Bone Regeneration Research Articles

Desirable outcome after bone grafting and implants in atropic anterior maxilla with reverse architecture

A significant advancement in dentistry has been made with the successful use of implants to replace missing teeth. Bone volume is frequently deficient in the anterior maxilla, and either the quality and quantity of accessible bone is frequently varying. But nowadays, implants are also being inserted in sites where ridge deficiency vary dimensions. For placing implants in deficient ridges, the surgical specialist has a variety of treatment options thanks to the numerous reconstruction techniques involving bone graft, guided bone regeneration, orthognathic surgery, or bone distraction. Almost every complicated situation involving jaws deficient bone can be effectively treated with these methods if performed appropriately. This case discusses the sequential steps taken in a situation where the anteriors were missing and replaced by implant with placement of bone graft.

Polarized M2 macrophages induced by glycosylated nano-hydroxyapatites activate bone regeneration in periodontitis therapy.

To investigate the association between periodontal macrophage polarization states and the alveolar bone levels, and to assess whether glycosylated nano-hydroxyapatites (GHANPs) could improve bone regeneration in periodontitis by inducing macrophage M2 polarization. The change of macrophage polarization state in inflammatory periodontal tissues (with bone loss) was examined using clinical gingival samples. The relationship between macrophage phenotype and bone level in periodontal bone loss and repair was evaluated using a mouse periodontitis model. The effect of GHANPs on macrophage polarization was assessed by the in vitro model of lipopolysaccharide (LPS)-stimulated inflammation. The polarization-related markers were detected by immunofluorescence staining, real-time polymerase chain reaction and enzyme-linked immunosorbent assay analysis. The therapeutic effect of GHANPs on alveolar bone loss was explored in experimental periodontitis by histological staining and micro-CT analysis. A lower macrophage M2/M1 ratio was observed in periodontitis-affected human gingival tissues. The results of animal experiments demonstrated a positive correlation between a lower Arg-1/iNOS ratio and accelerated alveolar bone loss; also, the proportion of Arg-1-positive macrophages increased during bone repair and regeneration. The administration of GHANPs partially restored M2 macrophage polarization after LPS stimulation. GHANPs increased alveolar bone repair and regeneration in experimental periodontitis induced by ligation, potentially related to their macrophage M2 transition regulation. The findings of this study indicate that the induction of macrophage M2 polarization can be considered a viable approach for enhancing inflammatory bone repair. Additionally, GHANPs show potential in the clinical treatment of periodontitis.

Bioinspired Bone Seed 3D‐Printed Scaffold via Trapping Black Phosphorus Nanosheet for Bone Regeneration

Significance of endogenous mineralization in bone reconstruction is paramount, as it facilitates the accumulation of calcium ions for bone tissue deposition. However, conventional 3D‐printed scaffolds lack the capacity for calcium ion enrichment and mineralization, coupled with their low bone inductive activity. Inspired from the development of natural plant seeds, a biomimetic 3D printing scaffold is developed by implanting photosensitive black phosphorus “bone seeds” (BS), guiding a sequential process mirroring rooting (osteoblast recruitment), sprouting (fibrous callus mineralization), flowering (osseous callus formation), and fruiting (callus plasticity). BS were trapped onto porous 3D polycaprolactone (PCL) scaffolds with aminated surfaces via electrostatic interactions between phosphates and amino groups, creating the PCL‐BS scaffold that can actively capture calcium ions for accelerating the endogenous regeneration of critical bone defects. In vitro and in vivo experiments show that the PCL‐BS scaffold has good biocompatibility and strong osteogenic ability for rapid new bone regeneration under near‐infrared (NIR) stimulation. In addition, whole transcriptome sequencing analysis is performed to reveal the transcriptomic mechanism of BS involved in signal transduction and network regulation during bone regeneration. This NIR light‐regulated biomimetic BS inspired by seed planting, introduces a pioneering concept in the design of 3D printing bone repair scaffolds.

HtrA3 paves the way for MSC migration and promotes osteogenesis

Mesenchymal stem cell (MSC) migration determines the healing capacity of bone and is crucial in promoting bone regeneration. Migration of MSCs is highly dependent on degradation of extracellular matrix by proteolytic enzymes. However, the underlying mechanisms of how enzymolysis paves the way for MSCs to migrate from their niche to the defect area is still not fully understood. Here, this study shows that high-temperature requirement A3 (HtrA3) overcomes the physical barrier and provides anchor points through collagen IV degradation, paving the way for MSC migration. HtrA3 is upregulated in MSCs at the leading edge of bone defect during the early stage of healing. HtrA3 degrades the surrounding collagen IV, which increases the collagen network porosity and increases integrin β1 expression. Subsequently, integrin β1 enhances the mechanotransduction of MSCs, thus remodeling the cytoskeleton, increasing cellular stiffness and nuclear translocation of YAP, eventually promoting the migration and subsequent osteogenic differentiation of MSCs. Local administration of recombinant HtrA3 in rat cranial bone defects significantly increases new bone formation and further validates the enhancement of MSC migration. This study helps to reveal the novel roles of HtrA3, explore potential targets for regenerative medicine, and offer new insights for the development of bioactive materials.

