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Objectives: Alendronate and raloxifene, a bisphosphonate and a selective estrogen modulator, respectively, are established osteoporosis therapies. Current evidence suggests that simultaneous application of osteoporosis therapies modulates osseointegration. However, alendronate shows inconsistent findings and raloxifene has not been studied comprehensively. This study aimed to evaluate the bone dynamics and molecular and microstructural features at the peri-implant bone interface in osteoporotic rats., Materials and Methods: Thirty female rats underwent ovariectomy and were fed a diet low in calcium and phosphate and treated with alendronate or raloxifene for 30 days or underwent fictional ovariectomy surgery (SHAM) prior to implant insertion in the tibia; osteoporosis therapies continued thereafter. After 42 days, peri-implant bone was evaluated by histometric and micro-CT analysis. Fluorochrome incorporation and gene expression was determined to evaluate bone turnover., Results: We report here that alendronate had no impact on bone-to-implant contacts and the mineral apposition rate. The RANKL/OPG ratio and local bone volume, however, were increased compared to the untreated osteoporotic rats. Even though signaling to bone resorption activity through RANKL production was observed in the alendronate group, the blockade of bone resorption activity that occurs in decorrence to alendronate activity took place and resulted in an increase in bone volume. Raloxifene significantly increased osseointegration in osteoporotic rats, as indicated by bone-to-implant contacts, mineral apposition, and local bone volume. Raloxifene, however, had no considerable impact on the RANKL/OPG ratio compared to untreated osteoporotic rats. As expected, the SH group showed higher bone-to-implant contacts and mineral apposition rates than the untreated osteoporotic rats., Conclusions: These findings suggest that raloxifene but not alendronate can compensate for the impaired osseointegration in osteoporotic rats., Clinical Relevance: Regarding the superiority of raloxifene observed in the improvement of bone dynamics response, this statement suggests that raloxifene could be a good option for osteoporosis patients in oral rehabilitation procedures.

Background: Current strategies to reduce medical device-associated infections propose zirconia as a potential implant material which may limit bacterial adhesion. Because multinucleated giant cells (MNGCs) have been detected on these implant surfaces, concerns have been raised regarding tissue integration., Purpose: The present study examined the presence of MNGCs and their subsequent effect upon tissue integration. Surface-modified implants made of yttria-stabilized (TZP) and alumina-toughened zirconia (ATZ) were compared with commercially pure titanium (Ti)., Materials and Methods: Seven miniature pigs received three implants on either side of the maxilla. After healing periods of 4 and 8 weeks, the tissue response at the implant surfaces was characterized according to three specific parameters: bone-to-implant contact (BIC), MNGC-to-implant contact (MIC), and the peri-implant bone density (BD)., Results: Despite being present on all tested implant surfaces, MNGCs were not associated with an inflammatory cell infiltrate or with fibrous encapsulation. MNGCs were less numerous on the Ti implants (range: 3.9-5.2%) compared with the ceramic implants (range: 17.6-30.3%, p < .0001). Even though the values of newly formed bone and pristine bone in direct contact with the implant surfaces were high at 4 weeks (tBIC: Ti = 82.3%, TZP = 64.3%, ATZ = 70%), a negative correlation was observed between the presence of MNGCs and newly formed bone at the implant surface (p < .001). Interestingly, the newly formed peri-implant bone density, defined as the percentage of new bone area inside the screw threads (nBD), was not diminished by the presence of MNGCs., Conclusions: Differences in the presence of MNGCs and the BIC parameters between Ti and the ceramic implants appear to be a local cellular phenomenon which is restricted to the implant-bone marrow interface and do not affect the peri-implant bone formation. Factors triggering MNGC differentiation and their persistence in response to biomaterial surface need to be investigated in future studies., (© 2015 Wiley Periodicals, Inc.)

Objectives: Uncontrolled diabetes mellitus is associated with impaired osseointegration. Diabetic individuals might benefit from bone anabolic therapies. Intermittent administration of 1-34 parathyroid hormone (PTH) stimulates bone formation in rodent models. However, this anabolic effect fails in diabetic rats. Whether the anabolic effect of PTH can be achieved in insulin-controlled diabetic rats has not been investigated yet., Materials and Methods: After diabetes induction with streptozotocin in 40 female Wistar rats, the animals were randomly divided into 4 groups: diabetes, diabetes plus PTH, insulin-treated diabetes, and insulin-treated diabetes plus PTH. After 1 week, miniscrews were inserted in the tibiae. Osmotic pumps with insulin or saline solution were implanted. Animals received 60 mg/kg PTH or saline solution. Histomorphometric analysis was performed., Results: In diabetic rats, no changes of medullary periimplant bone area or bone-to-implant contacts (BICs) were achieved with or without treatment with PTH. However, also animals treated with insulin failed to response significantly to PTH regarding bone area (7.4 ± 4.1% and 8.1 ± 4.1%) and BICs (33.7 ± 16.9% and 49.9 ± 11.9%)., Conclusion: These results demonstrate that the metabolic characteristics of the diabetic rats produced a condition unable to respond to PTH treatment, even when hyperglycemia was controlled with insulin.

