Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

The aging global population is generating an ever‐increasing demand for bone regeneration. Various materials, including blocks, granules, and sponges, are developed for bone regeneration. However, blocks require troublesome shaping and exhibit poor bone‐defect conformities; granules migrate into the surrounding tissues during and after filling of the defect, causing handling difficulties and complications; and sponges contain polymers that are subject to religious restrictions, lack osteoconductivity, and may cause inflammation and allergies. Herein, carbonate apatite chains that overcome the limitations of conventional materials are presented. Although carbonate apatite granules migrate, causing inflammation and ectopic calcification, the chains remain in the defects without causing any complications. The chains conform to the defect shape and transform into 3D porous structures, resulting in faster bone regeneration than that observed using granules. Thus, these findings indicate that even traditional calcium phosphates materials can be converted to state‐of‐the‐art materials via shape control.

DOI： 10.1002/adhm.202303245

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

The aging population has rapidly driven the demand for bone regeneration. The pore structure of a scaffold is a critical factor that affects its mechanical strength and bone regeneration. Triply periodic minimal surface gyroid structures similar to the trabecular bone structure are considered superior to strut-based lattice structures (e.g., grids) in terms of bone regeneration. However, at this stage, this is only a hypothesis and is not supported by evidence. In this study, we experimentally validated this hypothesis by comparing gyroid and grid scaffolds composed of carbonate apatite. The gyroid scaffolds possessed compressive strength approximately 1.6-fold higher than that of the grid scaffolds because the gyroid structure prevented stress concentration, whereas the grid structure could not. The porosity of gyroid scaffolds was higher than that of the grid scaffolds; however, porosity and compressive strength generally have a trade-off relationship. Moreover, the gyroid scaffolds formed more than twice the amount of bone as grid scaffolds in a critical-sized bone defect in rabbit femur condyles. This favorable bone regeneration using gyroid scaffolds was attributed to the high permeability (i.e., larger volume of macropores or porosity) and curvature profile of the gyroid structure. Thus, this study validated the conventional hypothesis using in vivo experiments and revealed factors that led to this hypothetical outcome. The findings of this study are expected to contribute to the development of scaffolds that can achieve early bone regeneration without sacrificing the mechanical strength.

DOI： 10.1021/acsami.3c06263

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Repository Public URL： https://hdl.handle.net/2324/7360317

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Although studies on scaffolds for tissue generation have mainly focused on the chemical composition and pore structure, the effects of scaffold shape have been overlooked. Scaffold shape determines the scaffold surface area (SA) at the single-scaffold level (i.e., microscopic effects), although it also affects the amount of interscaffold space in the tissue defect at the whole-system level (i.e., macroscopic effects). To clarify these microscopic and macroscopic effects, this study reports the osteogenesis abilities of three types of carbonate apatite granular scaffolds with different shapes, namely, irregularly shaped dense granules (DGs) and two types of honeycomb granules (HCGs) with seven hexagonal channels (∼255 μm in length between opposite sides). The HCGs possessed either 12 protuberances (∼75 μm in length) or no protuberances. Protuberances increased the SA of each granule by 3.24 mm2 while also widening interscaffold spaces and increasing the space percentage in the defect by ∼7.6%. Interscaffold spaces were lower in DGs than HCGs. On DGs, new bone formed only on the surface, whereas on HCGs, bone simultaneously formed on the surface and in intrascaffold channels. Interestingly, HCGs without protuberances formed approximately 30% more new bone than those with protuberances. Thus, even tiny protuberances on the scaffold surface can affect the percentage of interscaffold space, thereby exerting dominant effects on osteogenesis. Our findings demonstrate that bone regeneration can be improved by considering macroscopic shape effects beyond the microscopic effects of the scaffold.

DOI： 10.1021/acsnano.2c03776

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Surgical site infection (SSI) is a severe complication associated with orthopedic bone reconstruction. For both infection prevention and bone regeneration, the framework surface of osteoconductive and bioresorbable scaffolds must be locally modified by minimum antibacterial substances, without sacrificing the osteoconductivity of the scaffold framework. In this study, we fabricated antibacterial honeycomb scaffolds by replacing carbonate apatite, which is the main component of the scaffold, with silver phosphate locally on the scaffold surface via dissolution–precipitation reactions. When the silver content was 9.9 × 10–4 wt %, the honeycomb scaffolds showed antibacterial activity without cytotoxicity and allowed cell proliferation, differentiation, and mineralization. Furthermore, the antibacterial honeycomb scaffolds perfectly prevented bacterial infection in vivo in the presence of methicillin-resistant Staphylococcus aureus, formed new bone at 2 weeks after surgery, and were gradually replaced with a new bone. Thus, the antibacterial honeycomb scaffolds achieved both infection prevention and bone regeneration. In contrast, severe infection symptoms, including abscess formation, osteolytic lesions, and inflammation, occurred 2 weeks after surgery when honeycomb scaffolds without silver phosphate modification were implanted. Nevertheless, the unmodified honeycomb scaffolds eliminated bacteria and necrotic bone through their scaffold channels, resulting in symptom improvement and bone formation. These results suggest that the honeycomb structure is inherently effective in hindering bacterial growth. This novel insight may contribute to the development of antibacterial scaffolds. Moreover, our modification method is useful for providing antibacterial activity to various biomaterials.

DOI： 10.1021/acsami.1c20204

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

The development of synthetic granules with performances equivalent to those of autogenous bone grafts is critical for effective bone replacement. Herein, we report on the fabrication of low‐crystalline Mg‐doped biphasic carbonate apatite/β‐tricalcium phosphate (Mg‐CAp/β‐TCP) granules, with cylindrical shapes, concave surfaces, and multiscale pores, from sea urchin spines. The β‐TCP/CAp ratios and Mg contents in the Mg‐CAp/β‐TCP granules were controlled to remain within 0.46–0.87 and 6.03–9.32 mol%, respectively. The Mg‐CAp/β‐TCP granules preserved the multiscale pores and concave surfaces of the sea urchin spines. The Mg‐CAp/β‐TCP granules exhibited inner stereom micropores (3–25 µm), thickened stereom micropores (<14 µm), interseptal gaps (20–43 µm), and concavities (26–41 µm), along with micropores (<3 µm) and nanopores (<100 nm) corresponding to intercrystal spaces. The rounded and uniformly shaped Mg‐CAp/β‐TCP granules facilitated denser packing in a simulated defect mold. The Mg‐CAp/β‐TCP granules exhibited compressive and diametral tensile strengths of 1.12–1.51 and 0.17–0.21 MPa, respectively. The distinctive physicochemical and structural characteristics of the Mg‐CAp/β‐TCP granules can be anticipated to facilitate controlled resorption rates and promote osteogenesis and angiogenesis, facilitating rapid bone defect repair. Furthermore, the adequate mechanical features of the Mg‐CAp/β‐TCP granules enable ease of handling during bone defect filling and potential application in load‐bearing sites.

