Teru Okitsu

The University of Tokyo, Tōkyō, Japan

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Publications (132)533.6 Total impact

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    ABSTRACT: An implantable glucose monitoring device based on a CMOS line sensor combined with a glucose-responsive fluorescent hydrogel is developed. An implantable glucose monitoring device with sufficient sensitivity and response time is realised, which is an improvement over the authors' previous proof-of-concept device. A reduction of the sensor size made the device diameter injectable with a commercially available 16-gauge syringe needle. The sensor's performance was confirmed through both in vitro and in vivo experiments.
    Electronics Letters 05/2015; 51(10). DOI:10.1049/el.2015.0612 · 0.93 Impact Factor
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    ABSTRACT: The proper functioning of many organs and tissues containing smooth muscles greatly depends on the intricate organization of the smooth muscle cells oriented in appropriate directions. Consequently controlling the cellular orientation in three-dimensional (3D) cellular constructs is an important issue in engineering tissues of smooth muscles. However, the ability to precisely control the cellular orientation at the microscale cannot be achieved by various commonly used 3D tissue engineering building blocks such as spheroids. This paper presents the formation of coiled spring-shaped 3D cellular constructs containing circumferentially oriented smooth muscle-like cells differentiated from dedifferentiated fat (DFAT) cells. By using the cell fiber technology, DFAT cells suspended in a mixture of extracellular proteins possessing an optimized stiffness were encapsulated in the core region of alginate shell microfibers and uniformly aligned to the longitudinal direction. Upon differentiation induction to the smooth muscle lineage, DFAT cell fibers self-assembled to coiled spring structures where the cells became circumferentially oriented. By changing the initial core-shell microfiber diameter, we demonstrated that the spring pitch and diameter could be controlled. 21 days after differentiation induction, the cell fibers contained high percentages of ASMA-positive and calponin-positive cells. Our technology to create these smooth muscle-like spring constructs enabled precise control of cellular alignment and orientation in 3D. These constructs can further serve as tissue engineering building blocks for larger organs and cellular implants used in clinical treatments.
    PLoS ONE 03/2015; 10(3):e0119010. DOI:10.1371/journal.pone.0119010 · 3.23 Impact Factor
  • K. Ikeda · T. Okitsu · H. Onoe · S. Takeuchi ·
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    ABSTRACT: This paper reports the culturing and expansion of mouse induced pluripotent stem cells (iPSCs) in hydrogel core-shell microfibers; the core consists of iPSCs with or without extracellular matrix (ECM) proteins, and the shell is composed of calcium alginate. We revealed that mouse iPSCs cultured in the micro-scale space with ECM proteins sustain their pluriotency efficiently. This 3D culture system may be a useful tool to expand iPSCs for clinical use.
    Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS) 02/2015; 2015:463-464. DOI:10.1109/MEMSYS.2015.7050990
  • A.Y. Hsiao · T. Okitsu · S. Takeuchi ·
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    ABSTRACT: This paper describes the construction and differentiation of human adipose-derived stem cell (ADSC) fibers into the adipocyte lineage for breast reconstruction. Human ADSCs were encapsulated into the core region of hydrogel core-shell fibers by the cell fiber technology [1], induced for adipogenic differentiation, and maintained for over 2 months. After adipogenic induction, accumulation of lipid droplets of significant size was observed in the cells, and viability assay showed that most of the cells were alive. These findings suggest the use of ADSC fibers as a promising approach for breast reconstruction.
    Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS) 02/2015; 2015:643-645. DOI:10.1109/MEMSYS.2015.7051038
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    ABSTRACT: A CMOS image sensor-based implantable glucose sensor based on an optical-sensing scheme is proposed and experimentally verified. A glucose-responsive fluorescent hydrogel is used as the mediator in the measurement scheme. The wired implantable glucose sensor was realized by integrating a CMOS image sensor, hydrogel, UV light emitting diodes, and an optical filter on a flexible polyimide substrate. Feasibility of the glucose sensor was verified by both in vitro and in vivo experiments.