Mild Thermotherapy-Assisted GelMA/HA/MPDA@Roxadustat 3D-Printed Scaffolds with Combined Angiogenesis-Osteogenesis Functions for Bone Regeneration.

Early reconstruction of the vascular network is a prerequisite to the effective treatment of substantial bone defects. Traditional 3D printed tissue engineering scaffolds designed to repair large bone defects do not effectively regenerate the vascular network, and rely only on the porous structure within the scaffold for nutrient transfer and metabolic waste removal. This leads to delayed bone restoration and hence functional recovery. Therefore, strategies for generation scaffolds with the capacity to efficiently regenerate vascularization should be developed. This study loads roxarestat (RD), which can stabilize HIF-1α expression in a normoxic environment, onto the mesopore polydopamine nanoparticles (MPDA@RD) to enhance the reconstruction of vascular network in large bone defects. Subsequently, MPDA@RD is mixed with GelMA/HA hydrogel bioink to fabricate a multifunctional hydrogel scaffold (GHM@RD) through 3D printing. In vitro results show that the GHM@RD scaffolds achieve good angiogenic-osteogenic coupling by activating the PI3K/AKT/HSP90 pathway in BMSCs and the PI3K/AKT/HIF-1α pathway in HUVECs under mild thermotherapy. In vivo experiments reveal that RD and mild hyperthermia synergistically induce early vascularization and bone regeneration of critical bone defects. In conclusion, the designed GHM@RD drug delivery scaffold with mild hyperthermia holds great therapeutic value for future treatment of large bone defects.

Picein alleviates oxidative stress and promotes bone regeneration in osteoporotic bone defect by inhibiting ferroptosis via Nrf2/HO-1/GPX4 pathway.

Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.

Unveiling the potential of chitosan-coated lipid nanoparticles in drug delivery for management of critical illness: a review.

Chitosan (CT), a natural, cationic, chemically stable molecule, biocompatible, biodegradable, nontoxic, polysaccharide derived from the deacetylation of chitin, has very uniquely surfaced as a material of promise for drug delivery and biomedical applications. For the oral, ocular, cutaneous, pulmonary, and nose-to-brain routes, CT-coated nanoparticles (CTCNPs) have numerous advantages, consisting of improved controlled drug release, physicochemical stability, improved cell and tissue interactions, and increased bioavailability and efficacy of the active ingredient. CTCNPs have a broad range of therapeutic properties including anticancer, antiviral, antifungal, anti-inflammatory, antibacterial properties, treating neurological disorders, and other diseases. This has led to substantial research into the many potential uses of CT as a drug delivery vehicle. CT has also been employed in a wide range of biomedical processes, including bone and cartilage tissue regeneration, ocular tissue regeneration, periodontal tissue regeneration, heart tissue regeneration, and wound healing. Additionally, CT has been used in cosmeceutical, bioimaging, immunization, and gene transfer applications. CT exhibits a number of biological activities, which are the basis for its remarkable potential for use as a drug delivery vehicle, and these activities are covered in detail in this article. The alterations applied to CT to obtain the necessary properties have been described.

An Injectable Black Phosphorus Hydrogel for Rapid Tooth Extraction Socket Healing.

The excess production of reactive oxygen species (ROS) will delay tooth extraction socket (TES) healing. In this study, we developed an injectable thermosensitive hydrogel (NBP@BP@CS) used to treat TES healing. The hydrogel formulation incorporated black phosphorus (BP) nanoflakes, recognized for their accelerated alveolar bone regeneration and ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator aimed at enhancing angiogenesis. In vivo investigations strongly demonstrated that NBP@BP@CS improved TES healing due to antioxidation and promotion of alveolar bone regeneration by BP nanoflakes. The sustained release of NBP from the hydrogel promoted neovascularization and vascular remodeling. Our results demonstrated that the designed thermosensitive hydrogel provided great opportunity not only for ROS elimination but also for the promotion of osteogenesis and angiogenesis, reflecting the "three birds with one stone" concept, and has tremendous potential for rapid TES healing.

