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Histological results after 2 weeks: a Implant by itself, b Implant with ICBM-Carrier, c Implant with ICBM-Carrier and rhBMP-2, d Implant with ICBM, rhBMP-2 and VEGF, + indicates new bone formation around the windings of the implant, → indicates islands of newly formed osteoid matrix
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Background
Sufficient vertical and lateral bone supply and a competent osteogenic healing process are prerequisities for the successful osseointegration of dental implants in the alveolar bone. Several techniques including autologous bone grafts and guided bone regeneration are applied to improve quality and quantity of bone at the implantation sit...
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Context 1
... microscopic examinations of the control group and the ICBM group showed no or very little new bone formation after 2 weeks (Fig. 1). Around implants covered by ICBM + BMP-2 and ICBM + BMP-2 + VEGF islands of osteoid could be found within the area of the ICBMscaffold. After 4 weeks in all groups new bone was formed. In the ICBM + BMP-2 + VEGF group new bone grew circumferentially around the implant presenting trabecular bone and primary bone marrow. After 12 weeks ...
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Citations
... Many drugs have been suggested to promote the repair and regeneration of alveolar bone defects [12][13][14][15]. Immunostimulatory cytosine-phosphate-guanosine (CpG)-containing oligodeoxynucleotides (ODN) is a short single-strand DNA that is recognized by Toll-like receptor 9 (TLR9). ...
The immune system plays an important role in the skeletal system during bone repair and regeneration. The controlled release of biological factors from the immune system could facilitate and optimize the bone remodeling process through the regulation of the activities of bone cells. This study aimed to determine the effect of the controlled delivery of immunomodulatory biologicals on bone regeneration. Immunostimulatory cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODN) and glucosylxanthone Mangiferin (MAG)-embedded microbeads were incubated with P. gingivalis-challenged splenocytes, or co-cultured with RAW264.7 cells. The effect of CpG ODN/MAG-containing microbeads on bone regeneration was then tested in vivo in a mouse alveolar bone defect model. The results demonstrated that MAG significantly antagonized P. gingivalis proliferation and reduced the live/dead cell ratio. After the addition of CpG ODN + MAG microbeads, anti-inflammatory cytokines IL-10 and IL-4 were upregulated on day 2 but not day 4, whereas pro-inflammatory cytokine IL-1β responses showed no difference at both timepoints. RANKL production by splenocytes and TRAP+ cell formation of RAW264.7 cells were inhibited by the addition of CpG ODN + MAG microbeads. Alveolar bony defects, filled with CpG ODN + MAG microbeads, showed significantly increased new bone after 4 weeks. In summary, this study evaluated a new hydrogel-based regimen for the local delivery and controlled release of biologicals to repair and regenerate alveolar bony defects. The combined CpG ODN + MAG treatment may promote alveolar bone regeneration through the anti-microbial/anti-inflammatory effects and the inhibition of RANKL-mediated osteoclastogenesis.
... Furthermore, mature swine have a similar bone structure to humans, with a well-developed Haversian system and a similar bone regeneration rate [154]. Swine are large animals, which are difficult to handle and maintain under experimental conditions [155]. The sheep model for bone regeneration was used due to its similar bone turnover and bone modeling rates to those of humans [156]. ...
Citation: Desnica, J.; Vujovic, S.; Stanisic, D.; Ognjanovic, I.; Jovicic, B.; Stevanovic, M.; Rosic, G. Preclinical Evaluation of Bioactive Scaffolds for the Treatment of Mandibular Critical-Sized Bone Defects: A Systematic Review. Appl. Sci. 2023, 13, 4668. https://doi. Abstract: This systematic review evaluated current in vivo research on regenerating critical-sized mandibular defects and discussed methodologies for mandibular bone tissue engineering. Out of the 3650 articles initially retrieved, 88 studies were included, and all studies that used a scaffold reported increased bone formation compared to negative controls. Combining scaffolds with growth factors and mesenchymal stem cells improved bone formation and healing. Bone morphogenic proteins were widely used and promoted significant bone formation compared to controls. However, discrepancies between studies exist due to the various methodologies and outcome measures used. The use of scaffolds with bioactive molecules and/or progenitor cells enhances success in mandibular bone engineering. Scaffold-based mandibular bone tissue engineering could be introduced into clinical practice due to its proven safety, convenience, and cost-effectiveness.
