Department ofRadiology
Outline and Research Objectives
Department of Radiology was established in 1932. Our department covers three major
fields that are, diagnostic radiology (imaging and intervention), radiation oncology (radiotherapy) and nuclear medicine. Research activities of radiology are being carried out in cooperation with department of clinical radiology of the University of Tokyo Hospital and withdepartment of radiology of the institute of medical science (IMS), the University of Tokyo.

Research Objectives
Diagnostic Radiology
To develop new techniques in data acquisition of CT and MRI
To clarify pathologic background of radiological findings.
To develop new system for interventional procedures.
Radiation oncology
To develop high precision radiotherapy system
To improve radiotherapy planning.
To clarify biological mechanisms of radiotherapy from molecular viewpoints.
Nuclear Medicine
To develop new techniques and radiotracers in functional imaging.
To improve image quality and quantitative accuracy in radiotracer imaging

Faculties and Students
Professor and Chair
Kuni Ohtomo MD (diagnostic radiology 1998-)
Associate Professors
Manabu Minami MD (diagnostic radiology 1999-)
Shigeki Aoki MD (diagnostic radiology 2000-)
Keiichi Nakagawa MD (radiation oncology 2002-)
Kohki Yoshikawa MD (diagnostic radiology 1997-) (IMS)
Lecturers
Toshimitsu Momose MD (nuclear medicine 1999-)
Osamu Abe MD (diagnostic radiology 2000-)
Naoto Hayashi MD (diagnostic radiology 2000-)
Masao Tago MD (radiation oncology 2001-)
Yoshitaka Masutani ED (computer science 2002-)
Yusuke Inoue MD (nuclear medicine 1999-) (IMS)
Associates ...............................9
Postdoctoral Fellow ................1
Graduate Students ................14
Residents.................................6
Secretaries ...............................982

Past Research and Major Accomplishments
Diagnostic Radiology
1. Visualization of cerebral arteries by contrastenhanced CT and MRI with special attention to separate between the lumen and the wall. (select publications 1-7,12)
We have revealed that dynamic contrast enhanced
CT and MRI can be used to visualize vascular lumen
as well as its wall.
We developed 3D-CT angiography for cerebral
arteries to visualize lumen of the arteries andaneurysms. We developed a new MR angiographic
technique, named “MRDSA” which can show the
hemodynamics with a frame rate of subsecond. We
also established the technique to see the wall of theintracranial arteries, using contrast-enhanced MRwith suppression of the luminal signal by presaturation pulse. We used this technique to see the irradiated intracranial arterial wall, which sometimes show
marked enhancement. We then established the way
to see the dynamic contrast changes of the wall itself.
In addition to diagnosis, we performed fundamental studies of MR-guided intravascular procedures.

2. Temporal Changes of the Apparent Diffusion
Coefficients (ADCs) of Water and Metabolites in Rats
with Hemispheric Infarction. (select publication 15)
The purpose was to clarify the temporal changes of
ADCs of cerebral metabolites during early focal ischemia.
in order to assess the pathophysiology of the reduction
in diffusion properties observed both in the ischemic
hemisphere and in the contralateral hemisphere.
3. Fully-Automated Segmentation of Colonic Walls
and Pulmonary Vessels (select publications 19-20)
We developed new segmentation methods, which
are applicable in both visualization of the colon andcomputer-aided diagnosis in the detection of polyps in
CT colonoscopy. A new method for automated segmentation of the pulmonary vascular tree in spiral CT
angiography was developed based on 3D image analysis techniques and anatomic knowledge. The results
are able to be applied in detection of pulmonary
embolism by limiting search area of thrombi.
4. Radiologic –pathologic correlation of various diseases (select publications 8-1116.18.21-26)
In the study the images with high spatial and contrast resolution are compared with the pathologic
findings and this kind of information is helpful fordifferential diagnosis of diseases. This approach has
been successful in the field of the CNS, liver, andovaries.
5. New virtual CT endoscopy software
To overcome some of the disadvantages of virtual
endoscopy, new software called computed sectional
probe (CSP) method has been developed. This software can be applied to the diagnosis of the gastrointestinal tract and tracheobronchial tree with improved
detectability and more accurate tumor staging.

beam placement in the high precision radiation therapy.

Nuclear Medicine
1. Brain activation studies by positron emission
tomography (PET) (select publications 39.40)
We investigated the following issues; (I) reproducibility of regional cerebral blood flow of restingstate measured by H2O-PET;(II) effect of physiologicalstimulation on cerebral blood flow;(III) identificationof activation areas on anatomical structures. Our datasuggest that relative rCBF images and their paired
subtraction are more suitable for tapping functional
localization. The changes of rCBF in association cortex
for more complicated tasks are, in general, smaller
than those in primary cortex. PET images were taken
in two different conditions: blindfolded resting state
and anti-saccade. We applied these activation techniques using H2O and PET to exploring motor function and language processing of Japanese language.
We investigated functional neuroanatomy of chewing.
We investigated Japanese language processing in
the brain using H2O-PET. The results suggested that
Kanji and Kana are processed differently.
2. Evaluation of the prognostic value of FDG-PET forrectal cancer (select publications 41)
We compared several variations of a semi-quantification method, the Standardized Uptake Values (SUV)
and to determine the most appropriate parameter forthe prognostic prediction and to propose the quantitative guideline of the FDG-PET. SUV2 was considered
to be a good prognostic indicator for long-term prognosis of rectal cancer patients.

Current Research
Radiation Oncology
1. Development of a comprehensive system for precise radiation therapy (select publications 27.30.)
A total system for radiation therapy composed of alinear accelerator unit with a microcomputer-controlled multileaf collimator and a CT scanner installedin the same treatment room was developed 17 years
ago. It was a prototype system of the widely prevailing high precision radiotherapy system.
2. Megavoltage CT scanning with a medical accelerator (select publication 29 32)
Megavoltage CT scanner using 4 MV and 6 MV
radiotherapy beam was developed. A detector system
is composed of 120 pairs of Cadmium Tungstate scintillators. Although spatial resolution is limited, this system has been used to verify positioning errors andDiagnostic Radiology
1. Evaluation and treatment of cerebrovascular diseases with multimodality (CT, MR, US, angiography);especially with X-ray angio-open MR system.
2. MR Diffusion Tensor Analysis and Visualization(select publications 13.14)
A new display method for tractography in diffusion tensor imaging was developed. Local reliability ofdiffusion tracking is evaluated based on anisotropy,
and paths of tracking are displayed in colors andopacity according to tracking reliability. By using several clinical data sets of volunteers and patients, themethod was validated.