DOI： 10.1111/jace.20498

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

To restore functions of long bones and avoid reconstruction failure, segmental defects should be quickly repaired using abundant amounts of regenerated bone with high mechanical strength and orientation along the bone axis. Although both bone volume and bone matrix orientation are important for faster restoration of long bones with segmental defects, researchers have primarily focused on the former. Artificial bone scaffolds with uniaxial channels, (e.g., honeycomb (HC) scaffolds), are considered adequate for regenerating bone oriented along the bone axis. The channel size may affect the orientation, amount, and strength of the regenerated bone. In this study, we investigated the effects of channel size in carbonate apatite HC scaffolds on the orientation of bones regenerated in segmental bone defects and determined the adequate channel size. Carbonate apatite HC scaffolds, with different channel sizes (350, 550, 730, and 890 μm in length on the side of the square aperture), were fabricated by extrusion molding of a mixture of calcium carbonate and organic binder, debinding, and subsequent phosphatization to convert the composition from calcium carbonate to carbonate apatite. No significant difference in the amounts of regenerated bones was observed for different channel sizes. However, bone along the bone axis was formed in the channels ≤550 μm in size but not in channels ≥730 μm. The HC scaffolds with a channel size of 350 μm regenerated bone with higher bending strength than those with a channel size of 890 μm. However, bone regenerated with the HC scaffolds having channel sizes of 350, 550, and 730 μm showed equal bending strength. Thus, the adequate channel size for fast regeneration of high-strength bone, oriented to the bone axis, is ≤730 μm. To the best of our knowledge, this is the first study to report the effect of channel size on bone orientation and strength. The findings of this study are relevant to the fast repair of segmental bone defects.

DOI： 10.1016/j.bioadv.2024.214026

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Granular bone substitutes are commonly used in dental treatments owing to their adaptability to irregular bone defects. However, granule migration during and after implantation poses a significant challenge, impairing bone regeneration. This study addresses this issue by setting carbonate apatite (CAp) granules using crystal interlocking owing to the bassanite (calcium sulfate hemihydrate (CSH))-to-gypsum (calcium sulfate dihydrate (CSD)) transformation on the granule surface. CAp granules were mixed with CSH slurry (water/CSH ratio of 0.4) at varying CSH/CAp ratios of 0.33, 0.43, 0.54, 0.67, and 0.82. At all of these mixing ratios, needle-shaped CSD crystals formed on the CAp granule surface, and the CSD crystals interlocked with each other; consequently, CAp granules were set. As the CSH/CAp ratio increased from 0.33 to 0.82, the CSD crystal length increased from 6.58 to 6.79 μm, while the setting time decreased from 30.3 to 15.5 min. Although the porosity of the set CAp granules decreased with an increase in the CSH/CAp ratio, the set granules maintained intergranular spaces of 77.3 μm at a CSH/CAp ratio of 0.82 conducive to cellular infiltration. After immersion in saline for six days, the set CAp granules at a CSH/CAp ratio of 0.82 maintained their original shape, demonstrating enhanced stability compared to lower CSH/CAp ratios where partial or complete collapse occurred. The porosity and specific surface area increased to 59.9% and 3.66 m2/g, respectively, and the intergranular spaces increased to 176.4 μm. Therefore, mixing the CAp granules with CSH at a ratio of 0.82 may prevent granule migration during and after implantation. Moreover, the CSD component of the granules is likely to resorb more rapidly than the CAp component in vivo, promoting porosity in the set granules and facilitating efficient bone replacement.

DOI： 10.3390/app142311261

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Bone graft granules are valuable tools for ridge area bone grafting owing to their ease of manipulation and interconnected porous structure. Guided bone regeneration (GBR) using barrier membranes is commonly used for alveolar ridge augmentation; however, the surgical procedures are technically complicated. In this study, we fabricated bioresorbable mesh domes (BMDs) using two types of Vicryl mesh (woven and knitted types) containing carbonate apatite granules. BMD samples were prepared in three groups: upper sides made from the woven type (UW) and lower sides made from the woven type (LW) (the UW/LW group), upper sides made from the woven type (UW) and lower sides made from the knitted type (LK) (the UW/LK group), and upper sides made from the knitted type (UK) and lower sides made from the knitted type (LK) (the UK/LK group). The samples were subsequently implanted into rabbit calvaria, and radiomorphometric and histological analyses were conducted. The UK/LK group exhibited enhanced appositional bone formation because the knitted mesh on the skin side prevented the infiltration of a substantial amount of fibrous tissue. This increase in bone formation could be attributed to the interaction between granules and osteoprogenitors that pass through the mesh from the host bone. Conversely, the UW/LW and UW/LK groups presented limited appositional bone formation. Compared with knitted mesh, woven mesh might tend to be absorbed over a short span, allowing fibrous tissue invasion and inhibiting new bone formation. Additionally, BMDs could retain granules in a targeted location and avoid displacement of the granules to unintended locations. Graphical Abstract: (Figure presented.)

DOI： 10.1007/s10856-024-06833-8

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Other Link： https://link.springer.com/article/10.1007/s10856-024-06833-8/fulltext.html

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

In bone regeneration, synthetic materials are required to replace autogenous bone grafts. The shape, composition, surface, and porous structure of the material are key factors in bone formation and material resorption. In this study, we describe the fabrication of Mg-doped biphasic calcium phosphate (Mg-BCP) granules comprising hydroxyapatite (HAp) and beta-tricalcium phosphate (β-TCP) by exploiting the structural and chemical characteristics of sea urchin spines. The Mg-BCP granules were cylinders with a 1.2–1.8 mm diameter and height of 1.4–1.7 mm. The β-TCP/HAp ratio and Mg content in the Mg-BCP granules were controlled within the ranges of 0.36–0.45 and 2.40–6.21 mol%, respectively. Controlling the β-TCP/HAp ratio and Mg content may contribute to controlling the material resorption rate and promoting osteogenesis and angiogenesis. The Mg-BCP granules maintained the structural characteristics of the sea urchin spines. The granules comprised radial wedges termed septa, and a meshwork termed stereom. The interseptal gaps, or micropores, decreased from the granular exterior (24–29 μm) to the interior (14–28 μm). The septa in the outermost layer provide concavities on the sides of the cylindrical granules. The stereom meshworks in the core and outer layers involved micropores in the ranges of 3–15 and 3–10 μm, respectively. These multiscale pores and surface undulations may improve cell penetration and attachment, bodily fluid permeability, and protein adsorption. The compressive strengths of the Mg-BCP granules were in the range of 45.2–46.1 MPa, which are useful as bone grafts. Due to their rounded shapes, the Mg-BCP granules filled a mold more densely than the clinically used and irregularly shaped granules. These findings demonstrated that Mg-BCP granules are promising materials for bone regeneration.

DOI： 10.1016/j.ceramint.2024.04.341

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Bone graft granules implanted in bone defects come into physical contact with the host bone and form interconnected porous structure. However, there exists an accidental displacement of granules to unintended locations and leakage of granules from bone defects. Although covering the defect with a barrier membrane prevents granule emanation, this procedure is troublesome. To resolve these problems, we fabricated bioresorbable mesh cages (BRMc) in this study. Bone graft granules composed of carbonate apatite alone (Gr) and bioresorbable mesh cages (BRMc/Gr) introduced the bone graft granules and were implanted into the bone defect in the rabbit femur. Micro-computed tomography and histological analysis were conducted at 4 and 12 weeks after implantation. Osteoprogenitors in the bloodstream from the host bone passed through the pores of BRMc, penetrated the porous structure of graft granules, and might interact with individual granules. Then bone remodeling could progress actively and new bone was formed. The new bone formation was similar to the host bone at 12 weeks and there were minimal signs of local tissue inflammation. BRMc/Gr could reduce the risk of unwanted new bone formation occurring due to loss of granules from the bone defects compared with Gr because BRMc enclosed granules and prevent granules leakage from bone defects and BRMc could not induce unfavorable effects to forme new bone. Additionally, BRMc/Gr could keep granules assembled in one place, avoid displacement of granules to unintended locations, and carry easily. These results demonstrated that BRMc/Gr was effective in bone regeneration and improved clinical handling.

