The RNA Methyltransferase METTL3 Promotes Endothelial Progenitor Cell Angiogenesis in Mandibular Distraction Osteogenesis via the PI3K/AKT Pathway

Distraction osteogenesis (DO) is used to treat large bone defects in the field of oral and maxillofacial surgery. Successful DO-mediated bone regeneration is dependent upon angiogenesis, and endothelial progenitor cells (EPCs) are key mediators of angiogenic processes. The N6-methyladenosine (m6A) methyltransferase has been identified as an important regulator of diverse biological processes, but its role in EPC-mediated angiogenesis during DO remains to be clarified. In the present study, we found that the level of m6A modification was significantly elevated during the process of DO and that it was also increased in the context of EPC angiogenesis under hypoxic conditions, which was characterized by increased METTL3 levels. After knocking down METTL3 in EPCs, m6A RNA methylation, proliferation, tube formation, migration, and chicken embryo chorioallantoic membrane (CAM) angiogenic activity were inhibited, whereas the opposite was observed upon the overexpression of METTL3. Mechanistically, METTL3 silencing reduced the levels of VEGF and PI3Kp110 as well as the phosphorylation of AKT, whereas METTL3 overexpression reduced these levels. SC79-mediated AKT phosphorylation was also able to restore the angiogenic capabilities of METTL3-deficient EPCs in vitro and ex vivo. In vivo, METTL3-overexpressing EPCs were additionally transplanted into the DO callus, significantly enhancing bone regeneration as evidenced by improved radiological and histological manifestations in a canine mandibular DO model after consolidation over a 4-week period. Overall, these results indicate that METTL3 accelerates bone regeneration during DO by enhancing EPC angiogenesis via the PI3K/AKT pathway.

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Potential of Lyophilized Platelet Concentrates for Craniofacial Tissue Regenerative Therapies

Molecules ◽

10.3390/molecules26030517 ◽

2021 ◽

Vol 26 (3) ◽

pp. 517

Author(s):

Nurul Aida Ngah ◽

Jithendra Ratnayake ◽

Paul R. Cooper ◽

George J. Dias ◽

Darryl C. Tong ◽

...

Keyword(s):

Bone Regeneration ◽

Tissue Regeneration ◽

Maxillofacial Surgery ◽

Oral And Maxillofacial Surgery ◽

Platelet Concentrates ◽

Comprehensive Search ◽

Craniofacial Tissue ◽

Regenerative Therapies

Objective: The use of platelet concentrates (PCs) in oral and maxillofacial surgery, periodontology, and craniofacial surgery has been reported. While PCs provide a rich reservoir of autologous bioactive growth factors for tissue regeneration, their drawbacks include lack of utility for long-term application, low elastic modulus and strength, and limited storage capability. These issues restrict their broader application. This review focuses on the lyophilization of PCs (LPCs) and how this processing approach affects their biological and mechanical properties for application as a bioactive scaffold for craniofacial tissue regeneration. Materials and Methods: A comprehensive search of five electronic databases, including Medline, PubMed, EMBASE, Web of Science, and Scopus, was conducted from 1946 until 2019 using a combination of search terms relating to this topic. Results: Ten manuscripts were identified as being relevant. The use of LPCs was mostly studied in in vitro and in vivo craniofacial bone regeneration models. Notably, one clinical study reported the utility of LPCs for guided bone regeneration prior to dental implant placement. Conclusions: Lyophilization can enhance the inherent characteristics of PCs and extends shelf-life, enable their use in emergency surgery, and improve storage and transportation capabilities. In light of this, further preclinical studies and clinical trials are required, as LPCs offer a potential approach for clinical application in craniofacial tissue regeneration.

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Real-Time Wireless Platform for In Vivo Monitoring of Bone Regeneration

Sensors ◽

10.3390/s20164591 ◽

2020 ◽

Vol 20 (16) ◽

pp. 4591 ◽

Cited By ~ 1

Author(s):

Pablo Blázquez-Carmona ◽

Manuel Sanchez-Raya ◽

Juan Mora-Macías ◽

Juan Antonio Gómez-Galán ◽

Jaime Domínguez ◽

...