Shear Flow-Assembled Janus Membrane with Bifunctional Osteogenic and Antibacterial Effects for Guided Bone Regeneration.

Guided bone regeneration (GBR) membranes that reside at the interface between the bone and soft tissues for bone repair attract increasing attention, but currently developed GBR membranes suffer from relatively poor osteogenic and antibacterial effects as well as limited mechanical property and biodegradability. We present here the design and fabrication of a bifunctional Janus GBR membrane based on a shear flow-driven layer by a layer self-assembly approach. The Janus GBR membrane comprises a calcium phosphate-collagen/polyethylene glycol (CaP@COL/PEG) layer and a chitosan/poly(acrylic acid) (CHI/PAA) layer on different sides of a collagen membrane to form a sandwich structure. The membrane exhibits good mechanical stability and tailored biodegradability. It is found that the CaP@COL/PEG layer and CHI/PAA layer contribute to the osteogenic differentiation and antibacterial function, respectively. In comparison with the control group, the Janus GBR membrane displays a 2.52-time and 1.84-time enhancement in respective volume and density of newly generated bone. The greatly improved bone repair ability of the Janus GBR membrane is further confirmed through histological analysis, and it has great potential for practical applications in bone tissue engineering.

A Comparison of Guided Bone Regeneration vs. the Shell Technique Using Xenogeneic Bone Blocks in Horizontal Bone Defects: A Randomized Clinical Trial

In cases of severe horizontal atrophy, implant placement requires bone reconstruction procedures. The aim of this randomized controlled trial is to compare the outcomes of bone augmentation with simultaneous implant placement using the shell technique to the outcomes of guided bone regeneration (GBR) in cases of severely horizontal bone atrophy. This study was designed as a monocentric, parallel-group, randomized controlled trial with a six-month follow-up. Among the primary outcomes of this study, peri-implant bone regeneration and peri-implant bone defect closure were selected. Forty-four patients were recruited and equally divided between two groups. In the GRB group, a horizontal regeneration of 2.31 ± 0.23 mm was observed opposed to a horizontal regeneration of 2.36 ± 0.17 mm in the shell group (p = 0.87). A volumetric increase was observed in both groups, with an increase of 0.30 ± 0.12 cm3 in the GBR group and an increase of 0.39 ± 0.09 cm3 in the shell group, highlighting a significant difference between the two groups (p = 0.02). In conclusion, bone augmentation with simultaneous implant placement using the shell technique or guided bone regeneration in horizontal bone atrophy are both predictable therapeutic options.

Application and Perspectives: Magnesium Materials in Bone Regeneration.

The field of bone regeneration has always been a hot and difficult research area, and there is no perfect strategy at present. As a new type of biodegradable material, magnesium alloys have excellent mechanical properties and bone promoting ability. Compared with other inert metals, magnesium alloys have significant advantages and broad application prospects in the field of bone regeneration. By searching the official Web sites and databases of various funds, this paper summarizes the research status of magnesium composites in the field of bone regeneration and introduces the latest scientific research achievements and clinical transformations of scholars in various countries and regions, such as improving the corrosion resistance of magnesium alloys by adding coatings. Finally, this paper points out the current problems and challenges, aiming to provide ideas and help for the development of new strategies for the treatment of bone defects and fractures.

Design, In Vitro Evaluation and In Vivo Biocompatibility of Additive Manufacturing Three-Dimensional Printing of β beta-Tricalcium Phosphate Scaffolds for Bone Regeneration

The reconstruction of bone deficiencies remains a challenge due to the limitations of autologous bone grafting. The objective of this study is to evaluate the bone regeneration efficacy of additive manufacturing of tricalcium phosphate (TCP) implants using lithography-based ceramic manufacturing (LCM). LCM uses LithaBone TCP 300 slurry for 3D printing, producing cylindrical scaffolds. Four models of internal scaffold geometry were developed and compared. The in vitro studies included cell culture, differentiation, seeding, morphological studies and detection of early osteogenesis. The in vivo studies involved 42 Wistar rats divided into four groups (control, membrane, scaffold (TCP) and membrane with TCP). In each animal, unilateral right mandibular defects with a total thickness of 5 mm were surgically performed. The animals were sacrificed 3 and 6 months after surgery. Bone neoformation was evaluated by conventional histology, radiology, and micro-CT. Model A (spheres with intersecting and aligned arrays) showed higher penetration and interconnection. Histological and radiological analysis by micro-CT revealed increased bone formation in the grafted groups, especially when combined with a membrane. Our innovative 3D printing technology, combined with precise scaffold design and efficient cleaning, shows potential for bone regeneration. However, further refinement of the technique and long-term clinical studies are crucial to establish the safety and efficacy of these advanced 3D printed scaffolds in human patients.