    Biomedical Optics Express 11/2014; 5(11). DOI:10.1364/BOE.5.003859 · 3.65 Impact Factor
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    ABSTRACT: In living tissues, a cell is exposed to chemical substances delivered partially to its surface. Such a heterogeneous chemical environment potentially induces cell polarity. To evaluate this effect, we developed a microfluidic device that realizes spatially confined delivery of chemical substances at subcellular resolution. Our microfluidic device allows simple setup and stable operation for over 4 h to deliver chemicals partially to a single cell. Using the device, we showed that subcellular glucose exposure triggers an intracellular [Ca(2+)] change in the β-cells. In addition, the imaging of a cell expressing GFP-tagged insulin showed that continuous subcellular exposure to glucose biased the spatial distribution of insulin granules toward the site where the glucose was delivered. Our approach illustrates an experimental technique that will be applicable to many biological experiments for imaging the response to subcellular chemical exposure and will also provide new insights about the development of polarity of β-cells.
    Scientific Reports 02/2014; 4:4123. DOI:10.1038/srep04123 · 5.58 Impact Factor
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    ABSTRACT: After producing α1-3galactosyltransferase knockout (GT-KO) pigs, most of the organs of these pigs showed less antigenicity to the human body. However, wild-type adult pig islets (API) that originally contained negligible levels of α-Gal, now showed a clear antigenicity to human serum. In this study, N-glycans were isolated from both APIs & human islets. Their structures were then analyzed by a mapping technique based on their HPLC elution positions and MALDI-TOF-MS data.Both preparations contained substantial amounts of high-mannose structures. The N-glycans from human islets were separated into 17 neutral, 8 mono-sialyl and 4 di-sialyl glycans, the API glycans were comprised of 11 neutral, 8 mono-sialyl, 3 di-sialyl, 2 mono-sulfated, 3 mono-sialyl-mono-sulfated and one di-sulfated glycan. Among them, the API preparation contained one neutral, five mono-sialyl glycans and six sulfated glycans that were not detected in human islets. The structures of nine of these twelve could be clearly determined. In addition, a study of the sulfate-depleted API suggests that sulfate residues could be antigenic to humans. The data herein will be helpful for future studies of the antigenicity associated with API.
    Glycobiology 02/2014; 24(2):125-38. DOI:10.1093/glycob/cwt088 · 3.15 Impact Factor
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    ABSTRACT: The number of patients with diabetes is on an increasing trend, thus leading to the belief that diabetes will be the largest medical problem of the 21st century. Islet transplantation can improve glycometabolic control in patients with type 1 diabetes. We studied the viability of Rho-associated protein kinase (ROCK) inhibitor Y-27632 in a culture system in vitro on freshly isolated rat islets. Islet isolation was conducted on a Lewis rat, and studies of culture solutions were split into two groups, one group using ROCK inhibitor Y-27632, and another without. On the seventh day of culture, we evaluated the differences for the cell morphology, viability, and insulin secretion. The Y-27632 group maintained form better than the group without Y-27632. With strong expression of Bcl-2 observed with the Y-27632 group, and expression suppressed with Bax, inhibition of apoptosis by Y-27632 was confirmed. The Y-27632 group predominantly secreted insulin. For islet transplantation, Y-27632 inhibited cell apoptosis in a graft and was also effective in promoting insulin secretion. We were able to confirm effective morphological and functional culture maintenance by separating islets from a rat and adding ROCK inhibitor Y-27632 to the medium.
    12/2013; 6(1):15-23. DOI:10.3727/215517913X674199
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    ABSTRACT: Purpose: We performed lectin microarray analyses of islets from wild-type (WT) pigs and α1-3galactosyltransferase gene knockout (GKO) pigs and compared the results with the corresponding values for islets from healthy humans. Methods: Islets were isolated from the pancreas. After sonication and centrifugation, the proteins in the supernatant from each islet were labeled with Cy3 and applied to a lectin array. Results: Despite negligible expression of the Gal antigen on the adult pig islets (APIs), GKO-islets showed weaker signals, not only for GS-I-B4 but also for PNA, WFA, PTL-I, and GS-I-A4, than the WT islets, indicating reduced contents of α-linked GalNAc and Galβ1-3GalNAc. In comparing the islets of pigs vs. humans, human islets showed stronger signals for UEA-I, AAL, TJA-II, EEL, WFA, HPA, DBA, SBA and PTL-I, indicating that besides ABO blood type antigens, high levels of fucose and α-linked GalNAc are present. On the other hand, the high mannose form was very rich in the APIs. Conclusion: GKO reduced alpha-linked GalNAc, despite negligible expression of the Gal antigen on WT-API. On the other hand, the high-mannose form was richer in both APIs than in healthy human islets. These results provide useful information for future studies.