DOI： 10.1038/s41598-024-63067-y

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Other Link： https://www.nature.com/articles/s41598-024-63067-y

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：AccScience Publishing  

 In the reconstruction of bone defects close to soft tissue, preventing the invasion of fibrous tissue into the bone defect is key to successful bone reconstruction. In this study, we clarified the effects of the pore architecture of artificial bone grafts on the penetration of bone and fibrous tissue, and the orientation of regenerated bone. Carbonate apatite grafts with uniaxial pores along the long- (L-graft) or short-axis (S-graft) direction of the graft and biaxial pores along the long- and short-axes (LS-graft) were used. These grafts were implanted in bone defects created by rabbit ulnae amputation. The pores of the L-, S-, and LS-grafts opened into the bone stumps, muscles, and bone stumps and muscles together, respectively. In the L-graft, the graft pores developed bone from the bone stump to the graft center, while preventing excessive invasion of fibrous tissue. In S- and LS-grafts, the graft pores along the short axis allowed the invasion of fibrous tissue into the grafts. Consequently, although the bone grew to the edge regions in these grafts, further bone ingrowth was inhibited by the fibrous tissue. Furthermore, the pore architecture of the grafts affected the orientation of the regenerated bone. The degree of orientation of the bone formed in the L- and S-grafts was 1.6-fold higher than that formed in the LS-grafts. Thus, controlling the pore architecture allowed the growth of bone to predominate over that of fibrous tissue and induced the formation of bone with an ordered orientation

DOI： 10.36922/ijb.2323

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Generally, ceramics are brittle, and porosity is inversely correlated with strength, which is one of the challenges of ceramic scaffolds. Here, we demonstrate that lamellar septum-like carbonate apatite scaffolds have the potential to overcome these challenges. They were fabricated by exploiting the cellular structure of the cuttlebone, removing the organic components from the cuttlebone, and performing hydrothermal treatment. Scanning electron microscopy revealed that the scaffolds had a cellular structure with walls between lamellar septa. The interwall and interseptal sizes were 80–180 and 300–500 μm, respectively. The size of the region enclosed by the walls and septa coincided with the macropore size detected by mercury intrusion porosimetry. Although the scaffold porosity was extremely high (93.2%), the scaffold could be handled without disintegration. The compressive stress–strain curve demonstrated that the scaffolds showed layer-by-layer fracture behavior, which seemed beneficial for avoiding catastrophic failure under impact. When the scaffolds were implanted into rabbit femurs, new bone and blood vessels formed within the scaffold cells at 4 weeks. At 12 weeks, the scaffolds were almost entirely replaced with new bone. Thus, the lamellar septum-like cellular-structured carbonate apatite is a promising scaffold for achieving early bone regeneration and compression resistance.

DOI： 10.3390/biomimetics9020112

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Materials  

The internal structure of the scaffolds is a key factor for bone regeneration. In this study, we focused on the space dimensionality within the scaffold that may control cell migration and evaluated the effects on the size and orientation of blood vessels and the amount of bone formation in the scaffold. The carbonate apatite scaffolds with intrascaffold space allowing one-dimensional (1D), two-dimensional (2D), or three-dimensional (3D) cell migration were fabricated by 3D printing. These scaffolds had the same space size, i.e., distances between the struts (~300 µm). The scaffolds were implanted into the medial condyle of rabbit femurs for four weeks. Both the size and orientation degree of the blood vessels formed in the scaffolds allowing 1D cell migration were 2.5- to 4.0-fold greater than those of the blood vessels formed in the scaffolds allowing 2D and 3D cell migration. Furthermore, the amount of bone formed in the scaffolds allowing 1D cell migration was 1.4-fold larger than that formed in the scaffolds allowing 2D and 3D cell migration. These are probably because the 1D space limited the direction of cell migration and prevented the branching of blood vessels, whereas 2D and 3D spaces provided the opportunity for random cell migration and blood vessel branching. Thus, scaffolds with 1D space are advantageous for inducing large and oriented blood vessels, resulting in a larger amount of bone formation.

DOI： 10.3390/ma16247518

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Osteoconductive ceramics (OCs) are often used to endow polylactic acid (PLA) with osseointegration ability. Conventionally, OC powder is dispersed in PLA. However, considering cell attachment to the implant, OCs may be more favorable when they exist in the form of aggregations, such as granules, and are larger than the cells rather than being dispersed like a powder. In this study, to clarify the effects of the dispersion state of OCs on the osseointegration ability, carbonate apatite (CAp), a bone mineral analog that is osteoconductive and bioresorbable, powder–PLA (P-PLA), and CAp granule–PLA (G-PLA) composite implants were fabricated via thermal pressing. The powder and granule sizes of CAp were approximately 1 and 300–600 µm, respectively. G-PLA exhibited a higher water wettability and released calcium and phosphate ions faster than P-PLA. When cylindrical G-PLA, P-PLA, and PLA were implanted in rabbit tibial bone defects, G-PLA promoted bone maturation compared to P-PLA and pure PLA. Furthermore, G-PLA bonded directly to the host bone, whereas P-PLA bonded across the osteoid layers. Consequently, the bone-to-implant contact of G-PLA was 1.8- and 5.6-fold higher than those of P-PLA and PLA, respectively. Furthermore, the adhesive shear strength of G-PLA was 1.9- and 3.0-fold higher than those of P-PLA and PLA, respectively. Thus, G-PLA achieved earlier and stronger osseointegration than P-PLA or PLA. The findings of this study highlight the significance of the state of dispersion of OCs in implants as a novel strategy for material development.

DOI： 10.1016/j.colsurfb.2023.113588

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Synthetic bone grafts are in high demand owing to increased age-related bone disorders in the global aging population. Here, we report fabrication of gear-shaped granules (G-GRNs) for rapid bone healing. G-GRNs possessed six protrusions and a hexagonal macropore in the granular center. These were composed of carbonate apatite, i.e., bone mineral, microspheres with ∼1-μm micropores in the spaces between the microspheres. G-GRNs formed new bone and blood vessels (both on the granular surface and within the macropores) 4 weeks after implantation in the rabbit femur defects. The formed bone structure was similar to that of cancellous bone. The bone percentage in the defect recovered to that in a normal rabbit femur at week-4 post-implantation, and the bone percentage remained constant for the following 8 weeks. Throughout the entire period, the bone percentage in the G-GRN-implanted group was ∼10% higher than that of the group implanted with conventional carbonate apatite granules. Furthermore, a portion of the G-GRNs resorbed at week-4, and resorption continued for the following 8 weeks. Thus, G-GRNs are involved in bone remodeling and are gradually replaced with new bone while maintaining a suitable bone level. These findings provide a basis for the design and fabrication of synthetic bone grafts for achieving rapid bone regeneration.

