Modification of Titanium Implant and Titanium Dioxide for Bone Tissue Engineering.

Bone tissue engineering using titanium (Ti) implant and titanium dioxide (TiO2) with their modification is gaining increasing attention. Ti has been adopted as an implant material in dental and orthopedic fields due to its superior properties. However, it still requires modification in order to achieve robust osteointegration between the Ti implant and surrounding bone. To modify the Ti implant, numerous methods have been introduced to fabricate porous implant surfaces with a variety of coating materials. Among these, plasma spraying of hydroxyapatite (HA) has been the most commonly used with commercial success. Meanwhile, TiO2 nanotubes have been actively studied as the coating material for implants, and promising results have been reported about improving osteogenic activity around implants recently. Also porous three-dimensional constructs based on TiO2 have been proposed as scaffolding material with high biocompatibility and osteoconductivity in large bone defects. However, the use of the TiO2 scaffolds in load-bearing environment is somewhat limited. In order to optimize the TiO2 scaffolds, studies have tried to combine various materials with TiO2 scaffolds including drug, mesenchymal stem cells, Al2O3-SiO2 solid and HA. This article will shortly introduce the properties of Ti and Ti-based implants with their modification, and review the progress of bone tissue engineering using the TiO2 nanotubes and scaffolds.

3D cotton-type anisotropic biomimetic scaffold with low fiber motion electrospun via a sharply inclined array collector for induced osteogenesis.

Electrospinning is an effective method to fabricate fibrous scaffolds that mimic the ECM of bone tissue on a nano- to macro-scale. However, a limitation of electrospun fibrous scaffolds for bone tissue engineering is the structure formed by densely compacted fibers, which significantly impedes cell infiltration and tissue ingrowth. To address this problem, several researchers have developed numerous techniques for fabricating 3D fibrous scaffolds with customized topography and pore size. Despite the success in developing various 3D electrospun scaffolds based on fiber repulsion, the lack of contact points between fibers in those scaffolds has been shown to hinder cell attachment, migration, proliferation, and differentiation due to excessive movement of the fibers. In this article, we introduce a Dianthus caryophyllus-inspired scaffold fabricated using SIAC-PE, a modified collector under specific viscosity conditions of PCL/LA solution. The developed scaffold mimicking the structural similarities of the nature-inspired design presented enhanced cell proliferation, infiltration, and increased expression of bone-related factors by reducing fiber movements, presenting high space interconnection, high porosity, and controlled fiber topography.

Targeting class A GPCRs for hard tissue regeneration.

G protein-coupled receptors (GPCRs) play important roles in various pathogeneses and physiological regulations. Owing to their functional diversity, GPCRs are considered one of the primary pharmaceutical targets. However, drugs targeting GPCRs have not been developed yet to regenerate hard tissues such as teeth and bones. Mesenchymal stromal cells (MSCs) have high proliferation and multi-lineage differentiation potential, which are essential for hard tissue regeneration. Here, we present a strategy for targeting class A GPCRs for hard tissue regeneration by promoting the differentiation of endogenous MSCs into osteogenic and odontogenic progenitor cells. Through in vitro screening targeted at class A GPCRs, we identified six target receptors (LPAR1, F2R, F2RL1, F2RL2, S1PR1, and ADORA2A) and candidate drugs with potent biomineralization effects. Through a combination of profiling whole transcriptome and accessible chromatin regions, we identified that p53 acts as a key transcriptional activator of genes that modulate the biomineralization process. Moreover, the therapeutic potential of class A GPCR-targeting drugs was demonstrated in tooth pulpotomy and calvarial defect models. The selected drugs revealed potent regenerative effects in both tooth and bone defects, represented by newly formed highly mineralized regions. Consequently, this study provides translational evidence for a new regenerative strategy for damaged hard tissue.

Association of fluoride exposure with disease burden and neurodevelopment outcomes in children in South Korea.

