Publications by authors named "Dieter D Bosshardt"

112 Publications

The Effect of Coronal Implant Design and Drilling Protocol on Bone-to-Implant Contact: A 3-Month Study in the Minipig Calvarium.

Materials (Basel) 2021 May 18;14(10). Epub 2021 May 18.

Department of Periodontology and Dental Implantology, School of Dental Medicine, Tel-Aviv University, Tel-Aviv 6997801, Israel.

Stress concentrated at an implant's neck may affect bone-to-implant contact (BIC). The objective of this study was to evaluate four different implant neck designs using two different drilling protocols on the BIC. Ninety-six implants were inserted in 12 minipigs calvarium. Implants neck designs evaluated were: type 1-6 coronal flutes (CFs), 8 shallow microthreads (SMs); type 2-6 CFs,4 deep microthreads (DMs); type 3-4 DMs; type 4-2 CFs, 8 SMs. Two groups of forty-eight implants were inserted with a final drill diameter of 2.8 mm (DP1) or 3.2 mm (DP2). Animals were sacrificed after 1 and 3 months, total-BIC (t-BIC) and coronal-BIC (c-BIC) were evaluated by nondecalcified histomorphometry analysis. At 1 month, t-BIC ranged from 85-91% without significant differences between implant types or drilling protocol. Flutes on the coronal aspect impaired the BIC at 3 m. c-BIC of implant types with 6 CFs was similar and significantly lower than that of implant types 3 and 4. c-BIC of implant type 4 with SMs was highest of all implant types after both healing periods. BIC was not affected by the drilling protocol. CFs significantly impaired the -BIC. Multiple SMs were associated with greater c-BIC.
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http://dx.doi.org/10.3390/ma14102645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158354PMC
May 2021

[Cemental Tear].

Swiss Dent J 2021 Apr;131(4):358-359

Klinik für Parodontologie, Zahnmedizinische Kliniken der Universität Bern, Schweiz.

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April 2021

Horizontal bone grafting using equine-derived cancellous bone blocks is associated with severe complications: A prospective clinical and histological pilot study.

Clin Oral Implants Res 2020 Nov 17;31(11):1149-1158. Epub 2020 Sep 17.

Clinic of Oral- and Maxillofacial Surgery, Translational Implantology, Medical Center Freiburg - Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Aims: The aim of this prospective, clinical study was to evaluate the clinical performance and histological outcome of a new equine hydroxyapatite collagenated bone block (eHAC) for horizontal bone grafting prior to implant placement.

Materials And Methods: Five patients (two male/three female) with a mean age of 51.6 years (range 22-66 years) and a reduced horizontal bone width of the alveolar ridge (mean 3.5 mm) underwent horizontal bone grafting using eHAC at 10 grafting sites. Reentry was performed 6.9 months after the horizontal grafting procedure. Clinical follow-up (mean 28.9 month) considered width gain of the alveolar ridge, soft tissue healing, and complications. To evaluate graft incorporation, four additional patients underwent histological assessment of equine blocks adjacent to autologous blocks 3 and 6 months after grafting.

Results: The study was terminated after graft failure was observed in four of five patients. Mean horizontal bone width had increased by 3.6 ± 1.22 mm. Three out of nine implants placed had to be removed due to graft failure. Histological evaluation revealed large amounts of soft connective tissue within the grafts (mean 67.3 ± 9.5%). The proportion of new bone formation 3 months after the lateral grafting procedure revealed an average of 8.6%, compared to 11.4% after 6 to 7 months.

Conclusion: Lateral ridge grafting using eHAC achieved measurable horizontal width gain but revealed high rates of severe complications.

Clinical Implications: Within the limitations of this study, eHAC bone blocks cannot be recommended for horizontal bone grafting.
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http://dx.doi.org/10.1111/clr.13661DOI Listing
November 2020

Conventional finite element models estimate the strength of metastatic human vertebrae despite alterations of the bone's tissue and structure.

Bone 2020 12 20;141:115598. Epub 2020 Aug 20.

ARTORG Center for Biomedical Engineering Research, University of Bern, Freiburgstrasse 3, 3010 Bern, Switzerland. Electronic address:

Introduction: Pathologic vertebral fractures are a major clinical concern in the management of cancer patients with metastatic spine disease. These fractures are a direct consequence of the effect of bone metastases on the anatomy and structure of the vertebral bone. The goals of this study were twofold. First, we evaluated the effect of lytic, blastic and mixed (both lytic and blastic) metastases on the bone structure, on its material properties, and on the overall vertebral strength. Second, we tested the ability of bone mineral content (BMC) measurements and standard FE methodologies to predict the strength of real metastatic vertebral bodies.

Methods: Fifty-seven vertebral bodies from eleven cadaver spines containing lytic, blastic, and mixed metastatic lesions from donors with breast, esophageal, kidney, lung, or prostate cancer were scanned using micro-computed tomography (μCT). Based on radiographic review, twelve vertebrae were selected for nanoindentation testing, while the remaining forty-five vertebrae were used for assessing their compressive strength. The μCT reconstruction was exploited to measure the vertebral BMC and to establish two finite element models. 1) a micro finite element (μFE) model derived at an image resolution of 24.5 μm and 2) homogenized FE (hFE) model derived at a resolution of 0.98 mm. Statistical analyses were conducted to measure the effect of the bone metastases on BV/TV, indentation modulus (E), ratio of plastic/total work (W/W), and in vitro vertebral strength (F). The predictive value of BMC, μFE stiffness, and hFE strength were evaluated against the in vitro measurements.

Results: Blastic vertebral bodies exhibit significantly higher BV/TV compared to the mixed (p = 0.0205) and lytic (p = 0.0216) vertebral bodies. No significant differences were found between lytic and mixed vertebrae (p = 0.7584). Blastic bone tissue exhibited a 5.8% lower median E (p< 0.001) and a 3.3% lower median W/W (p<0.001) compared to non-involved bone tissue. No significant differences were measured between lytic and non-involved bone tissues. F ranged from 1.9 to 13.8 kN, was strongly associated with hFE strength (R=0.78, p< 0.001) and moderately associated with BMC (R=0.66, p< 0.001) and μFE stiffness (R=0.66, p< 0.001), independently of the lesion type.

Discussion: Our findings show that tumour-induced osteoblastic metastases lead to slightly, but significantly lower bone tissue properties compared to controls, while osteolytic lesions appear to have a negligible impact. These effects may be attributed to the lower mineralization and woven nature of bone forming in blastic lesions whilst the material properties of bone in osteolytic vertebrae appeared little changed. The moderate association between BMC- and FE-based predictions to fracture strength suggest that vertebral strength is affected by the changes of bone mass induced by the metastatic lesions, rather than altered tissue properties. In a broader context, standard hFE approaches generated from CTs at clinical resolution are robust to the lesion type when predicting vertebral strength. These findings open the door for the development of FE-based prediction tools that overcomes the limitations of BMC in accounting for shape and size of the metastatic lesions. Such tools may help clinicians to decide whether a patient needs the prophylactic fixation of an impending fracture.
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http://dx.doi.org/10.1016/j.bone.2020.115598DOI Listing
December 2020

Investigating the Response of Human Neutrophils to Hydrophilic and Hydrophobic Micro-Rough Titanium Surfaces.