MiR-26b-5p/TET3 regulates the osteogenic differentiation of human bone mesenchymal stem cells and bone reconstruction in female rats with calvarial defects

MiR-26b-5p/TET3 regulates the osteogenic differentiation of human bone mesenchymal stem cells and bone reconstruction in female rats with calvarial defects

Injectable Thermosensitive Gel CH-BPNs-NBP for Effective Periodontitis Treatment through ROS-Scavenging and Jaw Vascular Unit Protection.

Periodontitis, a prevalent inflammatory condition in the oral cavity, is closely associated with oxidative stress-induced tissue damage mediated by excessive reactive oxygen species (ROS) production. The jaw vascular unit (JVU), encompassing both vascular and lymphatic vessels, plays a crucial role in maintaining tissue fluid homeostasis and contributes to the pathological process in inflammatory diseases of the jaw. In this study, we present a novel approach for treating periodontitis through the development of an injectable thermosensitive gel (CH-BPNs-NBP). The gel formulation incorporated black phosphorus nanosheets (BPNs), which are notable for their ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator that promotes lymphatic vessel function within the JVU. Our results demonstrated that the designed thermosensitive gel served as a controlled release system, delivering BPNs and NBP to the site of inflammation. CH-BPNs-NBP not only protected macrophages and human lymphatic endothelial cells from ROS attack but also promoted M2 polarization and lymphatic function. In in vivo studies, we observed a significant reduction in inflammation and tissue damage, accompanied by a notable promotion of alveolar bone regeneration. This research introduces a promising therapeutic strategy for periodontitis, leveraging the unique properties of BPNs and NBP within an injectable thermosensitive gel. This article is protected by copyright. All rights reserved.

Multifunctional Composite Scaffold with Nanosilver, Graphene Oxide, and Macrophage Membrane Vesicles for Sequential Treatment of Infected Bone Defects.

The management of infected bone defects poses a significant clinical challenge, and current treatment modalities exhibit various limitations. This study focuses on the development of a multifunctional composite scaffold comprising nanohydroxyapatite/polyethyleneglycol diacrylate matrix, silver nanoparticles, graphene oxide (GO), sodium alginate, and M2-type macrophage membrane vesicles (MVs) to enhance the healing of infected bone defects. The composite scaffold demonstrates several key features: first, it releases sufficient quantities of silver ions to effectively eliminate bacteria; second, the controlled release of MVs leads to a notable increase in M2-type macrophages, thereby significantly mitigating the inflammatory response. Additionally, GO acts synergistically with nanohydroxyapatite to enhance osteoinductive activity, thereby fostering bone regeneration. Through meticulous in vitro and in vivo investigations, the composite scaffold exhibits broad-spectrum antimicrobial effects, robust immunomodulatory capabilities, and enhanced osteoinductive activity. This multifaceted composite scaffold presents a promising approach for the sequential treatment of infected bone defects, addressing the antimicrobial, immunomodulatory, and osteogenic aspects. This study introduces innovative perspectives and offers new and effective treatment alternatives for managing infected bone defects.

Optimized DLP 3D-printed high-resolution nano zirconia-hydroxyapatite scaffold with craniomaxillofacial soft tissue invasion resistance and pro-osteogenic properties via dectin-1/syk inflammatory axis

One major challenge of craniomaxillofacial bone regeneration is the direct contact of subcutaneous fibrous tissue towards bone regenerative region, which results in fast fibroblast invasion and suppression of bone regeneration. Dectin-1, a pattern recognition receptor expressed on activated macrophages, is crucial for directing fibrous invasion. Targeting Dectin-1 and its downstream signaling cascade could be an effective strategy to resist “craniomaxillofacial soft tissue invasion”. Nano zirconia can shelter the essential amino acids of Dectin-1 and was reported to deactivate the inflammation signals. Herein, we succeeded in incorporating nano zirconia into high-resolution 3D hydroxyapatite (HA) scaffolds via modified digital light processing (DLP) technique system. The incorporation of nano zirconia can endow high-resolution HA scaffolds with the capacity of regulating the key structure of extracellular C-type lectin-like domain (CTLD) of dectin-1, proved by computational simulation. This results in inhibiting the dectin-1/syk axis and pro-soft tissue proliferation cytokines production. In vivo experiments further validated the effects of HA/nano zirconia resisting craniomaxillofacial soft tissue invasion and promoting bone regeneration. Our work practices the concept of “soft tissue invasion resisting capacity” via targeting in manipulating dectin-1, which succeeds in attenuating fibrous invasion and craniomaxillofacial bone regeneration. The “soft tissue invasion resisting capacity” could become a valuable biological paradigm of craniomaxillofacial bone biomaterials.