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3. Further clinical application of 3D data acquired byMultidetector low CT (MDCT).
3-1. 3D display of secondary lobules of the lung
MDCT can generate contiguous thin section(1.25mm) CT images of the lung at every 0.6mm
under single-breath holding. 3-D data of lungparenchyma is abstracted and erosion of several pixels from the lung surface can be accomplished. The
structure of the secondary pulmonary lobule is clearly
seen. This information will be helpful to analyze diffuse lung diseases.
3-2. 3D display of the surface of the liver
Using multi-phase dynamic study of the liver,characteristics of enhancement in each pixel can be
abstracted. If the characteristics of enhancement of
the liver parenchyma are set on the time-density
curve, pixels showing similar enhancement pattern
will be differentiated automatically on computer. This
will be utilized to define the area of the liver
parenchyma and eventually the data of the area willshow the appearance of the liver surface three-dimensionally. The appearance will be almost the same as
the liver is observed by laparoscopy or at surgery.
This computer-aided automatic process will be useful
the overall evaluation of changes of the liver shapeand its deformity (atrophy and hypertrophy).
Radiation Oncology
1. Molecular analysis on reproductive tissue (selectpublications 34.35.38)
Radiation damage and recovery from ionizing radiation are being investigated from the molecular viewpoint.
2. Development of a C-arm mounted accelerator andof Dynamic Conical Conformal Radiation therapy(Dyconic CRT)
A C-arm mounted accelerator was developed. The
linac head was designed to move along the C-arm
with a maximum angle of 60 degrees (from a vertical
position toward the gantry). Simultaneous rotation of
the gantry creates a dynamic conical irradiation technique. Dyconic CRT was developed by combining thetechnique with continuous motion of multi-leaf collimator (MLC). Dyconic CRT enabled the precise delivery of non-coplanar beams without rotating the table.
Nuclear Medicine
1. Comparative studies of myocardial sympathetic
nerve function and striatal dopaminergic function in
Parkinson’s disease and its related disorders.
In all patients with parkinsonism, striatum to cerebellar (ST/CBL)Ratios were significantly reduced in
FDOPA-PET. Among them, only in PD and DLBD

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patients, heart to mediastinum (H/M) ratios, index of
myocardial sympathetic nerve function, were significantly reduced in I-123 MIBG scans. Now we are accumulating the number of patients and try to analyze
the data of larger series of parkinsonian patients.
2. Correlative studies of C-11 methionine (MET) and
FDG PET in the evaluation of the tumor grading of
preoperative brain tumor and in the differentiation ofrecurrent brain tumor from radiation necrosis. For thedifferentiation between tumor recurrence and radiation necrosis, we are trying to decide cut-off value ofboth MET and FDG uptake, lesion to normal graymatter tissue count ratio (L/N).

Future Prospects
Imaging and Intervention (Diagnostic Radiology
and Nuclear Medicine)
1. Neruointerventional therapy for stroke and otherneurological disorders using Xray angio-MR systemwith monitoring diffusion/perfusion and vascular wallby MR.
2. Molecular imaging in the future
In the era of molecular medicine, molecular imaging is attracting a great deal of attention in the field ofimaging science. Molecular imaging approaches themolecular basis of biological processes using imaging
technology. We intend to perform researches inmolecular imaging. In particular, we are planning toinvestigate non-invasive imaging of gene expression
in living animals. We hope to contribute to developing
methods for gene expression imaging and, subsequently, advancing molecular biology and molecular
medicine.
3. Molecular Imaging in clinical oncology
The first point is the evaluation of angiogenesis
representing activity of primary neoplasms. Withadvent of CT- PET system, the degree of FDG uptake
will be correlated with the degree of angiogenesis.
Another point is the evaluation of lymph node metastasis. New contrast materials having affinity withmacrophages or tumor cells itself in the node will beavailable on MRI in the near future.
4. Functional imaging using CT and MRI
Functional imaging focusing on perfusion will be
useful especially in the liver and kidney among thebody. Another functional imaging is related to theactivity of hepatocytes and Kuppfer cells of the liverusing tissue-specific MR contrast agents.

5. Functional imaging using radiotracers
Measurements of endogenous neurotransmitter
secretion under various physiological conditions andpharmacological manipulations. We are planning tomeasure the amount of endogenous dopamine releasefrom the terminals of nigrostriatal dopaminergic neurons during executing mental tasks, drug therapy anddeep brain electrical stimulation in patients with
Parkinson’s disease, using C-11 raclopride and PET.
We are also planning to develop the new radiolabeledtracers for opiate receptors, dopamine, serotonine,
GABA and glutamate receptors and transporters forthe evaluation of mental functions in patients withpsychiatric disorders such as panic disorder, depression and schizophrenia.

Radiation Oncology
1.Image-guided real-time high dose-rate radiotherapy:
Continuous image acquisition during the therapeutic radiation visualizes errors in target localization andmotion of normal structures. In rotational conformal
therapy, a separate X-ray tube mounted on the linac
gantry enables real-time CT imaging of the target andsurrounding organs. When the system is combinedwith a newly investigated extremely high dose rate Xray source (laser X-ray source), time and spatial resolution of radiotherapy will be drastically improved. It
will greatly enhance radiosurgey application.
2.Tailor-made prediction of radiation sensitivity byuse of DNA array tip:
Genetic factors define the radiation sensitivity of
the normal tissue. Fibroblast cultures are performed
sporadically but take too long time in clinical practice.
DNA array analyses of single nucleotide polymorphism (SNP) may clarity how the sensitivity is determined and contribute to the decision of indicationand tailor-made dose setting for radiation therapy.

Research Grants (Department of Radiology)
The Grant for Development of Advanced Medical
Practice of The Ministry of Education, Science, Sports
and Culture in Japan.
1. Ohtomo K. Clinical necessity of both state-of-the art
CT and MR examinations in the evaluation of thesame regions of the body (2000-2002 ￥30.000.000)
The Grant-in-Aid for Scientific Research (B)(2) of The
Ministry of Education, Science, Sports and Culture in
Japan.
2. Abe O.: Cerebral perfusion MR imaging using continuous arterial spin labeling with 2-coil system. (20012004 ￥13.600.000)
3. Hayashi N. Optical coherence tomography of thesuperficial vascular diseases: fundamental study.
(2002-2005 ￥13.000.000)

Grant-in-Aid for Scientific Research (C) of The
Ministry of Education, Science, Sports and Culture in
Japan.
4. Nakagawa K. Megavoltage CT-assisted Stereotactic
Radiosurgery for Thoracic Tumors (1999-2001,¥3,500,000)
5. Nakagawa K. Development of computerized questionnaire system for collecting QOL information ofcancer patients (2000-2001, ¥3,400,000)

