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BACKGROUND/PURPOSE: The incidence rate of oral and pharyngeal cancers in Taiwan has increased gradually over the past few decades. The standard treatment strategy for oral and pharyngeal cancers includes surgery or radiotherapy, with concurrent chemotherapy in certain types of tumors. Unfortunately, in-field recurrence is sometimes inexorable. Furthermore, re-irradiation of the recurrence site may cause severe complications due to the tolerance of normal tissue to radiation therapy. One fatal complication is carotid blowout syndrome (CBS). Boron neutron capture therapy (BNCT) is a new modality of radiation therapy, which is also mentioned as targeted radiotherapy. It is a feasible treatment that has the potential to spare normal tissue from being damaged by irradiation while simultaneously treating the primary tumor. In this presentation, we will share our experience with BNCT in treating recurrent head and neck cancers, as well as the prevention and management of CBS. MATERIALS AND METHODS: We evaluated 4 patients with head and neck cancers treated by BNCT in Taiwan. All patients had undergone surgery previously and had received postoperative concurrent chemoradiotherapy. RESULTS: The 4 patients in this study were diagnosed with head and neck malignancies. The median follow-up period after the first course of BNCT was 15.1 months. After BNCT, 2 patients developed impending CBS, and 1 of them died. The remaining 3 patients survived until the last date of follow-up. CONCLUSION: Pre-BNCT carotid artery evaluation through computed tomography angiography and early intervention if necessary is crucial when treating patients with recurrent head and neck cancers by BNCT.

DOI： 10.1016/j.jds.2020.12.013

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Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.

DOI： 10.1016/j.jconrel.2020.11.001

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We have been studying the effectiveness of direct action, which induces clustered DNA damage leading to cell killing, relative to indirect action. Here a new criterion Direct Ation-Based Biological Effectiveness (DABBLE) is proposed to understand the contribution of direct action for cell killing induced by C ions. DABBLE is defined as the ratio of direct action to indirect action. To derive this ratio, we describe survival curves of mammalian cells as a function of the number of OH radicals produced 1 ps and 100 ns after irradiation, instead of the absorbed dose. By comparing values on the vertical axis of the survival curves at a certain number of OH radicals produced, we successfully discriminate the contribution of direct action induced by C ions from that of indirect action. DABBLE increases monotonically with increasing linear energy transfer (LET) up to 140 keV/μm and then drops, when the survival curves are described by the number of OH radicals 1 ps after irradiation. The trend of DABBLE is in agreement with that of relative biological effectiveness (RBE) of indirect action. In comparison, the value of DABBLE increases monotonically with LET, when the survival curves are described by the number of OH radicals 100 ns after irradiation. This finding implies that the effectiveness of C ion therapy for cancer depends on the contribution of direct action and we can follow the contribution of direct action over time in the chemical phase.

DOI： 10.1093/jrr/rraa111

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The purpose of this study is to assess accelerator-based boron neutron capture reaction (BNCR) in human tumor cell lines by colony formation assay and modified high density survival assay (HDS assay). The results of post irradiation survival rate in human oral squamous cell carcinoma and osteosarcoma using both assays were similar. Therefore, HDS assay would be efficient to evaluate BNCR in not only tumor cells but also in normal cells as BNCT screening.

DOI： 10.1016/j.apradiso.2020.109271

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Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.