Objective: The first objective of this pilot study was to evaluate the impact of the hydrophilicity on the early phases of osseointegration. The second objective was to compare two hydrophilic implant surfaces with different geometries, surface roughness, and technologies achieving hydrophilicity., Material and Methods: Twelve weeks after extraction, all four quadrants of nine minipigs received three dental implants, alternating between hydrophilic microrough surfaces (INICELL and SLActive) and a conventional hydrophobic microrough surface. After 5, 10, and 15 days of submerged healing, ground sections were prepared and subjected to histologic and histomorphometric analysis., Results: The histologic analysis revealed a similar healing pattern among the hydrophilic and hydrophobic implant surfaces, with extensive bone formation occurring between day 5 and day 10. With BIC values of greater than 50% after 10 days, all examined surfaces indicated favorable osseointegration at this very early point in healing. At day 15, the mean new bone-to-implant contact (newBIC) of one hydrophilic surface (INICELL; 55.8 ± 14.4%) was slightly greater than that of the hydrophobic microrough surface (40.6 ± 20.2%). At day 10 and day 15, an overall of 21% of the implants had to be excluded from analysis due to inflammations primarily caused by surgical complications., Conclusion: Substantial bone apposition occurs between day 5 and day 10. The data suggest that the hydrophilic surface can provoke a slight tendency toward increased bone apposition in minipigs after 15 days. A direct comparison of two hydrophilic surfaces with varying geometries is of limited relevance., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Vitamin D deficiency is highly prevalent in the population and associated with impaired peri-implant bone regeneration. Yet, there is a gap in understanding the impact of vitamin D supplementation on the process of osseointegration. In this study, the effect of vitamin D supplementation on peri-implant bone regeneration was investigated., Methods: Fifty ovariectomized Sprague-Dawley rats were divided into three groups. The depletion group was fed a vitamin D-free diet for 8 weeks. The repletion group received vitamin D-free diet for 6 weeks, before animals were switched to standard diet containing 2400 IU/kg vitamin D. The control group was fed the standard diet. Two titanium mini-implants were placed in the tibia. All groups remained on their previous diet until sacrifice. Blood sample testing and histomorphometric analysis were performed., Results: Vitamin D depletion caused a significant reduction in 25-hydroxvitamin D in rat serum that returned to control levels in the repletion group. This vitamin deficiency was associated with a decrease in bone-to-implant contact in the cortical area, which was leveled to controls in the repletion group. No significant changes by vitamin D depletion were noticed in the medullar compartment. Moreover, also the peri-implant bone area and the mineral apposition rate remained unchanged upon vitamin D depletion., Conclusion: These results indicate that vitamin D deficiency has a negative impact on cortical peri-implant bone formation in ovariectomized rats, which can be compensated by vitamin D supplementation. This study provides first insight into the potential beneficial effect of vitamin D supplementation in implant dentistry., (© 2011 John Wiley & Sons A/S.)

Objectives: Diabetes is considered a risk factor in the osseointegration of dental implants, which suggests that these patients might benefit from anabolic therapies. Preclinical studies, including investigations by this research group, revealed that intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of titanium implants under physiological conditions. However, the anabolic effect of PTH on osseointegration under the hyperglycemic condition of diabetes is unknown., Methods: The ability of PTH to stimulate osseointegration was investigated in 40 female Wistar rats that were randomly divided into the following treatment groups: diabetes, diabetes plus PTH, control, and control plus PTH. Diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg) at 1 week before implantation. Rats received PTH at a dose of 60 μg/kg or a vehicle by subcutaneous injection starting at the day of implant insertion into the tibia. Histomorphometric analysis was performed after 4 weeks., Results: The medullary peri-implant bone area significantly increased in rats receiving PTH in comparison with the control group (41±12% to 20±12%; P<0.01). Moreover, there was an increased bone-to-implant contact (BIC) area in animals treated with PTH (47±18% to 27±16%; P<0.05). In contrast, diabetic rats failed to benefit from the anabolic treatment. A similar peri-implant bone area occurred in the diabetes group, independent of treatment with PTH (13±9% to 15±6%; P>0.05). Moreover, PTH did not affect the BIC area under hyperglycemic conditions (16±12% to 16±8%; P>0.05). No significant changes were observed in the cortical compartment of all groups., Conclusion: These results demonstrate that the metabolic characteristics of the diabetic rats produced a condition that was unable to respond to PTH treatment. These findings led us to hypothesize that metabolic control of diabetes might be a critical determinant when diabetic patients are undergoing anabolic therapy to enhance osseointegration., (© 2011 John Wiley & Sons A/S.)

