(2) = 0%). Similarly, no difference in post-operative infection between the use of two 3-dimensional (3D) and standard (2D) miniplates was determined (RR 1.26, 95% CI 0.19 to 8.13, P = 0.81, I(2) = 27%). The included studies involved a small number of participants with a low number of events. AUTHORS' CONCLUSIONS This review illustrates that there is currently inadequate evidence to support the effectiveness of a single approach in the management of mandibular fractures without condylar involvement. The lack of high quality evidence may be explained by clinical diversity, variability in assessment tools used and difficulty in grading outcomes with existing measurement tools. Until high level evidence is available, treatment decisions should continue to be based on the clinician's prior experience and the individual circumstances.

Callus massage after distraction osteogenesis using the concept of lengthening then dynamic plating.

Correction of complex deformities is a challenging procedure. Long-term wearing of a fixator after correction and lengthening are inconvenient and has a high rate of complication. The goals of the surgical treatment in the presented case were: (1) correction of the deformity and lengthening of the left leg by the Taylor spatial frame (TSF, Smith and Nephew, Marl, Germany); (2) reduction in the time the patient wears the TSF by changing the fixation system to a plate (lengthening then plating-LTP) and using a locking compression plate in conjunction with the 5.0 dynamic locking screws in order to accelerate bone healing.

ChronOS Inject in Children with Benign Bone Lesions – Does It Increase the Healing Rate?

Benign bone lesions in children although rare, can result in a pathological fracture. Although their etiology and pathogenesis are not yet entirely clear, the phenomenon of spontaneous healing is well known. Nevertheless, some benign bone lesions are unlikely to heal spontaneously due to the patient's age or high risk of fracture and deformity due to the lesion's location or size. The following study presents our results after treatment of these bone cysts with chronOS Inject.

Bone marrow-derived cells in palatal wound healing

OBJECTIVE: Myofibroblasts are responsible for contraction and scarring after cleft palate repair. This leads to growth disturbances in the upper jaw. We hypothesized that cells from the bone marrow are recruited to palatal wounds and differentiate into myofibroblasts. METHODS: We transplanted bone marrow from green fluorescent protein (GFP)-transgenic rats into lethally irradiated wild-type rats. After recovery, experimental wounds were made in the palatal mucoperiosteum, and harvested 2 weeks later. GFP-expressing cells were identified using immunostaining. Myofibroblasts, activated fibroblasts, endothelial cells, and myeloid cells were quantified with specific markers. RESULTS: After transplantation, 89 ± 8.9% of mononuclear cells in the blood expressed the GFP and about 50% of adherent cells in the bone marrow. Tissue obtained during initial wounding contained only minor numbers of GFP-positive cells, like adjacent control tissue. Following wound healing, 8.1 ± 5.1% of all cells in the wound area were positive, and 5.0 ± 4.0% of the myofibroblasts, which was significantly higher than in adjacent tissue. Similar percentages were found for activated fibroblasts and endothelial cells, but for myeloid cells it was considerably higher (22 ± 9%). CONCLUSIONS: Bone marrow-derived cells contribute to palatal wound healing, but are not the main source of myofibroblasts. In small wounds, the local precursor cells are probably sufficient to replenish the defect.

Healing of two and three wall intrabony periodontal defects following treatment with an enamel matrix derivative combined with autogenous bone

BACKGROUND: There are still limited data on the outcomes of regenerative periodontal surgery using a combination of an enamel matrix protein derivative (EMD) and autogenous bone (AB). AIM: To evaluate the healing of deep intrabony defects treated with either a combination EMD+AB or EMD alone. MATERIALS AND METHODS: Forty patients with advanced chronic periodontitis, with one deep intrabony defect, were randomly treated with either EMD+AB (test) or EMD (control). Clinical assessments were performed at baseline and at 1 year after treatment. The primary outcome variable was relative attachment level (RAL). RESULTS: Healing was uneventful in all patients. The test sites showed a reduction in the mean probing pocket depth (PPD) of 5.6 +/- 0.9 mm (p<0.001), a gain in the mean RAL of 4.2 +/- 1.1 mm (p<0.001) and a gain in the mean probing bone level (PBL) of 3.9 +/- 1.0 mm (p<0.001). The control group displayed a mean PPD reduction of 4.6 +/- 0.4 mm (p<0.001), a mean RAL gain of 3.4 +/- 0.8 mm (p<0.001) and a mean PBL gain of 2.8 +/- 0.8 mm (p<0.001). RAL gains of > or =4 mm were measured in 90% of the test defects and in 55% of the controls. PBL gains of > or =4 mm were obtained in 85% of the test defects and in 25% of the control ones. The test treatment resulted in statistically higher PPD reductions, RAL gains and PBL gains compared with the control (p<0.01). CONCLUSIONS: Within their limits, the present results indicate that: (i) at 1 year after surgery, both therapies resulted in statistically significant clinical improvements compared with baseline and (ii) although the combination of EMD+AB resulted in statistically significant higher soft and hard tissue improvements compared with treatment with EMD, the clinical relevance of this finding is unclear.

The role of bone debris in early healing adjacent to hydrophilic and hydrophobic implant surfaces in man

To evaluate morphologically and morphometrically the sequential healing and osseointegration events at moderately rough implant surfaces with and without chemical modification. Particularly the role of bone debris in initiating bone formation was emphasized.

Histological evaluation of healing after transalveolar maxillary sinus augmentation with bioglass and autogenous bone

The aim was to evaluate histologically the outcome of a bioglass and autogenous bone (at 1 : 1 ratio) composite implantation for transalveolar sinus augmentation.