DOI： 10.3390/cells9102149

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OBJECTIVE: This observational study on adult Taiwanese cadavers focused mainly on the intersection of buccal branches of the facial nerve with Stensen's duct, using the emergence of Stensen's duct as the reference landmark. MATERIALS AND METHODS: Thirty-five cadaveric hemifaces were included in our research. Samples with facial defects due to tumor, trauma, or surgery were all excluded. Buccal branches of the facial nerve were identified according to the Gray's Anatomy 40th edition definition. The distance was measured from the intersection to the emergence of Stensen's duct, running from the anterior border of the parotid gland. RESULTS: In the 35 hemifaces, the number of buccal branch/Stensen's duct intersections ranged from 1 to 5 (average 2.49 ± 1.15). Two-point intersections accounted for 37% (13 hemifaces) of the sample, forming the largest group. Samples of facial nerve buccal branches were divided into four types: Type 1, with two buccal branches, accounted for 37.15% (13/35); Type 2, with three buccal branches, made up 48.59% (17/35) of our samples - the biggest group (Type 2-a was the most frequent pattern among our samples, with two superior buccal branches and one inferior buccal branch, accounting for 34.31% of our samples); Type 3, with four buccal branches, accounted for only 5.7%. Three cases of double Stensen's duct were classified as Type 4, though this is supposed to be a very rare anatomical variation. With Type 2a, the most frequent pattern among our specimens, the distance from the emergence of the Stensen's duct to the emergence point of the first superior buccal branch along the anterior border of the parotid gland was 9.58 ± 5.68 mm. The distance from the emergence point to the emergence of the inferior buccal branch along the anterior border of the parotid gland was 11.03 ± 5.38 mm. The distance (D1) from Stensen's duct to the emergence of the first superiorly located buccal branch of the group Type 2-a was statistically different from the distance (D1) of the other groups (p = 0.02). No direct anastomoses or communicating fibers between upper and lower buccal branches were noted in 11 hemifaces (31%). CONCLUSION: The distribution of buccal branches was described using the emergence of Stensen's duct as a reference landmark. According to our observations, the relationship between the buccal branches and Stensen's duct was much more complicated than described in previous studies. This was the first study to investigate the complete distribution of buccal branches of the facial nerve emerging from the anterior of the parotid gland, and their relative locations and branching numbers.

DOI： 10.1016/j.jcms.2018.12.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：IOP PUBLISHING LTD  

We developed a thermal neutron source for performance tests of boron agents for Boron Neutron Capture Therapy (BNCT) at Neutron exposure Accelerator System for Biological Effect Experiments (NASBEE) in National Institute of Radiological Sciences, Japan. The thermal neutron flux at the experimental position was measured to be 2.18 x 10(8) n/cm(2)/s, the cadmium ratio was 9.21, and gamma ray dose ratewas 2.11 Gy/h. The neutron dose ratewas estimated to be 2.96 Gy/h. These values indicate that the neutron source can be applicable for tests of boron agents although application range is limited. An example of irradiation experiment is described.

DOI： 10.1088/1748-0221/14/06/T06010

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Tetrabone is a newly developed granular artificial bone. The 1-mm Tetrabone has a four-legged structure. In this study, the long-term effect of implanting Tetrabone or β-TCP granules in rabbit femoral cylindrical defects was evaluated. The rabbits were euthanized at 4, 13, and 26 weeks after implantation. Micro-CT was conducted to evaluate the residual material volume and the non-osseous tissue volume. New bone tissue areas were measured by histological analysis. Micro-CT imaging showed that the residual material volume in the β-TCP group had decreased significantly at 4 weeks after implantation (P < 0.05) and that the β-TCP granules had nearly disappeared at 26 weeks after implantation. In the Tetrabone group, it did not significantly change until 13 weeks after implantation; it then continued to decrease slightly until 26 weeks after implantation. The non-osseous volume increased in the β-TCP group, whereas that of the Tetrabone group decreased (P < 0.05). Histological examination showed that the new bone areas were significantly greater in the Tetrabone group than in the β-TCP group at 13 and 26 weeks. In conclusion, resorption of β-TCP granules occurs before sufficient bone formation, thereby allowing non-osseous tissue invasion. Tetrabone resorption progressed slowly while the new bone tissues were formed, thus allowing better healing. Tetrabone showed better osteoconductivity, whereas the β-TCP granules lost their function over a long duration. These results may be caused by the differences in the absorption rate of the granules, intergranular pore structure, and crystallinity of each granule.