Select Publications (1997-2002, except for1.27.39) (Department of Radiology)
Diagnostic Radiology○1. Aoki S, Shirouzu I, Sasaki Y, Okubo T, Hayashi N,
Machida T, Hoshi E, Suzuki K, Funada N, Araki T,
Sasaki Y. Enhancement of the intracranial arterial
wall at MR imaging: Relation ship to cerebral atherosclerosis. Radiology 194:477-481,1995
2. Aoki S, Osawa S, Yoshioka N, Yamashita H, Kumagai
H, Araki T. Velocity-coded color MR angiography.
AJNR 19: 691-693,1998
3. Aoki S, Aoki K, Ohsawa S, Nakajima H, Araki T.
Dynamic MR images of the carotid wall. J Magnetic
Reson Imaging 9:420-427,1999
4. Aoki S, Nakajima H, Kumagai H, Araki T. Dynamic
contrast-enhanced MR angiography and MR imagingof the carotid artery: high-resolution sequences indifferent acquisition planes. AJNR 21:381-385,2000
5. Aoki S, Yoshikawa T, Hori M, Nanbu A, Kumagai H,
Nishiyama Y, Nukui H, Araki T. MR digital subtraction angiography for the assessment of cranial arteriovenous malformations and fistulas. AJR 175:451453,2000
6. Aoki S, Yoshikawa T, Hori M, Ishigame K, Nambu A,
Kumagai H, Araki T. 2D thick-slice MR digital subtraction angiography for assessment of cerebrovascular occlusive diseases. Eur Radiol 10:1858-1864,2000
7. Aoki S, Hayashi N, Abe O, Shirouzu I, Ishigame K,
Okubo T, Nakagawa K, Ohtomo K, Araki T.
Radiation-induced arteritis: thickened wall withprominent enhancement on cranial MR imagesreport of five cases and comparison with 18 cases ofmoyamoya disease. Radiology 2002 223:683-688
8. Hayashi N, Yamamoto S, Okubo T, Yoshioka N,
Shirouzu I, Abe O, et al. Avulsion injury of cervicalnerve roots: enhanced intradural nerve roots at MR
imaging. Radiology 1998;206(3):817-22.
9. Hayashi N, Tsutsumi Y, Barkovich AJ. Morphologicalfeatures and associated anomalies of schizencephaly
in the clinical population: detailed analysis of MR
images. Neuroradiology 44(5):418-27,2002.
○10. Hayashi N, Masumoto T, Abe O, Aoki S, Ohtomo
K, Tajiri Y. Accuracy of Abnormal Paraspinal Muscle
Findings on Contrast-enhanced MR Images as
Indirect Signs of Unilateral Cervical Root-Avulsion
Injury. Radiology 223(2):397-402,2002.

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11. Hayashi N, Tsutsumi Y, Barkovich Polymicrogyria
without porencephaly/schizencephaly. MRI analysisof the spectrum and the prevalence of macroscopic
findings in the clinical population. Neuroradiology,
In print.
12. Yoshikawa T, Aoki S, Hori M, Nambu A, Kumagai H,
Araki T. Time-resolved two-dimensional thick-slice
magnetic resonance digital subtraction angiography
in assessing brain tumors. Eur Radiol 10: 736-744,
2000.
13. Yoshikawa T, Abe O, Tsuchiya K, Okubo T, Tobe K,
Masumoto T, Hayashi N, Mori H, Yamada H, Aoki S,
Ohtomo K. Diffusion-weighted magnetic resonanceimaging of the dural sinus thrombosis.
Neuroradiology 44: 481-488, 2002.
14.Abe O, Aoki S, Hayashi N, Yamada H, Kunimatsu A,
Mori H, Yoshikawa T, Okubo T, Ohtomo K. Normal
aging in the central nervous system:quantitative MR
diffusion-tensor analysis. Neurobiol Aging. 23:433441,2002.
○15. Abe O, Okubo T, Hayashi N, Saito N, Iriguchi N,
Shirouzu I, Kojima Y,Masumoto T, Ohtomo K, Sasaki
Y. Temporal changes of the apparent diffusion coefficients of water and metabolites in rats with hemispheric infarction: experimental study of transhemispheric diaschisis in the contralateral hemisphere at
7 tesla. J Cereb Blood Flow Metab. 20:726-735,2000
16. Mori H, Yoshioka H, Ahmadi T, Saida Y, Ohara K,
Itai Y. Early radiation effects on the liver demonstrated on superparamegnetic iron oxide-enhanced T1weighted MRI.
J Comput Assist Tomogr. 24(4):648-51,2000.
17. Mori H, Abe O, Okubo T, Hayashi N, Yoshikawa T,
Kunimatsu A, Yamada H, Aoki S, Ohtomo K.
Diffusion property in a hamartomatous lesion ofneurofibromatosis type 1. J Comput Assist Tomogr.
25(4):537-9,2001.
18. Okubo T; Yoshioka N; Hayashi N; Abe O; Masumoto
T; Sasaki T; Ohtomo K
Contrast-enhanced magnetic resonance imaging of
the cranial nerves in patients with acoustic schwannoma: correlation with surgical findings. Acta
Otolaryngol Suppl (Norway)542 :13-17,2000
19. Masutani Y et al. Automated Segmentation and
Visualization of the Pulmonary Vascular Tree in
Spiral CT Angiography: An Anatomy-Oriented
Approach based on Three-Dimensional Image
Analysis, J Comput Assist Tomogr 25(4):587-597,
2001
20. Masutani Y et al. Automated Segmentation ofColonic Walls for Computerized Detection of Polyps
in CT Colonography, J Comput Assist Tomogr
25(4):629-638, 2001
21. Matsuoka Y, Ohtomo K, Araki T, Kojima K,
Yoshikawa W, Fuwa S. MR imaging of clear cell carcinoma of the ovary. Eur Radiol 11: 946-951, 2001
22. Yoshioka N, Minami M, Inoue Y, Kawauchi N,
Nakajima J, Oka T, Yoshikawa K, Ohtomo K.
Pedunculated bronchogenic cyst mimicking pleurallesion. J Comput Assist Tomogr 24:581-583, 2000

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23. Okada Y, Ohtomo K, Kiryu S, Sasaki Y. Breath-holdT2-weighted MRI of hepatic tumors: value of echo
planar imaging with diffusion-sensitizing gradient. J
Comput Assist Tomogr, 22:364-371, 1998.
24. Kobayashi Y, Minami M, Ohtomo K, Matsuoka Y.
MR imaging and CT appearance of aggressive
angiomyxoma. AJR 169:1752-1753,1997.
25. Minami M, Itai Y, Charnsangavej C, Ohtomo K,
Kawauchi N, Sasaki Y. “Periportal collar” sign of theliver: pathophysiologic approach. In: Selected scientific exhibits in gastrointestinal radiology: RSNA
1996 Radiographics 17(suppl 2): 1616-1620(abstr)
1997
26. Ohtomo K, Matsuoka Y, Abe O, Okada M, Amo K,
Minami M, Kawauchi N, Sasaki Y. High-resolution
MR imaging evaluation of hepatocellular carcinoma.
Abdom Imaging 22:182-186,1997.