Materials (Basel) 2020 Aug 3;13(15). Epub 2020 Aug 3.

Department of Periodontics, Indiana University School of Dentistry, Indianapolis, IN 46202, USA.

Various treatments have been used to change both the topography and chemistry of titanium surfaces, aiming to enhance tissue response and reduce healing times of endosseous implants. Most studies to date focused on bone healing around dental implants occurring later during the healing cascade. However, the impact of the initial inflammatory response in the surgical wound site on the success and healing time of dental implants is crucial for implant integration and success, yet it is still poorly understood. The purpose of this study was to investigate the effect of titanium surface hydrophilicity on the response of human neutrophils by monitoring oxygen radical production, which was measured as chemiluminescence activity. Materials and Methods: Neutrophils were isolated from human donors' blood buffy coats using the double sucrose gradient method. Neutrophils were exposed to both hydrophilic and hydrophobic titanium surfaces with identical topographies in the presence and absence of human serum. This resulted in six experimental groups including two different implant surfaces, with and without exposure to human serum, and two control groups including an active control with cells alone and a passive control with no cells. Two samples from each group were fixed and analyzed by SEM. Comparisons between surface treatments for differences in chemiluminescence values were performed using analysis of variance ANOVA. Results and Conclusion: In the absence of exposure to serum, there was no significant difference noted between the reaction of neutrophils to hydrophilic and hydrophobic surfaces. However, there was a significant reduction in the mean and active chemiluminescence activity of neutrophils to serum-coated hydrophilic titanium surfaces than to serum-coated hydrophobic titanium surfaces. This suggests that surface hydrophilicity promotes enhanced adsorption of serum proteins, which leads to decreased provocation of initial immune cells and reduction of local oxygen radical production during wound healing. This can help explain the faster osseointegration demonstrated by hydrophilic titanium implants.
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http://dx.doi.org/10.3390/ma13153421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435731PMC
August 2020

Tissue Integration and Degradation of a Porous Collagen-Based Scaffold Used for Soft Tissue Augmentation.

Materials (Basel) 2020 May 25;13(10). Epub 2020 May 25.

Robert K. Schenk Laboratory of Oral Histology, School of Dental Medicine, University of Bern, 3010 Bern, Switzerland.

Collagen-based scaffolds hold great potential for tissue engineering, since they closely mimic the extracellular matrix. We investigated tissue integration of an engineered porous collagen-elastin scaffold developed for soft tissue augmentation. After implantation in maxillary submucosal pouches in 6 canines, cell invasion (vimentin), extracellular matrix deposition (collagen type I) and scaffold degradation (cathepsin k, tartrate-resistant acid phosphatase (TRAP), CD86) were (immuno)-histochemically evaluated. Invasion of vimentin cells (scattered and blood vessels) and collagen type I deposition within the pores started at 7 days. At 15 and 30 days, vimentin cells were still numerous and collagen type I increasingly filled the pores. Scaffold degradation was characterized by collagen loss mainly occurring around 15 days, a time point when medium-sized multinucleated cells peaked at the scaffold margin with simultaneous labeling for cathepsin k, TRAP, and CD86. Elastin was more resistant to degradation and persisted up to 90 days in form of packages well-integrated in the newly formed soft connective tissue. In conclusion, this collagen-based scaffold maintained long-enough volume stability to allow an influx of blood vessels and vimentin fibroblasts producing collagen type I, that filled the scaffold pores before major biomaterial degradation and collapse occurred. Cathepsin k, TRAP and CD86 appear to be involved in scaffold degradation.
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http://dx.doi.org/10.3390/ma13102420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287763PMC
May 2020

Crestal bone response to loaded zirconia and titanium implants: a radiographic and histometric analysis in canines.

Clin Oral Investig 2020 Oct 7;24(10):3609-3617. Epub 2020 Feb 7.

Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Freiburgstrasse 7, CH-3010, Bern, Switzerland.

Objectives: To evaluate the crestal bone response to a two-piece zirconia implant compared with a control titanium implant using periapical radiographs (PAs) and histometry.

Materials And Methods: Thirty zirconia and 30 titanium implants were placed in healed posterior mandibles of five canines. Full-ceramic single-tooth restorations were cemented after 6 weeks of healing. Three observers measured the distance between the implant shoulder and the crestal bone (DIB) at placement, loading, and harvesting after 4 or 16 weeks in function. The influence of implant material and loading time on DIB as well as the inter-observer agreement were analyzed. Additionally, histometric distance between implant shoulder and most coronal bone-to-implant contact (IS-cBIC) was compared with DIB.

Results: Mean DIB values increased between 4 and 16 weeks of loading for both zirconia (from 1.66 to 2.25 mm; P < 0.0001) and titanium (from 1.81 to 1.95 mm; P = 0.06). Zirconia yielded mean IS-cBIC values of 2.18 mm and 2.48 mm (P < 0.001) and titanium 2.23 mm and 2.34 mm (P = 0.27) after 4 and 16 weeks, respectively. The raters reached an excellent intraclass correlation coefficient. PAs underestimated the bone loss on average by 0.39 mm.

Conclusions: Zirconia implants showed a greater increase of DIB during early healing and function than titanium.

Clinical Relevance: Crestal peri-implant tissue dimensions may show more pronounced changes around two-piece zirconia implants during early healing. PAs may underestimate peri-implant bone loss.
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http://dx.doi.org/10.1007/s00784-020-03235-2DOI Listing
October 2020

Tissue Response to a Porous Collagen Matrix Used for Soft Tissue Augmentation.

Materials (Basel) 2019 Nov 11;12(22). Epub 2019 Nov 11.

Robert K. Schenk Laboratory of Oral Histology, School of Dental Medicine, University of Bern, 3010 Bern, Switzerland.

A short inflammatory phase and fast ingrowth of blood vessels and mesenchymal cells are essential for tissue integration of a biomaterial. Macrophages play a key role in this process. We investigated invasion of macrophages, blood vessels, and proliferating cells into a highly porous and volume-stable collagen matrix (VCMX) used for soft tissue augmentation around teeth and dental implants. The biomaterial was implanted in submucosal pouches in the canine maxilla, and the tissue response was analyzed at six different time points. Immunohistochemistry was done for proliferating cells (PCNA), macrophages (MAC387), multinucleated giant cells (CD86), and blood vessels (TGM2). Blood rapidly filled the VCMX pores. During the first week, MAC387+ cells populated the VCMX pores, blood vessels and PCNA+ cells invaded the VCMX, and CD86+ scattered cells were observed. At 15 days, MAC387+ cells were scanty, blood vessels had completely invaded the VCMX, the number of proliferating cells peaked, and fibroblasts appeared. At 30 days, MAC387+ were absent, the numbers of proliferating and CD86+ cells had declined, while blood vessel and fibroblast numbers were high. At 90 days, residual VCMX was well-integrated in soft connective tissue. In conclusion, the VCMX elicited a short inflammatory phase followed by rapid tissue integration.
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http://dx.doi.org/10.3390/ma12223721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888327PMC
November 2019

Excessive occlusal load on chemically modified and moderately rough titanium implants restored with cantilever reconstructions. An experimental study in dogs.

