Implant-assisted removable partial dentures: Part I. a scoping review of clinical applications.

PURPOSE: This scoping review aimed to systematically map research regarding implant-assisted removable partial dentures (IARPDs), and identify existing gaps in knowledge. STUDY SELECTION: Two reviewers independently conducted a search of the MEDLINE-PubMed and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) extension for Scoping Review and included articles published in English up to August 31, 2022, including human studies, reviews, and in vitro studies. Expert opinions, animal studies, and clinical studies involving complete overdentures were excluded, and ten aspects for establishing the treatment strategy for IARPDs were examined. RESULTS: One hundred and twelve articles were chosen. There were two treatment modalities: IARPDs retained by implant- and tooth-supported surveyed single crowns (SCs) or fixed partial dentures (FPDs). In IARPDs retained by tooth-supported surveyed SCs or FPDs, the survival rate of dental implants for IARPDs was relatively higher with a wide range of marginal bone loss and many complications, but with improved functional performance, oral health-related quality of life, and patient satisfaction. There were limited data on survival or success rates and designs of IARPDs, attachment selections, length and diameter, inclination, placement sites, and loading protocols of implants, regardless of prosthetic types. There was limited information on maxillary IARPDs except for survival rates of implants. CONCLUSIONS: Although IARPDs could become a useful treatment strategy, there is limited scientific consensus with gaps in knowledge about their use. Additional well-designed clinical and in vitro studies are necessary to scientifically establish IARPDs as definitive prostheses in implant dentistry.

Implant-assisted removable partial dentures: Part II. a systematic review of the effects of implant position on the biomechanical behavior.

PURPOSE: This systematic review aimed to evaluate the effects of implant placement sites on the biomechanical behavior of implant-assisted removable partial dentures (IARPDs) using finite element analysis (FEA). STUDY SELECTION: Two reviewers independently conducted manual searches of the PubMed, Scopus, and ProQuest databases for articles investigating implant location in IARPDs using FEA, according to the 2020 Systematic Reviews and Meta-analyses statement. Studies published in English up to August 1, 2022, were included in the analysis based on the critical question. RESULTS: Seven articles meeting the inclusion criteria were systematically reviewed. Six studies investigated mandibular Kennedy Class I and one study investigated mandibular Kennedy Class II. Implant placement reduced the displacement and stress distribution of the IARPD components, including dental implants and abutment teeth, regardless of the Kennedy Class type and dental implant placement site. Most of the included studies showed that, based on the biomechanical behavior, the molar region, rather than the premolar region, is the preferred implant placement site. None of the selected studies investigated the maxillary Kennedy Class I and II. CONCLUSIONS: Based on the FEA regarding mandibular IARPDs, we concluded that implant placement in both the premolar and molar regions improves the biomechanical behaviors of IARPD components, regardless of the Kennedy Class. Implant placement in the molar region results in more suitable biomechanical behaviors compared with implant placement in the premolar region in Kennedy Class I. No conclusion was reached for Kennedy Class II due to the lack of relevant studies.

Effect of intraoral administration of parathyroid hormone on osseous and soft tissue healing around implants in ovariectomized rat maxillae.

OBJECTIVES: Intermittent administration of parathyroid hormone (PTH) increases systemic bone mass. However, the effect of PTH on osseous and soft tissue healing around implants in osteoporosis patients remains unclear. This study aimed to investigate the effects of PTH on tissue healing around implants in ovariectomized rats and to compare systemic and intraoral administration routes. MATERIAL AND METHODS: Implants were placed at the healed sites of ovariectomized rats 3 weeks after maxillary first molar extraction. Rats were randomly divided into two groups that received either daily systemic subcutaneous or local intraoral PTH administration. Maxillae were dissected to examine bone architectures with micro-computed tomography images. Histomorphometric and immunohistochemical analyses were performed to evaluate osseous and soft tissue healing around the implants. RESULTS: Regardless of the administration route, PTH significantly increased bone area and the numbers of osteoblasts, osteoclasts, and osteocytes in the first and second inside and outside areas of implant threads, in addition to decreasing the number of sclerostin+ osteocytes. However, the intraoral PTH administration route was superior to the systemic route by significantly improving bone quality and promoting collagen production in the connective tissue around implants. CONCLUSIONS: Parathyroid hormone administration promoted both osseous and soft tissue healing around implants, irrespective of administration route. Interestingly, intraoral administration improved the evaluated parameters more than systemic administration. Thus, the intraoral route could become a useful treatment strategy for implant treatment in osteoporosis patients.