Radiation Oncology○27. Nakagawa K, Aoki Y, Akanuma A, Onogi Y,
Terahara A, Sakata K, Muta N and Sasaki Y. Realtime beam monitoring in dynamic conformation
therapy. International Journal of Radiation Oncology,
Biology, Physics 30, 1233-1238, 1994
28. Nakagawa K, Aoki Y, Kusama T, Ban N and
Nakagawa S. Radiotherapy during pregnancy and its
effects on fetuses and neonates. Clinical
Therapeutics 19, 770-777, 1997
29. Nakagawa K, Aoki Y and Sasaki Y. Improvement ofimage quality in megavoltage computed tomography
with second generation scanning mode. Radiation
Oncology Investigation 5, 257-263, 1997
○30. Nakagawa K, Aoki Y, Fujimaki T, Tago M,
Terahara A, Karasawa K, Sakata K, Sasaki Y,
Matsutani M and Akanuma A. High dose conformal
radiotherapy influenced pattern of failure, but did
not improve survival of glioblastoma multiforme.
International Journal of Radiation Oncology, Biology,
Physics 40, 1141-1149, 1998
31. Nakagawa K, Aoki Y, Ohtomo K, Albright N andGoer D. Dosimetry of leakage doses from a mobile
accelerator for IORT and legal issues for its clinicaluse in Japan. International Journal of ClinicalOncology 4, 215-219, 1999
○32. Nakagawa K, Aoki Y, Tago M, Terahara A andOhtomo K. Megavoltage CT-assisted stereotactic
radiosurgery for thoracic tumors: original research in
the treatment of thoracic neoplasms. International
Journal of Radiation Oncology, Biology, Physics 48,
449-457, 2000
33. Tago M, Terahara A, Nakagawa K, Aoki Y, Ohtomo
K, Shin M and Kurita H. Immediate neurologicaldeterioration after gamma knife radiosurgery for
acoustic neurinoma. J Neurosurg 93, 78-81, 2000
34. Kozuka T, Aoki Y, Nakagawa K, Ohtomon K,
Yoshikawa H, Matsumoto K, Yoshiike K and Kanda
T. Enhancer-promoter activity of human papillomavirus type 16 long control regions isolated fromcell lines SiHa and CaSKi and cervical cancer biop-

sies. Japanese Journal of Cancer Research 91, 271279, 2000
35. Takeuchi T, Kozuka T, Nakagawa K, Aoki Y,
Ohtomo K, Yoshiike K and Kanda T. Adeno-associated virus type 2 nonstructural protein rep78 suppresses translation in vitro. Virology 266, 196-202, 2000
36. Nakagawa K, Kozuka T, Akahane M, Suzuki G,
Akashi M, Hosoi Y, Aoki Y and Ohtomo,K.
Radiological findings of accidental radiation injury of
the fingers. Health Physics 80, 67-70, 2001
37. Nakagawa K, Tago M, Terahara A, Aoki Y, Sasaki T,
Kurita H, Shin M, Kawamoto S, Kirino T and
Ohtomo K. A single institutional outcome analysis of
gamma knife radiosurgery for single or multiple
brain metastases. Clinical Neurology and
Neurosurgery 102, 227-232, 2001
38. Igaki H, Nakagawa K, Aoki Y, Ohtomo K, Kukimoto I
and Kanda T. Characterization of the Bi-directionaltranscriptional control region between the human
UFD1L and CDC45L genes. Biochemical and biophysical Research Communications 283, 569-576,
2001

ene diphosphonate after nephron sparing surgery. J
Nucl Med 40: 418-421, 1999
47. Inoue Y, Ohtake T, Homma Y, Yoshikawa K,
Nishikawa J, Sasaki Y Evaluation of glomerular filtration rate by a camera-based method in children andadults. J Nucl Med 39: 1784-1788, 1998
48. Inoue Y, Ohtake T, Yoshikawa K, Nishikawa J,
Sasaki Y Estimation of deadtime in imaging humansubjects.Eur J Nucl Med 25: 1232-1237, 1998
49. Inoue Y, Momose T, Ohtake T, Asai S, Yoshikawa K,
Nishikawa J, Sasaki Y Effect of deadtime loss on
quantitative measurement of cerebral blood flow
with technetium-99m hexamethylpropyleneamine
oxime. Eur J Nucl Med 24: 1418-1421, 1997
50. Inoue Y, Momose T, Ohtake T, Nishikawa J, Sasaki
Y, Waritani T, Inoue M Metabolism of technetium99m-L,L-ethyl cysteinate dimer in rat and cynomolgus monkey tissue.J Nucl Med 38: 1731-1737, 1997

Nuclear Medicine○39. Momose T, Sasaki Y, Sakurai Y, Iwata M.
Functional studies with O-15 H2O PET. Biomed
Research 13(Suppl 1); 77-82, 1992.
○40. Momose T, Nishikawa J, Watanabe T, Sasaki Y,
Senda M, Kubota K, Sato Y, Funakoshi M andMinakuti S. Effect of mastication on regional cerebral
blood flow in humans examined by positron emission tomography with O-15 labelled water and magnetic resonance imaging. Archs oral Biol. 42; 5761,1997
41. Oku S, Nakagawa K, Momose T, Kumakura Y, Abe
A, Watanabe T and Ohtomo K FDG-PET after radiotherapy is the best prognostic indicator of rectal cancer. Annals Nucl Med :16(6), 2002,in press.
○42. Inoue Y, Abe O, Kawakami T, Ozaki T, Inoue M,
Yokoyama I, Yoshikawa K, Ohtomo K Metabolism of99m
Tc-ECD in infarcted brain tissue of rats.J Nucl Med
42: 802–807, 2001
○43. Inoue Y, Yoshikawa K, Yoshioka N, Watanabe T,
Saegusa S, Kaneko Y, Yokoyama I, Ohtomo K
Evaluation of renal function with 99mTc-MAG3 using
semiautomated regions of interest.J Nucl Med 41:
1947-54, 2000
4
4. Inoue Y, Yoshikawa K, Suzuki T, Katayama N,
Yokoyama I, Kohsaka T, Tsukune Y, Ohtomo K
Attenuation correction in evaluating renal function
by a camera-based method in children and adults. J
Nucl Med 41: 823-829, 2000
4
5. Inoue Y, Ohtake T, Yokoyama I, Yoshikawa K, Asai
S, Ohtomo K Evaluation of renal function from technetium-99m-MAG3 renography without blood sampling.J Nucl Med 40: 793-798, 1999
46. Inoue Y, Ohtake T, Kameyama S, Yamazaki S,
Kawabe K, Yoshikawa K, Nishikawa J, Sasaki Y
Increased renal retention of technetium-99m methyl-87