DOI： 10.1007/s10047-014-0778-9

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Several biomaterials have been introduced for bone augmentation. However, information is lacking about the mechanisms of bone regeneration and/or integration of these materials in the recipient bone. This study aimed to determine the molecular and structural events in bone defects after augmentation with synthetic tetrapod-shaped calcium phosphate (Tetrabone; TetraB) compared with natural deproteinized bovine bone (DBB). Defects were created in the epiphyses of rat femurs and filled with TetraB or DBB or left empty (Sham). After 3, 6, 14 and 28 d, samples were harvested for histology, histomorphometry, ultrastructure and gene expression analyses. At 3 d, higher expressions of bone formation (ALP and OC) and remodeling (CatK) genes were detected in TetraB compared with DBB and Sham. Downregulation of bone remodeling genes (TRAP and CatK) was detected in DBB as compared to Sham after 14 d. Histomorphometry at 6 and 14 d demonstrated greater bone contact with the granules in TetraB. At 28 d, a larger bone area per defect was found in TetraB. The present experiments show that a synthetic substitute, consisting of α-tricalcium and octacalcium phosphates, induces early osteogenic and osteoclastic activities and promotes bone formation in trabecular bone defects.

DOI： 10.1016/j.biomaterials.2013.12.084

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Language：Japanese   Publisher：(株)エムイー振興協会  

ホウ素中性子捕捉療法(BNCT)は、腫瘍に集積するホウ素薬剤を患者に投与した後に中性子線を腫瘍に照射する。腫瘍内に集積したホウ素が中性子を捕捉してヘリウム原子核とリチウム原子核に分裂し、これらの粒子が粒子線として腫瘍内部から狭い範囲に照射される。原子炉でないと施行できなかった本治療を一般病院で利用できるように開発、治験が進められている。BNCTは、治療困難な悪性腫瘍の予後改善に寄与することが期待される。(著者抄録)

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In this study, we aimed to determine the effect of trehalose coating and the optimal dose of basic fibroblast growth factor (bFGF), an osteoinductive protein, loaded onto tailor-made bone implants for implant-induced bone formation in vivo. We fabricated tailor-made α-tricalcium phosphate bone implants (11 mm diameter with 2 parallel cylindrical holes). bFGF 0, 1, 10, 100 or 200 μg/implant was incorporated into implants with and without a trehalose coating, and these were subsequently implanted into dogs to correct temporal bone defects of the same size and shape. Four weeks after implantation, we analyzed the bone implants and surrounding tissues by using micro-computed tomography imaging and histological analyses, as well as gross evaluation. No significant difference in new bone formation was observed between implants with and without a trehalose coating at any of the bFGF doses. Bone implants with 100 and 200 μg bFGF showed significantly more new bone formation at the implant site and within the cylindrical holes of the implants than those without bFGF (P<0.05). However, heterotopic bone formation on the skull near the implant was observed in the group that received 200 μg bFGF. These results suggest that 100 μg bFGF is the optimal dose for this implant in dogs, and that the trehalose coating may not be necessary in vivo, probably due to the presence of blood proteins and electrolytes at the implant site.

DOI： 10.1292/jvms.12-0244

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We have developed a novel form of granular artificial bone "Tetrabones" with a homogeneous tetrapod shape and uniform size. Tetrabones are four armed structures that accumulate to form the intergranular pores that allow invasion of cells and blood vessels. In this study we evaluated the physicochemical characteristics of Tetrabones in vitro, and compared their biological and biomechanical properties in vivo to those of conventional β-tricalcium phosphate (β-TCP) granule artificial bone. Both the rupture strength and elastic modulus of Tetrabone particles were higher than those of β-TCP granules in vitro. The connectivity of intergranular pores 100, 300, and 400 μm in size were higher in Tetrabones than in the β-TCP granules. Tetrabones showed similar osteoconductivity and biomechanical stiffness to β-TCP at 2 months after implantation in an in vivo study of canine bone defects. These results suggest that Tetrabones may be a good bone graft material in bone reconstruction.