Clin Oral Implants Res 2019 Nov 8;30(11):1142-1154. Epub 2019 Oct 8.

School of Dental Medicine, University of Berne, Berne, Switzerland.

Objective: To evaluate the outcomes of excessively loaded implants.

Material And Methods: In five dogs, all mandibular premolars were extracted. After 3 months, six implants (three SLA® and three SLActive®) were placed (S). After 4 weeks, implants were restored: one single crown with stable occlusal contacts (SC), one crown and a cantilever unit with excessive occlusal contacts (OL), and a non-loaded implant (NL). Bleeding-on-probing (BoP), attachment level (AL), mucosal margin (GM) were assessed. Resonance frequency analysis (RFA) was assessed weekly. Standardized X-rays were taken at S, 4 and 24 weeks.

Results: Similar findings were observed for SLA® and SLActive® implants regarding PlI, GI, GM, AL, and BL. No significant differences were detected between baseline and 24-weeks or between treatment modalities for all clinical parameters (p > .05). Six months after loading, RFA values were significantly greater than at implant placement. No significant differences between treatment modalities were found. Linear radiographic measurements yielded similar results between SLA® and SLActive® implants. SLA® OL implants yielded a statistically significant gain on peri-implant bone density over all other groups (p = .012). Radiographic results were confirmed by descriptive histology. Technically, loosened occlusal screws occurred in 13.3% (SC = 3.3%; OL = 10%), while abutment fractures totalized 23.3% (SC = 6.6%; OL = 16.6%).

Conclusions: Excessive occlusal load applied to implants (SLA® or SLActive®) restored with cantilevers did not cause loss of osseointegration or significant changes in their clinical, radiographic, or histologic outcomes. Early excessive occlusal load on SLA® implants promoted a gain in peri-implant bone density. Excessively loaded implants showed more technical complications.
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http://dx.doi.org/10.1111/clr.13539DOI Listing
November 2019

Hard and soft tissue evaluation of titanium dental implants and abutments with nanotubes in canines.

J Periodontol 2020 04 17;91(4):516-523. Epub 2019 Oct 17.

Department of Periodontics, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.

Background: Little is known regarding the interaction of dental implant surface nanotubes and oral soft and hard tissues. The purpose of this study was to evaluate both histologically and radiographically the qualitative and quantitative effects of dental implant surface nanotubes on hard and soft tissue in a canine model.

Methods: Three subgroups consisting of a combination of test and control implants and abutments (Group A: control implant/control abutment, Group B: control implant/test abutment: Group C: test implant/test abutment) were placed in edentulous mandibles of six large-breed canines. Implants and abutments were placed on one side at baseline, and on the opposite side of the mandible at week 10; sacrifice occurred at week 12. Quantitative and qualitative analyses were used to measure newly formed hard and soft tissues histologically and radiographically.

Results: The mean radiographic change in marginal bone level from weeks 0 to 12 between implant groups was not statistically significant (P > 0.05). Mean soft tissue contact (junctional epithelium + connective tissue) for Groups A, B, and C were 2.29, 2.33, and 2.31 mm, respectively, with no statistically significant difference (P > 0.05) between the groups. All connective tissue fibers were oriented parallel to the abutment regardless of surface treatment.

Conclusions: The findings of this study suggest that healing of hard and soft tissues around implants and abutments is similar when comparing grit-blasted surfaces to machined, turned surfaces with nanotubes. Both resulted in similar soft tissue contact values, as well as connective tissue fiber orientation.
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http://dx.doi.org/10.1002/JPER.18-0205DOI Listing
April 2020

Hyaluronic acid slows down collagen membrane degradation in uncontrolled diabetic rats.

J Periodontal Res 2019 Dec 12;54(6):644-652. Epub 2019 Jun 12.

Department of Periodontology and Dental Implantology, The Maurice and Gabriela Goldschleger School of Dental Medicine, Tel Aviv University, Tel Aviv, Israel.

Aim: To examine the in vitro biokinetics of hyaluronic acid (HA) from a collagen membrane (CM) and to evaluate the in vivo effect of immersion of the CM in HA solution on its degradation in streptozotocin (STZ)-induced diabetes conditions in a rat calvaria subcutaneous model.

Background: CM degradation is accelerated in uncontrolled diabetic rats. Immersion of CM in HA has been suggested to decrease their resorption rate without interfering with their tissue integration and structural degradation. However, it is unknown to what extent CM degradation may be influenced by its immersion in HA solution under a condition mimicking a medically compromised situation with an increased inflammatory level such as diabetes.

Materials And Methods: CMs were soaked in cross-linked HA. Protein adsorption and the HA release were quantified by ELISA. Diabetes was induced in sixteen rats, while 16 healthy rats served as control. CM was prepared and labeled prior to implantation with Biotin. Seventeen CM were immersed in HA and 17 CM in PBS. In each animal, one test or one control disk was implanted. In order to compare the collagen content, two similar non-implanted CM were used as baseline. Fourteen days after surgery, thirty-two animals were sacrificed. The entire calvaria including the skin above, was chemically fixed, decalcified, and embedded in paraffin. Five-μm-thick sections were analyzed histologically and histomorphometrically using H&E and avidin-peroxidase staining.

Results: The in vitro results demonstrated that the CM adsorbed roughly 80% of the total HA content. After 10 days, 36.3% of the initial HA remained on the CM. The in vivo results demonstrated that diabetes significantly reduced the thickness of the CM, while HA had a significant effect on keeping the membrane thickness. HA increased the residual collagen content in the diabetic group (P < 0.0001) but no such effect was observed in the healthy group.

Conclusion: Immersion of CM in HA prior to the implantation delays membrane degradation in uncontrolled diabetic compared with normoglycemic rats.
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http://dx.doi.org/10.1111/jre.12665DOI Listing
December 2019

Soft tissue response to dental implant closure caps made of either polyetheretherketone (PEEK) or titanium.

Clin Oral Implants Res 2019 Aug 12;30(8):808-816. Epub 2019 Jun 12.

Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Objective: Polyetheretherketone (PEEK) is a popular synthetic thermoplastic polymer for medical applications, but its clinical use suffers from several limitations. Therefore, the aim was to compare the soft tissue response to dental implant closure caps made of PEEK or titanium as evaluated by the occurrence of multinucleated giant cells (MNGCs).

Material And Methods: Forty-two implants were placed in the maxilla of seven miniature pigs. While commercially pure titanium (Ti) implants had a Ti closure cap, ceramic implants made of either zirconia (Zr) or alumina-toughened zirconia (Zr + Al) received a PEEK closure cap. Histomorphometry was performed to evaluate the number of small and large MNGCs being in contact with the PEEK or the Ti in different compartments of the implant systems.