The “Forgotten” Hydroxyapatite Crystals in Regenerative Bone Tissue Engineering: A Critical Review

Bone regeneration using Bone Morphogenetic Proteins (BMPs) alongside various engineered scaffolds has attracted considerable attention over the years. The field has seen extensive research in preclinical animal models, leading to the approval of two products and guiding the quest for new materials. Natural and synthetic polymers, ceramics, and composites have been used to fabricate the necessary porous 3D scaffolds and delivery systems for BMPs. Interestingly, all reported applications in the literature are triumphant. Evaluation of the results is typically based on histologic assessment after appropriate staining and radiological modalities, providing morphological identification of the newly formed bone and describing cells and the organic compound. Remarkably, while these evaluation methods illustrate mineralization, they are not capable of identifying hydroxyapatite crystals, the mineral component of the bone, which are crucial for its mechanical properties, structure, integrity, and long-term stability of regenerated bone tissue. This review aims to focus on the different scaffolds used in bone tissue engineering applications and underline the pressing need for techniques that could recognize the presence of hydroxyapatite crystals as well as their characteristics in bone tissue engineering, which will provide a more complete and comprehensive assessment of the successful results.

Diatomite-incorporated hierarchical scaffolds for osteochondral regeneration

Osteochondral regeneration involves the highly challenging and complex reconstruction of cartilage and subchondral bone. Silicon (Si) ions play a crucial role in bone development. Current research on Si ions mainly focuses on bone repair, by using silicate bioceramics with complex ion compositions. However, it is unclear whether the Si ions have important effect on cartilage regeneration. Developing a scaffold that solely releases Si ions to simultaneously promote subchondral bone repair and stimulate cartilage regeneration is critically important. Diatomite (DE) is a natural diatomaceous sediment that can stably release Si ions, known for its abundant availability, low cost, and environmental friendliness. Herein, a hierarchical osteochondral repair scaffold is uniquely designed by incorporating gradient DE into GelMA hydrogel. The adding DE microparticles provides a specific Si source for controlled Si ions release, which not only promotes osteogenic differentiation of rBMSCs (rabbit bone marrow mesenchymal stem cells) but also enhances proliferation and maturation of chondrocytes. Moreover, DE-incorporated hierarchical scaffolds significantly promoted the regeneration of cartilage and subchondral bone. The study suggests the significant role of Si ions in promoting cartilage regeneration and solidifies their foundational role in enhancing bone repair. Furthermore, it offers an economic and eco-friendly strategy for developing high value-added osteochondral regenerative bioscaffolds from low-value ocean natural materials.

Research progress on the application of magnesium phosphate bone cement in bone defect repair: A review.

Bone defects arising from diverse causes, such as traffic accidents, contemporary weapon usage, and bone-related disorders, present significant challenges in clinical treatment. Prolonged treatment cycles for bone defects can result in complications, impacting patients' overall quality of life. Efficient and timely repair of bone defects is thus a critical concern in clinical practice. This study aims to assess the scientific progress and achievements of magnesium phosphate bone cement (MPC) as an artificial bone substitute material. Additionally, the research seeks to explore the future development path and clinical potential of MPC bone cement in addressing challenges associated with bone defects. The study comprehensively reviews MPC's performance, encompassing e.g. mechanical properties, biocompatibility, porosity, adhesion and injectability. Various modifiers are also considered to broaden MPC's applications in bone tissue engineering, emphasizing drug-loading performance and antibacterial capabilities, which meet clinical diversification requirements. In comparison to alternatives such as autogenous bone transplantation, allograft, polymethyl methacrylate (PMMA), and calcium phosphate cement (CPC), MPC emerges as a promising solution for bone defects. It addresses limitations associated with these alternatives, such as immunological rejection and long-term harm to patients. MPC can control heat release during the curing process, exhibits superior mechanical strength, and has the capacity to stimulate new bone growth. MPC stands out as an artificial bone substitute with appropriate mechanical strength, rapid degradation, non-toxicity, and good biocompatibility, facilitating bone repair and regeneration. Modification agents can enhance its clinical versatility. Future research should delve into its mechanical properties and formulations, expanding clinical applications to create higher-performing and more medically valuable alternatives in bone defect repair.

Enhancing osteogenic bioactivities of coaxial electrospinning nano-scaffolds through incorporating iron oxide nanoparticles and icaritin for bone regeneration

Enhancing osteogenic bioactivities of coaxial electrospinning nano-scaffolds through incorporating iron oxide nanoparticles and icaritin for bone regeneration