DOI： 10.1016/j.actbio.2012.02.019

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Language：English   Publishing type：Part of collection (book)   Publisher：Pan Stanford Publishing Pte. Ltd.  

The performance of the scaffolds holds a key to the realization of tissue engineering/regenerative medicine in clinical settings. We have focused on the vital role of the dimensional compatibility of the scaffolds. By controlling the three-dimensional (3D) shape of the scaffolds, we have significantly improved the performance of the artificial bones, which have good dimensional compatibility, resultant reduction in the operation time and corresponding invasiveness, and resultant speedy union with the host bone tissues. We conclude that 3D shape control is vital to the performance of the scaffolds.We propose that it is worth considering at least once to attempt to control the 3D shape of the scaffold by optimizing the design and fabrication method, before using expensive and highrisk growth factors and cells. © 2012 Pan Stanford Publishing Pte. Ltd. All rights reserved.

DOI： 10.4032/9789814267861

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC VET SCI  

Artificial bone implants are often incorporated with osteoinductive factors to facilitate early bone regeneration. Calcium phosphate, the main component in artificial bone implants, strongly binds these factors, and in a few cases, the incorporated proteins are not released from the implant under conditions of physiological pH, thereby leading to reduction in their osteoinductivity. In this study, we coated tailor-made bone implants with trehalose to facilitate the release of basic fibroblast growth factor (bFGF). In an in vitro study, mouse osteoblastic cells were separately cultured for 48 hr in a medium with a untreated implant (T-), trehalose-coated implant (T+), bFGF-incorporated implant (FT-), and bFGF-incorporated implant with trehalose coating (FT+). In the FT+ group, cell viability was significantly higher than that in the other groups (P<0.05). Scanning electron microscopy (SEM) and X-ray diffraction (XRD) revealed that trehalose effectively covered the surface of the artificial bone implant without affecting the crystallinity or the mechanical strength of the artificial bone implant. These results suggest that coating artificial bone implants with trehalose could limit the binding of bFGF to calcium phosphate.

DOI： 10.1292/jvms.11-0016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

To effectively treat degenerative joint diseases including osteoarthritis (OA), small chemical compounds need to be developed that can potently induce chondrogenic differentiation without promoting terminal differentiation. For this purpose, we screened natural and synthetic compound libraries using a Col2GFP-ATDC5 system and identified oxytetracycline (Oxy) as a chondrogenic compound. Oxy induced cartilaginous matrix synthesis and mRNA expressions of chondrocyte markers in ATDC5 cells. In addition, Oxy suppressed mineralization and mRNA expressions of terminal chondrocyte differentiation markers in ATDC5 cells, primary chondrocytes, and cultured metatarsal bones. Oxy's induction of Col2 mRNA expression was decreased by the addition of Noggin and was increased by the addition of BMP2. Furthermore, Oxy increased mRNA expression of Id1, Bmp2, Bmp4, and Bmp6. These data suggest that Oxy induces chondrogenic differentiation in a BMP-dependent manner and suppresses terminal differentiation. Oxy may be useful for treatment of OA and also for regeneration of cartilage tissue.

DOI： 10.1007/s00774-010-0179-y

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：MEDIMOND S R L  

The objectives of this article are to describe a modified lateral approach for procuring cancellous bone graft from the proximal tibia. 80 consecutive jaw reconstruction utilizing tibial cancellous bone grafts in 78 patients from March 1998 through March 2008 were reviewed. Patient group consisted of 45 males and 33 females, aged 18 to 76. Unlike the traditional U-shaped trap door incision on the iliotibial tract, our curvilinear incision was made almost parallel to the fibers of that tract. Only mild complications were observed at donor sites. The average procured graft volume was 17.8 ml. We also presented the first case of reconstructing mandibular continuity defects of up to 6 similar to 7 cm lengthwise by tibial cancellous bone grafting. The modified incision on iliotibial tract allowed access to obtain equally good amount of bone volume from lateral aspect of proximal tibia and it rendered wound closure much easier than the procuring techniques described earlier in the literatures.