Department of Radiation Oncology(Experimental Radiology)
Outline and Research Objectives
The department was founded in 1966 to carry out education and research on clarification of radiation effect on cells and tissues through biological and biochemical understanding.
Our recent research program(s) have focused on the basic studies for radiation oncology
and radiotherapy through understanding molecular biological basis of radiation responses incells and tissues.
The standardized radiotherapy has been daily fractionated irradiation of 2 Gy for about 6
weeks by which tumor cells lose clonogenic potential while normal tissues involved are
saved and recover. To clarify the mechanisms involved in the process and to devise bettermethods for radiotherapy have been the subject of vigorous study for decades. DNA has
been considered as the target for radiation action on the cells causing mitotic or reproductive cell death while a fertilized egg divides into various tissue cells and organs with thesame DNA but with different radiosensitivity. Tumors and normal tissues differ in radiosensitivity depending on intrinsic cellular radiosensitivity, cell kinetics, schedule of fractionation, type or quality of radiation used, radiation dose, assay systems used and physiologicalconditions such as pO2, pH, nutrient etc. However, the molecular mechanisms for the differences have been little clarified.
Toward this goal the specific projects aimed at the following problems have beenplanned and in progress.
Specific Aims:
1) To clarify biological mechanisms underlying radiation responses of normal tissues andtumors.
2) To clarify mechanism(s) and signal-transduction pathway(s) of cell death, tissue damage
and regeneration after irradiation and/or heat treatment, especially of apoptosis (programmed cell death)3) To establish predictive assay method(s) such as DNA and protein (antibody) arrays tohelp select treatment methods, i.e., type of radiation source(s) and irradiating protocol(s)suitable to individual patient and tumor.
4) To develop new methods for sensitization of tumor cells and for prevention of normal tissue damages.

Faculties and Students
Professor and Chair Norio Suzuki, M.D., Ph.D. (1986~)
Associate Professor Yoshio Hosoi, M.D., Ph.D.
Associates ...............................2
Graduate students...................2
Research students...................2

Past Research and Major Accomplishments
1. Quantitative assay system for mutation of cultured mammalian cells
2. Quantification of radiation induced mutation frequencies of mammalian cells in vitro or in vivo
3. Method to determine DNA synthesis point during
S-phase using mutation marker

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4. Variability and instability of tumor cells in DNA
and various malignant properties
5. Clarification of metastatic processes and their relevance to radiation responses in mouse tumor system
6. Cell cycle dependence of metastatic lung colonization in mouse tumor system
7. New assay methods of metastasizing tumor cells
released into the blood of mice
8. Characterization of normal tissue stem cells especially testicular spermatogenic stem cells of mouse
9. Existence of hypoxic cells among mouse spermatogenic stem cells
10. Random lifetime and exponential decrease ofmouse spermatogenic stem cells

11. Activation of immune response by low dose irradiation
12. Inhibition of metastasis by low dose total body
irradiation
13. Sensitization of cells to ionizing radiation by
Chlorin e6Na

Current Research
Regarding radiation induced cell death, mitotic or
reproductive cell death has been traditionally considered significant and meaningful one underlying tumor
cure and tissue damages. DNA double-strand breaks(DSBs) are considered most harmful among various
DNA damages induced by ionizing radiation and theprimary cause for cell death. Thus, cellular repair
capacity of DSBs is a critical factor of radiosensitivity.
DSBs are mainly repaired by homologous recombination and non-homologous end joining (NHEJ). DNAdependent protein kinase (DNA-PK) is required for
NHEJ. We have previously reported that inactivationof DNA-PK by wortmannin or other drugs sensitizedcells to ionizing radiation.
On the other hand, tumor cells and normal tissue
cells have also been known to express apoptotic(interphase) cell death after irradiation and various
tumor cells are defective in apoptotic pathway andprocess. The role and significance of apoptotic cell
death in tumor cure or tissue damages depend on histological type or individual tumors and tissues.
We have been focusing currently on clarification of
signal transduction and process of cell death, especially apoptotic cell death after irradiation or heat treatment. T cell lymphoma, MOLT-4 cells (p53 wild), andmonoblastic U937 cells (p53 null) were mainly used.
The other focus has been clarification of the function
and the role of DNA-PK in signal transduction of DSB
repair and cell death.
1. Signal transduction mechanisms involved inradiation- or heat-induced cell death
As for involvement of receptor-mediated signaling
including Fas and TNFR, MOLT-4 cells stimulated bythese ligand did not undergo apoptosis, and irradiatedcells did not exhibit any mature form of caspase-8,
although Fas expression of MOLT-4 was upregulated
by irradiation. Dose dependency of p53 expression
and dominant negative effect of p53 on radiationinduced cell death of MOLT-4 cells have been reported. Expression of p53-related genes and the mechanism of the mitochondrial pathway are under-investigation.
1-1) Ceramide-JNK pathway
We have recently demonstrated the importantroles of ceramide-JNK pathway as well as p53 pathway in radiation-induced cell death of MOLT-4 cells;1) acid sphingomylinase inhibitor suppressed X-rayinduced apoptosis of MOLT-4 cells. 2) Rh-1a clone, aclone selected for radio-resistance from MOLT-4 cells,
was found resistant also to C2-ceramide-induced
apoptosis, with less activation of JNK. 3) the activation of JNK after X-irradiation or the treatment with a
JNK activator anisomycin caused the decrease of cMyc expression, 4) the reduction and/or inactivationof c-Myc by c-Myc inhibitor led to apoptotic cell
death.
We also demonstrated that the important roles ofceramide-JNK pathway in heat-induced cell death in
p53 null U937 cells by the transfection with the dominant negative c DNA of JNK into the cultured cells or
the treatment with acid sphingomylinase inhibitor.
We are studying further the mechanisms of heatinduced apoptosis and the role of ceramide-JNK signaltransduction pathway in the thermo-tolerance development.
1-2) p41-induction in radiation-induced apoptosis
p41, an acidic 41-kDa protein (pI=4.0) was newly
found in our laboratory as a radiation-induced protein
during apoptotic cell death of irradiated MOLT-4. The
protein was detected in two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and silver staining. The protein appeared radiation dose and timedependent. Amino acid sequence analysis of partial
peptides showed homology between p41 and a putative oncogene, set (also known as template activating
factor I, TAF-I). A polyclonal antibody was raised
against a synthetic partial peptide of p41.
Immunoblotting analysis of irradiated MOLT-4 cells
showed two spots, p41 and an additional 42-kDa protein, p42 (pI=4.1). p42 was detectable also in untreated cells. N-terminal amino acid sequencing of partiallypurified p41 and p42, and polyclonal antibodies
newly raised against different partial peptide
sequences revealed that p41 was a N-terminal truncation form of p42, and p42 was identified as SETb
(TAF-Ib), one of two SET isoforms. The cleavage site
was at carboxyl end of SNHD 18 of p42. A caspasespecific inhibitor or overexpressing of Bcl-2 suppressed radiation-induced p42 cleavage as well as
apoptotic cell death of MOLT-4. In vitro cleavage
experiments with recombinant p42 and either irradiated cell extracts or recombinant caspases, concluded
that the cleavage of p42 into p41 was catalyzed by
caspase(s) mainly by caspase-7.
One of newly raised antibodies specific to p41 or
specific to cleavage site of p42, was found usefulenabling simple detection of p41 by 1-D PAGE insteadof laborious 2-D PAGE. p41 would serve as a marker
of apoptotic cell death. The study on the role and sig-