BACKGROUND: Community water fluoridation is an effective public health strategy for preventing dental caries, yet. Concerns exist about potential health problems. This study explores associations between tap water fluoride levels and pediatric disease burden, as well as neurodevelopmental outcomes at 6 years of age. METHODS: This nationwide population-based cohort study included children born in Korean cities with and without tap water fluoridation projects, between 2006 and 2012, aiming for a fluoride concentration of 0.8 ± 0.2 mg/L in treated tap water. Data from the National Health Insurance Service were used, spanning from birth to 2018. The relationship between exposure to fluoridated tap water and incidence of 16 childhood diseases that were previously identified as potentially linked to fluoride exposure were examined. Additionally, we evaluated the neurodevelopmental outcomes across various domains, including gross motor, fine motor, cognition, language, social skills, and self-help functions. These assessments were performed using data from a comprehensive national health screening program for children aged six years. RESULTS: A fluoride-unexposed group included 22,881 children, whereas a fluoride-exposed group comprised 29,991 children (52% males). Children in the fluoride-exposed group had a decreased risk of dental caries and bone fractures [hazard ratio (95% confidence interval, CI), 0.76 (0.63-0.93) and 0.89 (0.82-0.93), respectively] and increased risk of hepatic failures [1.85, (1.14-2.98)] compared to those in the unexposed group. Additionally, the risk ratio of abnormal neurodevelopmental screening outcomes increased by 9%, but this was statistically uncertain (95% CI, 0.95-1.26). CONCLUSIONS: Fluoridated tap water was associated with an increased risk of hepatic failure but a decreased risk of bone fractures in children. The association between fluoridated tap water and neurodevelopmental screening outcomes at 6 years remains unclear, highlighting the need for further studies to clarify this association.

Fabrication of Dentin-Pulp-Like Organoids Using Dental-Pulp Stem Cells.

We developed a novel dentin-pulp-like organoid. It has both stem-cell and odontoblast characteristics using a mesenchymal cell lineage of human dental-pulp stem cells (hDPSCs). The mixture of hDPSCs and Matrigel was transferred into the maintenance medium (MM) and divided into four different groups according to how long they were maintained in the odontogenic differentiation medium (ODM). All organoids were harvested at 21 days and analyzed to find the optimal differentiation condition. To assess the re-fabrication of dentin-pulp-like organoid, after dissociation of the organoids, it was successfully regenerated. Additionally, its biological activity was confirmed by analyzing changes of relevant gene expression and performing a histology analysis after adding Biodentine® into the ODM. The organoid was cultured for 11 days in the ODM (ODM 11) had the most features of both stem cells and differentiated cells (odontoblasts) as confirmed by relevant gene expression and histology analyses. Micro-computed tomography and an electron microscope also showed mineralization and odontoblastic differentiation. Finally, ODM 11 demonstrated a biologically active response to Biodentine® treatment. In conclusion, for the first time, we report the fabrication of a dentin-pulp-like organoid using mesenchymal stem cells. This organoid has potential as a future therapeutic strategy for tooth regeneration.

Pharmacokinetics and osteogenic potential of PEGylated NELL-1 in vivo after systemic administration.

Osteoporosis is a skeletal disorder attributable to an imbalance in osteoblast and osteoclast activity. NELL-1, a secretory protein that promotes osteogenesis while suppressing osteoclastic activity, holds potential as an osteoporosis therapy. Recently, we demonstrated that PEGylation of NELL-1 significantly improves its thermostability while preserving its bioactivity in vitro. However, the effect of PEGylation on the pharmacokinetics and osteogenic potential of NELL-1 in vivo have yet to be investigated. The present study demonstrated that PEGylation of NELL-1 significantly increases the elimination half-life time of the protein from 5.5 h to 15.5 h while distributing more than 2-3 times the amount of protein to bone tissues (femur, tibia, vertebrae, calvaria) in vivo when compared to naked NELL-1. In addition, microCT and DXA analyses demonstrated that systemic NELL-PEG therapy administered every 4 or 7 days significantly increases not only femoral and lumbar BMD and percent bone volume, but also new bone formation throughout the overall skeleton after four weeks of treatment. Furthermore, immunohistochemistry revealed increased osteocalcin expression, while TRAP staining showed reduced osteoclast numbers in NELL-PEG groups. Our findings suggest that the PEGylation technique presents a viable and promising approach to further develop NELL-1 into an effective systemic therapeutic for the treatment of osteoporosis.