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BACKGROUND: Bone and cartilage act as reservoirs for a number of elements, and the perturbation of these elements is suggested to contribute to various diseases. Even so, little is known about their respective temporal and spatial distribution. METHODS: Three knee joints of three mice on the first day after birth, three knee joints of 3-week-old mice, and three knee joints of 20-week-old mice were prepared. We performed element mapping in the bone and cartilage of normal mouse knee joints. We measured element distribution in articular cartilage, trabecular bone, cortical bone, joint cartilage, growth plates, and joint cavities using energy dispersive X-ray spectrometry. RESULTS: The analysis revealed the following: (1) The main elements in articular cartilage of 1-day-old mice were Na, O, P, S, and Ca; and those in bone were Na, O, P, S, K, Ca, and Mg. (2) The main elements in the growth plate of 3-week-old mice were Na, N, O, P, S, Cl, K, and Ca; those in joint cartilage were Na, O, P, S, Cl, and K; and those in bone were Na, O, P, Ca, and Mg. (3) The main elements in the growth plate of 20-week-old mice were Na, O, P, S, Cl, K, and Ca; and those in bone were Na, O, P, S, K, Ca, and Mg. After corrections were made for the Na ratios of these elements, we investigated the temporal and spatial changes in the distribution of each element. On the first day after birth, a spatial change was seen in the growth plate cartilage: the more the cartilage matured toward hypertrophy, the more S and Ca it contained. Temporal changes in element distribution in the growth plate cartilage, articular cartilage, and bone were observed. Growth plate cartilage of the older mice contained more S and Ca than that of the younger mice. Bone of the older mice contained more Ca and Mg than that of the younger mice. Spatial changes in element distribution in the cortical bone were also seen; that is, the more the cortical bone matured toward diaphysis, the more Mg and the less S it contained. In contrast, no temporal or spatial changes in element distribution were observed in the joint space. No significant temporal or spatial changes in the distribution of P, Cl, or K were seen. CONCLUSIONS: These results suggest that element mapping may be useful for identifying the age and maturity of different skeletal tissues. In particular, it may help distinguish between immature cartilage and mature cartilage based on the Ca and S contents.

DOI： 10.1007/s00776-008-1315-6

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Ideally, artificial bones should be dimensionally compatible with deformities, and be biodegradable and osteoconductive; however, there are no artificial bones developed to date that satisfy these requirements. We fabricated novel custom-made artificial bones from alpha-tricalcium phosphate powder using an inkjet printer and implanted them in ten patients with maxillofacial deformities. The artificial bones had dimensional compatibility in all the patients. The operation time was reduced due to minimal need for size adjustment and fixing manipulation. The postsurgical computed tomography analysis detected partial union between the artificial bones and host bone tissues. There were no serious adverse reactions. These findings provide support for further clinical studies of the inkjet-printed custom-made artificial bones.

DOI： 10.1007/s10047-009-0462-7

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A new tailor-made bone implant (TI) with six horizontal cylindrical holes fabricated from alpha-tricalcium phosphate powder, as described in our previous report, was modified to include five additional vertical holes (TI-v) in an attempt to accelerate the bone regeneration through the holes. This TI-v implant and hydroxyapatite implants (HI) as controls were transplanted into experimental skull defects in dogs. Computed tomography (CT) was performed immediately after the surgery and then every 4 weeks. The dogs were killed for histological analysis at 24 weeks of implantation. On CT, bone bridging between the implant and the skull was observed in the TI-v group from 8 weeks of implantation, whereas a clear bone bridge was not formed in the HI group after 24 weeks of implantation. Histological analysis revealed collagen tissues and new bone formation in the horizontal cylindrical holes in most of the TI-v group, whereas mainly connective tissues invaded the porous structures in the HI group. In the Ti-v group, at the middle of the horizontal holes where they crossed the vertical holes, fibrous collagen tissues and muscular tissue filled up the hole and new bone formation seemed to be blocked. However, in the TI-v group more collagen and bone tissues were formed than in the HI group; when compared with the data in our previous report, however, the total volume of regenerated bone in the horizontal cylindrical holes in the TI-v seemed to be less than that in the TI. Thus, the addition of vertical cylindrical holes in the TI-v was not effective in promoting the faster stabilization of the TI-v in the skull of the dog.

