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Purpose: The host tissue reaction to the xenogeneic bone substitute Bio-Oss™ (Geistlich Biomaterials, Wolhousen, Switzerland) was investigated focusing on the participating inflammatory cells and implantation bed vascularization. Materials and Methods: Bio-Oss™ was implanted subcutaneously into CD1 mice for up to 60 days and analyzed by means of specialized histological and histomorphometrical techniques after explantation. Results: Bio-Oss™ induced within the first 15 days an early high vascularization combined with a marked presence of multinucleated giant cells. The latter cells were associated mainly with the smaller sized granules within the implantation bed. Toward the end of the study the number of multinucleated giant cells decreased while the tissue reaction to the larger granules was mainly mononuclear. Conclusion: The results of the present study showed that smaller xenogeneic bone substitute granules induce multinucleated giant cells, whereas the larger-sized ones became integrated within the implantation bed by means of a mononuclear cell-triggered granulation tissue. Obviously, the presence of multinucleated giant cells within biomaterial implantation beds is not only related to the type of synthetic bone substitute material, but also to the granule size of the “natural-based” xenogeneic bone substitute material. [ABSTRACT FROM AUTHOR]

Background: The development of malocclusion is related to various factor, many of which are still not fully explained. The steroid hormone, 1,25-dihydroxyvitamin D3, has pleiotropic effects. It plays a key role in skeletal metabolism and the control of cell repair by attaching to the nuclear vitamin D steroid receptor (VDR). This vitamin affects bone turnover through the processes of bone tissue formation and resorption via its action on cells of the osteoblastic and osteoclastic lineage, exerts a modulating effect on the immune system, and is involved in the regulation of cell proliferation and differentiation. The role of vitamin D3 (VD3) and its receptor polymorphisms is a rarely studied topic in dentistry. Due to the proven influence on bone turnover processes and immune responses, the main research topic is its relation to periodontal diseases, but so far, its role in the formation and development of malocclusions has not been assessed., Objectives: This study aimed to assess the association of selected VDR polymorphisms: Cdx2 (rs11658820), TaqI (rs7975232), BsmI (rs1544410), ApaI (rs7975232), and FokI (rs2228570) with the development of malocclusions., Material and Methods: A prospective observational study was performed. The examination consisted of a medical interview, intraand extraoral orthodontic diagnosis, alginate impression, cone beam computed tomography (CBCT), and venous blood sample to obtain genomic DNA and assess VDR polymorphisms., Results: The rs11658820 polymorphism causes an almost 4-fold increase in the probability of the presence of a malocclusion. GT and TT genotypes of rs7975232 are also associated with a similar risk - almost 6 and almost 5 times higher, respectively. In turn, the effect of the rs2228570-AG and GG genotype polymorphisms on the occurrence of transversal anomalies was demonstrated (odds ratio (OR) = 8.46 and OR = 6.92, respectively)., Conclusions: The association of individual polymorphisms with specific malocclusions should be carefully assessed, especially since some trends have been indicated.

Based on the evidence of a significant communication and connection pathway between the bone and immune systems, a new science has emerged: osteoimmunology. Indeed, the immune system has a considerable impact on bone health and diseases, as well as on bone formation during grafts and its stability over time. Chronic inflammation induces the excessive production of oxidants. An imbalance between the levels of oxidants and antioxidants is called oxidative stress. This physio-pathological state causes both molecular and cellular damage, which leads to DNA alterations, genetic mutations and cell apoptosis, and thus, impaired immunity followed by delayed or compromised wound healing. Oxidative stress levels experienced by the body affect bone regeneration and maintenance around teeth and dental implants. As the immune system and bone remodeling are interconnected, bone loss is a consequence of immune dysregulation. Therefore, oral tissue deficiencies such as periodontitis and peri-implantitis should be regarded as immune diseases. Bone management strategies should include both biological and surgical solutions. These protocols tend to improve immunity through antioxidant production to enhance bone formation and prevent bone loss. This narrative review aims to highlight the relationship between inflammation, oxidation, immunity and bone health in the oral cavity. It intends to help clinicians to detect high-risk situations in oral surgery and to propose biological and clinical solutions that will enhance patients' immune responses and surgical treatment outcomes.

