Papers by Author: Mamoru Aizawa

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Authors: Michiyo Honda, Toshiisa Konishi, Minori Mizumoto, Mamoru Aizawa
Abstract: Cancers frequently metastasize to bone, where it leads to secondary tumor growth, and osteolytic bone degradation. Bone metastases are often associated with fractures and severe pain resulting in decreased quality of life. Accordingly, effective therapies to inhibit the development or progression of bone metastases will have important clinical benefits. Bone cement, one of the powerful tools as bone substitutes, is used to fill the resection voids. The aim of this study was to develop a local drug delivery system using HAp cement as a carrier of chemotherapeutic agents. In the present study, we have fabricated chelate-setting apatite cements (IP6-HAp cements) using HAp particles surface-modified with inositol hexaphosphate (IP6) and evaluated their anti-tumor effect. Human osteosarcoma (HOS) cultured on IP6-HAp cements (over 3000 ppm IP6) resulted in inhibition of cell growth. DNA microarray analysis indicated changes in the expression of apoptosis-related genes on IP6-HAp cement surface-modified with 5000 ppm IP6 compared with HAp cement, suggesting activation of apoptosis machinery by IP6-HAp cement. To clarify the mechanism of anti-tumor effect of IP6-HAp cement, the properties of cement were investigated. The release kinetics of IP6 from IP6-HAp cement showed that the level of released IP6 was insufficient to induce anti-tumor activity. These results led us to consider that locally high concentration of IP6 which was released from cement acts on the cells directly as anti-tumor agent and induces the apoptosis. Consequently, IP6-HAp cement might gain the anti-tumor effect and act as a carrier for local drug delivery system.
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Authors: Yusuke Nakashima, Michiyo Honda, Toshiisa Konishi, Minori Mizumoto, Mamoru Aizawa
Abstract: In our previous study, silicon-containing hydroxyapatite (Si-HAp) powder was prepared via an aqueous precipitation reaction. The Si-HAp powders were synthesized with desired Si contents (0, 0.4, 0.8, 1.6, and 2.4 mass%) as a nominal composition. Another previous study in our group demonstrated surface-modification of HAp powder with inositol phosphate (IP6) enhanced the compressive strength of apatite cement. Thus, to fabricate the cements with higher bioactivity, the above Si-HAp powders were surface-modified with IP6 (IP6-Si-HAp). The IP6-Si-HAp cements with various Si contents were fabricated by mixing with pure water at the powder/liquid ratio of 1/0.4 [w/v]. In order to clarify biocompatibility of the IP6-Si-HAP cements in the present work, MC3T3-E1 cells as a model of osteoblast were seeded on the cement specimens. As for the numbers of cells cultured on the IP6-Si-HAp cements, the substitution of lower levels of Si into HAp lattice did not greatly influence the cell proliferation. However, the substitution of Si amount over 0.8 mass% enhanced the cell proliferation. Especially, the IP6-Si-HAp cement with the Si content of 2.4 mass% showed excellent cell proliferation among examined specimens. Therefore, to fabricate the cements with higher bioactivity, it is necessary to control the amount of Si in the IP6-Si-HAp cements. The usage of these IP6-Si-HAp cements may make it possible to fabricate the cements with higher bioactivity, compare to conventional pure HAp cements.