89

nificance of p41-induction in radiation-induced apoptosis will be continued.
2. The function and the role of DNA-dependent
protein kinase (DNA-PK)
2-1) Target molecules and phosphorylation.
Although more than 30 proteins have been reported as DNA-PK substrates in vitro , it has been
unknown whether these were true targets in vivo. We
recently demonstrated XRCC4, a DNA ligase IV-associated protein, as the first example of in vivo substrate in response to radiation. We also identified a
new phosphorylation site in p53. Through the generation of phosphorylation-specific antibodies and theanalysis of phosphorylation-site-disruptants, we are
now attempting to clarify the role of the phosphorylation of XRCC4 and p53 in the repair and/or the signaltransduction of DNA double-strand breaks.
2-2) Hyperthermic lability and hyperthermic
radiosensitization
Radiosensitizing effect of hyperthermia has been
widely accepted and applied in cancer therapy.
Although many studies proposed various mechanisms
for the sensitization, the problem has not been solved
and still controversial. We examined hyperthermicstability of purified DNA-PK and its subunits. We
found and proposed heat lability of Ku subunit as apossible mechanism for hyperthermic radiosensitization. We also found that the heat stability of DNA-PK
was much higher in human cells than in rodent cells,
which may reflect the fact that many human cancer
cells are more refractory than mouse tumor cells tohyperthermia. We are now studying to modify stability of DNA-PK for improved hyperthermia-radiation
therapy.
2-3)Wortmannin affects apoptosis other than
repairHigher concentration of wortmannin such as 5μ
M or above, which were required for inhibition of
DNA-PK and ATM, caused enhanced radiation or heat
induced apoptotic cell death in MOLT-4 and V79 cells.
The apoptotic process overrode ongoing repair
process.
2-4) Prediction of radiation sensitivity.
We found that DNA-PK activity was high inhuman esophageal and colon cancer tissues comparedwith control normal tissues. The protein and mRNA
expressions of Ku70, Ku80, and DNA-PKcs were alsohigh in the esophageal and colon cancer tissues. The
protein and mRNA expressions of Ku70/80 correlatedwith DNA-PK activity. However, other studies including our own showed various results and the studies
are inconclusive.

902-5) Phosphorothioate oligonucleotide and its
analogues as inhibitiors of DNA-dependent protein kinase
We are currently studying the functions, the properties and the regulation mechanisms such as posttranslational modifications, of key enzymes in DSB
repair. We reported that phosphorothioate oligonucleotide and its analogue inhibited DNA-PK activity
and sensitized cells to ionizing radiation. The results
also showed 1) Correlation between DNA-PK activity
and radiation sensitivity 2)) Roles of DNA-PK and
ATM in cell-cycle-dependent radiation sensitivity 3)
Activation of epidermal growth factor receptor by ionizing radiation

Future Prospects
We hope that these studies will eventually lead us
to understanding mechanisms of difference in radiation responses among tissues and tumors, to the discovery and development of radiosensitizers/protectors, and also to the construction of gene/protein
array for predictive assay.

Research Grants
1. Scientific Research in Priority Areas (2) (1998-2000,
2001-2002)
P. I. Norio Suzuki"Molecular mechanisms of Radiation-responses andradiosensitivity"
2. Exploratory Research (2002-2003)
P. I. Norio Suzuki"DNA- and Protein-array for radiosensitivity"
3. Scientific Research in Priority Areas (2) (2001)
P. I. Yoshio Hosoi"Prediction of radiation sensitivity and radio-sensitization using DNA-dependent protein kinase"
4. Scientific Research in Priority Areas (2) (2001-2002)
P. I. Yoshihisa Matsumoto"The function of DNA-dependent protein kinase inradiation response and its possible application incancer radiation therapy I"
5. Grant-in-Aid for Young Scientists (B) (2001-2002)
P. I. Atsushi Enomoto"Analysis of the signal-transduction pathways andthe gene expressions using DNA micro-array systemon radiation effects"

Select Publications
1. Suzuki, N., Kawabe, S., Matsushima, T., and
Sugimura,T. Molecular species of aldolase in the liverof tumor-bearing rats. Gann 60, 433-437, 1969.