Objective: To evaluate the clinical benefits of liquid platelet-rich fibrin (PRF) in patients with temporomandibular joint (TMJ) pain and dysfunction., Methods: Forty-eight TMJs in 37 patients with painful internal derangement (ID) (Wilkes' I-V) were included. Patients were injected with 1.5-2cc of PRF within the superior joint space at 2-week intervals. Pain and subjective dysfunction were recorded using a visual analog scale. Statistical analyses were done using the ANOVA test., Results: Thirty-three of 48 TMJs (69%) showed significant reduction in pain at 8 weeks, and at 3, 6, and 12 months (Responders). Fifteen of 48 TMJs (31%) did not improve (Non-responders). The best Responders to liquid PRF injections were ID stages Wilkes' IV (78.5%) and V (100%), compared to Wilkes' I (0%), II (47%), and III (33%). A non-significant, but notable decrease in dysfunction was found., Conclusion: Preliminary findings support that liquid PRF exhibits long-term analgesic effects in most patients with painful TMJ ID.

Platelet-rich fibrin (PRF) is a blood concentrate derived from venous blood that is processed without anticoagulants by a one-step centrifugation process. This three-dimensional scaffold contains inflammatory cells and plasma proteins entrapped in a fibrin matrix. Liquid-PRF was developed based on the previously described low-speed centrifuge concept (LSCC), which allowed the introduction of a liquid-PRF formulation of fibrinogen and thrombin prior to its conversion to fibrin. Liquid-PRF was introduced to meet the clinical demand for combination with biomaterials in a clinically applicable and easy-to-use way. The aim of the present study was to evaluate, ex vivo, the interaction of the liquid-PRF constituents with five different collagen biomaterials by histological analyses. The results first demonstrated that large variability existed between the biomaterials investigated. Liquid-PRF was able to completely invade Mucograft ® (MG; Geistlich Biomaterials, Wolhusen, Switzerland) and to partly invade Bio-Gide ® (BG; Geistlich Biomaterials, Wolhusen, Switzerland) and Mucoderm ® (MD; Botiss Biomaterials, Berlin, Germany), and Collprotect ® (CP; Botiss Biomaterials, Berlin, Germany) showed only a superficial interaction. The BEGO ® collagen membrane (BCM; BEGO Implant Systems) appeared to be completely free of liquid-PRF. These results were confirmed by the different cellular penetration and liquid-PRF absorption coefficient (PAC) values of the evaluated membranes. The present study demonstrates a system for loading biomaterials with a complex autologous cell system (liquid-PRF) in a relatively short period of time and in a clinically relevant manner. The combination of biomaterials with liquid-PRF may be clinically utilized to enhance the bioactivity of collagen-based biomaterials and may act as a biomaterial-based growth factor delivery system.

Different tissue engineering techniques are used to support rapid vascularisation. A novel technique is the use of platelet-rich fibrin (PRF), an autologous source of growth factors. This study was the first to investigate the influence of PRF matrices, isolated following different centrifugation protocols, on human dermal vascular endothelial cells (ECs) in mono-culture and co-culture with human primary fibroblasts (HFs) as an in vitro model for tissue regeneration. Focus was placed on vascular structure formation and growth factor release. HFs and ECs were cultivated with PRF prepared using a high (710 ×g) or low (44 ×g) relative centrifugation force (RCF) over 14 d. Immunofluorescence staining and immunohistochemistry were used to evaluate the microvascular formation. Cell culture supernatants were collected for evaluation of growth factor release. The results showed a PRF-mediated effect on the induction of angiogenesis in ECs. Microvessel-like structure formation was promoted when ECs were combined with low-RCF PRF as compared to high-RCF PRF or control group. The percentage of vascular lumen area was significantly higher in low-RCF PRF, especially at day 7, which coincided with statistically significantly higher growth factor [vascular endothelial factor (VEGF), transforming growth factor β1 (TGF-β1) and platelet derived growth factor (PDGF)] concentration measured in low-RCF PRF as compared to high-RCF PRF or control group. In conclusion, reducing the RCF according to the low-speed centrifugation concept (LSCC) resulted in increased growth factor release and angiogenic structure formation with EC mono-culture, suggesting that PRF may be a highly beneficial therapeutic tool for tissue engineering applications.