Modeling of intramembranous ossification using human pluripotent stem cell-derived paraxial mesoderm derivatives.

Vertebrates form their skeletal tissues from three distinct origins (the neural crest, paraxial mesoderm, and lateral plate mesoderm) through two distinct modes of ossification (intramembranous and endochondral ossification). Since the paraxial mesoderm generates both intramembranous and endochondral bones, it is thought to give rise to both osteoprogenitors and osteo-chondroprogenitors. However, it remains unclear what directs the paraxial mesoderm-derived cells toward these different fates in distinct skeletal elements during human skeletal development. To answer this question, we need experimental systems that recapitulate paraxial mesoderm-mediated intramembranous and endochondral ossification processes. In this study, we aimed to develop a human pluripotent stem cell (hPSC)-based system that models the human intramembranous ossification process. We found that spheroid culture of the hPSC-derived paraxial mesoderm derivatives generates osteoprogenitors or osteo-chondroprogenitors depending on stimuli. The former induced intramembranous ossification, and the latter endochondral ossification, in mouse renal capsules. Transcriptional profiling supported the notion that bone signatures were enriched in the intramembranous bone-like tissues. Thus, we developed a system that recapitulates intramembranous ossification, and that enables the induction of two distinct modes of ossification by controlling the cell fate of the hPSC-derived paraxial mesoderm derivatives.

Medication-related Osteonecrosis of the Jaw Induced by Regenerative Therapy in Implant Dentistry: A Scoping Review.

OBJECTIVES: There is limited scientific evidence regarding the medication-related osteonecrosis of the jaw (MRONJ) induced by regenerative therapy (RT) associated with dental implant treatment. Thus, the current scoping review systematically maps the MRONJ research induced by RTs in implant dentistry and recognizes the existing gaps in knowledge. DATA: Original studies and reviews investigating the impact of RT on the development of MRONJ were included. SOURCES: Two reviewers independently searched the MEDLINE-PubMed and Scopus databases according to the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) extension for Scoping Review and included articles published in English up to March 31, 2023. STUDY SELECTION: Eighteen articles that fulfilled the inclusion and exclusion criteria were included in this study. Ten mapping parameters for investigating the association of RTs with MRONJ development were examined and evaluated within the selected articles. RESULTS: There was severely limited information regarding the procedures of RTs including; the grafting materials, surgical protocols, and success and failure rates. The RT associated with MRONJ cases was sinus floor augmentation in patients taking bisphosphonate and denosumab. Moreover, there were limited data on the implant treatment associated with RTs such as time of insertion, implant length and diameter, and loading protocol. CONCLUSION: The current scoping review revealed that some specific RTs associated with other factors hold a potential risk of MRONJ occurrence. However, the scientific evidence is limited with many gaps. Further investigations are needed to establish an evidence-based clinical guideline for treating high-risk patients. CLINICAL SIGNIFICANCE: Clinicians should cautiously assess the risk of MRONJ development during implant treatment planning for patients undertaking antiresorptive medications. The adverse outcome of RT procedures should not be underestimated and a complete explanation of the possible risks should be given to the patients.

Depletion of macrophages deteriorates bisphosphonate-related osteonecrosis of the jaw-like lesions in mice.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a potentially intractable disease with no definitive pathophysiology and no treatment and prevention strategies. This study aimed to investigate whether time-selective depletion of macrophages worsens BRONJ-like lesions in mice. A murine model of high-prevalence BRONJ-like lesions in combination with zoledronate/chemotherapeutic drug administration and tooth extraction was created according to the methods of our previous studies. Daily intra-oral submucosal administration of clodronate-loaded liposomes, which temporarily depletes systemic macrophages, was performed immediately after tooth extraction. Spleens, femora, tibiae, and maxillae were dissected 2 weeks after extraction to evaluate BRONJ-like lesions and systemic conditions by micro-computed tomography analysis, histomorphometric and immunofluorescent analyses, and serum chemistry with ELISA. Depletion of macrophages significantly decreased the numbers of local and systemic macrophages and osteoclasts on the bone surface, which markedly worsened osseous healing, with increased necrotic bone and empty lacunae in the existing alveolar bone and newly formed bone in the extraction sockets, and soft tissue healing, with decreased collagen production and increased infiltration of polymorphonuclear cells. Interestingly, the depletion of macrophages significantly shifted macrophage polarization to M1 macrophages through an increase in F4/80+CD38+ M1 macrophages and a decrease in F4/80+CD163+ M2 macrophages, with decreases in the total number of F4/80+ macrophages. These data demonstrated that severe inhibition of osteoclasts in bone tissue and polarization shifting of macrophages in soft tissue are essential factors associated with BRONJ.