    Surgery Today 12/2013; 43(12):1439-47. DOI:10.1007/s00595-013-0569-6 · 1.53 Impact Factor
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    ABSTRACT: Besides α-Gal expression, the differences of glycosylation and antigenicity between adult pig islets (APIs) and neonatal porcine islet-like cell clusters (NPCCs) are altogether unclear. In this study, lectin microarray analyses of NPCCs were performed and the results compared with the corresponding values for wild-type APIs and NPCCs from α-Gal transferase knockout (GalT-KO) pig. NPCCs were isolated from 1-3-d-old neonatal wild-type pigs and cultured for 1 d, 5 d, and 9 d, using a previously described technique. Alternatively, the isoration of APIs were isolated based on the method for human islets. In a comparison between NPCCs and APIs, all of the NPCCs showed higher signals for Sambucus nigra, Sambucus sieboldiana, and Trichosanthes japonica I and the binding of α2,6 sialc acid, whereas the APIs showed stronger signals for Lotus tetragonolobus, Aleuria aurantia, Narcissus pseudonarcissus, and Galanthus nivalis, suggesting that APIs contain high levels of high-mannose forms. Among the NPCCs, NPCC (day1) appeared to be richer than the others in Lotus tetragonolobus, Narcissus pseudonarcissus, Galanthus nivalis, and Urtica dioica, implying the presence of high-mannose forms. However, as a whole, the signals for many lectins for NPCCs were very similar. The NPCCs from a GalT-KO pig indicated not only the downregulation of α-Gal expression but α-GalNAc as well, and α2-6 sialic acid was upregulated. The results reported herein contain useful information for the future production of immunomodified pigs with less antigenicity than GalT-KO pigs toward clinical applications of NPCCs.
    Journal of Surgical Research 07/2013; 183(1):412-8. DOI:10.1016/j.jss.2012.12.037 · 1.94 Impact Factor
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    ABSTRACT: Preserving isolated islets at low temperature appears attractive because it can keep islet quantity comparable to freshly isolated islets. In this study, we evaluated the effect of serum as an additive to preservation solutions on islet quality after short-term hypothermic storage. Isolated mouse islets were preserved at 4°C in University of Wisconsin solution (UW) alone, UW with serum, M-Kyoto solution (MK) alone or MK with serum. We then assessed islet quantity, morphology, viability and function in vitro as well as in vivo. Islet quantity after storage in all four solutions was well maintained for up to 120 h. However, islets functioned for different duration; glucose-stimulated insulin release assay revealed that the duration was 72 h when islets were stored in UW with serum and MK with serum, but only 24 h in UW alone, and the islet function disappeared immediately in MK alone. Viability assay confirmed that more than 70% islet cells survived for up to 48 h when islets are preserved in UW with serum and MK with serum, but the viability decreased rapidly in UW alone and MK alone. In in vivo bioassays using 48-h preserved isogeneic islets, all recipient mice restored normal blood glucose concentrations by transplants preserved in UW with serum or MK with serum, whereas 33.3% recipients and no recipient restored diabetes by transplants preserved in UW alone and in MK alone respectively. Adding serum to both UW and MK improves their capability to store isolated islets by maintaining islet functional viability.