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Authors: Y. Kinoshita, S.M. Best, Mamoru Aizawa
Abstract: The aim of the present investigation was to examine Si release from the silicon-containing apatite fiber scaffold (Si-AFS) and the biocompatibility of the Si-AFS. We have successfully synthesized silicon-containing apatite fibers (Si-AF) by a homogenous precipitation method. Three-dimensional Si-AFS were fabricated using these Si-AFs. The concentrations of Si in the starting solution were 0 (AF) and 0.8 (0.8Si-AF) mass%. The 0.8Si-AFS1000 were fabricated by firing Si-AF slurry compacts (carbon/Si-AF [w/ ratio: 10/1) at 1300 °C for 5 h. Solubility experiments were carried out in 0.05 mol/dm3 Tris-HCl buffer solutions at pH 7.30 using 0.8Si-AFS1000 (porosity: ~98%), together with Si-free AFS1000 (~98%) for 21 days. The Ca2+, PO43- and SiO44- concentrations in the solution were determined by inductively-coupled plasma atomic emission spectrometry (ICP-AES). The biocompatibility of the Si-AFS was examined in vitro using osteoblastic cell, MC3T3-E1 for 21 days. The results of the ICP-AES analysis indicated that the amount of SiO44- ions released from 0.8Si-AFS1000 rapidly increased at 1 day, and then the released SiO44- ions remained constant over a period for 21 days. The cells seeded on/in the 0.8Si-AFS1000 well-proliferated as compared to those on/in the AFS1000. Consequently, we can conclude that the 0.8Si-AFS offers as a potential novel scaffold material, creating a three-dimensional cell culture environment.
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Authors: Mamoru Aizawa, Yuki Chibu, Kohei Nagata, Toshiisa Konishi, Ken Ishii, Haruki Funao, Yoshiaki Toyama, Morio Matsumoto, Michiyo Honda
Abstract: Hydroxyapatite (HAp) is one of components of bone and teeth, and has an osteoconductivity. Thus, the HAp has been used as biomaterials for bone graftings. We have succeeded in development of the novel chelate-setting calcium-phosphate cement (CPC) using pure HAp particles surface-modified with inositol phosphate (IP6). While, biological apatite presented in bone and teeth of mammals contains various ions: Na+, K+, Mg2+, Cl-, F- and CO32-, in addition to Ca2+ and PO43- ions. In this work, in order to create the chelate-setting CPC with enhanced osteoconductivity, the above-mentioned biological apatite powder (hereafter, bone HAp), instead of pure HAp, was used as a starting powder for fabrication of the chelate-setting cement. The biocompatibility of the resulting chelate-setting bone HAp cement (hereafter, IP6-bone HAp cement) was examined using a rabbit’s tibia model. When the living reaction to hard tissue was histologically examined after 4 weeks implantation, we could observe that newly-formed bone directly bonded to the surface of the specimen. The newly-formed bone was also present around the cement specimen. The amounts of newly-formed bone around IP6-bone HAp cement was about 1.5 times those around IP6-pure HAp cement without bone minerals. The above findings demonstrate that the present IP6-bone HAp cements are one of the promising candidates as novel CPC with enhanced osteoconductivity.
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Authors: Akimitsu Miyazaki, Mamoru Aizawa
Abstract: There are two crystal planes in hydroxyapatite (Ca10(PO4)6(OH)2; HAp) that is clinically applied to artificial bone or dental root. The two crystal planes, a- and c-planes, are anisotropy. We have successfully fabricated dense HAp ceramics with preferred orientation to a-plane from single-crystal apatite fibers (AF) and apatite gels (AG). We examined the cellular response, such as adhesion, proliferation and morphology, of orthoclastic MC3T3-E1 cells, to the surface of the HAp ceramics with preferred orientation to a-plane. The initial cell attachment efficiency of the HAp ceramics with a-plane was lower than that of isotropic HAp ceramics as a control. This may be due to the difference of surface potential of the examined HAp ceramics. The proliferation of cells cultured on the HAp ceramics with a-plane was almost the same as that of isotropic HAp one.