Profile of Nagasaki Islands Study (NaIS): A Population-Based Prospective Cohort Study on Multi-disease.

In an aging society, it is important to visualize the conditions of people living with diseases or disabilities, such as frailty and sarcopenia, and determine the environmental and genetic factors underlying such conditions. Atherosclerosis and arterial stiffness are key conditions between these factors and noncommunicable diseases. In 2014, we launched a population-based prospective open-cohort study, the Nagasaki Islands Study (NaIS), which was conducted in Goto City, located in the remote islands of Nagasaki Prefecture, Japan, mostly involving middle-aged and older residents. We conducted our own health checkups along with the annual standardized checkups organized by the municipality; recruited study participants; and started to follow-up with them for vital status (death), migration, and occurrence of diseases such as myocardial infarction, stroke, fracture, and human T-cell leukemia virus type 1 (HTLV-1) -associated uveitis. Our checkups were conducted as baseline surveys in different areas of Goto City during the fiscal years 2014-2016, secondary surveys during 2017-2019, and tertiary surveys since 2021, consisting of medical interviews, physical examinations, blood and urine tests, body composition measurements, osteoporosis screening, arterial stiffness measurements, carotid ultrasonography, and dental examination. A total of 4,957 residents participated in either the baseline or secondary surveys and were followed-up; and 3,594 and 3,364 residents (aged 27-96 and 28-98 years) participated in the baseline and secondary surveys, respectively. In conclusion, the NaIS has been undertaken to reveal the influence of aging and risk factors of noncommunicable diseases and disabilities, with an aim to contribute towards better healthcare in the future.

Effects of ceramic microbeads on bonding between a zirconia framework and layered resin composite.

This study was conducted to evaluate the effects of ceramic microbeads on the bond strength between resin and zirconia. Microbeads made of zirconia (TZ) and zircon (ZS) were treated with and without hydrofluoric acid (HF). The microbeads were sintered to zirconia disks using intermediate feldspathic porcelains. Two control groups, NB (without microbeads) and AS (without porcelain and microbeads), were also prepared. All specimens were treated with a phosphate primer and veneered with a light-curing resin composite. The 24-h shear bond strengths were determined and analyzed by the Tukey-Kramer test (α=0.05, n=10). The TZ-HF specimen exhibited the highest bond strength, followed by TZ, ZS-HF, ZS, AS, and NB. Scanning electron microscopy observations revealed that the TZ-HF specimen had a complicated debonded surface, and it included microconcavities where the microbeads were detached. Sintering etched zirconia beads onto a zirconia framework with feldspathic porcelains is useful for bonding layered resin composite materials.

Zoledronate/Anti-VEGF Neutralizing Antibody Combination Administration Increases Osteal Macrophages in a Murine Model of MRONJ Stage 0-like Lesions.

The pathophysiology, pathogenesis, histopathology, and immunopathology of medication-related osteonecrosis of the jaw (MRONJ) Stage 0 remain unclear, although 50% of MRONJ Stage 0 cases could progress to higher stages. The aim of this study was to investigate the effects of zoledronate (Zol) and anti-vascular endothelial cell growth factor A (VEGFA) neutralizing antibody (Vab) administration on polarization shifting of macrophage subsets in tooth extraction sockets by creating a murine model of MRONJ Stage 0-like lesions. Eight-week-old, female C57BL/6J mice were randomly divided into 4 groups: Zol, Vab, Zol/Vab combination, and vehicle control (VC). Subcutaneous Zol and intraperitoneal Vab administration were performed for 5 weeks with extraction of both maxillary first molars 3 weeks after drug administration. Euthanasia was conducted 2 weeks after tooth extraction. Maxillae, tibiae, femora, tongues, and sera were collected. Structural, histological, immunohistochemical, and biochemical analyses were comprehensively performed. Tooth extraction sites appeared to be completely healed in all groups. However, osseous healing and soft tissue healing of tooth extraction sites were quite different. The Zol/Vab combination significantly induced abnormal epithelial healing, and delayed connective tissue healing due to decreased rete ridge length and thickness of the stratum granulosum and due to decreased collagen production, respectively. Moreover, Zol/Vab significantly increased necrotic bone area with increased numbers of empty lacunae compared with Vab and VC. Most interestingly, Zol/Vab significantly increased the number of CD169+ osteal macrophages (osteomacs) in the bone marrow and decreased F4/80+ macrophages, with a slightly increased ratio of F4/80+CD38+ M1 macrophages compared to VC. These findings are the first to provide new evidence of the involvement of osteal macrophages in the immunopathology of MRONJ Stage 0-like lesions.