DOI： 10.1016/j.csbj.2023.03.053

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

In a globally aging society, synthetic bone blocks are in increasing demand. An ideal synthetic bone block fuses early with bone and is replaced with new bone at a suitable speed while withstanding the weight load. Herein, we report carbonate apatite honeycomb (HC) blocks with superior mechanical strength, osteoconductivity, and bioresorbability compared to a clinically used synthetic porous block (control block). Three types of HC blocks were fabricated via the debinding of HC green bodies at 600, 650, and 700 °C and subsequent phosphatization, designated as HC-600, HC-650, and HC-700, respectively. The macropores in these HC blocks uniaxially penetrated the blocks, whereas those in the control block were not interconnected. Consequently, the HC blocks exhibited higher open macroporosities (18%-20%) than the control block (2.3%). In contrast, the microporosity of the control block (46.4%) was higher than those of the HC blocks (19%-30%). The compressive strengths of the HC-600, HC-650, HC-700, and control blocks were 24.7, 43.7, 103.8, and 38.9 MPa, respectively. The HC and control blocks were implanted into load-bearing segmental bone defects of rabbit ulnae. Uniaxial HC macropores enabled faster bone ingrowth than the poorly interconnected macropores in the control block. Microporosity in the HC blocks affected bone formation and osteoclastic resorption over a period of 24 weeks. The resorption of HC-650 corresponded to new bone formation; therefore, new bone with strength equal to that of the original bone bridged the separated bones. Thus, the HC blocks achieved the reconstruction of segmental bone defects while withstanding the weight load. The findings of this study contribute to the design and development of synthetic bone blocks for reconstructing segmental defects.

DOI： 10.1021/acsmaterialsau.3c00008

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The main reason for revision arthroplasty with an alumina-based prosthesis is aseptic loosening of the prosthesis. To prevent loosening of the prosthesis, endowing bioinert alumina with osteogenic ability is deemed an effective approach. Hence, we developed an alumina substrate with carbonate apatite and evaluated its effectiveness for early binding to the bone. Alumina substrates were coated with carbonate apatite using the following procedures: (1) etching the alumina substrate by alkaline hydrothermal treatment; (2) calcium carbonate coating of the etched alumina substrate; and (3) composition conversion of calcium carbonate coating into carbonate apatite by phosphatization. The tensile bond strength of carbonate apatite coating to alumina substrate was 17.6 MPa, which satisfied the criteria defined by the International Organization for Standardization. Contrary to the results of etched alumina substrates, the carbonate apatite-coated alumina substrates promoted the proliferation and osteogenic differentiation of mesenchymal stem cells and induced mineralization. Furthermore, the carbonate apatite-coated alumina substrates strongly adhered to the rabbit tibia 4 weeks after implantation compared to the etched alumina substrates. The contact area and adhesion strength of carbonate apatite-coated alumina substrates to bone were approximately 19- and 6-fold higher than those of etched alumina substrates, respectively. Thus, carbonate apatite coating may contribute to preventing the loosening of alumina prostheses.

DOI： 10.1016/j.surfin.2022.102617

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Carbonate apatite (CO₃Ap) granules are useful as a bone substitute because they can be remodeled to new natural bone in a manner that conforms to the bone remodeling process. However, reconstructing large bone defects using CO₃Ap granules is difficult because of their granular shape. Therefore, we fabricated CO₃Ap honeycomb blocks (HCBs) with continuous unidirectional pores. We aimed to elucidate the tissue response and availability of CO₃Ap HCBs in the reconstruction of rabbit mandibular bone defects after marginal mandibulectomy. The percentages of the remaining CO₃Ap area and calcified bone area (newly formed bone) were estimated from the histological images. CO₃Ap area was 49.1 ± 4.9%, 30.3 ± 3.5%, and 25.5 ± 8.8%, whereas newly formed bone area was 3.0 ± 0.6%, 24.3 ± 3.3%, and 34.7 ± 4.8% at 4, 8, and 12 weeks, respectively, after implantation. Thus, CO₃Ap HCBs were gradually resorbed and replaced by new bone. The newly formed bone penetrated most of the pores in the CO₃Ap HCBs at 12 weeks after implantation. By contrast, the granulation tissue scarcely invaded the CO₃Ap HCBs. Some osteoclasts invaded the wall of CO₃Ap HCBs, making resorption pits. Furthermore, many osteoblasts were found on the newly formed bone, indicating ongoing bone remodeling. Blood vessels were also formed inside most of the pores in the CO₃Ap HCBs. These findings suggest that CO₃Ap HCBs have good osteoconductivity and can be used for the reconstruction of large mandibular bone defects.

Graphical Abstract

DOI： 10.1007/s10856-022-06710-2

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

IntroductionCases of intractable dental implant require vertical bone augmentation; however, the predicted bone height and volume are difficult to obtain. In vertical bone augmentation, the contact surface between the scaffold and the bone is limited to the bottom face of the scaffold. Furthermore, the strength decrease caused by scaffold resorption leads to collapse of the augmented site, leading to a decrease in the bone volume and height.ObjectivesTo promote bone ingrowth, we fabricated carbonate apatite (i.e., bone mineral) honeycomb (HC) scaffolds with uniaxial channels vertically penetrating the scaffold. Furthermore, we controlled the scaffold resorption rate, eventually the endurability for compression, and the bone height and volume by controlling the strut thickness.MethodsThe channel aperture was controlled to be 230–260 μm to promote bone ingrowth. Furthermore, the strut thicknesses of the HC scaffolds were adjusted to 100, 200, and 300 μm to control the scaffold resorption; these scaffolds were designated as HC100, HC200, and HC300, respectively.ResultsAt 4 weeks post-implantation on rabbit calvarium, all scaffolds had already vertically augmented new bone close to the top surface of the scaffold. In the following 8 weeks, the height and amount of new bone in all scaffolds increased. Notably, HC300 was resorbed synchronously with new bone formation, allowing it to endure the compression from the fasciae for 12 weeks post-implantation. Furthermore, HC300 formed larger-diameter blood vessels than those of HC100 and HC200.ConclusionThe HC scaffolds surpassed the various combined scaffolds and growth factors or stem cells in the ability for vertical bone augmentation. Thus, the HC structure is inherently suitable for vertical bone augmentation. Notably, the HC scaffolds with 300-μm-thick struts enhanced both new bone formation and angiogenesis. This study revealed a structurally suitable design for achieving an outstanding outcome in vertical bone augmentation.

DOI： 10.1016/j.jare.2021.12.010

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Synthetic scaffolds with the ability to prevent fibrous tissue penetration and promote bone augmentation may realize guided bone regeneration without the use of a barrier membrane for dental implantation. Here, we fabricated two types of honeycomb scaffolds of carbonate apatite, a bone mineral analog, whose channel apertures were square (HC-S) and rectangular (HC-R). The side lengths of the HC-Ss and HC-Rs were 265.8 ± 8.9; 817.7 ± 2.4 and 267.1 ± 5.2 μm, respectively. We placed cylindrical HC-Ss and HC-Rs on the rabbit calvaria. At 4 weeks post-implantation, the HC-Ss prevented fibrous tissue penetration from the top face via the channels, which allowed the new bone to reach the top of the scaffold from the bottom face or the calvarium. In contrast, in the HC-Rs, fibrous tissues filled the channels in the top region. At 12 weeks post-implantation, the HC-Ss were partially replaced with new bone. In the top region of the HC-Rs, although new bone had formed, fibrous tissue remained. According to the findings here and in our previous study, the longer side length rather than the shorter side length of a rectangular scaffold channel aperture is the dominant factor that affects fibrous tissue penetration and new bone augmentation. Furthermore, even though channel aperture areas are similar, bone and fibrous tissue ingrowths are different when the aperture shapes are different.