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Authors: Toshiisa Konishi, Minori Mizumoto, Michiyo Honda, Mamoru Aizawa
Abstract: We have previously developed hydroxyapatite (HAp) cement based on the chelate-setting mechanism of sodium inositol hexaphosphate (IP6), in which HAp powder was prepared by surface-modification with IP6 after ball-milling of the HAp powder (conventional process). Meanwhile, we have recently established novel powder preparation process (modified process). In the present study, the adsorption behavior of IP6 on the surface of HAp at both the processes was circumstantially examined to clarify the chelating mechanism of IP6. The adsorbed amount of IP6 increased with the IP6 concentration in both the processes; however, the adsorbed amount of IP6 at the modified process was lower than that at the conventional process. X-ray photoelectron spectroscopic study revealed that the IP6 adsorbed on the surface of HAp powders. The degree in dispersion of the HAp particles at the modified process was higher than that at conventional process. Furthermore, the elution of IP6 from the powders prepared at the novel process was lower than that of the powders at the conventional process.
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Authors: Hide Ishii, Yuya Mukai, Mamoru Aizawa, Nobuyuki Kanzawa
Abstract: Heart disease is the second most common cause of mortality in Japan. Most cases of late stage heart failure can only be effectively treated by a heart transplant. Cardiac tissue engineering is emerging both as a new approach for improving the treatment of heart failure and for developing new cardiac drugs. Apatite-fiber scaffold (AFS) was originally designed as a substitute material for bone. AFS contains two sizes of pores and is appropriate for the three dimensional proliferation and differentiation of osteoblasts. To establish engineered heart tissue, a pluripotent embryonal carcinoma cell line, P19.CL6, was cultured in AFS. P19.CL6 cells seeded into AFS proliferated well. Generally, cardiac differentiation of P19.CL6 cells is induced by treating suspension-cultured cells with dimethyl sulfoxide (DMSO), after which the cells form spheroids. However, our results showed that P19.CL6 cells cultured in AFS differentiated into myocytes without forming spheroidal aggregates, and could be cultured for at least one month. Thus, we conclude that AFS is a good candidate as a scaffold for cardiac tissue engineering.
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Authors: Mamoru Aizawa, Toshiki Ohno, N. Kanomata, K. Yano, M. Emoto
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Authors: Hidenori Konishi, Michiyo Honda, Mamoru Aizawa, Nobuyuki Kanzawa
Abstract: The anti-tumor activity of hydroxyapatite (HAp) cements, which had been developed using a novel setting mechanism termed chelate bonding, against the human osteosarcoma cell line (HOS) and rat bone marrow stromal cells (BMSC) was examined. We aimed to understand the mechanism of the anti-tumor activity of the cement, thereby facilitating improvement of its biological activity. HAp powders were surface-modified with three different concentrations of inositol hexaphosphate (IP6), which were then used to fabricate three different IP6-HAp cements. The amount of IP6 that was bound to the HAp powder, and the amount that was released from the HAp cement, was measured for each sample. Approximately 1/200 to 1/1600 of the bound IP6 was released into the culture medium by day 4. Surface-modification of HAp with high concentration of IP6 inhibits the proliferation of both HOS cells and BMSCs, and appears to induce their apoptotic cell death. HOS cells were slightly more sensitive to IP6 than BMSCs. Thus, novel, chelate-bonded HAp cements are a candidate bone substitution material that exhibit anti-tumor activity.
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Authors: K. Kida, Y. Horiguchi, Kazuya Oribe, H. Morisue, Morio Matsumoto, Y. Toyama, Mamoru Aizawa
Abstract: We have successfully developed novel “chelate-setting apatite cement” using hydroxyapatite (HAp) particles surface-modified with inositol phosphate (IP6) . The HAp particles surface-modified with IP6 were mixed with water (HAp/water ratio = 1.00/0.50[w/w]) to fabricate apatite cements. We have examined the biocompatibility of the apatite cement using the culture system of MC3T3-E1 cells and the rabbit model. The cell-culture test using MC3T3-E1 cells has shown that the apatite cement has noncytotoxicity. This cement has been implanted into tibiae of rabbits. When tissue response was examined histologically up to 24 weeks, new bone formation was observed around the surface of the cement. The present work demonstrates that this apatite cement is useful as a material for artificial bone grafting.
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