    Islets 04/2013; 5(1). DOI:10.4161/isl.24025 · 1.49 Impact Factor
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    ABSTRACT: Artificial reconstruction of fibre-shaped cellular constructs could greatly contribute to tissue assembly in vitro. Here we show that, by using a microfluidic device with double-coaxial laminar flow, metre-long core-shell hydrogel microfibres encapsulating ECM proteins and differentiated cells or somatic stem cells can be fabricated, and that the microfibres reconstitute intrinsic morphologies and functions of living tissues. We also show that these functional fibres can be assembled, by weaving and reeling, into macroscopic cellular structures with various spatial patterns. Moreover, fibres encapsulating primary pancreatic islet cells and transplanted through a microcatheter into the subrenal capsular space of diabetic mice normalized blood glucose concentrations for about two weeks. These microfibres may find use as templates for the reconstruction of fibre-shaped functional tissues that mimic muscle fibres, blood vessels or nerve networks in vivo.
    Nature Material 03/2013; 12(6). DOI:10.1038/nmat3606 · 36.50 Impact Factor
  • M. Takahashi · Y.J. Heo · T. Kawanishi · T. Okitsu · S. Takeuchi ·
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    ABSTRACT: We present a portable glucose monitoring system comprised of an implantable fluorescent-hydrogel sensor, wearable photo detector, microcontroller, wireless device and software for transdermal, continuous glucose monitoring. Although we showed the potential of the fluorescent-hydrogel fibers for applying to long-term, implanted glucose monitoring, “true” continuous glucose monitoring with a portable monitoring system has yet to be realized. In the system that we propose here, the calculated glucose values show a good correlation with the actual blood glucose concentrations. The portable device attached to the ear of a rat and measured the fluorescence intensity for three days. Therefore, our system shows the potential for practical, “true,” continuous glucose monitoring.
    Micro Electro Mechanical Systems (MEMS), 2013 IEEE 26th International Conference on; 02/2013
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    ABSTRACT: In bottom-up tissue engineering, a method to integrate a pathway of nutrition and oxygen into the resulting macroscopic tissue has been highly desired, but yet to be established. This paper presents a cellular building unit made from microstrand-shaped bacterial cellulose (BC microstrand) covered with mammalian cells. The BC microstrands are fabricated by encapsulating Acetobacter xylinum with a calcium alginate hydrogel microtube using a double co-axial microfluidic device. The mechanical strength and porous property of the BC microstrands can be regulated by changing the initial density of the bacteria. By folding or reeling the building unit, we demonstrated the multiple shapes of millimeter-scale cellular constructs such as coiled and ball-of-yarn-shaped structures. Histological analysis of the cellular constructs indicated that the BC microstrand served as a pathway of nutrition and oxygen to feed the cells in the central region. These findings suggest that our approach facilitates creating functional macroscopic tissue used in various fields such as drug screening, wound healing, and plastic surgery.
    Biomaterials 01/2013; 34(10). DOI:10.1016/j.biomaterials.2012.12.013 · 8.56 Impact Factor
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    ABSTRACT: This paper describes the self-assembly of “cell springs” using smooth muscle-like cells differentiated from multipotent dedifferentiated fat (DFAT) cells. Using a microfluidic co-axial device, DFAT cells suspended in extracellular matrix (ECM) mixture of fibrin and collagen were encapsulated within tubular alginate microfibers and formed into 3D fiber-shaped micro-constructs. Such DFAT cell fibers were then induced to differentiate into smooth muscle cells (SMCs) under various conditions. Upon differentiation induction, DFAT cell fibers spontaneously contracted into coiled spring structures within 3 days. After 3 weeks of differentiation, the differentiated DFAT cell fibers showed synchronized contraction upon electrical stimulation.
    2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS); 01/2013

  • Transplantation 11/2012; 94(10S):781. DOI:10.1097/00007890-201211271-01530 · 3.83 Impact Factor
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    ABSTRACT: Polyacrylamide (PAM) hydrogels are widely used in bioanalysis and biosensing applications. Scaling down of PAM patterns to micro/nanosize extends PAM applications to lab-on-a-chip, highly sensitive biosensors and cell/tissue analysis. Proposed is a replica moulding technique to pattern the PAM surface down to nanosize. Various patterns on silicon moulds successfully transferred to PAM with a minimum dimension of 60 nm and aspect ratio of up to ~9. PAM is characterised as a platform for a single cell array and the analysis of cell responses to topographic cues. Moreover, micro/nanopatterned PAM samples were implanted under the back skin of rats to study the topological effects on immuno responses in vivo. Therefore the use of micro/nanoreplica moulding to pattern PAM hydrogel provides opportunities for studying the relationship between soft nanoscaled structures and cell/tissue.