Prosthodontic treatment can improve the ingestible food profile in Japanese adult outpatients.

PURPOSE: To investigate the effect of prosthodontic treatment on the ingestible food profile in adult Japanese outpatients, and to identify the related risk factors that can deteriorate the profile. METHODS: The participants were 277 outpatients who visited university-based specialty clinics in Japan for prosthodontic treatment. The demographic data, number of present teeth assessed via intraoral examination, and oral health-related quality of life assessed by the total Oral Health Impact Profile (OHIP-J54) scores of all participants were recorded before treatment. Ingestible food profile score (IFS) was recorded using a validated food intake questionnaire. Eligible participants who answered the questionnaire before and after treatment were categorized into five groups based on the prosthodontic treatments they received (i.e., crowns, bridges, removable partial dentures, removable complete dentures, and removable complete and partial dentures). RESULTS: Multivariate analysis of covariance revealed a statistically significant main effect of prosthodontic intervention (time course: before and after treatment) on mean IFS (P=0.035, F=4.526), even after adjusting for covariates (age, number of present teeth, and treatment modality). Multiple linear regression analysis revealed that the low number of present teeth (r=0.427, P<0.001) and a high OHIP-J54 total score (r=-0.519, P<0.001) of the patients at the baseline were significantly associated with their baseline IFSs, even after adjusting for confounding variables. CONCLUSIONS: The findings of this multicenter follow-up study indicate the importance of prosthodontic rehabilitation in improving patients' ingestible food profiles.

Orally administrable peptides derived from egg yolk promote skeletal repair and ameliorate degenerative skeletal disorders in mouse models.

Introduction: Aging, genetic mutations, and other pathological conditions cause impairment of skeletal growth and bone metabolism, which affect activities of daily living and quality of life in all life stages. Although several drugs have been used in clinical settings and new drugs have been developed for the treatment of skeletal degenerative disorders such as osteoporosis and genetic disorders such as osteogenesis imperfecta (OI), there is clear demand for development of new drugs, especially orally available anabolic drugs that are applicable for a wide range of skeletal disorders. Methods: To identify therapeutic candidates for skeletal disorders, peptide screening was performed. To validate the identified peptides, we performed a bone histomorphometric analysis with rat bone tissues and in vitro cell proliferation assays of skeletal cells. To understand the metabolism of the peptides, we performed a biochemical analysis, followed by in vitro assays for proliferation and differentiation of skeletal cells. We examined the therapeutic efficacy of the identified peptides with several mouse models representing skeletal disorders including bone fracture, osteoporosis, and osteogenesis imperfecta. In vivo therapeutic effects of the candidate were assessed with radiological analysis and mechanical property tests. Results: We identified the egg yolk-derived functional peptide PF201. PF201 promoted in vivo bone formation in rodents and enhanced proliferation of osteoblasts and chondrocytes in vitro. D2, a metabolite of PF201, was present and circulated after digestion and absorption in the digestive tract. D2 had positive impacts on the proliferation and differentiation of mesenchymal stem cells and preosteoblasts. Oral administration of D2 accelerated bone healing in a mouse fracture model. D2 also improved bone strength and fracture healing under ovariectomy-induced osteoporotic conditions in mice, and D2 showed a therapeutic effect in a mouse OI model. Conclusion: D2 is likely to be a candidate for an orally available therapeutic for a range of skeletal disorders.

Medication-related osteonecrosis of the jaw: A literature review and update.