Purpose: Osteoporosis and diabetes are physiologic determinants that affect the process of osseointegration. The demand for dental implants is high in these patients, who have benefited from progress in preclinical research. Osseointegration has been extensively studied in rat models of osteoporosis and diabetes. The aim of this study is to present an assessment of the published data and provide consideration for future studies., Materials and Methods: The present study summarizes information through a systematic review of the literature from 1997 to 2008 available through PUBMED. The authors found 20 and 13 articles that report on osseointegration of implants in osteoporotic and diabetic rats, respectively. The survey was extended to recent publications on relevant aspects related to species, strains, and quality of endpoint data., Results: Differences in experimental variables such as timing of implant insertion, location of implants, or duration of disease prior to implant placement were reported and can be justified based on the experimental questions. Moreover, heterogeneity was further caused by variations in the age of rats and in reporting of the main parameters of osseointegration in the cortical and medullary compartments. Regardless of these differences, the evidence indicates consistently that ovariectomy results in reduced osseointegration, while there is only moderate evidence for impaired osseointegration in diabetic rats., Conclusions: Selection of the appropriate protocol is critical when studying implant osseointegration in rats. This overview highlights the demand for quality endpoint data related to animal numbers, data collection, and the way to establish osseointegration. Because of the differences in research questions, general recommendations for uniform models for osteoporosis and diabetes cannot be made.

Objective: Graft consolidation follows a gradient that reflects the properties of bone substitutes at sites of sinus augmentation. Here we present an analytical method to investigate the process of graft consolidation taking the distance from the maxillary host bone into account., Material and Methods: We therefore evaluated histological specimens, 6 and 12 weeks after the sinus of minipigs was augmented with Bio-Oss((R)), a deproteinized bovine bone mineral, and Ostim((R)), an aqueous paste of synthetic nanoparticular hydroxyapatite. A curve was drawn that represents the changes in histomorphometric parameters within a given distance from the maxillary host bone., Results: Based on this curve, three regions of interest were defined: R1 (0-1 mm) the bridging distance where new bone is laid onto the host bone, R2 (2-3 mm) a region of osteoconduction where new bone exclusively grows on the biomaterial, R3 (4-5 mm) and a region of osteoconduction where bone formation has reached its maximal extension. Qualitative and quantitative analysis of the three regions can reveal differences in graft consolidation, depending on the bone substitutes and the observation period [Bone volume (BV) per tissue volume after 6 weeks: R1: 19+/-8.4% for Bio-Oss((R)) and 42.9+/-13.2% for Ostim((R)) (P=0.03), R2: 3+/-2.4% for Bio-Oss((R)) and 14.7+/-9.5% for Ostim((R)) (P=0.03), R3: 5+/-4.1% for Bio-Oss((R)) and 5.3+/-5.3% for Ostim((R)) (P=0.86). BV per tissue volume after 12 weeks: R1: 38.0+/-13.3% for Bio-Oss((R)) and 53.3+/-6.6 for Ostim((R)) (P=0.04), R2: 14+/-12.2 for Bio-Oss((R)) and 26.4+/-11 for Ostim((R)) (P=0.18), R3: 6.6+/-7 for Bio-Oss((R)) and 10.7+/-5.8 for Ostim((R)) (P=0.32) after 12 weeks]., Conclusion: Based on the graft consolidation gradient, the impact of bone substitutes to modulate the process of bone formation and the kinetic of degradation within a distinct region of the augmented sinus can be investigated.

Objective: Aging is a physiological determinant that can distinguish the outcome of a pharmaceutical therapy to improve osseointegration of titanium implants. Here we examined the possible interaction of intermittent parathyroid hormone (PTH) and the age of the recipient on the parameters of osseointegration in a rat tibia implantation model., Material and Methods: Twenty female Wistar rats aged 8 months and 20 female rats aged 2 months received PTH at 60 microg/kg body weight or a vehicle by a subcutaneous injection three times a week. After 4 weeks, histomorphometric analysis of the peri-implant area was performed. The possible interaction of the two factors on 'bone volume per tissue volume' (BV/TV) and 'bone-to-implant contact' (BIC) was tested by two-way analysis of variance., Results: Based on data from the medullary compartment, two-way analysis of variance revealed that the effect of 'intermittent PTH' depends on the 'age of the recipient' when BV/TV is considered the dependent variable (P=0.04). Post hoc tests indicated that PTH leads to an increase of BV/TV of adult and young rats. However, when BIC was considered the dependent variable, no interaction was observed (P=0.14). PTH but not aging has a significant impact on BIC. In the cortical compartment, no effects of PTH on osseointegration were observed., Conclusions: The findings indicate that treatment with PTH is more effective on the peri-implant bone regeneration in adult than in young animals, supporting the importance to consider the influences of age on the development of pharmaceutical therapies to increase the process of osseointegration.