Keyword(s):

Bone Regeneration ◽

Real Time ◽

Ex Vivo ◽

Low Cost ◽

Bone Lengthening ◽

Bone Callus ◽

Reliable Solution ◽

Regeneration Processes

For the monitoring of bone regeneration processes, the instrumentation of the fixation is an increasingly common technique to indirectly measure the evolution of bone formation instead of ex vivo measurements or traditional in vivo techniques, such as X-ray or visual review. A versatile instrumented external fixator capable of adapting to multiple bone regeneration processes was designed, as well as a wireless acquisition system for the data collection. The design and implementation of the overall architecture of such a system is described in this work, including the hardware, firmware, and mechanical components. The measurements are conditioned and subsequently sent to a PC via wireless communication to be in vivo displayed and analyzed using a developed real-time monitoring application. Moreover, a model for the in vivo estimation of the bone callus stiffness from collected data was defined. This model was validated in vitro using elastic springs, reporting promising results with respect to previous equipment, with average errors and uncertainties below 6.7% and 14.04%. The devices were also validated in vivo performing a bone lengthening treatment on a sheep metatarsus. The resulting system allowed the in vivo mechanical characterization of the bone callus during experimentation, providing a low-cost, simple, and highly reliable solution.

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Role of β2-integrins for homing and neovascularization capacity of endothelial progenitor cells

Journal of Experimental Medicine ◽

10.1084/jem.20041402 ◽

2004 ◽

Vol 201 (1) ◽

pp. 63-72 ◽

Cited By ~ 230

Author(s):

Emmanouil Chavakis ◽

Alexandra Aicher ◽

Christopher Heeschen ◽

Ken-ichiro Sasaki ◽

Ralf Kaiser ◽

...

Keyword(s):

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Ex Vivo ◽

Limb Ischemia ◽

Endothelial Progenitor ◽

Cell Monolayers ◽

Β2 Integrins

The mechanisms of homing of endothelial progenitor cells (EPCs) to sites of ischemia are unclear. Here, we demonstrate that ex vivo–expanded EPCs as well as murine hematopoietic Sca-1+/Lin− progenitor cells express β2-integrins, which mediate the adhesion of EPCs to endothelial cell monolayers and their chemokine-induced transendothelial migration in vitro. In a murine model of hind limb ischemia, Sca-1+/Lin− hematopoietic progenitor cells from β2-integrin–deficient mice are less capable of homing to sites of ischemia and of improving neovascularization. Preactivation of the β2-integrins expressed on EPCs by activating antibodies augments the EPC-induced neovascularization in vivo. These results provide evidence for a novel function of β2-integrins in postnatal vasculogenesis.

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Tissue Integration and Biological Cellular Response of SLM-Manufactured Titanium Scaffolds

Metals ◽

10.3390/met10091192 ◽

2020 ◽

Vol 10 (9) ◽

pp. 1192

Author(s):

Anida-Maria Băbțan ◽

Daniela Timuș ◽

Olga Sorițău ◽

Bianca Adina Boșca ◽

Reka Barabas ◽

...

Keyword(s):

Mechanical Properties ◽

Cellular Response ◽

Maxillofacial Surgery ◽

Oral And Maxillofacial Surgery ◽

Physical Interaction ◽

High Porosity ◽

Tissue Integration ◽

Mesh Terms

Background: SLM (Selective Laser Melting)–manufactured Titanium (Ti) scaffolds have a significant value for bone reconstructions in the oral and maxillofacial surgery field. While their mechanical properties and biocompatibility have been analysed, there is still no adequate information regarding tissue integration. Therefore, the aim of this study is a comprehensive systematic assessment of the essential parameters (porosity, pore dimension, surface treatment, shape) required to provide the long-term performance of Ti SLM medical implants. Materials and methods: A systematic literature search was conducted via electronic databases PubMed, Medline and Cochrane, using a selection of relevant search MeSH terms. The literature review was conducted using the preferred reporting items for systematic reviews and meta-analysis (PRISMA). Results: Within the total of 11 in vitro design studies, 9 in vivo studies, and 4 that had both in vitro and in vivo designs, the results indicated that SLM-generated Ti scaffolds presented no cytotoxicity, their tissue integration being assured by pore dimensions of 400 to 600 µm, high porosity (75–88%), hydroxyapatite or SiO2–TiO2 coating, and bioactive treatment. The shape of the scaffold did not seem to have significant importance. Conclusions: The SLM technique used to fabricate the implants offers exceptional control over the structure of the base. It is anticipated that with this technique, and a better understanding of the physical interaction between the scaffold and bone tissue, porous bases can be tailored to optimize the graft’s integrative and mechanical properties in order to obtain structures able to sustain osseous tissue on Ti.