Platelet-rich fibrin is a blood concentrate system used for soft tissue and bone tissue regeneration. In the last decade, platelet rich fibrin (PRF) has been widely used in different indication fields, particularly in oral and maxillofacial surgery. This review investigates the level of scientific evidence of published articles related to the use of PRF for bone and soft tissue regeneration in dentistry and maxillofacial surgery. An electronic literature research using the biomedical search engine "National Library of Medicine" (PubMed-MEDLINE) was performed in May 2017. A total of 392 articles were found, 72 of which were classified for each indication field. When comparing PRF with biomaterials vs biomaterial alone in sinus lift (5 studies; IIa), no statistically significant differences were detected. Socket preservation and ridge augmentation using PRF significantly enhanced new bone formation compared to healing without PRF (7 studies Ib, IIa, IIb). Reepithelialization and bone regeneration was achieved in 96 of 101 patients diagnosed with medication-related osteonecrosis of the jaw (5 studies, III). In periodontology, PRF alone (6 studies; Ib, IIa, IIb) or its combination with biomaterials (6 studies; Ib, IIa, IIb) significantly improved the pocket depth and attachment loss compared to a treatment without PRF. Over 70% of the patients were part of studies with a high level of scientific evidence (randomized and controlled prospective studies). This published evidence (38 articles), with a high scientific level, showed that PRF is a beneficial tool that significantly improves bone and soft tissue regeneration. However, the clinical community requires a standardization of PRF protocols to further examine the benefit of PRF in bone and soft tissue regeneration in reproducible studies, with a higher scientific level of evidence.

Background: Primary care patients are often cited as a cause of Emergency Department overcrowding (ED). The aim of this study was to evaluate a physician led redirection procedure of selected patients towards an out of hours general practice (OHGP) in an Emergency Department with 55,000 admissions per year., Methods: Observational monocentric study over a period of 2 months. Every patient redirected to the OHGP was included and subsequently contacted by telephone to answer a standardized questionnaire, in order to measure: Redirection rate over the entire period and during weekdays or weekends/holiday Rate of redirected patients who went to the OHGP Rate of redirected patients who consulted in an ED in the next 72 h for the same reason Redirected patients' satisfaction rate RESULTS: During the study period 9551 patients presented to the ED, of which 288 were redirected towards the OHGP (3%). The redirection rate was 1.9% during weekdays and 5.7% during weekends/holiday (p < 0.001). Of the redirected patients, 77% answered the telephone interview. Ninety percent of these patients consulted the OHGP. The main reasons for not consulting were: unduly long wait, opening hours not suitable, too costly. The rate of redirected patients who consulted in an ED in the following 72 h for the same reason was 4.1%. The satisfaction rate was 79.6% among interviewed patients., Conclusions: A physician led procedure to redirect selected patients from the ED towards an OHGP results in a low redirection rate, unlikely to have a significant effect on ED patient flow. However, the procedure is safe and well accepted by a majority of patients.

Platelet rich fibrin (PRF) is a blood concentrate system obtained by centrifugation of peripheral blood. First PRF matrices exhibited solid fibrin scaffold, more recently liquid PRF-based matrix was developed by reducing the relative centrifugation force and time. The aim of this study was to systematically evaluate the influence of RCF (relative centrifugal force) on cell types and growth factor release within injectable PRF- in the range of 60-966 g using consistent centrifugation time. Numbers of cells was analyzed using automated cell counting (platelets, leukocytes, neutrophils, lymphocytes and monocytes) and histomorphometrically (CD 61, CD- 45, CD-15+, CD-68+, CD-3+ and CD-20). ELISA was utilized to quantify the concentration of growth factors and cytokines including PDGF-BB, TGF-β1, EGF, VEGF and MMP-9. Leukocytes, neutrophils, monocytes and lymphocytes had significantly higher total cell numbers using lower RCF. Whereas, platelets in the low and medium RCF ranges both demonstrated significantly higher values when compared to the high RCF group. Histomorphometrical analysis showed a significantly high number of CD61+, CD-45+ and CD-15+ cells in the low RCF group whereas CD-68+, CD-3+ and CD-20+ demonstrated no statistically significant differences between all groups. Total growth factor release of PDGF-BB, TGF-β1 and EGF had similar values using low and medium RCF, which were both significantly higher than those in the high RCF group. VEGF and MMP-9 were significantly higher in the low RCF group compared to high RCF. These findings support the LSCC (low speed centrifugation concept), which confirms that improved PRF-based matrices may be generated through RCF reduction. The enhanced regenerative potential of PRF-based matrices makes them a potential source to serve as a natural drug delivery system. However, further pre-clinical and clinical studies are required to evaluate the regeneration capacity of this system.