Objectives: To determine the effect of magnetron-sputtered calcium phosphate coating of implants on the later stages of osseointegration in a non-human primate model., Material and Methods: Eighteen and 20 implants with a 0.1 microm amorphous calcium phosphate coating and a turned surface, respectively, were inserted in the anterior upper and lower jaw of adult non-human primates. Following a 7.5 months healing period, one part of the implants remained in the submerged position. The other part of implants was connected to healing abutments to allow peri-implant inflammation to occur. After another 20 months, histologic and histomorphometric analysis of the peri-implant area was performed., Results: Submerged implants with a calcium phosphate coating and a turned surface showed no signs of an inflammatory reaction. The histomorphometric parameters 'bone volume per tissue volume' (BV/TV) and 'bone-to-implant contacts' (BIC) were not affected by calcium phosphate coating. Non-submerged implants of both groups showed occasionally signs of inflammation at the implant-abutment junction. Histomorphometric analysis revealed that the distance between the implant-abutment junction and the most coronal level (where bone was attached to the implant) as well as BV/TV and BIC were independent from the surface modification., Conclusion: Our results show that dental implants with calcium phosphate coating behave similar to turned implants independently whether they are connected to healing abutments or remain submerged. Ultra-thin calcium phosphate coating can combine the positive effects of calcium phosphate during the early stage of osseointegration without causing impairment of the later stages.

Introduction: Onplants serve as subperiosteal anchorage in the maxilla to facilitate tooth movement. We determined the applicability of onplants and the process of osseointegration in the mandible of minipigs., Methods: Thirty-six onplants (OnPlants, Nobel Biocare USA, Yorba Linda, Calif) were positioned in 9 adult animals, 2 on each side. At 3, 6, and 12 weeks after surgery, 3 minipigs were killed. Undecalcified ground sections were evaluated histologically and histomorphometrically., Results: Nineteen onplants were lost during the observation period. Newly formed bone per tissue volume was 7% +/- 5% (n = 4), 21% +/- 9% (n = 5), and 22% +/- 13% (n = 8) at the 3 observation times. The corresponding percentages of bone-to-implant contact were 15% +/- 22%, 30% +/- 27%, and 44% +/- 35%. The number of bone-to-implant contacts remained stable over time at 1.0 +/- 0.9 contacts per millimeter. The average lengths of bone-to-implant contacts were 0.2 +/- 0.1 mm, 0.3 +/- 0.2 mm, and 0.5 +/- 0.3 mm., Conclusions: These results showed a low survival rate of onplants in the mandible and that the early stage of healing is central to the process of osseointegration. Stable placement is a prerequisite for onplant survival in the mandible.

Objectives: To study the osseointegration of dental implants under the conditions of impaired blood vessel formation in a rabbit model., Material and Methods: Twenty-four titanium implants were placed in the diaphyses of 12 rabbits, two in each tibia. After 2 days, six animals received TNP-470, an anti-angiogenic substance, 10 mg/kg body weight, three times a week, by subcutaneous injection. The remaining six animals served as controls. All animals were sacrificed 6 weeks post implantation., Results: The amount of newly formed bone (NFB) within a peri-implant distance of 0.2 mm and the percentage of bone-to-implant contacts (BIC) were determined in undecalcified ground sections. In both groups, appositional bone growth originating from the cortex was associated with a dense network of blood vessels. Within 1 mm apical from the implant shoulder, NFB was 29.3+/-6.7% in TNP-470 treated animals vs. 44.2+/-13.1% in the controls (P=0.03). In the adjacent cortical area NFB was 46.1+/-10.0% in TNP-470 treated animals and 58.4+/-3.0% in the control group (P=0.02). In the endosteal area, 3 mm from the implant shoulder NFB was 24.8+/-11.8% in TNP-470-treated animals and 27.0+/-9.6% in controls (P=0.73) and in the most apical peri-implant area corresponding to the bone marrow cavity 4.3+/-3.2% in TNP-470-treated animals and 10.5+/-5.2% in the controls (P=0.03). No decrease in BIC in response to TNP-470 was observed., Conclusion: The data suggest that TNP-470 decreases the formation of peri-implant bone, whereas BIC overall are not affected by it. The rabbit model presented here supports the importance of angiogenesis in the process of peri-implant bone formation.

Purpose: To determine the effects of platelet-released growth factors (PRGF) on bone-to-implant contact (BIC) in minipig cortical bone., Materials and Methods: In each of 8 adult minipigs, 2 implants were placed in the facial wall of the mandible, one implant with and one without PRGF. PRGF was defined as the supernatant from washed, thrombin-activated, allogenic, platelet-rich plasma cells obtained after centrifugation. Four animals were sacrificed at 4 weeks, and the remaining 4 were sacrificed at 8 weeks. For histomorphometric analyses, undecalcified ground specimens were prepared and stained with the Levai-Laczko stain., Results: For the entire follow-up time, 55.30% BIC was found with PRGF versus 38.91% without PRGF (P = .0198). At 4 weeks, BIC was 44.20% with PRGF versus 29.62% without PRGF (P = .0632), and at 8 weeks there was 70.36% BIC with PRGF versus 48.20% without PRGF (P = .1221)., Discussion: Growth factors and other molecules released upon activation of platelet-rich plasma cells can enhance implant anchorage in cortical bone. PRGF obtained from allogenic sources does not impair healing., Conclusion: The results indicated that a single application of PRGF before implant placement can be sufficient to increase the percent BIC in minipig cortical bone.