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Allogeneic Bone-Marrow Mesenchymal Stem Cell with Moldable Cryogel for Craniofacial Bone Regeneration

Journal of Personalized Medicine ◽

10.3390/jpm11121326 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1326

Author(s):

Cheng-Feng Chu ◽

Shih-Hsuan Mao ◽

Victor Bong-Hang Shyu ◽

Chih-Hao Chen ◽

Chien-Tzung Chen

Keyword(s):

Bone Marrow ◽

Bone Regeneration ◽

Ex Vivo ◽

Cell Lineage ◽

Allogeneic Bone Marrow ◽

Allogeneic Bone ◽

Micro Computed Tomography ◽

Alternative Source

Allogeneic bone-marrow mesenchymal stem cells (BMSCs) can promote bone regeneration and substitute for autologous BMSCs if autologous sources are unavailable, but the efficacy of bone regeneration by allogeneic BMSCs is still inconsistent. A Lewis rat cranium defect model was used to investigate the efficacy of bone regeneration between autologous and allogeneic BMSCs in gelatin-nanohydroxyapatite cryogel scaffolds. BMSCs from Wistar rats served as the allogeneic cell lineage. The full-thickness cranium defects were treated by either blank control, cryogel only, allogeneic BMSC-seeded cryogel, or autologous BMSC-seeded cryogel (n = 5). Bone regeneration was monitored by micro-computed tomography and examined histologically at week 12. In addition, we assessed the immune responses in vitro by mixed lymphocyte reaction (MLR) assay and CD4+ immunochemistry staining ex vivo. The MLR showed that allogeneic BSMCs elicited a weak immune response on day 14 that progressively attenuated by day 28. In vivo, the bone regeneration in allogeneic BMSCs was inferior at week 4, but progressively matched the autologous BMSCs by week 12. Our results suggest that allogeneic BMSCs can serve as an alternative source for bone regeneration.

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Cilostazol Improves Proangiogenesis Functions in Human Early Endothelial Progenitor Cells through the Stromal Cell-Derived Factor System and Hybrid Therapy Provides a Synergistic EffectIn Vivo

BioMed Research International ◽

10.1155/2016/3639868 ◽

2016 ◽

Vol 2016 ◽

pp. 1-18 ◽

Cited By ~ 2

Author(s):

Shih-Ya Tseng ◽

Ting-Hsing Chao ◽

Yi-Heng Li ◽

Chung-Lung Cho

Keyword(s):

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Stromal Cell ◽

Ex Vivo ◽

Akt Signaling ◽

Endothelial Progenitor ◽

Hybrid Therapy ◽

Stromal Cell Derived Factor

This study investigated the effect of cilostazol on proangiogenesis functions in human early endothelial progenitor cells (EPCs)in vitroand the therapeutic implication of hybrid therapy with cilostazol and human early EPCsin vivo. Cilostazol significantly increased colony-forming units and enhanced differentiation of EPCs toward endothelial lineage. Treatments resulted in antiapoptotic effects and stimulated proliferation and migration andin vitrovascular tube formation through activation of stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)/phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway. Blood flow recovery and capillary density in murine ischemic hindlimbs were significantly improved in cilostazol-treated, human early EPCs-treated, and cotreatment groups. The effects were attenuated with SDF-1αinhibition. Plasma SDF-1αlevels were significantly higher in 3 active treatment groups after surgery, with greatest effects observed in hybrid therapy. The angiogenic effects of transplanted EPCs pretreated with cilostazolex vivowere superior to untreated EPCs usingin vivoMatrigel assay. Implanted EPCs were incorporated into the capillary, with pretreatment or cotreatment with cilostazol resulting in enhanced effects. Taken together, cilostazol promotes a large number of proangiogenic functions in human early EPCs through activation of SDF-1/CXCR4/PI3K/Akt signaling, and hybrid therapy provides a synergistic effectin vivo. Cotreatment may be beneficial in ischemic disease.