DOI： 10.3390/bioengineering9110627

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Beta-tricalcium phosphate (βTCP) granules are commonly used as an artificial bone graft material. Meanwhile, the surface morphology of the bone graft is an important factor for cellular response. In this study, feasibility study on surface morphology regulation of βTCP bone graft for enhancing cellular response were investigated. The regulation was achieved on the basis of a multistep heating process. Briefly, initial heat treatment of βTCP granules at 1300 °C for 12 h resulted in fabrication of alpha-tricalcium phosphate (αTCP) granules with interconnected micropores. In the second heat treatment, exposure of αTCP granules to 100% relative humidity at 100 °C resulted in partial hydrolysis of αTCP, leading to the fabrication of needle-like calcium-deficient hydroxyapatite (cdHAp) crystals on the αTCP surface. After the third heat treatment at 1100 °C, both cdHAp and αTCP converted back to βTCP, and interconnected micropores with a roughened surface structure were formed. In vitro cell evaluation demonstrated that βTCP granules obtained by the series of heat treatments exhibited 24 times higher cell proliferation at day 9, and four times higher alkaline phosphatase activity compared with untreated βTCP granules. Therefore, we concluded that regulation of surface morphology by a series of heat treatments is useful for improving cellular response to βTCP bone grafting materials.

DOI： 10.1016/j.ceramint.2022.02.200

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Granular porous calcium phosphate scaffolds are used for bone regeneration in dentistry. However, in conventional granules, the macropore interconnectivity is poor and has varying size. Herein, we developed a productive method for fabricating carbonate apatite honeycomb granules with uniformly sized macropores based on extrusion molding. Each honeycomb granule possesses three hexagonal macropores of ∼290 ​μm along its diagonal. Owing to these macropores, honeycomb granules simultaneously formed new and mature bone and blood vessels in both the interior and exterior of the granules at 4 weeks after implantation. The honeycomb granules are useful for achieving rapid osteogenesis and angiogenesis.

DOI： 10.1016/j.mtbio.2022.100247

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Osteomyelitis is a potentially devastating inflammatory bone disease that leads to bone destruction and loss. Treatment of osteomyelitis requires the removal of residual bacteria as well as osteogenesis with angiogenesis at the site of treatment. Use of an appropriate amount of copper (Cu) in treatment scaffolds may achieve these goals without the risk of toxicity. In this study, the surface of the carbonate apatite honeycomb scaffold was functionalized with Cu through a dissolution–precipitation reaction. The resulting scaffolds retained the honeycomb structure after immersion in CuCl2 solution, and Cu was precipitated on the surface as libethenite [Cu2(OH)PO4]. The surface Cu concentration was controlled by the concentration of the CuCl2 solution. Scaffolds with a surface Cu concentration of 23.8 wt% exhibited antibacterial and cytotoxic effects, whereas those with concentrations of ≤4.6 wt% exerted antibacterial effects without negatively affecting the cellular adhesion, proliferation, differentiation, and calcification of osteoblast-like cells. Furthermore, scaffolds with a surface Cu concentration of 4.6 wt% Cu inhibited bacterial growth for at least 28 days and displayed proangiogenic and pro-osteogenic activities in vivo. These data confirm the success in functionalizing scaffolds with Cu that may be utilized as an innovative osteomyelitis therapy.

DOI： 10.1016/j.bioadv.2022.212751

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

The reconstruction of critical-sized segmental bone defects is a key challenge in orthopedics because of its intractability despite technological advancements. To overcome this challenge, scaffolds that promote rapid bone ingrowth and subsequent bone replacement are necessary. In this study, we fabricated three types of carbonate apatite honeycomb (HC) scaffolds with uniaxial channels bridging the stumps of a host bone. These HC scaffolds possessed different channel and micropore volumes. The HC scaffolds were implanted into the defects of rabbit ulnar shafts to evaluate the effects of channels and micropores on bone reconstruction. Four weeks postoperatively, the HC scaffolds with a larger channel volume promoted bone ingrowth compared to that with a larger micropore volume. In contrast, 12 weeks postoperatively, the HC scaffolds with a larger volume of the micropores rather than the channels promoted the scaffold resorption by osteoclasts and bone formation. Thus, the channels affected bone ingrowth in the early stage, and micropores affected scaffold resorption and bone formation in the middle stage. Furthermore, 12 weeks postoperatively, the HC scaffolds with large volumes of both channels and micropores formed a significantly larger amount of new bone than that attained using HC scaffolds with either large volume of channels or micropores, thereby bridging the host bone stumps. The findings of this study provide guidance for designing the pore structure of scaffolds.

DOI： 10.3389/fbioe.2022.825831

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The use of scaffolds with pores ranging from macroscale to nanoscale (i.e., multiscale pores), is an effective strategy to achieve favorable bone regeneration. Here, we report the fabrication of multiscale porous scaffolds (MPSs) and evaluate the effects of macropores (>100 μm) and micropores (<10 μm) on bone regeneration in the early to medium term. MPSs were constructed from interconnecting carbonate apatite honeycomb granules. The uniaxial macropores penetrating the honeycomb granules linked the gaps among the granules, creating an interconnected macroporous architecture. MPSs with different proportions of macropores and micropores were implanted into rabbit femurs. In an early stage, macropores played a crucial role in promoting new bone formation. In the medium term, micropores, rather than macropores, were the dominant factor affecting the replacement of MPSs with new bone. Notably, micropores of 100 nm to 10 μm primarily promoted MPS resorption by osteoclasts, stimulating secondary osteogenesis. Our findings demonstrated that pore size distribution, rather than porosity, was crucial for osteogenesis in the early-to-medium term. Although conventional scaffold development sacrifices mechanical strength to improve bone formation, our findings indicate that optimizing the pore size distribution is a promising strategy to develop scaffolds that satisfy the requirements of both osteogenesis and mechanical strength.

DOI： 10.1016/j.matdes.2022.110468

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Metastable vaterite blocks are expected to show high reactivity. However, they have not been reported to date. In this study, the feasibility of fabricating an artificial vaterite block was investigated by exposing a Ca(OH)2 compact to CO2 under several conditions. Under a 100% H2O atmosphere, a calcite block was formed within three days. Under a 100% methanol atmosphere, no carbonation was observed for seven days. Under 90% methanol without atmospheric flow, a vaterite block containing 5 mass% of unreacted Ca(OH)2 and 3 mass% of calcite was formed after 24 h. On day 7, it was transformed into a block with 70 mass% of calcite, 27 mass% of vaterite, and 3 mass% of unreacted Ca(OH)2. By contrast, under 90% methanol with atmospheric flow to remove the accumulated H2O in the compact, a pure CaCO3 block of 98 mass% vaterite and 2 mass% calcite was formed on day 3. Therefore, the regulation of the amount of H2O is important for fabricating vaterite blocks. Porosimetry measurements revealed that the calcite block fabricated under 90% methanol without atmospheric flow demonstrated a pore size profile closer to that of the vaterite block than that of the calcite block fabricated under 100% H2O atmosphere because the vaterite with small spherical crystals was formed initially before its transformation to calcite.