Simple Summary: This research investigated the impact of different surface modifications on the osseointegration of dental implants. The study conducted experiments on rabbit tibiae comparing conventional machined surfaces (MSs) with those modified using a laser beam (LSs) or a laser beam incorporating hydroxyapatite (HA) by means of biomimetic methods without thermic treatment (LHSs). Utilizing scanning electron microscopy coupled with energy-dispersive X-ray spectrometry (SEM/EDX) and fluorochrome labeling techniques, the study evaluated bone formation over a four-week period. The results demonstrated significantly improved bone contact and newly formed bone area with LSs and LHSs compared to MSs. These findings suggest that surface modifications, particularly LS modifications and LHS modifications, enhance osseointegration, potentially leading to an enhanced longevity and performance of dental implants in clinical settings. (1) Objective: The aim of this study was to assess the biological behavior of bone tissue on a machined surface (MS) and modifications made by a laser beam (LS) and by a laser beam incorporated with hydroxyapatite (HA) using a biomimetic method without thermic treatment (LHS). (2) Methods: Scanning electron microscopy coupled with energy-dispersive X-ray spectrometry (SEM/EDX) was performed before and after installation in the rabbit tibiae. A total of 20 Albinus rabbits randomly received 30 implants of 3.75 × 10 mm in the right and left tibias, with two implants on each surface in each tibia. In the animals belonging to the 4-week euthanasia period group, intramuscular application of the fluorochromes calcein and alizarin was performed. In implants placed mesially in the tibiofemoral joint, biomechanical analysis was performed by means of a removal torque (N/cm). The tibias with the implants located distally to the joint were submitted for analysis by confocal laser microscopy (mineral apposition rate) and for histometric analysis by bone contact implant (%BIC) and newly formed bone area (%NBA). (3) Results: The SEM showed differences between the surfaces. The biomechanical analysis revealed significant differences in removal torque values between the MSs and LHSs over a 2-week period. Over a 4-week period, both the LSs and LHSs demonstrated removal torque values statistically higher than the MSs. BIC of the LHS implants were statistically superior to MS at the 2-week period and LHS and LS surfaces were statistically superior to MS at the 4-week period. Statistical analysis of the NBA of the implants showed difference between the LHS and MS in the period of 2 weeks. (4) Conclusions: The modifications of the LSs and LHSs provided important physicochemical modifications that favored the deposition of bone tissue on the surface of the implants. [ABSTRACT FROM AUTHOR]

Objectives: Chronic liver disease increases the risk for periodontal disease and osteoporotic fractures, but its impacts on bone regeneration remain unknown. Herein, we studied the impact of liver cirrhosis on peri‐implant bone formation. Material and Methods: A total of 20 male Wistar rats were randomly divided into two groups: one with the common bile duct ligated (BDL) and the respective sham‐treated control group (SHAM). After four weeks of disease induction, titanium mini‐screws were inserted into the tibia. Successful induction of liver cirrhosis was confirmed by the presence of clinical symptoms. Another four weeks later, peri‐implant bone volume per tissue volume (BV/TV) and bone‐to‐implant contact (BIC) were determined by histomorphometric analysis. Results: Peri‐implant bone formation was not significantly different between the SHAM and BDL groups. In the cortical compartment, the median percentage of peri‐implant new bone was 10.1% (95% CI of mean 4.0–35.7) and 22.5% (13.8–30.6) in the SHAM and BDL groups, respectively (p =.26). Consistently, the new bone in direct contact with the implant was 18.1% (0.4–37.8) and 23.3% (9.2–32.8) in SHAM and BDL groups, respectively (p =.38). When measuring the medullary compartment, the new bone area was 7.1% (4.8–10.4) and 10.4% (7.2–13.5) in the SHAM and BDL groups, respectively (p =.17). Medullary new bone in direct contact with the implant was 10.0% (1.2–50.4) and 20.6% (16.8–35.3) in SHAM and BDL groups, respectively, and thus comparable between the two groups (p =.46). Conclusions: Bile duct ligation has no significant impact on the early stages of peri‐implant bone formation. [ABSTRACT FROM AUTHOR]