... In the animal model, the delivery of rhBMP-2 around dental implants varied from calcium phosphate deriva- [32]. The lowest concentration of 0.2 µg was tried in an animal study with a calcium phosphate carrier [38]. ...
... Lyu et al. [31], had also observed an insignificant increase in bone gain at 4 weeks, while Schorn et al. [32] and Chao et al. [34], also observed the same; they revealed maximum gain with BMP was achieved at 12 wee- between BMP and non-BMP groups respectively [32]. Whereas with HA/βTCP/Collagen increase in bone vol-ume density was insignificant, that varied between 50-60% with the highest percent for the BMP group [34]. ...
... Lyu et al. [31], had also observed an insignificant increase in bone gain at 4 weeks, while Schorn et al. [32] and Chao et al. [34], also observed the same; they revealed maximum gain with BMP was achieved at 12 wee- between BMP and non-BMP groups respectively [32]. Whereas with HA/βTCP/Collagen increase in bone vol-ume density was insignificant, that varied between 50-60% with the highest percent for the BMP group [34]. ...
Statement of the Problem: Bone morphogenetic protein (BMP), a potential osteoinductive agent, was systematically reviewed for merits and demerits when used as a bone additive that was intervened during the surgical phase of dental implant placement; and suitable drug carriers that could withstand the functional load and deliver BMP at its lowest concentration. Purpose: To identify the carriers and concentration of BMP acceptable during surgical phase of implant placement and evaluate its efficacy in bone gain and osseointegration. Materials and Method: The study design was systematic review. Literature search as per PICO format was carried out within a time range from 2000 to July 2021. The review followed PRISMA guidelines and registered with the PROSPERO (CRD42020171667). The focus question included the population with an intra-oral implant placed in both animal and human models that were intervened with BMP-2 as an external additive biomaterial during the surgical phase. 2631 articles selected from the initial search were systematically filtered and yielded 16 articles that were qualitatively analysed. Results: The inter-rater reliability and level of agreement were 93.71%, κ(Kappa)>0.81 respectively. Results revealed the collagen carrier was commonly used for BMP delivery but lacked the property to withstand functional load and sustained release. BMP concentration varied in the range of 0.215µg to 0.8mg and the study revealed significantly indifferent outcome with low dose compared to the highest dose. BMP supplement showed better osseointe-gration in comparison with non-supplemented sites during the early period (within 6 months). Conclusion: BMP at lower concentrations and with appropriate carriers, collagen sponge, hydroxyapatite/tricalcium phosphate (HA/TCP) with a bio ceramic bulking agent, and poly (D, L-lactide-co-glycolic acid) (PLGA) reinforced with gelatin/HA/TCP accelerated bone growth during the initial stages of healing. Further long-term clinical trials for dental implant, analysing the sustained release of BMP with biodegradable and load-bearing carriers should be considered.
... Adsorption and covalent bonding are also the common routes employed to functionalize bioceramics with recombinant full length growth factors (Hajimiri et al., 2015;Damia et al., 2021). The main growth factors chosen to functionalize bioceramics for application in bone repair are the osteogenic bone morphogenetic protein-2 (BMP-2) and the vascular endothelial growth factor VEGF (Aryal et al., 2014;Damia et al., 2021), alone Casarrubios et al., 2020) or in combination together (Kanczler et al., 2010;Schorn et al., 2017) or with other growth factors (Ratanavaraporn et al., 2011;Shen et al., 2016;Kuhn et al., 2021). BMP-2 and VEGF, as signaling molecules, play central roles in the molecular events controlling the spatial-temporal accomplishment of bone healing (Salhotra et al., 2020). ...