Since the initial description of medication-related osteonecrosis of the jaw (MRONJ) almost two decades ago, the potential pathophysiology and risk factors have been elaborated on in many investigations and guidelines. However, the definitive pathophysiology based on scientific evidence remains lacking. Consequently, the optimal clinical treatment and prevention strategies for MRONJ have not been established. Despite their different mechanisms of action, many drugs, including bisphosphonates, denosumab, angiogenesis inhibitors, and other medications, have been reported to be associated with MRONJ lesions in cancer and osteoporosis patients. Importantly, MRONJ occurs predominantly in the jawbones and other craniofacial regions, but not in the appendicular skeleton. In this up-to-date review, the currently available information and theories regarding MRONJ are presented from both clinical and basic science perspectives. The definition and epidemiology of MRONJ, triggering medication, and histopathology are comprehensively summarized. The immunopathology and the potential pathophysiology based on immune cells such as neutrophils, T and B cells, macrophages, dendritic cells, and natural killer cells are also discussed. In addition, antiangiogenesis, soft tissue toxicity, necrotic bone, osteocyte death, and single-nucleotide polymorphisms are examined. Moreover, other possible mechanisms of MRONJ development are considered based on the unique embryological characteristics, different cell behaviors between jawbones and appendicular skeleton, unique anatomical structures, and sustained bacterial exposure in the oral cavity as a basis for MRONJ site specificity. Based on the literature review, it was concluded that multiple factors may contribute to the development of MRONJ, although which one is the key player triggering MRONJ in the craniofacial region remains unknown.

Controlled mechanical early loads improve bone quality and quantity around implants: An in vivo experimental study.

OBJECTIVES: This study aimed to investigate the effects of early loads on bone quality and quantity around implants and to compare the effects of early loads on bone quality and quantity with the effects of conventional loads. MATERIALS AND METHODS: Grade IV-titanium implants with buttress threads were placed in rat maxillary bone 4 weeks after extraction of first molars. A controlled mechanical load (10 N, 3 Hz, 1800 cycles, 2 days/week) was started via the implants 1 and 3 weeks after implant placement for 2 weeks (early and conventional loads, respectively). Bone quality, defined as distribution of bone cells, types and orientation of collagen fibers, and production of semaphorin3A, its receptor neuropilin-1, and sclerostin, were quantitatively evaluated. RESULTS: Early loads substantially and positively affected bone quality by changing the preferential alignment of collagen fibers with increased production of type I and III collagens, semaphorin3A, and neuropilin-1, increased osteoblast numbers, decreased production of sclerostin, and decreased osteoclast numbers both inside and outside the implant threads, when compared with non-loaded conditions. Conventional loads changed bone quality around implants slightly. Interestingly, early loads had significantly stronger effects on bone quality and quantity based on the evaluation parameters than conventional loads. CONCLUSIONS: This is the first report to provide scientific evidence for load initiation time based on both bone quality and quantity around implants. These new findings show that implants with buttress threads transmitted early loads optimally to bone tissue by improving bone quality and quantity inside and outside the implant threads.

Zoledronic Acid Deteriorates Soft and Hard Tissue Healing of Murine Tooth Extraction Sockets in a Dose-Dependent Manner.

The pathophysiology, histopathology, and immunopathology of bisphosphonate-related osteonecrosis of the jaw (BRONJ) Stage 0 remain unclear. The aim of this study was to investigate the effects of high-dose bisphosphonates on tooth extraction socket healing by creating a murine model of BRONJ Stage 0-like lesions using 8-week-old female C57BL/6J mice. Zoledronic acid (Zol) was administered subcutaneously twice a week for 7 weeks at doses of 0.1 mg/kg/week (moderate dose; Zol-M), 0.5 mg/kg/week (high dose; Zol-H1), and 1.0 mg/kg/week (higher dose; Zol-H2). Saline was used as a control (VC). Both maxillary first molars were extracted 3 weeks after drug treatment. Maxillae, long bones, and sera were collected 4 weeks post-extraction (n = 7 mice/group). Microcomputed tomography, histological, immunohistochemical, and ELISA analyses were performed. A ceiling effect for Zol was noted at the Zol-H1 dose. Osseous healing of extraction sites was significantly impaired with increased necrotic bone and the number of empty lacunae in a Zol dose-dependent manner. Zol significantly decreased epithelial thickness, due to a decrease in thickness of the stratum spinosum, in both Zol-H1 and Zol-H2. Both Zol-H1 and Zol-H2 significantly suppressed the distribution of F4/80+ macrophages in the connective tissue of tooth extraction sockets, although gross healing appeared to be normal. Intriguingly, both Zol-H1 and Zol-H2 significantly increased the numbers of TRAP+ mononuclear cells and detached osteoclasts in the connective tissue and bone marrow of extraction sites compared to VC and Zol-M, correlated with serum TRAcP5b levels. The created murine model of BRONJ Stage 0-like lesions becoming more severe in a dose-dependent manner may help to understand the pathophysiology and histopathology of BRONJ Stage 0 in humans.