DOI： 10.1016/j.ceramint.2021.10.206

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
Porous architecture in bone substitutes, notably the interconnectivity of pores, is a critical factor for bone ingrowth. However, controlling the pore interconnectivity while maintaining the microarchitecture has not yet been achieved using conventional methods, such as sintering. Herein, we fabricated a porous block using the crystal growth of calcium sulfate dihydrate, and controlled the pore interconnectivity by limiting the region of crystal growth. The calcium sulfate dihydrate blocks were transformed to bone apatite, carbonate apatite (CO3Ap) through dissolution−precipitation reactions. Thus, CO3Ap blocks with 15% and 30% interconnected pore volumes were obtained while maintaining the microarchitecture: they were designated as CO3Ap-15 and CO3Ap-30, respectively. At 4 weeks after implantation in a rabbit femur defect, new bone formed throughout CO3Ap-30, whereas little bone was formed in the center region of CO3Ap-15. At 12 weeks after implantation, a large portion of CO3Ap-30 was replaced with new bone and the boundary with the host bone became blurred. In contrast, CO3Ap-15 remained in the defect and the boundary with the host bone was still clear. Thus, the interconnected pores promote bone ingrowth, followed by replacement of the material with new bone. These findings provide a useful guide for designing bone substitutes for rapid bone regeneration.

DOI： 10.1093/rb/rbac010

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

The porous architecture of artificial bones plays a pivotal role in bone ingrowth. Although salt leaching methods produce predictable porous architectures, their application in the low-temperature fabrication of ceramics remains a challenge. Carbonate apatite (CO3Ap) blocks with three ranges of pore sizes: 100–200, 200–400, and 400–600 μm, were fabricated from CaCO3 blocks with embedded Na2HPO4 crystals as a porogen and accelerator for CaCO3-to-CO3Ap conversion. CaCO3 blocks were obtained from Ca(OH)2 compacts with Na2HPO4 by CO2 flow at 100% humidity. When carbonated under 100% water humidity, the dissolution of Na2HPO4 and the formation of hydroxyapatite were observed. Using 90% methanol and 10% water were beneficial in avoiding the Na2HPO4 consumption and generating the metastable CaCO3 vaterite, which was rapidly converted into CO3Ap in a Na2HPO4 solution in 7 days. For the histological evaluation, the CO3Ap blocks were implanted in rabbit femur defects. Four weeks after implantation, new bone was formed at the edges of the blocks. After 12 weeks, new bone was observed in the central areas of the material. Notably, CO3Ap blocks with pore sizes of 100–200 μm were the most effective, exhibiting approximately 23% new bone area. This study sheds new light on the fabrication of tailored porous blocks and provides a useful guide for designing artificial bones.

DOI： 10.1002/jbm.a.37374

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/jbm.a.37374

Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

Fracture-related infections require both treatments for bacteria removal and bone reconstruction. The use of combined broad-spectrum antibacterial silver compounds and artificial bone with high osteogenic activity is considered to be an effective strategy for achieving these treatments in one surgery. However, silver compounds are toxic for living tissues even at low concentrations. Herein, we investigated the no-observed-effect level (NOEL) of silver phosphate (Ag3PO4) in a bone substitute composed of carbonate apatite (CO3Ap), a bone mineral, using in vitro and in vivo experiments. In vitro experiments demonstrated that the CO3Ap artificial bone containing ≥0.1 wt % Ag3PO4 exerted antibacterial effects against Staphylococcus epidermidis, while those containing ≤0.3 wt % Ag3PO4 did not affect cellular adhesion, proliferation, differentiation, and calcification of osteoblast-like MC3T3-E1 cells. In vivo experiments demonstrated that the CO3Ap artificial bone containing ≤0.3 wt % Ag3PO4 replaced a new bone to the same levels as those without Ag3PO4 4 weeks after implantation into the bone defect of the rabbit femur condyle. However, the CO3Ap artificial bone containing 0.3 wt % Ag3PO4 caused an inflammatory reaction, whereas those containing ≤0.1 wt % Ag3PO4 did not. Thus, both bone regeneration and infection control without any adverse effects were achieved using the CO3Ap artificial bone containing 0.1 wt % Ag3PO4, indicating that the NOEL of Ag3PO4 was 0.1 wt %. Our results provide an effective strategy for the treatments of fracture-related infections.

DOI： 10.1021/acsinfecdis.1c00480

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Carbonate apatite (CO3Ap) artificial bone has attracted much attention due to its high osteoconductivity and replacement to bone. CO3Ap is an inorganic component of bone, and has been fabricated by compositional transformation through a dissolution–precipitation reaction in Na2HPO4 solution using calcium carbonate as a precursor. In this study, the effects of the CO32− concentration in the Na2HPO4 solution on the CO3Ap fabrication reaction and the properties of the fabricated CO3Ap were investigated. The rate of the compositional transformation became faster, and more CO3 containing CO3Ap was fabricated using CO32− concentrated in Na2HPO4 solution. The crystal shape of CO3Ap changed from scale-like to hexagonal crystals. In addition, the crystallite size increased with increasing CO32− concentration in the Na2HPO4 solution. These changes lead to larger pores (≥0.02 μm) and decreased number of small pores (<0.02 μm) according to the CO3 content in CO3Ap, even though the total pore volume remained the same. These findings indicate that the CO32− concentration in Na2HPO4 solution is an important factor for the CO3Ap fabrication reaction and affects the properties of the fabricated CO3Ap.

DOI： 10.1016/j.ceramint.2021.09.188

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DOI： https://doi.org/10.1021/acsinfecdis.1c00480

Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/nano.202000283

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/nano.202000283

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Barrier membrane-free guided bone regeneration (GBR) with a synthetic scaffold may resolve the current challenges in vertical bone augmentation. To realize such GBR, we fabricated carbonate apatite honeycomb (HC) scaffolds capable of preventing soft tissue invasion and enhancing bone ingrowth. These HC scaffolds with 230-, 460-, and 630 μm-aperture channels were designated as HC230, HC460, and HC630, respectively. They were constructed by interconnecting carbonate apatite microspheres; they possessed micropores and nanopores in the struts and were implanted on the rabbit calvarium. The amount of new bone and soft tissues in the HC scaffolds significantly increased and decreased, respectively, with the decrease in the channel aperture size. The new bone height in HC230 at 4 and 12 weeks post-implantation was 3.4 ± 0.5 and 3.8 ± 0.2 mm, respectively, reaching the top edge of the struts. The percent volume of new bone in HC230 at 4 and 12 weeks post-implantation was 38.6% ± 2.2% and 49.9% ± 1.5%, respectively. These findings demonstrated that HC230 augmented faster, higher, and a greater amount of vertical bone growth than the reported combinations of scaffolds and growth factors or barrier membranes. Therefore, the multiscale-architectural control of HC scaffolds may pioneer barrier membrane-free GBR.