Calcium phosphate ceramics, including hydroxyapatite (HA), have been used as bone substitutes for more than 40 years. Their chemical composition, close to that of the bone mineral, confers them good biological and physical properties. However, they are not sufficient to meet all the needs in bone regenerative medicine, such as in the context of critical bone lesions. Therefore, it is essential to improve their biological performances in order to extend their application domains. In this aim, three approaches are mainly followed on the assumption that the biological response can be tuned by modifications of the chemical physical properties of the ceramic: 1) Incorporation of specific chemical species into the calcium phosphate crystalline lattice of chemical elements to stimulate bone repair. 2) Modulation of the bioceramic architecture to optimize the cellular responses at the interface. 3) Functionalization of the bioceramic surface with bioactive molecules. These approaches are supposed to act on separate parameters but, as they are implemented during different steps of the ceramic processing route, they cannot be considered as exclusive. They will ineluctably induces changes of several other physical chemical properties of the final ceramic that may also affect the biological response. Using examples of recent works from our laboratory, the present paper aims to describe how biology can be affected by the bioceramics modifications according to each one of these approaches. It shows that linking biological and chemical physical data in a rational way makes it possible to identify pertinent parameters and related processing levers to target a desired biological response and then more precisely tune the biological performance of ceramic biomaterials. This highlights the importance of integrating the biological evaluation into the heart of the processes used to manufacture optimized biomaterials.
... Examples of bovine xenogeneic bone grafts are insoluble collagenous bone matrix (ICBM) and BioOss ® Collagen. Both have proven to be excellent materials for bone augmentation in previous studies [5,6]. ICBM mainly consists of collagen type I [7], whereas BioOss ® Collagen consists of a mixture of cancellous granules and collagen [8]. ...
... ICBM mainly consists of collagen type I [7], whereas BioOss ® Collagen consists of a mixture of cancellous granules and collagen [8]. ICBM is predominately used in research settings [6,7], BioOss ® is often used in clinical routines [9,10]. Augmentative results of xenogeneic materials vary in literature [11,12]. ...
... ICBM is a bovine-derived scaffold mainly consisting of collagen type 1. It has proven to provide excellent grounds for cell proliferation and growth [6,22]. BO is also bovinederived, consisting of a mixture of spongious granules and collagen. ...
Alloplastic and xenogeneic bone grafting materials are frequently used for bone augmentation. The effect of these materials on precursor cells for bone augmentation is yet to be determined. The aim of this study was to ascertain, in vitro, how augmentation materials influence the growth rates and viability of human unrestricted somatic stem cells. The biocompatibility of two xenogeneic and one alloplastic bone graft was tested using human unrestricted somatic stem cells (USSCs). Proliferation, growth, survival and attachment of unrestricted somatic stem cells were monitored after 24 h, 48 h and 7 days. Furthermore, cell shape and morphology were evaluated by SEM. Scaffolds were assessed for their physical properties by Micro-CT imaging. USSCs showed distinct proliferation on the different carriers. Greatest proliferation was observed on the xenogeneic carriers along with improved viability of the cells. Pore sizes of the scaffolds varied significantly, with the xenogeneic materials providing greater pore sizes than the synthetic inorganic material. Unrestricted somatic stem cells in combination with a bovine collagenous bone block seem to be very compatible. A scaffold’s surface morphology, pore size and bioactive characteristics influence the proliferation, attachment and viability of USSCs.
... A synergistic effect was observed when rhBMP2 and vascular endothelial growth factor (VEGF) were used together to enhance bone generation around implant sites via an insoluble collagenous bone matrix (Schorn et al., 2017). In this combination, VEGF promotes angiogenesis and enhances osteoblastic differentiation, thereby facilitating craniofacial ossification (Duan et al., 2016), while the matrix acts as a scaffold for migrating osteoblasts. ...
... In this combination, VEGF promotes angiogenesis and enhances osteoblastic differentiation, thereby facilitating craniofacial ossification (Duan et al., 2016), while the matrix acts as a scaffold for migrating osteoblasts. This combination product can reduce surgery time and minimize donor site morbidity while maintaining bone stability, as little resorption was observed over time (Schorn et al., 2017). ...