Results: No histological signs of inflammation were noticed, and MNGCs were observed on both PEEK and Ti closure caps and on all three implant types. Significantly higher numbers of MNGCs were found on closure caps made of PEEK than on closure caps made of Ti on the external closure cap surface facing both soft (p = 0.0008 for PEEK on Zr and p = 0.0016 for PEEK on Zr + Al) and hard tissues (p = 0.016 for PEEK on Zr and p = 0.003 for PEEK on Zr + Al) as well as in the internal closure cap surface (p = 0.014 for PEEK on Zr and p = 0.0088 for PEEK on Zr + Al). No statistically significant differences in the number of MNGCs were observed on the three implant types.

Conclusions: Significantly more MNGCs were in contact with PEEK than with Ti closure caps.
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http://dx.doi.org/10.1111/clr.13487DOI Listing
August 2019

Self-regenerative capacity of intra-oral bone defects.

J Clin Periodontol 2019 06;46 Suppl 21:70-81

Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Objective: To provide an overview on the self-regenerative capacity of various types of intra-oral bone defects.

Materials And Methods: This paper has narratively reviewed the most important aspects of bone biology and the healing outcomes related to the self-regenerative capacity (i.e. without the placement of any biomaterial) of bone defects that occur following tooth extraction, autogenous graft harvesting, periapical lesions, cystic lesions of the jaws, third molar extraction and experimentally created ridge defects.

Results: In animals (i.e. dogs and monkeys), the greatest changes in horizontal and vertical dimension occur during the first 6 months following tooth extraction. In humans, bone remodelling may take from several months to years and exhibits marked inter-individual variability. Following tooth extraction at compromised sites (e.g. presence of severe bone loss at the time-point of extraction), the healing may occur slower and a substantial volume reduction can be expected than following tooth extraction at non-compromised sites. In the mandibular symphysis and ramus, the bone defects resulting following bone block harvesting are gradually healing to a large extent, but complete healing appears not to occur due to poorer space provision and wound stability capacities. Defects after peri-apical surgery display a substantial self-regenerative capacity and heal at a great extent without the use of any adjunct measures. The vast majority of jawbone defects after cystectomy heal at a great extent and without apparent influence in the shape of the jaw, without the need of adjunct measures. After surgical removal of mandibular third molars, bone fill can be observed over a period of at least 12 months, with the most substantial change (e.g. the greatest bone fill) occurring during the first 3 months after surgery. However, complete fill of these residual bone defects does not always occur.

Conclusions: Intra-oral bone defects possess a high self-regenerative capacity. Factors such as extent of bone loss, presence of bony walls, closed healing environment, space provision and mechanical wound stability substantially influence healing/regeneration.
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http://dx.doi.org/10.1111/jcpe.13075DOI Listing
June 2019

20-Year Follow-up in Maxillary Sinus Floor Elevation Using Bovine-Derived Bone Mineral: A Case Report with Histologic and Histomorphometric Evaluation.

Int J Oral Maxillofac Implants 2018 Nov/Dec;33(6):1345-1350

Bovine-derived bone mineral demonstrated good osteoconductive properties as grating material for maxillary sinus floor elevation, but the long-term behavior of this material has not been reported. The purpose of this report was to analyze and compare histomorphometric measurements of new bone, bone graft, and medullar spaces 6 months, 12 months, and 20 years after grafting. In the grafted area, the amount of mineralized bone was 16.96% at 6 months, 22.53% at 12 months, and 22.05% at 20 years, respectively. The amount of bovine-derived bone mineral ranged from 35.87% to 4.85% in the same period. The volume of the newly formed mineralized bone does not increase over time, conversely to nonmineralized bone.
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http://dx.doi.org/10.11607/jomi.6884DOI Listing
December 2018

Macrophage behavior and interplay with gingival fibroblasts cultured on six commercially available titanium, zirconium, and titanium-zirconium dental implants.

Clin Oral Investig 2019 Aug 10;23(8):3219-3227. Epub 2018 Nov 10.

Department of Periodontology, University of Bern, 3010, Bern, Switzerland.

Objectives: The host-material interface has been a crucial relationship dictating the successful integration of biomaterials, including dental implants. The aim of the present study was to first investigate how macrophages behaved on various dental implant surfaces and thereafter to investigate their effect on soft tissue cells.

Materials And Methods: Macrophage adhesion, proliferation, and polarization towards either an M1 or M2 phenotype were investigated on six implant surfaces fabricated from pure titanium (Ti), pure zirconium (ZLA), and a titanium-zirconium (Ti-Zi) alloy of various surface topographies/chemistries. Thereafter, conditioned media (CM) collected from macrophages seeded on these various implant surfaces was cultured with murine gingival fibroblasts and investigated for their ability to promote collagen synthesis.

Results: Macrophages attached and proliferated in similar levels on all implant surfaces; however, the modSLA hydrophilic surfaces tended to decrease the pro-inflammatory response by lowering the gene expression of TNF-alpha, IL-1, and IL-6 and promoting tissue resolution through the expression of an M2-macrophage cytokine IL-10. Thereafter, CM from macrophages were seeded with gingival fibroblasts on each implant surface. In general, CM from macrophages significantly promoted gingival fibroblast cell attachment on all implant surfaces at either 4 or 8 h and, most notably, significantly promoted fibronectin and TGF-beta gene expression on both Ti and Ti-Zi hydrophilic surfaces.

Conclusions And Clinical Relevance: The present study found that implant surface topography and chemistry substantially impacted macrophage behavior. Most notably, modifications via hydrophilicity to both the pure Ti and Ti-Zi were shown to favor the secretion of macrophage pro-resolution markers and favored subsequent gingival fibroblast cell behavior when cultured with CM, whereas surface composition (Ti vs ZLA vs Ti-Zi) had little effect on macrophage polarization or gingival fibroblast behavior. This finding suggests that surface hydrophilicity would improve the soft tissue integration of dental implants, irrespective of material composition.
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http://dx.doi.org/10.1007/s00784-018-2736-zDOI Listing
August 2019

Bone response to functionally loaded, two-piece zirconia implants: A preclinical histometric study.

Clin Oral Implants Res 2018 Mar 30;29(3):277-289. Epub 2017 Dec 30.

Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Objective: To evaluate the bone response to a two-piece zirconia implant in comparison with a control titanium implant in the canine mandible 4 and 16 weeks after restoration.

Material And Methods: Zirconia and titanium implants were alternately placed bilaterally in healed mandibular molar and premolar sites of five canines. Full-ceramic single-tooth restorations were cemented after 6 weeks of transmucosal healing, allowing for full functional loading of the implants. Histologic and histometric analyses were performed on orofacial and mesiodistal undecalcified sections of the specimens obtained upon sacrifice after 4 and 16 weeks of functional loading. Bone-to-implant contact (BIC), multinucleated giant cells-to-implant contact (MIC), crestal bone level, and peri-implant bone density were histometrically assessed.

Results: All 60 implants and 60 restorations were still in function after 4 and 16 weeks of loading in both test and control groups. No implant loss, no implant or abutment fracture, and no chipping of the restorations could be detected. Histometric analysis showed no statistically significant differences between zirconia and titanium implants in BIC, crestal bone level, and peri-implant bone density at both time points. Between 4 and 16 weeks, the crestal bone level around zirconia implants showed a small but statistically significant increase in its distance from the implant shoulder. MIC was very low on both implant types and both time points and decreased statistically significantly overtime.