Various strategies have been employed to speed tissue regeneration using bioactive molecules. Interestingly, platelet concentrates derived from a patient's own blood have been utilized as a regenerative strategy in recent years. In the present study, a novel liquid platelet formulation prepared without the use of anti-coagulants (injectable-platelet-rich fibrin, i-PRF) was compared to standard platelet-rich plasma (PRP) with gingival fibroblasts cultured on smooth and roughened titanium implant surfaces. Standard PRP and i-PRF (centrifuged at 700 rpm (60× g ) for 3 min) were compared by assays for fibroblast biocompatibility, migration, adhesion, proliferation, as well as expression of platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), collagen1 (COL1) and fibronectin (FN). The results demonstrate that i-PRF induced significantly higher cell migration, as well as higher messenger RNA (mRNA) levels of PDGF, TGF-β, collagen1 and fibronectin when compared to PRP. Furthermore, collagen1 synthesis was highest in the i-PRF group. These findings demonstrate that liquid platelet concentrates can be formulated without the use of anticoagulants and present much translational potential for future research. Future animal and clinical trials are now necessary to further investigate the potential of utilizing i-PRF for soft tissue regenerative protocols in combination with various biomaterials.

Bone substitute materials of different origin and chemical compositions are frequently used in augmentation procedures to enlarge the local bone amount. However, relatively little data exist on the long-term tissue reactions. The presented case reports for the first time histological and histomorphometrical analyses of a nanocrystaline hydroxyapatite-based bone substitute material implanted in the human sinus cavity after an integration period of 3 years. The extracted biopsy was analyzed histologically and histomorphometrically with focus on the tissue reactions, vascularization, new bone formation, and the induction of a foreign body reaction. A comparably high rate of connective tissue (48.25%) surrounding the remaining bone substitute granules (42.13%) was observed. Accordingly, the amount of bone tissue (9.62%) built the smallest fraction within the biopsy. Further, tartrate-resistant acid phosphatase-positive and -negative multinucleated giant cells (4.35 and 3.93 cells/mm(2), respectively) were detected on the material-tissue interfaces. The implantation bed showed a mild vascularization of 10.03 vessels/mm(2) and 0.78%. The present case report shows that after 3 years, a comparable small amount of bone tissue was observable. Thus, the foreign body response to the bone substitute seems to be folded without further degradation or regeneration.

In this study, the tissue reactions to 2 new porcine dermis-derived collagen membranes of different thickness were analyzed. The thicker material (Mucoderm) contained sporadically preexisting vessel skeletons and fatty islands. The thinner membrane (Collprotect) had a bilayered structure (porous and occlusive side) without any preexisting structures. These materials were implanted subcutaneously in mice to analyze the tissue reactions and potential transmembranous vascularization. Histological and histomorphometrical methodologies were performed at 4 time points (3, 10, 15, and 30 days). Both materials permitted stepwise connective tissue ingrowth into their central regions. In the Mucoderm matrix, newly built microvessels were found within the preexisting vessel and fatty island skeletons after 30 days. This vascularization was independent of the inflammation-related vascularization on both material surfaces. The Collprotect membrane underwent material disintegration by connective tissue strands in combination with vessels and multinucleated giant cells. The histomorphometric analyses revealed that the thickness of Mucoderm did not decrease significantly, while an initial significant decrease of membrane thickness in the case of Collprotect was found at day 15. The present results demonstrate that the 2 analyzed collagen membranes underwent a multinucleated giant cell-associated vascularization. Neither of the materials underwent transmembraneous vascularization. The microvessels were found within the preexisting vessel and fatty island skeletons. Additional long-term studies and clinical studies are necessary to determine how the observed foreign body giant cells affect tissue regeneration.

The present preclinical and clinical study assessed the inflammatory response to a high-temperature-treated xenogeneic material (Bego-Oss) and the effects of this material on the occurrence of multinucleated giant cells, implantation bed vascularization, and regenerative potential. After evaluation of the material characteristics via scanning electron microscopy, subcutaneous implantation in CD-1 mice was used to assess the inflammatory response to the material for up to 60 days. The clinical aspects of this study involved the use of human bone specimens 6 months after sinus augmentation. Established histologic and histomorphometric analysis methods were applied. After implantation, the material was well integrated into both species without any adverse reactions. Material-induced multinucleated giant cells were observed in both species and were associated with enhanced vascularization. These results revealed the high heat treatment led to an increase in the inflammatory tissue response to the biomaterial, and a combined increase in multinucleated giant cell formation. Further clarification of the differentiation of the multinucleated giant cells toward so-called osteoclast-like cells or foreign-body giant cells is needed to relate these cells to the physicochemical composition of the material.