DOI： 10.1007/s10047-009-0474-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

To effectively treat osteoporosis and other bone-loss disorders, small compounds that potently induce bone formation are needed. The present study initially attempted to establish a monitoring system that could detect osteogenic differentiation easily, precisely, and noninvasively. For this purpose, we established pre-osteoblastic MC3T3E1 cells stably transfected with the GFP reporter gene driven by a 2.3 kb fragment of rat type I collagen promoter (Col1a1GFP-MC3T3E1). Among these cells, we selected a clone that fluoresced upon osteogenic stimulation by BMP2. The GFP fluorescence intensity corresponded well to the intensity of alkaline phosphatase (ALP) staining and to the level of osteocalcin (Oc) mRNA. Using this system, we screened natural and synthetic compound libraries and thus identified an isoflavone derivative, glabrisoflavone (GI). GI induced ALP staining and Oc mRNA in a dose-dependent manner. The Col1a1GFP-MC3T3E1 system may be useful for identifying novel osteogenic drugs.

DOI： 10.1016/j.bbrc.2008.08.167

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In this work, we demonstrated that biological cells could be cultured in a continuous-perfusion glass microchip system for drug screening. We used mouse Col1a1GFP MC-3T3 E1 osteoblastic cells, which have a marker gene system expressing green fluorescent protein (GFP) under the control of osteoblast-specific promoters. With our microchip-based cell culture system, we realized automated long-term monitoring of cells and sampling of the culture supernatant system for osteoblast differentiation assay using a small number of cells. The system successfully monitored cells for 10 days. Under the 3D microchannel condition, shear stress (0.07 dyne/cm(2) at a flow rate of 0.2 microL/min) was applied to the cells and it enhanced the GFP expression and differentiation of the osteoblasts. Analysis of alkaline phosphatase (ALP), which is an enzyme marker of osteoblasts, supported the results of GFP expression. In the case of differentiation medium containing bone morphogenetic protein 2, we found that ALP activity in the culture supernatant was enhanced 10 times in the microchannel compared with the static condition in 48-well dishes. A combined system of a microchip and a cell-based sensor might allow us to monitor osteogenic differentiation easily, precisely, and noninvasively. Our system can be applied in high-throughput drug screening assay for discovering osteogenic compounds.

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

Although current treatment modalities for bone defects include autograft, allograft, and artificial bone substitutes, they have problems concerning invasiveness, safety, and performance, respectively, calling for development of innovative artificial bones with better handling and mechanical strength, better control of external and internal structures, and better biodegradability and osteo-inductive ability. We propose to fabricate novel high performance artificial bones using 3D inkjet printer based on the image data of bone deformity. Shape precisely fitting to the deformity, internal structure facilitating cell invasion, and good biodegradability are achieved. Bioactive substances can be incorporated by printing in combination with drug delivery system to induce bone regeneration at desired locations. These osteo-inductive artificial bones will help efficiently treat various types of bone deformity in a less invasive and safe manner.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