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Advance on Resveratrol Application in Bone Regeneration: Progress and Perspectives for Use in Oral and Maxillofacial Surgery

Biomolecules ◽

10.3390/biom9030094 ◽

2019 ◽

Vol 9 (3) ◽

pp. 94 ◽

Cited By ~ 13

Author(s):

Denise Murgia ◽

Rodolfo Mauceri ◽

Giuseppina Campisi ◽

Viviana De Caro

Keyword(s):

Biological Effects ◽

Maxillofacial Surgery ◽

Oral And Maxillofacial Surgery ◽

Positive Effects ◽

Natural Polyphenol ◽

Regeneration Of Bone Tissue ◽

Experimental Findings ◽

Regeneration Of Bone

The natural polyphenol Resveratrol (RSV) claims numerous positive effects on health due to the well documented biological effects demonstrating its potential as a disease-preventing agent and as adjuvant for treatment of a wide variety of chronic diseases. Since several studies, both in vitro and in vivo, have highlighted the protective bone aptitude of RSV both as promoter of osteoblasts’ proliferation and antagonist of osteoclasts’ differentiation, they could be interesting in view of applications in the field of dentistry and maxillofacial surgery. This review has brought together experimental findings on the use of RSV in the regeneration of bone tissue comprising also its application associated with scaffolds and non-transfusional hemocomponents.

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Mesenchymal stem cells: A comprehensive methods for odontoblastic induction

Biological Procedures Online ◽

10.1186/s12575-021-00155-7 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Benson Koh ◽

Nadiah Sulaiman ◽

Sharifah Nursyazwani Shahirah Wan Ismadi ◽

Roszalina Ramli ◽

Siti Salmiah Mohd Yunus ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Maxillofacial Surgery ◽

Oral And Maxillofacial Surgery ◽

Inclusion Criteria ◽

Pulp Tissue ◽

Odontoblastic Differentiation ◽

Differentiation Induction

Abstract Background In the area of oral and maxillofacial surgery, regenerative endodontics aims to present alternative options to conventional treatment strategies. With continuous advances in regenerative medicine, the source of cells used for pulp tissue regeneration is not only limited to mesenchymal stem cells as the non-mesenchymal stem cells have shown capabilities too. In this review, we are systematically assessing the recent findings on odontoblastic differentiation induction with scaffold and non-scaffold approaches. Methods A comprehensive search was conducted in Pubmed, and Scopus, and relevant studies published between 2015 and 2020 were selected following the PRISMA guideline. The main inclusion criteria were that articles must be revolving on method for osteoblast differentiation in vitro study. Therefore, in vivo and human or animal clinical studies were excluded. The search outcomes identified all articles containing the word “odontoblast”, “differentiation”, and “mesenchymal stem cell”. Results The literature search identified 99 related studies, but only 11 articles met the inclusion criteria. These include 5 odontoblastic differentiation induction with scaffold, 6 inductions without scaffolds. The data collected were characterised into two main categories: type of cells undergo odontoblastic differentiation, and odontoblastic differentiation techniques using scaffolds or non-scaffold. Conclusion Based on the data analysis, the scaffold-based odontoblastic induction method seems to be a better option compared to the non-scaffold method. In addition of that, the combination of growth factors in scaffold-based methods could possibly enhance the differentiation. Thus, further detailed studies are still required to understand the mechanism and the way to enhance odontoblastic differentiation.

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CoCrMo alloy as biomaterial for bone reconstruction in oral and maxillofacial surgery: A scoping review.

Journal Of Oral Research ◽

10.17126/joralres.2020.075 ◽

2020 ◽

Vol 9 (4) ◽

pp. 336-349

Author(s):

Jésica Zuchuat ◽

◽

Andrea Cura ◽

Adriana Manzano ◽

Oscar Decco ◽

...