Sufficient alveolar bone is a safeguard for achieving desired outcomes in orthodontic treatment. Moving a tooth into an alveolar bony defect may result in a periodontal defect or worse–tooth loss. Therefore, when facing a pathologic situation such as periodontal bone loss, alveolar clefts, long-term tooth loss, trauma, and thin phenotype, bone grafting is often necessary to augment bone for orthodontic treatment purposes. Currently, diverse bone grafts are used in clinical practice, but no single grafting material shows absolutely superior results over the others. All available materials demonstrate pros and cons, most notably donor morbidity and adverse effects on orthodontic treatment. Here, we review newly developed graft materials that are still in the pre-clinical stage, as well as new combinations of existing materials, by highlighting their effects on alveolar bone regeneration and orthodontic tooth movement. In addition, novel manufacturing techniques, such as bioprinting, will be discussed. This mini-review article will provide state-of-the-art information to assist clinicians in selecting grafting material(s) that enhance alveolar bone augmentation while avoiding unfavorable side effects during orthodontic treatment.
... The combined use of VEGF and rhBMP-2 can increase angiogenesis and blood supply, promote the formation of new bone and solve the Frontiers in Bioengineering and Biotechnology | www.frontiersin.org problem of vertical bone regeneration in clinical work (Schorn et al., 2017). There is also TGF (Tan et al., 2021) similar to BMP synergistic osteogenesis. ...
Guided bone regeneration (GBR) is a widely used technique for alveolar bone augmentation. Among all the principal elements, barrier membrane is recognized as the key to the success of GBR. Ideal barrier membrane should have satisfactory biological and mechanical properties. According to their composition, barrier membranes can be divided into polymer membranes and non-polymer membranes. Polymer barrier membranes have become a research hotspot not only because they can control the physical and chemical characteristics of the membranes by regulating the synthesis conditions but also because their prices are relatively low. Still now the bone augment effect of barrier membrane used in clinical practice is more dependent on the body’s own growth potential and the osteogenic effect is difficult to predict. Therefore, scholars have carried out many researches to explore new barrier membranes in order to improve the success rate of bone enhancement. The aim of this study is to collect and compare recent studies on optimizing barrier membranes. The characteristics and research progress of different types of barrier membranes were also discussed in detail.
... Kombination mit BMP-2 soll es die Knochenregeneration fördern (Schorn et al., 2017). ...
Ziel dieser Arbeit war es, Unterschiede in der Proteinexpression von Alveolar- und Beckenknochen aufzuzeigen, um Gründe für die unterschiedliche Transplantatkompetenz der beiden Knochenentitäten zu ermitteln. Darunter sollten Kandidatenproteine ermittelt werden, welche zur Verbesserung von Knochenersatzmaterialien verwendet werden können. Nach aktuellen Kenntnissen ist dies die erste experimentelle Arbeit, die das Proteom von Beckenknochen und Alveolarknochen aus derselben Spenderin untersucht und miteinander vergleicht. Mit der Methodik der LC-MS/MS Analyse konnten viele Proteine identifiziert werden, dessen vorkommen im Knochen bisher unbekannt waren. Diese Proteine gilt es weiter zu erforschen und deren Funktion im Knochen zu ermitteln. Zudem konnten auch Proteine identifiziert werden, worüber bereits in anderen Arbeiten bei der Analyse von Alveolar- oder Beckenknochen berichtet wurde. Sowohl bei der Analyse der einzelnen Knochenentitäten, als auch beim Vergleich zeigte sich, dass im Alveolarknochen vermehrt strukturgebende Proteine und Proteine der extrazellulären Matrix exprimiert wurden. Im Beckenknochen wurden dagegen Proteine, welche an Energiemetabolismen beteiligt und immunologisch aktiv sind vermehrt identifiziert. Diese Erkenntnis kann eine Ursache dafür sein, weshalb Beckenknochen anderen autologen Knochenersatzmaterialien überlegen ist. Ein gesteigerter Energiemetabolismus ist für das Bone-remodelling wichtig. Um dies jedoch zu verifizieren, sollte in weiteren Studien der direkte Einfluss, der in BK identifizierten Proteine auf den Knochenstoffwechsel und der Knochenregeneration erforscht werden. Erst dann kann entschieden werden, ob die identifizierten Proteine Potential zur Verbesserung von Knochenersatzmaterialien haben.