Purpose: Osteogenic cells contribute to the process of osseointegration and graft consolidation. However, whether the cells survive low oxygen tension and maintain their responsiveness to natural and therapeutic growth and differentiation factors remains unknown. Materials and Methods: To determine the effects of low oxygen tension on osteogenic cell viability and responsiveness in vitro, human bone cells were placed into plastic pouches intended to create anaerobic conditions and were either simultaneously or subsequently exposed to supernatants from activated platelets or recombinant bone morphogenetic protein (BMP)-6. Results: Bone cells cultured for up to 72 hours under hypoxia moderately decreased their metabolic activity, which was paralleled by morphologic changes but not by cleavage of the apoptosis markers caspase-3 and poly(ADP)ribose polymerase. Hypoxia suppressed the mitogenic response of bone cells to platelet-released supernatant and the expression of osteogenic differentiation markers alkaline phosphatase and osteocalcin upon incubation with BMP-6. Stimulation of bone cells with platelet-released supernatant and BMP-6 immediately after re-establishment of normoxia caused a moderate cellular response. However, when bone cells were allowed to recover for 7 days under normoxia, their responsiveness was equal to that of cells not previously exposed to low oxygen tension. Conclusions: These findings suggest that osteogenic cells can survive transient hypoxia and retain their potential to respond to growth and differentiation factors once normoxia is re-established. The data also implicate that reoxygenation, and thus blood vessel formation, may be an important determinant for the process of osseointegration and graft consolidation. [ABSTRACT FROM AUTHOR]

Aim: Osteoimmunology covers the cellular and molecular mechanisms responsible for inflammatory osteolysis that culminates in the degradation of alveolar bone. Osteoimmunology also focuses on the interplay of immune cells with bone cells during bone remodelling and regeneration. The aim of this review was to provide insights into how osteoimmunology affects alveolar bone health and disease. Method: This review is based on a narrative approach to assemble mouse models that provide insights into the cellular and molecular mechanisms causing inflammatory osteolysis and on the impact of immune cells on alveolar bone regeneration. Results: Mouse models have revealed the molecular pathways by which microbial and other factors activate immune cells that initiate an inflammatory response. The inflammation‐induced alveolar bone loss occurs with the concomitant suppression of bone formation. Mouse models also showed that immune cells contribute to the resolution of inflammation and bone regeneration, even though studies with a focus on alveolar socket healing are rare. Conclusions: Considering that osteoimmunology is evolutionarily conserved, osteolysis removes the cause of inflammation by provoking tooth loss. The impact of immune cells on bone regeneration is presumably a way to reinitiate the developmental mechanisms of intramembranous and endochondral bone formation. [ABSTRACT FROM AUTHOR]

Objectives: Osteoblasts lay down new bone on implant surfaces. The underlying cellular mechanism and the spatio‐temporal mode of action, however, remain unclear. It can be proposed that growth factors released upon acidification by osteoclasts adsorb to the implant surface and control the early stages of osseointegration. Methods: To simulate bone lysis by osteoclasts, titanium discs were exposed to acid bone lysate (ABL) followed by vigorous washing and seeding of oral fibroblasts. The expression of TGF‐β target genes interleukin 11 (IL11) and NADPH oxidase 4 (NOX4) was evaluated by reverse transcriptase polymerase chain reaction and IL11 ELISA. TGF‐β signaling activation was assessed via Smad2/3 immunofluorescence. The impact of ABL on osteogenic differentiation was determined with murine ST2 mesenchymal stromal cells. Results: We report here that ABL‐conditioned titanium discs, independent of turned or rough surface, increased the expression of IL11 and NOX4. This increase was blocked by the TGF‐β receptor 1 antagonist SB431542. Further support for the TGF‐β signaling activation came from the translocation of Smad2/3 into the nucleus of oral fibroblasts. Moreover, titanium discs exposed to ABL decreased alkaline phosphatase and osteopontin in ST2 cells. Conclusions: These in vitro findings suggest that titanium can adsorb TGF‐β from ABLs. The data provide a strong impetus for studies on the protein adsorption on implant surfaces in vitro and in vivo, specifically for growth factors including bone‐derived TGF‐β during successful and failed osseointegration. [ABSTRACT FROM AUTHOR]

Objective: Hypertension is not only associated with cardiovascular diseases but also with alterations in bone quality. Hypertension therefore might be a risk factor for osseointegration. Preclinical studies suggest that losartan, an angiotensin II receptor blocker widely used to treat hypertension, has a beneficial effect in graft consolidation. Here, we determine the effect of hypertension and losartan on osseointegration. Methods: We used spontaneously hypertensive rats (SHR) and normotensive Wistar albinus rats receiving losartan (30 mg/kg, p.o.) or left untreated. After 1 week, titanium miniscrews were inserted into the tibia. Sixty days after implantation, implant stability was evaluated by removal torque measurement considered the primary endpoint. Microcomputed tomography and histomorphometric analysis were secondary endpoints. Results: Losartan increased the removal torque in the hypertensive SHR group to levels of the Wistar controls. While the cortical parameters of osseointegration remained unchanged, losartan increased medullary bone formation. Microcomputed tomography revealed a higher bone volume per tissue volume and trabecular thickness in the SHR rats treated with losartan. Histomorphometric analysis further showed that losartan significantly increased the thickness of newly formed bone in medullary area in hypertensive SHR rats. Losartan did not significantly alter the parameters of osseointegration in normotensive rats. Conclusions: The data presented suggest that the angiotensin II receptor antagonist losartan increases the medullary parameters of osseointegration in a tibia model of spontaneously hypertensive rats. Considering the study limitations, understanding the impact of hypertension and the respective drugs on osseointegration requires further research. [ABSTRACT FROM AUTHOR]