2. Sugimura, T., Sato, S., Kawabe, S., Suzuki, N., Chen,
T. C., and Takakura, K. Aldolase C in brain tumor.
Nature 222, 1070, 1969.
3. Suzuki, N., and Okada,S. Location of Ala 32 gene
replication in the cell cycle of cultured mammaliancells, L5178Y. Mutat. Res. 30, 111-116, 1975.
4. Suzuki, N., and Okada,S. Isolation of nutrient deficient mutants and quantitative mutation assay byreversion of alaniene-requiring L5178Y cells. Mutat.
Res. 34, 489-506, 1976.
5. Suzuki, N., and Okada,S. γ-Ray mutagenesis of cultured mammalian cells in vitro and in vivo.
Mutat.Res. 43, 81-90, 1977.
6. Suzuki, N., Withers, H. R., and Hunter, N.
Radiosensitization of mouse spermatogenic stem
cells by Ro-07-0582. Radiat.Res. 69, 598-601, 1977.
7. Suzuki, N., Frapart, M., Gardina, D. J., Meistrich, M.
L., and Withers, H. R. Cell cycle dependency ofmetastatic lung colony formation. Cancer Res. 37,
3690-3693,1977.
8. Nakamura, N., Suzuki, N., Harakawa, H., andOkada,S. Mutagenicity of furylfuramide, a food preservative tested by using alanine-requiring mouse
L5178Y cells in vitro and in vivo. Mutat.Res. 46,355364, 1977.
9. Okamura, S., Suzuki, N., Ishikawa, H., and Yamada,E. Quantitative changes in organelles during the cell
cycle of mouse leukemia cells as studied by electron
microscopy. Cell Struct. and Func. 2, 229-240, 1977.
10. Mian, T. A., Suzuki, N., Glenn, H. J., Haynie, T. P.,
and Meistrich, M. L. Radiation damage to mouse
testis cells from 99mTc pertechnetate. J. Nucl. Med.
18,1116-1122, 1977.
11. Suzuki, N., Withers, H. R., and Lee, L. Y. Variabilityof DNA content of murine fibrosarcoma cells. Nature
269, 531-532, 1977.
12. Suzuki, N., Withers, H. R., and Williams, M.
Radiation response in vitro in vivo of various clones
from a fibrosarcoma. Radiat.Res. 74, 503-504, 1978.
13. Suzuki, N., and Withers, H. R. Isolation from amurine fibrosarcoma of cell lines with enhanced plating efficiency in vitro. J.Natl.Cancer Inst. 60,179-183,
1978.
14. Suzuki, N., Withers, H. R., and Williams, M.
Heterogeneity and variability of artificial lung colony
forming ability among clones from a mouse offibrosarcoma. Cancer Res. 38, 3349-3351, 1978.
15. Meistrich, M, L., Hunter, N. R., Suzuki, N., Trostle, P.
K., and Withers, H.R. Gradual regeneration of mouse
testcular stem cells after ionizing radiation. Radiat.
Res. 74, 371-384, 1978.
16. Suzuki, N., and Withers, H. R. Exponential decraese
duringaging
andrandomlifetimeof mouse spermatogonial stem cells. Science 202,
1214-1215, 1978.
17. Suzuki, N., and Withers, H. R. Lung colony formation as a selective cloning process for lung colony
forming ability. Br. J. Cancer 39, 196-199, 1979.
18. Suzuki, N., Williams, M., Hunter, N. M., andWithers, H. R. Malignant properties and DNA con-tent of daughter clones from a mouse fibrosarcoma
differentiation among malignant properties. Br. J.
Cancer 42, 765-771, 1980.
19. Suzuki, N. Spontaneous versus artificial lung metastasis discrepant effect of whole-body irradiation in
NFSA2ALM and NFSA1SLM tumor systems. J. Natl.
Cancer Institute 71, 835-839, 1983.
20. Suzuki, N. New method to quantitate clonogenic
tumor cells in the blood circulation of mice. Cancer
Res. 43, 5451-5455, 1983.
21. Suzuki, N. Variant selection and blood-borne“Clonogenic” tumor cells in metastasis of FSA cellclones. Br. J. Cancer 48, 827-833, 1983.
22. Suzuki, N. Radiation response of “Clonogenic” tumorcell release from NFSA2ALM1 tumors. Radiat. Res.
98, 649-655, 1984.
23. Suzuki, N. Centrifugal elutriation and characterization of tumor cells from the venous blood of tumorbearing-mice possible relevance to metastasis. Cancer
Res. 44, 3505-3511, 1984.
24. Sakai, K., Suzuki, N., Nakamura, N., and Okada, S.
Induction and subsequent rapair of DNA damage by
fast neutrons in cultured mammalian cells.
Radiat.Res. 110, 311-320, 1987.
25. Suzuki, N., and Mizukoshi, T. Effect of low dosed ofwhole body irradiation on spontaneous lung metastasis of NFSA-2-ALM1 mouse tumors. Radiat.Med. 5,801-803, 1987.
26. Kobayashi, Y., Okabe, T., Urabe, A., Suzuki, N., andTakaku,F. Human granulocyte colony stimulating
factor produced by escherichia coli shortens the period of granulocytopenia induced by irradiation in
mice. Jpn. J. Cancer Res. 78, 763-766, 1987.
27. Sakata, K., Okada, S., Majima, H., and Suzuki, N.
Linear quadratic model of radiocurability on multicellular spheroids of human lung adenocarcinoma LCT1
and mouse ficrosarcoma FSA., Int. J. Radiat. Biol. 61,
269-274, 1992.
28. Majima, H., Kashiwado, K., Egawa, S., and Suzuki, N.
Interaction between the kinetics of thermotolerance
and effect of cis-diamminedichloroplatinum(II) or
bleomycin given at 37 ℃ or 43 ℃ . Int. J.
Hyperthermia 8, 431-442, 1992.
29. Kobayashi, S., Kasuya, M., Ishii, Y., Takehana, M.,
Sakai, K., Suzuki, N., and Itoi, M.
30. Effects of 2-mercaptopropionylglycine on the development of X-ray-induced cataract in rats. Current
Eye Reseach 11, 1099-1103, 1992.
31. Takakura, K., Ishikawa, M., Minegishi, A., Sakai, K.,
Suzuki,N., and Okada, S. Inverse dose-rate effect of
DNA breaks and inactivation of transforming activity induced by tritated water and 60Co gamma-rays.
Radiat. Envitron. Biophys. 31, 299-310,1992.
32. Hosoi, Y., and Kapp, Y. Expression of a candidate
ataxia-telangiectasia group D gene in cultured fibroblast cell lines and human tissues. Int. J. Radiat. Biol.
66, s71-s76, 1994.
33. Morimatsu, A., Suzuki, N., Hirano, K., Sakai, K., andMatsumoto, Y. Identification and characterization of91