Conclusion: The present two-piece zirconia implant showed a similar bone integration compared to the titanium implant with similar surface morphology after 4 and 16 weeks of loading.
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http://dx.doi.org/10.1111/clr.13112DOI Listing
March 2018

The periodontal pocket: pathogenesis, histopathology and consequences.

Periodontol 2000 2018 02 30;76(1):43-50. Epub 2017 Nov 30.

The conversion of junctional epithelium to pocket epithelium is regarded as a hallmark in the development of periodontitis. Knowledge of factors contributing to the initiation and progression of pocket formation is important and may result in the development of better preventive measures and improve healing outcomes after therapeutic interventions. The periodontal pocket is a pathologically deepened gingival sulcus. In healthy periodontal conditions, the defense mechanisms are generally sufficient to control the constant microbiological challenge through a normally functioning junctional epithelium and the concentrated powerful mass of inflammatory and immune cells and macromolecules transmigrating through this epithelium. In contrast, destruction of the structural integrity of the junctional epithelium, which includes disruption of cell-to-cell contacts and detachment from the tooth surface, consequently leading to pocket formation, disequilibrates this delicate defense system. Deepening of the pocket apically, and also horizontal expansion of the biofilm on the tooth root, puts this system to a grueling test. There is no more this powerful concentration of defense cells and macromolecules that are discharged at the sulcus bottom and that face a relatively small biofilm surface in the gingival sulcus. In a pocket situation, the defense cells and the macromolecules are directly discharged into the periodontal pocket and the majority of epithelial cells directly face the biofilm. The thinning of the epithelium and its ulceration increase the chance for invasion of microorganisms and their products into the soft connective tissue and this aggravates the situation. Depending on the severity and duration of disease, a vicious circle may develop in the pocket environment, which is difficult or impossible to break without therapeutic intervention.
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http://dx.doi.org/10.1111/prd.12153DOI Listing
February 2018

Healing of two-wall intra-bony defects treated with a novel EMD-liquid-A pre-clinical study in monkeys.

J Clin Periodontol 2017 Dec 10;44(12):1264-1273. Epub 2017 Nov 10.

Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Aim: To investigate the effect of a novel enamel matrix derivative formulation (EMD-liquid or Osteogain) combined with an absorbable collagen sponge (ACS) on periodontal wound healing in intra-bony defects in monkeys.

Materials And Methods: Chronic two-wall intra-bony defects were created at the distal aspect of eight teeth in three monkeys (Macaca fascicularis). The 24 defects were randomly assigned to one of the following treatments: (i) open flap debridement (OFD) + ACS alone, (ii) OFD + Emdogain + ACS (Emdogain/ACS), (iii) OFD + Osteogain + ACS (Osteogain/ACS) or (iv) OFD alone. At 4 months, the animals were euthanized for histologic evaluation.

Results: Osteogain/ACS resulted in more consistent formation of cementum, periodontal ligament and bone with limited epithelial proliferation compared to OFD alone, Emdogain/ACS and OFD + ACS. Among the four treatment groups, the Osteogain/ACS group demonstrated the highest amount of regenerated tissues. However, complete periodontal regeneration was not observed in any of the defects in the four groups.

Conclusions: The present findings indicate that in two-wall intra-bony defects, reconstructive surgery with Osteogain/ACS appears to be a promising novel approach for facilitating periodontal wound healing/regeneration, thus warranting further clinical testing.
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http://dx.doi.org/10.1111/jcpe.12825DOI Listing
December 2017

Multinucleated Giant Cells: Good Guys or Bad Guys?

Tissue Eng Part B Rev 2018 02 4;24(1):53-65. Epub 2017 Oct 4.

1 Department of Periodontology, University of Bern , Bern, Switzerland .

Multinucleated giant cells (MNGCs) are a special class of giant cell formed by the fusion of monocytes/macrophages abundantly found in human tissues. While historically their role around certain classes of biomaterials have been directly linked to a foreign body reaction leading to material rejection, recent accumulating evidence has put into question their role around certain classes of bone biomaterials. It was once thought that specifically in bone tissues, all giant cells were considered osteoclasts characterized by their ability to resorb and replace bone grafts with newly formed native bone. More recently, however, a special subclass of bone biomaterials has been found bordered by large MNGCs virtually incapable of resorbing bone substitutes even years after their implantation yet surrounded by stable bone. Interestingly, research from the field of cardiovascular disease has further shown how a shift in macrophage polarization from M1 "tissue-inflammatory" macrophages toward M2 "wound-healing" macrophages in atherosclerotic plaque may lead to MNGC formation and ectopic calcification of arteries. Despite the growing observation that MNGC formation occurs around certain bone biomaterials, their role in these tissues remains extremely poorly understood and characterized. In summary, four central aspects of this review are discussed with a focus on (1) the role of MNGCs in bone/tissue biology, and their ability to induce vascularization/new bone formation, their role around, (2) bone substitutes for bone augmentation, (3) dental implants, as well as (4) during peri-implant infection. The authors express the necessity to no longer refer to MNGCs as "good" or "bad" cells, but instead point toward the necessity to more specifically characterize them scientifically and appropriately as M1-MNGC and M2-MNGC accordingly. Future research investigating the factors influencing their polarization as a "center of control" is also likely to act as a key factor in the progression/resolution of various diseases.
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http://dx.doi.org/10.1089/ten.TEB.2017.0242DOI Listing
February 2018

The role of macrophage polarization on fibroblast behavior-an in vitro investigation on titanium surfaces.

Clin Oral Investig 2018 Mar 14;22(2):847-857. Epub 2017 Jul 14.

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, People's Republic of China.

Objectives: This study investigated the effect of smooth and rough titanium surface topographies on macrophage polarization and their influence on gingival fibroblast behavior cultured on titanium surfaces.

Materials And Methods: RAW 264.7 macrophages were seeded on smooth (pickled titanium (PT)) and rough Sand-blasted with Large grit particles followed by Acid-etching (SLA) titanium surfaces and first investigated for macrophage polarization towards tissue-inflammatory M1 macrophages or wound-healing M2 macrophages. Thereafter, culture media collected from macrophages on both surfaces were cultured with gingival fibroblasts seeded on their respective topographies. All experiments were performed in triplicate with three independent experiments.

Results: Macrophages seeded on SLA surfaces polarized towards tissue-inflammatory M1 macrophages at early time points. Immunofluorescent staining and RT-PCR analysis demonstrated higher levels of iNOS and gene expression of IL-1β, IL-6, and TNF-alpha on SLA surfaces at 3 days when compared to both tissue culture plastic (TCP) and PT surfaces (p < 0.001). Very little differences were found between smooth PT surfaces and TCP. Interestingly, proliferation assay (CCK-8) suggested that conditioned media (CM) from macrophages seeded on SLA surfaces drastically inhibited gingival fibroblast proliferation at 3 and 5 days (p < 0.001). Meanwhile, CM from macrophages cultured on SLA surfaces also significantly reduced collagen 1 synthesis on SLA surfaces at 14 days as assessed by immunofluorescent staining (p < 0.001).