Keyword(s):

Scoping Review ◽

Maxillofacial Surgery ◽

Oral And Maxillofacial Surgery ◽

Bone Reconstruction ◽

Cocrmo Alloy ◽

Thomson Reuters

Antecedentes: La osteointegración ha permitido un gran avance en biomateriales y técnicas, y ha contribuido un mayor uso de implantes dentales. Sin embargo, la existencia de un nivel óseo insuficiente es un problema frecuente y crea una base anatómicamente menos favorable para la colocación de implantes. El primer procedimiento quirúrgico debe comprender la reconstrucción de la altura del hueso alveolar. Las aleaciones de CoCrMo se consideran hoy en día como materiales altamente resistentes a la corrosión y biocompatibles en odontología y, por lo tanto, se ha sugerido como un biomaterial adecuado para la regeneración ósea guiada y la ingeniería de tejidos. Objetivo: Determinar el uso de la aleación CoCrMo para dispositivos implantables en cirugía oral y maxilofacial y discutir sobre el potencial de esta aleación para la regeneración y reparación ósea a través de una revisión de alcance. Material y Métodos: La búsqueda se realizó utilizando varias bases de datos, incluidas PubMed, Thomson Reuters y Scopus. Se seleccionó literatura inglesa relacionada con estudios que informan sobre las propiedades de CoCrMo y los procesos de fabricación y los hallazgos relacionados con las técnicas de formación de huesos. Los datos se compararon cualitativamente. Resultados: Se seleccionaron 90 estudios según los criterios de inclusión. y se reportaron diferentes técnicas de fabricación y sus ventajas relacionadas con propiedades mecánicas, químicas y biocompatibles. Conclusión: Las reacciones tisulares mejoradas de los dispositivos de implante CoCrMo pueden adquirirse mediante la aplicación de nuevas técnicas y modificaciones de la superficie. Además, varios procesos han demostrado mejorar la biocompatibilidad in vitro e in vivo de la aleación CoCrMo para promover la unión, proliferación y diferenciación guiada de las células de siembra.

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A Narrative Review of u-HA/PLLA, a Bioactive Resorbable Reconstruction Material: Applications in Oral and Maxillofacial Surgery

Materials ◽

10.3390/ma15010150 ◽

2021 ◽

Vol 15 (1) ◽

pp. 150

Author(s):

Huy Xuan Ngo ◽

Yunpeng Bai ◽

Jingjing Sha ◽

Shinji Ishizuka ◽

Erina Toda ◽

...

Keyword(s):

Mechanical Strength ◽

Maxillofacial Surgery ◽

Narrative Review ◽

In Vivo Studies ◽

Oral And Maxillofacial Surgery ◽

Bone Reconstruction ◽

New Era ◽

Dental Applications

The advent of bioresorbable materials to overcome limitations and replace traditional bone-reconstruction titanium-plate systems for bone fixation, thus achieving greater efficiency and safety in medical and dental applications, has ushered in a new era in biomaterial development. Because of its bioactive osteoconductive ability and biocompatibility, the forged composite of uncalcined/unsintered hydroxyapatite and poly L-lactic acid (u-HA/PLLA) has attracted considerable interest from researchers in bone tissue engineering, as well as from clinicians, particularly for applications in maxillofacial reconstructive surgery. Thus, various in vitro studies, in vivo studies, and clinical trials have been conducted to investigate the feasibility and weaknesses of this biomaterial in oral and maxillofacial surgery. Various technical improvements have been proposed to optimize its advantages and limit its disadvantages. This narrative review presents an up-to-date, comprehensive review of u-HA/PLLA, a bioactive osteoconductive and bioresorbable bone-reconstruction and -fixation material, in the context of oral and maxillofacial surgery, notably maxillofacial trauma, orthognathic surgery, and maxillofacial reconstruction. It simultaneously introduces new trends in the development of bioresorbable materials that could used in this field. Various studies have shown the superiority of u-HA/PLLA, a third-generation bioresorbable biomaterial with high mechanical strength, biocompatibility, and bioactive osteoconductivity, compared to other bioresorbable materials. Future developments may focus on controlling its bioactivity and biodegradation rate and enhancing its mechanical strength.

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