Hard tissue reconstruction is very useful for bony defects of the maxillofacial region. Autogenous bone, allogeneic bone, and artificial bone have been used to reconstruct maxillofacial bone; however, the use of autogenous bone involves high surgical invasiveness because of the need to harvest the bone. The use of allogeneic bone is associated with infections, raises ethical concerns, and is not widely used in Japan. Artificial bone has several advantages, including no need for bone harvesting, excellent biocompatibility, and a relatively easy surgical procedure. Use of artificial bone avoids the much greater invasiveness of harvesting bone, and several types of artificial bone have been developed. Design requirements for artificial bone include surgical manipulability, structural compatibility with the defective area, support properties, and the ability to induce bone regeneration; however, no artificial bone meeting all these requirements has yet been developed. Artificial bone is used in many patients in our medical center, and we have been active in developing the next generation of artificial bone with better properties. In this article, we present a case history and discuss the future development of artificial bone for use in maxillofacial reconstruction.

DOI： 10.1007/s10047-008-0425-4

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2008&ichushi_jid=J01205&link_issn=&doc_id=20080422220001&doc_link_id=40016023678&url=http%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F40016023678&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

To effectively treat serious bone defects using bone regenerative medicine, there is a need for the development of a small chemical compound that potently induces bone formation. We now report a novel osteogenic helioxanthin-derivative, TH. TH induced osteogenic differentiation in MC3T3-E1 cells, mouse primary osteoblasts, and mouse embryonic stem cells. The combination of TH and bone morphogenetic protein (BMP) 2 induced the mRNA expression of osteoblast marker genes and calcification in primary fibroblasts. The TH induced the mRNA of the inhibitor of DNA-binding 1 (Id-1), and its osteogenic effect was inhibited by Smad6 or Noggin. Furthermore, TH induced the mRNA expression of Bmp4 and Bmp6. These data suggest that TH exerts its potent osteogenic effect in a BMP-dependent manner by enhancing the effects of the existing BMPs and/or increasing the expression of Bmp4 and Bmp6. TH may help establish a more efficient bone regeneration system.

DOI： 10.1016/j.bbrc.2007.03.173

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(一社)日本人工臓器学会  

頭蓋顎顔面骨における骨再建に対して、より良い人工骨を求めて次世代人工骨の開発に取り組んだ。18歳女。汎発性強皮症に伴う顔面変形を主訴で受診した。顔面は非対称性で、右側の中〜下顔面に陥凹を認めた。術後における脂肪組織の下垂や二次変形、女性における採取部の傷を避けることなどを考慮し、硬組織再建を選択した。すなわち陥凹部にカスタムメイド人工骨を移植することにより硬組織を再建し、顔貌の改善を図った。人工骨の作製には3次元造形モデルを応用した。術後3ヵ月経過した3次元CT画像では人工骨の位置のズレは認めず、顔貌形態についても満足した形態が得られた。さらに、術後6ヵ月経過した現在、大きな合併症を併発することなく経過している。

DOI： 10.11392/jsao1972.36.113

J-GLOBAL

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2007&ichushi_jid=J00706&link_issn=&doc_id=20070717290015&doc_link_id=10.11392%2Fjsao1972.36.113&url=https%3A%2F%2Fdoi.org%2F10.11392%2Fjsao1972.36.113&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

FK506 is an immunosuppressant that exerts effects by binding to FK506-binding protein 12 (FKBP12). Recently, FK506 has also been reported to promote osteogenic differentiation when administered locally or in vitro in combination with bone morphogenetic proteins (BMPs), although the underlying mechanism remains unclarified. The present study initially showed that FK506 alone at a higher concentration (1 mu M) induced osteogenic differentiation of mesenchymal cell lines, which was suppressed by adenoviral introduction of Smad6. FK506 rapidly activates the BMP-dependent Smads in the absence of BMPs, and the activation was blocked by Smad6. Overexpression of FKBP 12, which was reported to block the ligand-independent activation of BMP type I receptor A (BMPRIA), suppressed Smad signaling induced by FK506, but not that induced by BMP2. BMPRIA and FKBP12 bound to each other, and this binding was suppressed by FK506. These data suggest that FK506 promotes osteogenic differentiation by activating BMP receptors through interacting with FKBP12. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.10.024