DOI： 10.1039/d1ma00698c

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ceramint.2021.06.252

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acsabm.1c00533

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DOI： 10.1002/jbm.a.37157

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1016/j.ceramint.2021.03.324

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Although the channel architecture of a scaffold is critical for bone regeneration, little is known for the channel direction. In this study, four types of carbonate apatite cylindrical scaffolds; scaffolds with biaxial channels (VH-scaffold), with uniaxial vertical channels (V-scaffold), with uniaxial horizontal channels (H-scaffold), and without channels (N-scaffold), were implanted in a rabbit femur defect for 4 and 12 weeks. Although the largest bone was formed 4 weeks post-implantation in the VH-scaffold, newly formed bone disappeared with the scaffold after 12 weeks. Thus, biaxial channels resulted in the rapid dissolution of the scaffold and were counterproductive in long-term bone regeneration. The V-scaffold that had channels connected to the periosteum was gradually resorbed throughout 12 weeks post-implantation. The percentage of mineralized bone in the V-scaffolds was equal to that in the natural bone. The resorption and bone percentage of H-scaffolds that had no channels connected to the periosteum were slower and lower, respectively, than those of V-scaffolds. Thus, channels should be connected to the periosteum to achieve smooth replacement by the new bone. In the N-scaffold, much less bone was formed inside the scaffold. This study contributes to providing a design guide for scaffold development in bone engineering.

DOI： 10.1016/j.matdes.2021.109686

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/acsabm.0c01279

Repository Public URL： https://hdl.handle.net/2324/7360320

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.colsurfb.2020.111527

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The scaffold chemical composition and pore architecture are critical for successful bone regeneration. Although the effects of chemical composition, micron-scale pores, and macropores (Z100 mm) are known, those of nanometer-scale pores (nanopores) are unknown. Here, honeycomb scaffolds (HCSs) composed of carbonate apatite and bone mineral, were fabricated with three distinct nanopore volumes, while other parameters were comparable between HCSs. Their compressive strengths and nanopore volumes linearly correlated. The HCSs were implanted into critical-sized bone defects (CSDs) in the rabbit femur distal epiphyses. The nanopore volume affected both osteoclastogenesis and osteogenesis. HCSs with nanopore volumes of Z0.15 cm3 g-1 promoted osteoclastogenesis, contributing to bone maturation and bone formation within 4 weeks. However, HCSs with nanopore volumes of 0.07 cm3 g-1 promoted significantly less bone maturation and neoformation. Nevertheless, HCSs with nanopore volumes of Z0.18 cm3 g-1 did not undergo continuous bone regeneration throughout the 12 week period due to excessive osteoclastogenesis, which favored HCS resorption over bone neoformation. When the nanopore volume was 0.15 cm3 g-1, osteoclastogenesis and osteogenesis progressed harmonically, resulting in HCS replacement with new bone. Our results demonstrate that the nanopore volume is critical for controlling osteoclastogenesis and osteogenesis. These insights may help establish a coherent strategy for developing scaffolds for different applications.

DOI： 10.1039/D0TB01498B

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DOI： 10.1039/10.3390/ma13163637

Language：English   Publishing type：Research paper (scientific journal)  

Thiol-organosilica nanoparticles that are internally functionalized with IR-820 (thiol-OS/IR820) were prepared via a one-pot process for near-infrared (NIR) fluorescence in vivo imaging. Thiol-OS/IR820 demonstrated broad-band emissive NIR fluorescence with multiple new fluorescent peaks that differed from those of the IR-820 molecule and upconversion fluorescence originated from thiol-OS. Thiol-OS/IR820 was biocompatible and did not show significant toxicity in vitro and in vivo. We conducted in vivo tracking of in situ labeled cells against subcutaneous xenograft cells. The in vivo imaging showed a migration and an accumulation of the in situ labeled cells to the site of xenograft cells. Then, a reduction of the grafted cells was observed after 3 weeks. Next, we conducted in vivo tumor imaging of a mouse with a subcutaneous xenograft tumor using intravenous administration of thiol-OS/IR820. Using three wavelengths of light emission, depth-dependent NIR fluorescence imaging of a mouse with a subcutaneous xenograft tumor was conducted. The accumulation of particles in the tumor tissue due to the enhanced permeability and retention (EPR) effect was observed depth-dependently. NIR fluorescence in vivo imaging using thiol-OS/IR820 is useful for long-term observation and shows substantial promise for the visualization of novel biological phenomena in vivo.

DOI： 10.1021/acs.chemmater.0c01414

Language：English   Publishing type：Research paper (scientific journal)  

Titanium (Ti) implants that realize rapid osseointegration are required for favorable outcomes. Rough implant surfaces favor osseointegration, hence, coating implants with natural bone mineral, i.e., carbonate apatite (CO3Ap), may be effective for osseointegration. To achieve rapid osseointegration, rough-Ti substrates are coated with CO3Ap (CO3Ap-Ti) and the effects are evaluated in vitro and in vivo. For comparison, rough-Ti without coating (rough-Ti) and calcite-coated rough-Ti (calcite-Ti) substrates are fabricated. The adhesive strengths of calcite and CO3Ap to the substrates are ≈56.6 and ≈76.8 MPa, respectively, being significantly higher than the strength defined in ISO13779-2 (15 MPa). Calcite and CO3Ap coatings significantly promote preosteoblastic MC3T3-E1 cell proliferation. Additionally, the CO3Ap coating promotes higher osteogenic differentiation activity than the calcite coating. Implantation of CO3Ap-Ti into rabbit tibia defects prompts bone maturation, compared to calcite-Ti or rough-Ti implantation. The bone-implant contact percentage with CO3Ap-Ti and calcite-Ti is higher than that with rough-Ti. Consequently, CO3Ap-Ti acquires a robust bond with the host bone at an early stage (4 weeks postimplantation), compared to calcite-Ti or rough-Ti: the CO3Ap-Ti–bone bonding strength is ≈1.9- and ≈5.5-fold higher than that of calcite-Ti and rough-Ti, respectively. Thus, CO3Ap coating of Ti implants effectively achieve rapid osseointegration.

DOI： 10.1002/admi.202000636

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

The pore architecture of scaffolds is a critical factor for angiogenesis and bone regeneration. Although the effects of scaffold macropore size have been investigated, most scaffolds feature macropores with poor uniformity and interconnectivity, and other parameters (e.g., microporosity, chemical composition, and strut thickness) differ among scaffolds. To clarify the threshold of effective macropore size, we fabricated honeycomb scaffolds (HCSs) with distinct macropore (i.e., channel) sizes (~100, ~200, and ~300 μm). The HCSs were composed of AB-type carbonate apatite with ~8.5% carbonate ions, i.e., the same composition as human bone mineral. Their honeycomb architecture displayed uniformly sized and orderly arranged channels with extremely high interconnectivity, and all the HCSs displayed ~100-μm-thick struts and 0.06 cm3 g−1 of micropore volume. The compressive strengths of
HCSs with ~100-, ~200-, and ~300-μm channels were higher than those of reported scaffolds, and decreased with increasing channel size: 62 ± 6, 55 ± 9, and 43 ± 8 MPa, respectively. At four weeks after implantation in rabbit femur bone defects, new bone and blood vessels were formed in all the channels of these HCSs. Notably, the ~300-μm channels were extensively occupied by new bone. We demonstrated that high interconnectivity and uniformity of channels can decrease the threshold of effective macropore size, enabling the scaffolds to maintain high mechanical properties and osteogenic ability and serve as implants for weight-bearing areas.