Lactoferrin with Zn-ion protects and recovers fibroblast from H2O2-induced oxidative damage.

Lactoferrin (LF) has attracted great attention due to its various bioactivities, which depend on the degree of saturation with different cations. This study focused on the synergistic effect of LF and Zn2+ on human gingival fibroblasts (hGFs), considering antioxidant activities, cell proliferation, and collagen gene expression levels in these cells to improve the wound healing. The hGFs were cultured in an experimental medium, containing 1000 µg/mL of LF and various concentrations of ZnCl2. The cells were subjected to oxidative damage by exposure to 600 µM H2O2 for 30 min before incubation in the experimental medium. The cell proliferation rate and the relative gene expression levels of genes associated with apoptosis, antioxidant enzymes, and collagen were compared. H2O2 decomposition by LF was also measured using a colorimetric assay. LF enhanced hGF proliferation and the expression of collagen. Furthermore, LF directly scavenged H2O2 and prevented lipid peroxidation by enhancing the expression of glutathione peroxidase 4 gene expression, resulting in the prevention of apoptosis and recovery of the cells from H2O2-induced oxidative damage. The addition of ZnCl2 enhanced these results. The results indicated that LF with Zn-ion could play an important role in modulating the functions related to wound healing.

Clinical considerations for medication-related osteonecrosis of the jaw: a comprehensive literature review.

BACKGROUND: Medication-related osteonecrosis of the jaw (MRONJ), which was first reported as bisphosphonate-related osteonecrosis of the jaw (BRONJ) in bisphosphonate users, is a rare but severe soft and hard tissue disease induced by several types of medications. There has been a deluge of information about MRONJ, such as epidemiology, risk factors, clinical recommendations for dental treatment to prevent it, and treatment strategies in medication-prescribed users. The aim of this study was to comprehensively review recent articles and provide the current scientific information about MRONJ, especially clinical considerations or recommendations for dental treatment to prevent its occurrence. MATERIALS AND METHODS: The current literature review was mainly based on 14 systematic reviews with or without meta-analysis, 4 position papers, 1 consensus statement, 1 clinical guideline, and 2 clinical reviews regarding MRONJ after a PubMed database and manual searches according to inclusion and exclusion criteria. Moreover, 53 articles were selected by manual search in regard to all references from selected articles and other articles identified on the PubMed search, irrespective of publication date, and inclusion and exclusion criteria. RESULTS: The incidence and prevalence of MRONJ are relatively low, although they are clearly higher in cancer patients receiving high-dose antiresorptive agents or angiogenesis inhibitors rather than osteoporosis patients receiving oral bisphosphonates or denosumab. There are many types of local, systemic, and other risk factors for the development of MRONJ. Clinical recommendations are provided for each clinical situation of patients to prevent MRONJ. There are also treatment strategies for MRONJ in each stage. CONCLUSIONS: General dentists should perform appropriate dental treatment to prevent MRONJ in the patients prior to or when receiving medications that could induce MRONJ. Moreover, there are treatment strategies for MRONJ in each stage that oral surgeons could follow. Adequate and updated clinical information regarding MRONJ based on scientific data is required whenever possible.

Gene expression analysis of fresh extraction wounds prior to onset of bisphosphonate-related osteonecrosis of the jaw-like lesions in mice: A preliminary animal study.

Purpose The aim of the present study was to investigate the effects of chemotherapeutic/bisphosphonate combination therapy with tooth extraction on gene expression patterns of fresh extraction wounds during initial stages prior to their diagnosis as bisphosphonate-related osteonecrosis of the jaw (BRONJ)-like lesions in mice.Methods Female C57BL/6J mice were used. To create a high-prevalence BRONJ mouse model, combination therapy with the chemotherapy drug cyclophosphamide (CY) and zoledronic acid (ZA) was performed (CY/ZA). Both maxillary first molars were extracted 3 weeks after drug therapy. Saline was used as the control (VC). Soft tissues near the fresh extraction wounds were dissected at 72 h postextraction to investigate the gene expression patterns. Maxillae and long bones at 2 and 4 weeks postextraction were also analyzed.Results CY/ZA significantly increased the relative expression levels of IL-6 and decreased those of IL-10 and IGF-1 when compared with those in VC. Moreover, CY/ZA significantly reduced the relative expression levels of CCR-7, cxcl12, cxcr4, and CD105 when compared with those in VC, whereas the level of F4/80 was significantly increased by CY/ZA. Furthermore, CY/ZA significantly decreased the relative expression levels of VEGFA, VEGFB, and VEGFC at 72 h postextraction compared with those in VC.Conclusions Considering that the present study lacked adequate in vitro models, CY/ZA markedly changed the gene expression patterns associated with wound healing from the initial stages prior to onset of BRONJ-like lesions, which may help us to understand the pathophysiology of BRONJ in humans.