Conclusion: The results from this study demonstrate that the polarization of macrophages towards a pro-inflammatory (M1) phenotype on SLA surfaces may have a negative impact on gingival fibroblast behavior on titanium surfaces. Future strategies to better modulate macrophage polarization should be investigated to support a favorable immune response and encourage tissue integration.

Clinical Relevance: As SLA surfaces have a potential to shift macrophages towards tissue-inflammatory M1 macrophages, this might be a negative impact for soft tissue healing. Therefore, SLA surfaces should be kept within the bone, as when in contact with soft tissue, they are prone to support a lack of soft tissue integration leading to inflammation.
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http://dx.doi.org/10.1007/s00784-017-2161-8DOI Listing
March 2018

Variable expressivity of TCTEX1D2 mutations and a possible pathogenic link of molar-incisor malformation to ciliary dysfunction.

Arch Oral Biol 2017 Aug 20;80:222-228. Epub 2017 Apr 20.

Department of Operative and Restorative Dentistry, Medical University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Electronic address:

Objective: Clarification of the molecular basis of a ciliopathy associated with molar-incisor malformation in a consanguineous Turkish family.

Design: Full dental and clinical examinations, histologic analysis, comprehensive genetic analyses including exome sequencing, ciliary function tests and transmission electron microscopy of ciliary biopsies in the surviving patient.

Results: Two siblings had situs inversus and complex heart defects suggestive of ciliary dysfunction. The affected girl who died in utero showed severe chest abnormalities compatible with Jeune syndrome which were not present in the affected boy. Dental investigations in the boy showed typical signs of molar-incisor-malformation. Exome sequencing identified a homozygous intragenic deletion in TCTEX1D2 which is predicted to completely remove protein function. Ciliary function tests and electron microscopy showed mild irregularities of motile cilia such as compound cilia and loss of membranes.

Conclusions: Our findings support the suggestion that TCTEX1D2 mutations have variable expressivity and may be associated with disturbances of embryonic development caused by both, ciliary signaling and motile dysfunction. The presence of molar-incisor-malformation in the living patient raises the possibility of a pathogenetic link of this rare dental anomaly to ciliary dysfunction during tooth development at least in some individuals.
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http://dx.doi.org/10.1016/j.archoralbio.2017.04.009DOI Listing
August 2017

Combination of Collagen Barrier Membrane with Enamel Matrix Derivative-Liquid Improves Osteoblast Adhesion and Differentiation.

Int J Oral Maxillofac Implants 2017 Jan/Feb;32(1):196-203

Purpose: Collagen barrier membranes were first introduced to regenerative periodontal and oral surgery to prevent fast ingrowing soft tissues (ie, epithelium and connective tissue) into the defect space. More recent attempts have aimed at combining collagen membranes with various biologics/growth factors to speed up the healing process and improve the quality of regenerated tissues. Recently, a new formulation of enamel matrix derivative in a liquid carrier system (Osteogain) has demonstrated improved physico-chemical properties for the adsorption of enamel matrix derivative to facilitate protein adsorption to biomaterials. The aim of this pioneering study was to investigate the use of enamel matrix derivative in a liquid carrier system in combination with collagen barrier membranes for its ability to promote osteoblast cell behavior in vitro.

Materials And Methods: Undifferentiated mouse ST2 stromal bone marrow cells were seeded onto porcine-derived collagen membranes alone (control) or porcine membranes + enamel matrix derivative in a liquid carrier system. Control and enamel matrix derivative-coated membranes were compared for cell recruitment and cell adhesion at 8 hours; cell proliferation at 1, 3, and 5 days; and real-time polymerase chain reaction (PCR) at 3 and 14 days for genes encoding Runx2, collagen1alpha2, alkaline phosphatase, and bone sialoprotein. Furthermore, alizarin red staining was used to investigate mineralization.

Results: A significant increase in cell adhesion was observed at 8 hours for barrier membranes coated with enamel matrix derivative in a liquid carrier system, whereas no significant difference could be observed for cell proliferation or cell recruitment. Enamel matrix derivative in a liquid carrier system significantly increased alkaline phosphatase mRNA levels 2.5-fold and collagen1alpha2 levels 1.7-fold at 3 days, as well as bone sialoprotein levels twofold at 14 days postseeding. Furthermore, collagen membranes coated with enamel matrix derivative in a liquid carrier system demonstrated a sixfold increase in alizarin red staining at 14 days when compared with collagen membrane alone.

Conclusion: The combination of enamel matrix derivative in a liquid carrier system with a barrier membrane significantly increased cell attachment, differentiation, and mineralization of osteoblasts in vitro. Future animal testing is required to fully characterize the additional benefits of combining enamel matrix derivative in a liquid carrier system with a barrier membrane for guided bone or tissue regeneration.
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http://dx.doi.org/10.11607/jomi.5011DOI Listing
March 2017

The influence of collagen membrane and autogenous bone chips on bone augmentation in the anterior maxilla: a preclinical study.

Clin Oral Implants Res 2017 Nov 25;28(11):1368-1380. Epub 2016 Dec 25.

Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Objectives: To evaluate the effect of a resorbable collagen membrane and autogenous bone chips combined with deproteinized bovine bone mineral (DBBM) on the healing of buccal dehiscence-type defects.

Material And Methods: The second incisors and the first premolars were extracted in the maxilla of eight mongrels. Reduced diameter, bone-level implants were placed 5 weeks later. Standardized buccal dehiscence-type defects were created and grafted at implant surgery. According to an allocation algorithm, the graft composition of each of the four maxillary sites was DBBM + membrane (group D + M), autogenous bone chips + DBBM + membrane (group A + D + M), DBBM alone (group D) or autogenous bone chips + DBBM (group A + D). Four animals were sacrificed after 3 weeks of healing and four animals after 12 weeks. Histological and histomorphometric analyses were performed on oro-facial sections.

Results: The pattern of bone formation and resorption within the grafted area showed high variability among the same group and healing time. The histomorphometric analysis of the 3-week specimens showed a positive effect of autogenous bone chips on both implant osseointegration and bone formation into the grafted region (P < 0.05). The presence of the collagen membrane correlated with greater bone formation around the DBBM particles and greater bone formation in the grafted region after 12 weeks of healing (P < 0.05). The oro-facial width of the augmented region at the level of the implant shoulder was significantly reduced in cases where damage of the protection splints occurred in the first week of healing (P < 0.05).

Conclusions: The addition of autogenous bone chips and the presence of the collagen membrane increased bone formation around DBBM particles. Wound protection from mechanical noxa during early healing may be critical for bone formation within the grafted area.
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http://dx.doi.org/10.1111/clr.12996DOI Listing
November 2017

Osseointegration of titanium, titanium alloy and zirconia dental implants: current knowledge and open questions.