Objective: Adhesion of osteogenic cells on titanium surfaces is a prerequisite for osseointegration. Alkali treatment can increase the hydrophilicity of titanium implant surfaces, thereby supporting the adhesion of blood components. However, it is unclear if alkali treatment also supports the adhesion of cells with a fibroblastic morphology to titanium. Materials and methods: Here, we have used a titanium alloy (Ti-6AL-4V) processed by alkali treatment to demonstrate the impact of hydrophilicity on the adhesion of primary human gingival fibroblast and bone cells. Also included were the osteosarcoma and fibroblastoma cell lines, MG63 and L929, respectively. Cell adhesion was determined by scanning electron microscopy. We also measured viability, proliferation, and protein synthesis of the adherent cells. Results: Alkali treatment increased the adhesion of gingival fibroblasts, bone cells, and the two cell lines when seeded onto the titanium alloy surface for 1 h. At 3 h, no significant changes in cell adhesion were observed. Cells grown for 1 day on the titanium alloy surfaces processed by alkali treatment behave similarly to untreated controls with regard to viability, proliferation, and protein synthesis. Conclusion: Based on these preliminary In vitro findings, we conclude that alkali treatment can support the early adhesion of cells with fibroblastic characteristics to a titanium alloy surface. [ABSTRACT FROM AUTHOR]

Background: Contour augmentation around early-placed implants (Type 2 placement) using autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) and a collagen barrier membrane has been documented to predictably provide esthetically satisfactory clinical outcomes. In addition, recent data from cone beam computed tomography studies have shown the augmented volume to be stable long-term. However, no human histologic data are available to document the tissue reactions to this bone augmentation procedure. Methods: Over an 8-year period, 12 biopsies were harvested 14 to 80 months after implant placement with simultaneous contour augmentation in 10 patients. The biopsies were subjected to histologic and histomorphometric analysis. Results: The biopsies consisted of 32.0% ± 9.6% DBBM particles and 40.6%± 14.6%mature bone. 70.3%± 14.5%ofthe DBBM particle surfaces were covered with bone. On the remaining surface, multinucleated giant cells with varying intensity of tartrate-resistant acid phosphatase staining were regularly present. No signs of inflammation were visible, and no tendency toward a decreasing volume fraction of DBBM over time was observed. Conclusions: The present study confirms previous findings that osseointegrated DBBM particles do not tend to undergo substitution over time. This low substitution rate may be the reason behind the clinically and radiographically documented long-term stability of contour augmentation using a combination of autogenous bone chips, DBBM particles, and a collagen membrane. [ABSTRACT FROM AUTHOR]

Background Zirconia ( ZrO2) has received interest as a dental material; however, little information is available on the impact of surface modifications on the osseointegration of zirconia implants. Purpose The aim of the present study was to determine the effect of acid or alkaline etching of sandblasted ZrO2 implants on bone apposition in vivo. Methods Cylindrical ZrO2 implants with two circumferential grooves were placed in the maxilla of 12 miniature pigs. Biopsies were harvested after 1, 2, 4, and 8 weeks of healing. Undecalcified toluidine blue-stained ground sections were produced. The bone-to-implant contact, the bone area, and the presence of multinucleated giant cells were determined by histomorphometry. An uncorrected explorative statistical analysis was performed. Results Acid etching but not alkaline etching of sandblasted ZrO2 implants caused more bone-to-implant contact than sandblasted ZrO2 implants. The bone area was unaffected by the surface modifications. Acid and alkaline etching both increased the formation of multinucleated giant cells at the implant surface. Conclusions This study provides a scientific basis to further investigate the impact of acid etching of sandblasted ZrO2 implants on osseointegration and the role of multinucleated giant cells in this process. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate the osteoconductive properties and the volume stability of an injectable paste-like inorganic bone matrix (PBM) in porcine calvaria defects. Material and methods: We created six circumferential defects in the calvaria of 12 adult iberico pigs. The defects were filled with either PBM, Bio-Oss® of different particle size, carrier alone, or left empty. PBM was composed of Bio-Oss® with a particle size ranging from 250 to 500 μm and a hydrogel-carrier of carboxymethylcellulose and collagen. After 6 and 12 weeks of healing, the animals were sacrificed and undecalcified ground sections were prepared and subjected to histologic and histomorphometric analysis. To quantify the osteoconductive properties of PBM, bone volume per tissue volume (BV/TV) in the defect area was determined. To determine the volume stability, bone substitute volume per tissue volume (BSV/TV) was measured. Results: After 6 weeks, PBM particles in the center of the defect were surrounded by fibrous connective tissue, which was later replaced by bone. BV/TV in the PBM group increased from 29.7±12.7% (minimum 12.2%, maximum 43.7%) after 6 weeks to 43.9±14.9% (minimum 27.8%, maximum 63.9%) after 12 weeks (Mann–Whitney test; P=0.6). According to the Friedman test, BV/TV in groups containing Bio-Oss® of different particle sizes, the carrier and the empty defects was similar to the results obtained with PBM (6 weeks P=0.8; 12 weeks P=0.22). BSV/TV in the PBM group was stable over time, with 10.1±9% (minimum 3.3%, maximum 27.6%) and 16.5±12.9% (minimum 1%, maximum 32.7%), after 6 and 12 weeks, respectively ( P=0.72). BSV/TV in the PBM group was comparable to the results obtained with the Bio-Oss® particles of different sizes (Friedman test; 6 weeks P=0.0503; 12 weeks P=0.56). Conclusions: The results of this preclinical study showed that the PBM is osteoconductive and maintains the augmented volume, similar to commercial Bio-Oss®. These data suggest that the osteoconductive properties of Bio-Oss® are maintained at the smaller particle size and in the presence of the carrier. [ABSTRACT FROM AUTHOR]