Choukroun's platelet-rich fibrin (PRF) is obtained from blood without adding anticoagulants. In this study, protocols for standard platelet-rich fibrin (S-PRF) (2700 rpm, 12 minutes) and advanced platelet-rich fibrin (A-PRF) (1500 rpm, 14 minutes) were compared to establish by histological cell detection and histomorphometrical measurement of cell distribution the effects of the centrifugal force (speed and time) on the distribution of cells relevant for wound healing and tissue regeneration. Immunohistochemistry for monocytes, T and B -lymphocytes, neutrophilic granulocytes, CD34-positive stem cells, and platelets was performed on clots produced from four different human donors. Platelets were detected throughout the clot in both groups, although in the A-PRF group, more platelets were found in the distal part, away from the buffy coat (BC). T- and B-lymphocytes, stem cells, and monocytes were detected in the surroundings of the BC in both groups. Decreasing the rpm while increasing the centrifugation time in the A-PRF group gave an enhanced presence of neutrophilic granulocytes in the distal part of the clot. In the S-PRF group, neutrophils were found mostly at the red blood cell (RBC)-BC interface. Neutrophilic granulocytes contribute to monocyte differentiation into macrophages. Accordingly, a higher presence of these cells might be able to influence the differentiation of host macrophages and macrophages within the clot after implantation. Thus, A-PRF might influence bone and soft tissue regeneration, especially through the presence of monocytes/macrophages and their growth factors. The relevance and feasibility of this tissue-engineering concept have to be proven through in vivo studies.

Purpose: The host tissue reaction to the xenogeneic bone substitute Bio-Oss™ (Geistlich Biomaterials, Wolhousen, Switzerland) was investigated focusing on the participating inflammatory cells and implantation bed vascularization., Materials and Methods: Bio-Oss™ was implanted subcutaneously into CD1 mice for up to 60 days and analyzed by means of specialized histological and histomorphometrical techniques after explantation., Results: Bio-Oss™ induced within the first 15 days an early high vascularization combined with a marked presence of multinucleated giant cells. The latter cells were associated mainly with the smaller sized granules within the implantation bed. Toward the end of the study the number of multinucleated giant cells decreased while the tissue reaction to the larger granules was mainly mononuclear., Conclusion: The results of the present study showed that smaller xenogeneic bone substitute granules induce multinucleated giant cells, whereas the larger-sized ones became integrated within the implantation bed by means of a mononuclear cell-triggered granulation tissue. Obviously, the presence of multinucleated giant cells within biomaterial implantation beds is not only related to the type of synthetic bone substitute material, but also to the granule size of the natural-based xenogeneic bone substitute material.

Following a failure of a bone graft or an implant placement, the hypothesis of a biological abnormality is rarely considered as a possible cause. A systematic search of peer-reviewed literature for dyslipidemia or vitamin D deficiency may explain this lack of consideration. Excess low-density lipoprotein cholesterol (dyslipidemia) is responsible for a slower bone metabolism or lower dental implant osseointegration. In addition, vitamin D is a key factor for linking innate and adaptive immunity. Both of these factors are compromised under the conditions of vitamin D deficiency. Therefore, vitamin D deficiency slows implant osseointegration and increases the risk of graft infection. Vitamin D is also involved in immune function and therefore allergic reactions.

The present study reports on a 3-year clinical and radiologic follow-up investigation of dental implants placed 3 and 6 months after sinus augmentation in 14 patients. Augmentation was performed with a synthetic bone substitute material composed of nanocrystalline hydroxyapatite. The aim of the study was to determine how the integration period of the bone substitute material, that is, 3 months or 6 months, influences implant integration within the patient's upper jaw. Therefore, the following clinical and radiologic parameters were investigated: implant being in situ; Periotest value; and presence of peri-implant osteolysis, bleeding on probing, plaque, and soft tissue recession around the implants. At the follow-up investigation 3 years after placement, 23 of 24 implants were in situ and suitable for prosthetic rehabilitation. No implants in either study group were mobile or showed peri-implant osteolysis. Only a few implants showed plaque or soft tissue variations. Within its limits, the present study showed comparable clinical performance of dental implants placed 3 months after sinus floor augmentation to implants placed 6 months after augmentation. The results of all investigated parameters were in accordance with results found in the literature. It can be concluded that augmentation with the applied synthetic bone substitute material already forms a sufficient implantation bed 3 months after augmentation, which enables long-term, stable, implant-retained restoration. These findings might contribute to a reduced healing time after augmentation, which would be favorable for patients and clinicians.