Periodontol 2000 2017 02;73(1):22-40

Bone healing around dental implants follows the pattern and sequence of intramembraneous osteogenesis with formation of woven bone first of all followed later by formation of parallel-fibered and lamellar bone. Bone apposition onto the implant surface starts earlier in trabecular bone than in compact bone. While the first new bone may be found on the implant surface around 1 week after installation, bone remodeling starts at between 6 and 12 weeks and continues throughout life. Bone remodeling also involves the bone-implant interface, thus transiently exposing portions of the implant surface. Surface modifications creating micro-rough implant surfaces accelerate the osseointegration process of titanium implants, as demonstrated in numerous animal experiments. Sandblasting followed by acid-etching may currently be regarded as the gold standard technique to create micro-rough surfaces. Chemical surface modifications, resulting in higher hydrophilicity, further increase the speed of osseointegration of titanium and titanium-zirconium implants in both animals and humans. Surface modifications of zirconia and alumina-toughened zirconia implants also have an influence on the speed of osseointegration, and some implant types reach high bone-to-implant contact values in animals. Although often discussed independently of each other, surface characteristics, such as topography and chemistry, are virtually inseparable. Contemporary, well-documented implant systems with micro-rough implant surfaces, placed by properly trained and experienced clinicians, demonstrate high long-term survival rates. Nevertheless, implant failures do occur. A low percentage of implants are diagnosed with peri-implantitis after 10 years in function. In addition, a low number of implants seem to be lost for primarily reasons other than biofilm-induced infection. Patient factors, such as medications interfering with the immune system and bone cells, may be an element contributing to continuous bone loss and should therefore be monitored and studied in greater detail.
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http://dx.doi.org/10.1111/prd.12179DOI Listing
February 2017

Effects of EMD liquid (Osteogain) on periodontal healing in class III furcation defects in monkeys.

J Clin Periodontol 2017 03 6;44(3):298-307. Epub 2017 Feb 6.

Department of Periodontology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Aim: To evaluate the effect of a novel liquid carrier system of enamel matrix derivative (Osteogain) soaked on an absorbable collagen sponge (ACS) upon periodontal wound healing/regeneration in furcation defects in monkeys.

Materials And Methods: The stability of the conventional enamel matrix derivative (Emdogain) and Osteogain adsorbed onto ACS was evaluated by ELISA. Chronic class III furcation defects were created at teeth 36, 37, 46, 47 in three monkeys (Macaca fascicularis). The 12 defects were assigned to one of the following treatments: (1) open flap debridement (OFD) + ACS, (2) OFD+Emdogain/ACS, (3) OFD+Osteogain/ACS, and (4) OFD alone. At 16 weeks following reconstructive surgery, the animals were killed for histological evaluation.

Results: A 20-60% significantly higher amount of total adsorbed amelogenin was found for ACS-loaded Osteogain when compared to Emdogain. The histomorphometric analysis revealed that both approaches (OFD + Emdogain/ACS and OFD + Osteogain/ACS) resulted in higher amounts of connective tissue attachment and bone formation compared to treatment with OFD + ACS and OFD alone. Furthermore, OFD + Osteogain/ACS group showed higher new attachment formation, cementum, and new bone area.

Conclusions: Within their limits, the present data indicate that Osteogain possesses favourable physicochemical properties facilitating adsorption of amelogenin on ACS and may additionally enhance periodontal wound healing/regeneration when compared to Emdogain.
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http://dx.doi.org/10.1111/jcpe.12663DOI Listing
March 2017

Ridge preservation after ridge expansion with simultaneous guided bone regeneration: a preclinical study.

Clin Oral Implants Res 2016 Nov 9;27(11):e116-e124. Epub 2015 Mar 9.

Department of Oral Surgery and Stomatology, School of Dental Medicine, University of Bern, Bern, Switzerland.

Objective: To evaluate ridge preservation after ridge splitting with simultaneous implant placement and guided bone regeneration (GBR) in a miniature pig model.

Material And Methods: In miniature pigs, the mandibular premolars and first molars were extracted together with removal of the interdental and buccal bone. Three months later, ridge splitting and expansion of the buccal plate were performed with simultaneous placement of two titanium implants per quadrant. On the test side, access by a mucoperiosteal flap followed by GBR with a biphasic calcium phosphate and a collagen membrane was performed. On the contralateral control side, a mucosal flap (MF), leaving the periosteum attached to the buccal bone, was elevated. After healing periods of 6 and 12 weeks, eight and four animals, respectively, were sacrificed for histological and histometric evaluation.

Results: In the MF group, all 16 implants were osseointegrated, while in the GBR group, one bone fracture occurred, and six of 16 implants were lost. After 6 weeks, significantly higher bone crest levels were found for the GBR group than for the MF group both buccally and lingually (P < 0.001), and buccal bone thickness was greater in the GBR group than in the MF group (P < 0.001 at the implant shoulder [IS]). After 12 weeks, bone was significantly higher in the GBR group compared to the MF group. Furthermore, buccal bone thickness in the GBR group was 0.93, 4.5, and 5.94 mm at, and 2 and 4 mm apical to the IS, respectively. The corresponding values in the MF group were greatly reduced (0, 0.21, and 2.56 mm). Bone loss on the buccal side compared to the lingual side was significantly greater only in the MF group.

Conclusions: In this ridge expansion model in miniature pigs, the buccal bone volume was significantly better preserved with GBR when compared to a mucosal access flap, provided that soft tissue healing occurred complication free.
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http://dx.doi.org/10.1111/clr.12574DOI Listing
November 2016

Giant cells around bone biomaterials: Osteoclasts or multi-nucleated giant cells?

Acta Biomater 2016 12 22;46:15-28. Epub 2016 Sep 22.

Department of Oral Surgery and Stomatology, Department of Periodontology, University of Bern, Switzerland. Electronic address:

Recently accumulating evidence has put into question the role of large multinucleated giant cells (MNGCs) around bone biomaterials. While cells derived from the monocyte/macrophage lineage are one of the first cell types in contact with implanted biomaterials, it was originally thought that specifically in bone tissues, all giant cells were bone-resorbing osteoclasts whereas foreign body giant cells (FBGCs) were found associated with a connective tissue foreign body reaction resulting in fibrous encapsulation and/or material rejection. Despite the great majority of bone grafting materials routinely found with large osteoclasts, a special subclass of bone biomaterials has more recently been found surrounded by large giant cells virtually incapable of resorbing bone grafts even years after their implantation. While original hypotheses believed that a 'foreign body reaction' may be taking place, histological data retrieved from human samples years after their implantation have put these original hypotheses into question by demonstrating better and more stable long-term bone volume around certain bone grafts. Exactly how or why this 'special' subclass of giant cells is capable of maintaining long-term bone volume, or methods to scientifically distinguish them from osteoclasts remains extremely poorly studied. The aim of this review article was to gather the current available literature on giant cell markers and differences in expression patterns between osteoclasts and MNGCs utilizing 19 specific markers including an array of CD-cell surface markers. Furthermore, the concept of now distinguishing between pro-inflammatory M1-MNGCs (previously referred to as FBGCs) as well as wound-healing M2-MNGCs is introduced and discussed.