DOI： https://doi.org/10.1016/j.msec.2020.110848

Repository Public URL： https://hdl.handle.net/2324/7360323

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1016/j.ceramint.2020.05.076

Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1016/j.ceramint.2020.04.094

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： https://doi.org/10.1021/acsabm.0c00060

Repository Public URL： https://hdl.handle.net/2324/7360322

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DOI： https://doi.org/10.3390/ma12233997

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Synthetic scaffolds exhibiting bone repair ability equal to that of autogenous bone are required in the fields of orthopedics and dentistry. A suitable synthetic bone graft substitute should induce osteogenic differentiation of mesenchymal stem cells, osteogenesis, and angiogenesis. In this study, three types of honeycomb blocks (HCBs), composed of hydroxyapatite (HAp), β-tricalcium phosphate (TCP), and carbonate apatite (CO3Ap), were fabricated, and the effects of HCB composition on bone formation and maturation were investigated. The HC structure was selected to promote cell penetration and tissue ingrowth. HAp and β-TCP HCBs were fabricated by extrusion molding followed by sintering. The CO3Ap HCBs were fabricated by extrusion molding followed by sintering and dissolution-precipitation reactions. These HCBs had similar macroporous structures: all harbored uniformly distributed macropores (∼160 ​μm) that were regularly arrayed and penetrated the blocks unidirectionally. Moreover, the volumes of macropores were nearly equal (∼0.15 ​cm3/g). The compressive strengths of CO3Ap, HAp, and β-TCP HCBs were 22.8 ​± ​3.5, 34.2 ​± ​3.3, and 24.4 ​± ​2.4 ​MPa, respectively. Owing to the honeycomb-type macroporous structure, the compressive strengths of these HCBs were higher than those of commercial scaffolds with intricate three-dimensional or unidirectional macroporous structure. Notably, bone maturation was markedly faster in CO3Ap HCB grafting than in β-TCP and HAp HCB grafting, and the mature bone area percentages for CO3Ap HCBs at postsurgery weeks 4 and 12 were 14.3- and 4.3-fold higher and 7.5- and 1.4-fold higher than those for HAp and β-TCP HCBs, respectively. The differences in bone maturation and formation were probably caused by the disparity in concentrations of calcium ions surrounding the HCBs, which were dictated by the inherent material resorption behavior and mechanism; generally, CO3Ap is resorbed only by osteoclastic resorption, HAp is not resorbed, and β-TCP is rapidly dissolved even in the absence of osteoclasts. Besides the composition, the microporous structure of HC struts, inevitably generated during the formation of HCBs of various compositions, may contribute to the differences in bone maturation and formation.

DOI： 10.1016/j.mtbio.2019.100031

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Magnetite-nanoparticle-containing red-blood-cell-like-microparticles (M-RBC-MPs) with a selective ability for trapping cortisol (COR) were synthesized by an electrospray technique of a molecularly imprinted ethyl(hydroxyethyl) cellulose (EHEC)-based precursor. The as-synthezied M-RBC-MPs were ∼3-μm-disks with a dent. MRBC-MPs contained magnetite nanoparticles below 15 nm in diameter, which exhibited magnetization and no room-temperature coercivity. The molecularly imprinted M-RBC-MPs (MI-M-RBC-MPs) passed through pores less than their diameter. The MI-M-RBC-MPs selectively trapped COR from a solution containing molecules similar to COR, whereas non-imprinted M-RBC-MPs did not trap COR. Furthermore, magnets were used to capture the water-dispersed MI-M-RBC-MPs flowing in a tube. Based on the above results, MI-M-RBC-MPs may selectively trap COR while simultaneously circulating in the blood, followed by their removal from the blood using magnets.

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Current therapeutic options for the treatment of liver fibrosis are limited, and transplantation is often the only effective option for end-stage fibrotic diseases. To overcome this problem, a nanoparticle-based treatment as an alternative to transplantation is developed. Multifunctional organic–inorganic hybrid hollow nanoparticles (HNPs) containing silibinin are synthesized by mixing precursors in ammonia water at 60 °C for 1 min. The HNPs are mainly composed of siloxanes and disulfides and have surface thiols. The disulfides are cleaved by intracellular glutathione and reduced to thiols, leading to the deformation of the HNPs. Silibinin molecules are released through the cracks formed by HNP deformation. Furthermore, the HNPs suppress the generation of hydroxyl radicals, a major cause of liver fibrosis, via sulfenylation reactions of HNP thiols. Retinol-modified HNPs target Kupffer cells and hepatic stellate cells, which are essential for hepatic fibrogenesis. The combined suppression of hydroxyl radical generation and release of silibinin using the HNPs decreases the proportion of fibrotic tissues and improves hepatic function. The therapeutic efficacy is greater than can be achieved by the suppression of hydroxyl radical generation alone and the injection of silibinin alone. Thus, HNPs are promising for the treatment of liver fibrosis.

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.biomaterials.2017.11.031

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DOI： 10.1002/adfm.201603394

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DOI： 10.1002/adfm.201504215

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DOI： 10.7150/thno.9199

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DOI： 10.1002/adfm.201301771

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DOI： 10.7150/thno.5860

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DOI： 10.1002/adhm.201200238

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/adfm.201200219

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Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/cm200826c

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1002/smll.201000399

Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/am100237p

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/cm100810g

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1021/cm803113e

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Event date： 2023.9

Language：Japanese  

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Event date： 2023.7

Language：Japanese  

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Event date： 2023.3

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Event date： 2022.11

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Event date： 2022.10

Language：English   Presentation type：Oral presentation (invited, special)  

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Event date： 2021.10

Language：Japanese  

Country：Japan  

Event date： 2021.10

Language：English  

Country：Japan  

Event date： 2021.9

Language：Japanese  

Country：Japan  

Event date： 2021.2

Language：English   Presentation type：Oral presentation (invited, special)  

Venue：Fukuoka   Country：Japan  

Event date： 2020.7

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：津   Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：塩尻   Country：Japan  

Event date： 2019.6

Language：Japanese  

Country：Japan  

Event date： 2019.6

Language：Japanese  

Country：Japan  

Event date： 2019.6

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2019.6

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2019.6

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2019.6

Language：Japanese  

Country：Japan  

Event date： 2019.6

Language：Japanese  

Country：Japan  

Event date： 2019.6

Language：English  

Country：Spain  

Event date： 2018.11

Language：Japanese  

Venue：神戸国際会議場   Country：Japan  

Event date： 2018.10

Language：Japanese  

Venue：Nagoya   Country：Japan  

Event date： 2018.9

Language：Japanese  

Venue：Maastricht   Country：Netherlands  

Event date： 2018.7

Language：Japanese  

Venue：London   Country：United Kingdom  

Event date： 2017.11

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2017.11

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2017.10

Language：English  

Venue：Fukuoka   Country：Japan  

Event date： 2017.9 - 2017.10

Language：English  

Venue：Nagoya   Country：Japan  

Event date： 2017.9

Language：Japanese  

Venue：京都   Country：Japan  

Event date： 2017.8

Language：Japanese  

Venue：大阪   Country：Japan  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

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Language：English  

Language：Japanese  

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Language：Japanese  

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Language：English  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)