Web of Science

PubMed

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Language：Japanese  

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Language：Japanese   Publisher：(公社)日本医学放射線学会  

J-GLOBAL

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J-GLOBAL

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(公社)日本獣医学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese   Publisher：(公社)日本獣医学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC BONE & MINERAL RES  

Web of Science

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Language：English  

Rapid prototyping (RP) is a molding technique that builds a three-dimensional (3D) model from computer-aided design (CAD) data. We fabricated new tailor-made bone implants (TIs) from α-tricalcium phosphate powder using an RP ink-jet printer based on computed tomography (CT) data, and evaluated their safety and efficacy. CT data of the skulls of seven beagle dogs were obtained and converted to CAD data, and bone defects were virtually made in the skull bilaterally. TIs were designed to fit the defects and were fabricated using the 3D ink-jet printer with six horizontal cylindrical holes running through the implants, designed for possible facilitation of vascular invasion and bone regeneration. As a control, hydroxyapatite implants (HIs) were cut manually from porous hydroxyapatite blocks. Then, craniectomy was performed to create real skull defects, and TIs and HIs were implanted. After implantation, CT was performed regularly, and the animals were euthanized at 24 weeks. No major side effects were observed. CT analysis showed narrowing of the cylindrical holes
bony bridging between the implants and the temporal bone was observed only for TIs. Histological analysis revealed substantial new bone formation inside the cylindrical holes in the TIs, while mainly connective tissues invaded the porous structures in HIs. Bone marrow was observed only in TIs. Osteoclasts were seen to resorb regenerated bone from inside the cylindrical holes and to invade and probably resorb the TIs. These data suggest that TIs are a safe and effective bone substitute, possessing osteoconductivity comparable with that of HIs. © 2006 The Japanese Society for Artificial Organs.

DOI： 10.1007/s10047-006-0347-y

Scopus

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CiNii Article

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本形成外科学会  

今回,われわれは顎顔面手術症例に対して,積層造形法による三次元モデルを用いて手術シミュレーションを行い,その有用性を確認したので報告する.まず,術前のCTデータをStandard Template Library(STL)データとして出力し,これをインクジェット三次元プリンターに入力して,三次元モデルを作製し,このモデルをもとに手術シミュレーションを行い,手術時間の短縮を図ることができた.従来型の光造形モデルはプラスチック製であったために,その切削は生体骨での感触とかけ離れており,非常に労力を要するものであった.また,モデルの作製に費用と時間を費やした.本モデルはワックスコーティングした石膏でできており,生体骨の感触に近い切削が可能で,安価かつ短時間でのモデルの作製が可能であった.しかしながら,現在のところ厳密な咬合を再現した造形モデルの作製は依然としてむずかしいため今後の課題とされた(著者抄録)

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Language：Japanese   Publisher：The Japan Geriatrics Society  

Regenerative medicine, which takes advantage of the unique capacity of stem cells, is a novel medical strategy to cure irreversible organ failure. There are three important elements in regenerative medicine: cells, scaffolds and signals. Although substantial progress regarding each element has been made in the past few years, it still falls short of clinical applications. In the geriatric field, osteoporosis, osteoarthritis and periodontitis are the major targets of regenerative medicine. They are usually not life-threatening, but often severely affect QOL of elderly patients. Since elderly people have already reduced number of stem cells in bone and cartilage, we need to know the sufficient conditions for osteogenesis and chondrogenesis by comprehensively screening various conditions. We developed a marker gene system expressing green fluorescence protein (GFP) under the control of osteoblast- and chondrocyte-specific promoters. This system helps us monitor osteoblast and chondrocyte differentiation easily, precisely and non-invasively. Using this system, we are now trying to find the sufficient conditions for osteogenesis and chondrogenesis, and to discover osteogenic and chondrogenic small compounds.

DOI： 10.3143/geriatrics.41.582

PubMed

CiNii Article

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