Statement Of Significance: This review article presents 19 specific cell-surface markers to distinguish between osteoclasts and MNGCs including an array of CD-cell surface markers. Furthermore, the concept of now distinguishing between pro-inflammatory M1-MNGCs (often previously referred to as FBGCs) as well as wound-healing M2-MNGCs is introduced and discussed. The proposed concepts and guidelines aims to guide the next wave of research facilitating the differentiation between osteoclast/MNGCs formation, as well as provides the basis for increasing our understanding of the exact function of MNGCs in bone tissue/biomaterial homeostasis.
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http://dx.doi.org/10.1016/j.actbio.2016.09.029DOI Listing
December 2016

High-dose irradiation of bone chips preserves the in vitro activity of bone-conditioned medium.

J Oral Sci 2016 ;58(3):325-31

Department of Cranio Maxillofacial Surgery, Inselspital, University of Bern.

Extracorporeal irradiation sterilizes resected tumor bone used as autografts in reconstruction surgery. Therapeutic irradiation is a standard technique in head and neck cancer therapy that aims to preserve organ function. Bone irradiation has a complex, mostly inhibitory, effect on remodeling and regeneration, although the underlying mechanisms are still not fully understood. It remains unclear if extracorporeal irradiation affects the paracrine-like activity of the corresponding autografts. We recently reported that bone-conditioned medium from autogenous bone chips contains a number of factors that might affect cell activity. In the present study, we investigated the effects of extracorporeal irradiation of porcine cortical bone chips on the activity of the corresponding bone-conditioned medium. The effects of bone-conditioned medium on the expressions of transforming growth factor-beta (TGF-β) target genes in oral fibroblasts were assessed. Bone-conditioned medium from bone chips exposed to a total radiation dose up to 120 Gy did not affect expressions of TGF-β target genes, including adrenomedullin, BTB/POZ domain-containing protein 11, proteoglycan 4, NADPH oxidase 4, and interleukin 11, in oral fibroblasts. In conclusion, bone irradiation does not alter the capability of the corresponding bone-conditioned medium to provoke a robust fibroblastic cell response in vitro. (J Oral Sci 58, 325-331, 2016).
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http://dx.doi.org/10.2334/josnusd.16-0042DOI Listing
April 2017

Bone conditioned media (BCM) improves osteoblast adhesion and differentiation on collagen barrier membranes.

BMC Oral Health 2016 Jul 4;17(1). Epub 2016 Jul 4.

Department of Oral Surgery and Stomatology, Laboratory of Oral Cell Biology, University of Bern, Freiburgstrasse 7, Bern, 3010, Switzerland.

Background: The use of autogenous bone chips during guided bone regeneration procedures has remained the gold standard for bone grafting due to its excellent combination of osteoconduction, osteoinduction and osteogenesis. Recent protocols established by our group have characterized specific growth factors and cytokines released from autogenous bone that have the potential to be harvested and isolated into bone conditioned media (BCM). Due to the advantageous osteo-promotive properties of BCM, the aims of the present study was to pre-coat collagen barrier membranes with BCM and investigate its effect on osteoblast adhesion, proliferation and differentiation for possible future clinical use.

Methods: Scanning electron microscopy (SEM) was first used to qualitative assess BCM protein accumulation on the surface of collagen membranes. Thereafter, undifferentiated mouse ST2 stromal bone marrow cells were seeded onto BioGide porcine derived collagen barrier membranes (control) or barrier membranes pre-coated with BCM (test group). Control and BCM samples were compared for cell adhesion at 8 h, cell proliferation at 1, 3 and 5 days and real-time PCR at 5 days for osteoblast differentiation markers including Runx2, alkaline phosphatase (ALP), osteocalcin (OCN) and bone sialoprotein (BSP). Mineralization was further assessed with alizarin red staining at 14 days post seeding.

Results: SEM images demonstrated evidence of accumulated proteins found on the surface of collagen membranes following coating with BCM. Analysis of total cell numbers revealed that the additional pre-coating with BCM markedly increased cell attachment over 4 fold when compared to cells seeded on barrier membranes alone. No significant difference could be observed for cell proliferation at all time points. BCM significantly increased mRNA levels of osteoblast differentiation markers including ALP, OCN and BSP at 5 days post seeding. Furthermore, barrier membranes pre-coated with BCM demonstrated a 5-fold increase in alizarin red staining at 14 days.

Conclusion: The results from the present study suggest that the osteoconductive properties of porcine-derived barrier membranes could be further improved by BCM by significantly increasing cell attachment, differentiation and mineralization of osteoblasts in vitro. Future animal testing is required to fully characterize the additional benefits of BCM for guided bone regeneration.
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http://dx.doi.org/10.1186/s12903-016-0230-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948089PMC
July 2016

Osteogenic gene array of osteoblasts cultured on a novel osteoinductive biphasic calcium phosphate bone grafting material.

Clin Oral Investig 2017 Apr 23;21(3):801-808. Epub 2016 Apr 23.

The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, 237 Luoyu Road, Wuhan, 430079, People's Republic of China.

Objectives: Recently, novel biphasic calcium phosphate (BCP) scaffolds have emerged as a new class of bone grafts with osteoinductive potential demonstrating the ability to form ectopic bone in extra-skeletal sites. The aim of the present study was to perform an osteogenic gene array to target possible genes responsible for eliciting the changes in cell expression responsible for inducing osteoblast differentiation.

Materials And Methods: Human MG63 osteoblast-like cells were seeded for 24 h on tissue culture plastic or osteoinductive BCP particles and analyzed for upregulated genes using an osteogenesis super-array. Osteoblast-related genes including those transcribed during bone mineralization, bone metabolism, cell growth and differentiation, as well as gene products representing extracellular matrix molecules, transcription factors, and cell adhesion molecules were investigated.

Results: An upregulation of genes transcribing biglycan (1.7-fold), bone morphogenetic proteins 1, 2, 4, 6, and 7 (1.5-2.1-fold), various collagen isoforms including 1a1, 1a2, 2a1, and 5a1 (1.73-2.72-fold), colony stimulating factor 2 (2.59-fold), fibroblast growth factor receptor 2 (1.79-fold), fibronectin (2.56-fold), integrin alpha 1, 2, and 3 (1.82-2.24-fold), SOX9 (2.75-fold), transforming growth factor beta receptor 2 (1.72-fold), vitamin D (1.89-fold), and vascular endothelial growth factor A and B (2.00, 1.75-fold) were all significantly (p < 0.05) increased on BCP particles when compared to control tissue culture plastic.

Conclusion: In summary, a number of activated genes were involved in bone formation following osteoblast attachment to BCP particles. The involvement of key chondrogenic genes hints that bone grafts capable of spontaneously inducing ectopic bone formation may implicate endochondral ossification. Further investigations in the triggered pathways involved in the process of ectopic bone formation are necessary to understand the key inductive properties of these novel osteoinductive BCP particles.

Clinical Relevance: Novel osteoinductive BCP particles demonstrate a wide range of significant increases over several key molecules implicated in osteogenesis that may be implicated in their ability to form ectopic bone formation.
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http://dx.doi.org/10.1007/s00784-016-1825-0DOI Listing
April 2017