Background Receptor activator of NF-κB ligand (RANKL), a member of the tumor necrosis factor superfamily, is a key mediator of osteoclast formation, activation, and survival. Thus, it is reasonable to hypothesize that there might be a functional relationship between RANKL expression and peri-implantitis. Purpose This pilot study was performed to determine the reference levels for soluble RANKL (sRANKL) in peri-implant crevicular fluid and to correlate them with the clinical parameters associated with inflammatory reactions and bone destruction. Materials and Methods The clinical parameters probing depth (PD), modified bleeding index (MBI), and modified plaque index (MPI) served as indicators for bone resorption and inflammation. Exclusion criteria for calculations were the detection limit of the immunoassay and the minimum acceptable crevicular volume for measurement. From the 84 collected samples of 16 patients, 30–84 years of age, with a total of 19 implants, 29 met these criteria. The absolute amount of sRANKL within crevicular fluid adsorbed to filter strips was a median of 0.18 femtomol (fmol; range, 0.08–0.53) and 0.26 nM (range, 0.09–1.21) when normalized by volume. PD was 4 mm in median and varied within a range between 2 and 12 mm. Results Absolute amounts of sRANKL showed no correlation with the adsorbed volume and the clinical parameters PD, MBI, and MPI. When sRANKL was normalized by volume, no correlation with the clinical parameters PD, MBI, and MPI was observed either. The patients’ age was not associated with total sRANKL and the concentration of RANKL within crevicular fluid. Absolute levels of sRANKL and sRANKL concentration did not show any differences based on the sampling sites buccal and lingual, or on the patients’ gender. A significant difference in sRANKL concentration was detectable when samples from maxillary implants (0.31 nM median; range, 0.12–1.21) were compared with samples from mandibular implants (0.21 nM median; range, 0.09–0.6) ( p=.03). Absolute levels of sRANKL were not different between the maxilla and the mandible. Conclusion Given the limited sample size, our data provide a basis for future prospective longitudinal studies on the possible relevance of sRANKL as a prognostic marker in peri-implantitis, and for an understanding of the pathophysiologic process of the disease as a prerequisite for the design of treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Age related changes in periodontal bone regeneration, osseointegration of dental implants, and graft consolidation are increasingly considered in treatment planning. This study was intended to show whether aging is associated with a diminished responsiveness of osteoprogenitor cells to growth and differentiation factors. Methods: We compared the capacity of bone marrow stromal cells harvested from young and adult rats to proliferate, migrate, and differentiate into the osteogenic lineage following exposure to platelet-released supernatant (PRS) or bone morphogenetic protein 6 (BMP-6). Bone marrow stromal cells were isolated from 12 young rats aged 6 weeks and 12 adult rats aged 9 months. Proliferation was assessed by ³[H]thymidine incorporation, migration was evaluated with the Boyden chamber assay, and osteogenic differentiation was deduced from alkaline phosphatase activity. Results: irrespective of the donor age, bone marrow stromal cells showed increased mitogenic activity and chemotactic motility when exposed to PRS. Adult bone marrow stromal cells had higher alkaline phosphatase activities at baseline and upon incubation with BMP-6 than cells obtained from young animals. There was no difference between the two groups in the slope of the alkaline phosphatase activity curve following stimulation with BMP-6. Conclusions: The data demonstrate that, irrespective of their age, bone marrow stromal cells respond similarly to PRS and BMP-6 under in vitro conditions. These findings suggest that osteoprogenitor cells within the bone marrow of adult rats retain their juvenile potential to respond to growth and differentiation factors, which are released naturally or are applied therapeutically at sites of bone regeneration. [ABSTRACT FROM AUTHOR]

Hypertension is related with cardiovascular diseases but also with changes in bone metabolism and bone quality. Hypertension consequently might be a risk factor for osseointegration. _B_Aim/Hypothesis_b_The aim was to use the tibia model to study the osseointegration under hypertensive condition treated with losartan. [ABSTRACT FROM AUTHOR]