    Micro & Nano Letters 11/2012; 7(11):1108-1111. DOI:10.1049/mnl.2012.0525 · 0.85 Impact Factor
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    ABSTRACT: The pig pancreas is considered to be the most suitable source of islets for clinical xenotransplantation. Two types of islet transplantation are: adult pig islets and neonatal porcine islet-like cell clusters (NPCC). However, besides a-Gal expression, differences in glycosylation and xenoantigenicity between both types were not clear so fat to date. In this study, we performed lectin microarray analyses of NPCCs cultured for 1, 5, or 9 days. We studied differences in gycoantigens among several kinds of wild-type NPCCs isolated from 1- to 3-day-old neonatal wild-type pigs (Large White/Landrace × Duroc) and cultured for 1, 5 and 9 days in Ham's 10 in the presence of nicotinamide, using a previously published technique. After sonication and centrifugation, supernatant proteins from each islet were labeled with Cy3, applied to a lectin array and scanned with an SC-Profiler for evaluation using an Array Pro Analyzer. The overall signals of NPCC at days 5 and 9, showed almost the same values to most lectins, whereas those on day 1 showed differences, suggesting that the NPCC on day 1 contain immature cells that gradually turn to mature NPCCs in culture.
    Transplantation Proceedings 05/2012; 44(4):1134-5. DOI:10.1016/j.transproceed.2012.03.019 · 0.98 Impact Factor
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    ABSTRACT: For islet transplantation, maintaining organ viability after pancreas procurement is critically important for optimal graft function and survival. We recently reported that islet yield was significantly higher in the modified ET-Kyoto (MK) solution, which includes a trypsin inhibitor (ulinastatin), compared with the UW solution, and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with other trypsin inhibitors, gabexate mesilate, and nafamostat mesilate, in preservation solution for islet isolation. Ulinastatin was easily dissolved in ET-Kyoto solution, while ET-Kyoto with gabexate mesilate and nafamostat mesilate became cloudy immediately after addition. Although there were no significant differences in islet yield among the three groups, viability was significantly higher for the MK group than for the GK group or the NK group. The stimulation index was significantly higher for the MK group than for the GK group. In summary, there are no other trypsin inhibitors that are more effective than ulinastatin. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation.
    Cell Transplantation 02/2012; 21(2-3):509-16. DOI:10.3727/096368911X605420 · 3.13 Impact Factor
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    ABSTRACT: We present a nano-patterned poly-acrylamide (PAAm) hydrogel that can reduce inflammatory effects after subcutaneous implantation. Although hydrogel is considered as an excellent biomaterial for implants due to its biocompatibility, hydrogel still induces inflammation after implantation. To enhance biocompatibility for subcutaneous implantable sensors, we modified hydrogel surface with nano-patterns using simple molding process. To test the anti-inflammatory effect, we implanted the samples to rat's back. Since macrophages play an important role in the immune response and development of encapsulation after inflammation reaction, we counted macrophages neighboring the implanted nano-patterned hydrogels after 3 and 7 days and measured thickness of encapsulation after 21 days from implantation. We found that the sample with the line-and-space pattern of 600 nm in space successfully suppressed the inflammation reaction. Therefore, nano-patterned hydrogel is promising for long-term subcutaneous implantable sensors.
    Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS) 01/2012; DOI:10.1109/MEMSYS.2012.6170195

Publication Stats

2k Citations
533.60 Total Impact Points


  • 2009-2015
    • The University of Tokyo
      • Institute of Industrial Science
      Tōkyō, Japan
  • 2008-2009
    • Fujita Health University
      • Department of Surgery
      Nagoya, Aichi, Japan
  • 2005-2009
    • Kyoto University
      • Department of Pharmacy
      Kioto, Kyoto, Japan
  • 2001-2007
    • Okayama University
      • Medical School
      Okayama, Okayama, Japan