... The skeleton microstructure is made up of mineralized extracellular matrix and bone remodeling units, including osteocytes, osteoblasts, osteoclasts, and lining cells. According to this complex structure and limitations in the self-healing ability of defected bones, reconstruction of bone tissue remains challenging [1,2]. Autologous bone graft is the conventional therapeutic approach that has been known as the gold standard [3][4][5][6]. ...
... The LT-CAGE is a commercial form of rhBMP-2 loaded in a collagen sponge in the USA, used for the clinical treatment of degenerative lumbar disc disease [26]. Several studies mentioned successful results of the controlled release of BMP2 in bone regeneration [2,[28][29][30]. Meanwhile, some drawbacks have been reported, including soft tissue swelling, cyst formation, implant migration, local inflammation, and, more importantly, increased risk of malignancy in high-dose administration [31]. ...
Recently, the translational application of noncoding RNAs is accelerated dramatically. In this regard, discovering therapeutic roles of microRNAs by developing synthetic RNA and vector-based RNA is attracting attention. Here, we studied the effect of BMP2 and miR-424 on the osteogenesis of Wharton’s jelly-derived stem cells (WJSCs). For this purpose, human BMP2 and miR-424 DNA codes were cloned in the third generation of lentiviral vectors and then used for HEK-293T cell transfection. Lentiviral plasmids contained miR424, BMP-2, miR424-BMP2, green fluorescent protein (GFP) genes, and helper vectors. The recombinant lentiviral particles transduced the WJSCs, and the osteogenesis was evaluated by real-time PCR, Western blot, Alizarin Red staining, and alkaline phosphatase enzyme activity. According to the results, there was a significant increase in the expression of the BMP2 gene and secretion of Osteocalcin protein in the group of miR424-BMP2. Moreover, the amount of dye deposition in Alizarin Red staining and alkaline phosphatase activity was significantly higher in the mentioned group (p<0.05). Thus, the current study results clarify the efficacy of gene therapy by miR424-BMP2 vectors for bone tissue engineering. These data could help guide the development of gene therapy-based protocols for bone tissue engineering.
... Therefore, primary stability, implant stability quotient, and removal torque can be measured in the same way as in clinical practice [252]. This model can also be used to test the viability and mechanical properties of new implants [253] or compare different models [251,254]. ...
... A range of surgical techniques can be performed, such as (i) site preparation with different osteotomies [273], (ii) flap procedures [274,275], or (iii) bone surgery with osteodistraction [276], creation of bone defects [277], and bone grafting [271,278,279]. Biomaterials such as scaffold [280] and disc-shaped matrices for vertical bone regeneration [254,280] have been tested in pigs prior to use in human surgery. Biological coating functionalization with chondroitin sulfate and sulfated hyaluronan with collagen molecules [281][282][283] is often tested on this model, avoiding the process of miniaturization of a new model to be put on the market. ...
Biomedical research seeks to generate experimental results for translation to clinical settings. In order to improve the transition from bench to bedside, researchers must draw justifiable conclusions based on data from an appropriate model. Animal testing, as a prerequisite to human clinical exposure, is performed in a range of species, from laboratory mice to larger animals (such as dogs or non-human primates). Minipigs appear to be the animal of choice for studying bone surgery around intraoral dental implants. Dog models, well-known in the field of dental implant research, tend now to be used for studies conducted under compromised oral conditions (biofilm). Regarding small animal models, research studies mostly use rodents, with interest in rabbit models declining. Mouse models remain a reference for genetic studies. On the other hand, over the last decade, scientific advances and government guidelines have led to the replacement, reduction, and refinement of the use of all animal models in dental implant research. In new development strategies, some in vivo experiments are being progressively replaced by in vitro or biomaterial approaches. In this review, we summarize the key information on the animal models currently available for dental implant research and highlight (i) the pros and cons of each type, (ii) new levels of decisional procedures regarding study objectives, and (iii) the outlook for animal research, discussing possible non-animal options.