Alendronate/dexamethasone combination therapy worsens soft and hard tissue wound healing around implants in rat maxillae.

Dental implant treatment in patients prescribed medications is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) around the implants. However, there is no scientific information on how bisphosphonate and/or steroid therapies affect wound healing around implants after implant placement. The aim of this study was to histopathologically and immunopathologically investigate the effects of bisphosphonate and/or steroid therapy on the early stages of soft and hard tissue wound healing around implants in rat maxillae. Eight-week-old female Wistar rats were used. Alendronate (ALN) monotherapy, dexamethasone (DEX) monotherapy, and ALN/DEX combination therapy were started 4 weeks after tooth extraction of right maxillary first molars. Saline was used as a control (n = 14/group). Implant placement was carried out after grossly and manually confirming no open wounds at 16 weeks post-extraction. Euthanasia was performed at 18 weeks post-extraction. Microcomputed tomography, histological stains and immunostaining to detect blood vessels and macrophages were performed to quantitatively analyze wound healing around implants. ALN/DEX combination therapy significantly increased necrotic bone with more empty lacunae and polymorphonuclear cell infiltration with open wounds when compared with all other therapy groups. Necrotic bone was broadly distributed from the crestal bone to the lower area near the apex of the implants in the ALN/DEX group. Interestingly, both ALN/DEX combination therapy and DEX monotherapy significantly increased the number of CD68+NG2- macrophages, whereas only ALN/DEX combination therapy, not DEX monotherapy, significantly shifted the M1/M2 ratio to M1 by significant increases in M1 macrophages and unchanged M2 macrophages in the connective tissue around implants. Within the limitations of this study, these findings may contribute to understanding the early stages of the histopathology and immunopathology of BRONJ-like lesions around dental implants. Continuous accumulation of M1 macrophages without alteration of M2 macrophages may be associated with developing BRONJ around implants.

Effects of surface sub-micrometer topography following oxalic acid treatment on bone quantity and quality around dental implants in rabbit tibiae.

BACKGROUND: To explore the effects of topographical modification of titanium substrates at submicron level by oxalic acid treatment on bone quality and quantity around dental implants in rabbit tibiae. METHODS: A total of 60 blasted CP-grade IV titanium dental implants were used. Twenty-eight control implant surfaces were treated with a mixture of HCl/H2SO4, whereas 28 other test implant surfaces were treated with oxalic acid following HCl/H2SO4 treatment. Two randomly selected sets of control or test implants were placed in randomly selected proximal tibiae of 14 female Japanese white rabbits. Euthanasia was performed 4 and 8 weeks post-implant placement. Bone to implant contact (BIC), bone area fraction (BAF), ratios of mature and immature bone to total bone, and the amount and types of collagen fibers were evaluated quantitatively. Two control and two test implants were used to analyze surface characteristics. RESULTS: Treatment by oxalic acid significantly decreased Sa and increased Ra of test implant surfaces. BIC in test implants was increased without alteration of BAF and collagen contents at 4 and 8 weeks after implant placement when compared with control implants. The ratios of immature and mature bone to total bone differed significantly between groups at 4 weeks post-implantation. Treatment by oxalic acid increased type I collagen and decreased type III collagen in bone matrices around test implants when compared with control implants at 8 weeks after implant placement. The effects of topographical changes of implant surfaces induced by oxalic acid on BAF, mature bone, collagen contents, and type I collagen were significantly promoted with decreased immature bone formation and type III collagen in the later 4 weeks post-implantation. CONCLUSIONS: Treatment of implant surfaces with oxalic acid rapidly increases osseointegration from the early stages after implantation. Moreover, submicron topographical changes of dental implants induced by oxalic acid improve bone quality based on bone maturation and increased production of type I collagen surrounding dental implants in the late stage after implant placement.