X-ray-induced proteins in human T cell leukemia. J.
Radiat. Res. 37, 1-11, 1996.
34. Matsumoto, Y., Suzuki, N., Sakai, K., Morimatsu, A.,
Hirano, K., and Murofushi, H. A possible mechanism
for hyperthermic radiosensitization mediatedthrough hyperthermic lability of Ku subunits in
DNA-dependent protein kinase. Biochem. Biophys.
Res. Commun. 234, 568-572, 1997.
35. Hosoi, Y., Miyachi, H., Matsumoto, Y., Ikehata, H.,
Komura, J., Ishii, K., Zhao, H. J., Yoshida, M., Takai,Y., Yamada, S., Suzuki, N., and Ono, T. A phosphatidylionsitol 3-kinase inhibitor, wortmannin,
induces radioresistant DNA synthesis, and sensitizes
cells to bleomycin and ionizing radiation. Int. J.
Cancer 78, 642-647, 1998.
36. Matsumoto, Y., Umeda, N., Suzuki, N., Sakai, K., andHirano, K. A gel-electrophoretic analysis for
improved sensitivity and specificity of DNA-dependent protein kinase activity. J. Radiat. Res. 40, 183186, 1999.
37. Morita, A., Suzuki, N., Matsumoto, Y., Hirano, K.,
Enomoto, A., Zhu, J., and Sakai, K. p41 as a possible
marker for cell death is generated by caspase cleavage of p42/SETβ in irradiated MOLT-4 cells.
Biochem. and Biophys. Res. Commun. 278, 627-632,
2000.
38. Enomoto, A., Suzuki, N., Hirano, K., Matsumoto, Y.,
Morita, A., Sakai, K., and Koyama, H. Involvement of
SAPK/JNK pathway in X-ray-induced rapid cell deathof human T-cell leukemia cell line MOLT-4. Cancer
lett. 155, 137-144, 2000.
39. Matsumoto, Y., Suzuki, N., Namba, N., Umeda, N.,
Ma, X.-J., Morita, A., Tomita, M., Enomoto, A.,
Serizawa, S., Hirano, K., Sakai, K., Yasuda, and H.,
Hosoi, Y. Cleavage and phosphorylation of XRCC4
protein induced by X-irradiation. FEBS lett, 478, 6771, 2000.
40. Kang, Y., Hirano, K., Suzuki, N., Enomoto, A.,
Morita, A., Irimura, T., and Sakai,K. Increased
expression after X-irradiation of MUC1 in cultured
human colon carcinoma HT-29 cells. Jpn. J. Cancer
Res. 91, 324-330, 2000.
41. Tomita, M., Suzuki, N., Matsumoto, Y., Hirano,K.,
Umeda, N., and Sakai, K. Sensitization by wortmannin of heat-or X-ray induced cell death in cultured
chineses hamster V79 cells. J. Radiat. Res. 41, 93102, 2000.
42. Zhao, H.-J., Hosoi, Y., Miyachi, H., Ishii, K., Yoshida,M., Nemoto, K., Takai, Y., Yamada, S., Suzuki, N.,
and Ono, T. DNA-dependent protein kinase activity
correlates with Ku70 expression and radiation sensitivity in esophageal cancer cell lines. Clin. Cancer
Res. 6, 1073-1078, 2000.
43. Ono, T., Ikehata, H., Nakamura, S., Saito, Y., Hosoi,
Y., Takai, Y., Yamada, S., Onodera, J., andYamamoto, K. Age-associated increase of spontaneous mutant frequency and molecular nature ofmutation in newborn and old lacZ-transgenic mouse.
Mutat. Res. 447 165-177, 2000.

92

44. Nakamura, S., Ikehata, H., Komura, J., Hosoi, Y.,
Inoue, H., Gondo, Y., Yamamoto, K., Ichimasa, Y.,
and Ono, T. Radiation-induced mutation in spleen
and brain of plasmid-based lacZ transgenic mouse.
Int. J. Radiat. Biol. 76, 431-440, 2000.
45. Sakata, K., Matsumoto, Y., Tauchi, H., Satoh, M.,
Oouchi, A., Nagakura, H., Koito, K., Hosoi, Y.,
Suzuki, N., Komatsu, K., and Hareyama, M.
Expression of genes involved in repair of DNA double-strand breaks in normal and tumor tissues. Int. J.
Radiat. Oncol. Biol. Phys. 49, 161-167, 2001.
46. Sakata, K., Matsumoto, Y., Satoh, M., Oouchi, A.,
Nagakura, H., Koito, K., Hosoi, Y., Hareyama, M.,
and Suzuki, N. Clinical studies of immunohistochemical staining of DNA-dependent protein kinase inoropharyngeal and hypopharyngeal carcinomas.
Radiat. Med. 19, 93-97, 2001.
47. Enomoto, A., Suzuki, N., Liu, C., Kang, Y., Zhu, J.,
Serizawa, S., Matsumoto, Y., Morita, A., Ito, M., andHosoi,Y. Involvement of c-Jun NH2-terminal kinase1 in heat-induced apoptotic cell death of humanmonoblastic leukemia U937 cells. Int. J. Radiat. Biol.
77, 867-874, 2001.
48. Mori, N., Matsumoto, Y., Okumoto, M., Suzuki, N.,
and Yamate, J. Variations in Prkdc encoding the catalytic subunit of DNA-dependent protein kinase(DNA-PKcs) and susceptibility to radiation-induced
apoptosis and lymphomagenesis. Oncogene 20,
3609-3619, 2001.
49. Ishii, T., Futami, S., Nishida, M., Suzuki, T.,
Sakamoto, T., Suzuki, N., and Maekawa, K. Briefnote and evaluation of acute-radiation syndrome andtreatment of a tokai-mura criticality accident patient.
J. Radit. Res. 42, S167-S182, 2001.
50. Nakagawa, K., Kozuka, T., Akahane, M., Suzuki, G.,
Akashi, M., Hosoi, Y., Aoki, Y., Ohtomo, K.
Radiological findings of accidental radiation injury of
the fingers A case report. Healph phys. 80, 67-79,
2001.
51 Hosoi, Y., Matsumoto, Y., Tomita, M., Enomoto, A.,
Morita, A., Sakai, K.,Nakagawa, K., Umeda, N., Zhao,
H,-J., Ono, T., and Suzuki, N. Phosphorothioate
oligonucleotides, suramin and heparin inhibit DNAdependent protein kinase activity. Br. J. Cancer 86,
1143-1149, 2002.
52 Yoshida, M., Hosoi, Y., Miyachi, H., Ishii, N.,
Matusmoto, Y., Enomoto, A.,Nakagawa, K., Yamada,S., Suzuki, N., and Ono, T. Roles of DNA-dependent
protein kinase and ATM in cell-cycle dependent radiation sensitivity in human cells. Int. J. Radiat. Biol.
78, 503-512, 2002.
53 Komuro, Y., Watanabe, T., Hosoi, Y., Matsumoto, Y.,
Nakagawa, K., Kitayama, J., Suzuki, N., and Nagawa,H. The expression pattern of Ku correlates withtumor radiosensitivity and disease free survival inpatients with rectal carcinoma. Cancer 95, 11991205, 2002.

Department of
System Physiology
Outline and Research Objectives
This department was originally a part of the Research Institute of Medical Electronics
operated by the School of Medicine, but in 1997, when the University of Tokyo restructured
its system of education and research, the Institute became the Division of Biomedical
Engineering in the Graduate School of Medicine. The Division of Biomedical Engineering
consists of three departments: Bioimaging and Biomagnetics, Biosystem Construction andControl, and our own System Physiology.
This laboratory has been pursuing research on the biomechanics of phenomena in thehuman body, especially focusing on cellular sensing and response mechanisms to mechanical stimuli. The main theme of our work has been the relationships between the mechanicalforce generated by blood flow, shear stress and the cells exposed to it, vascular endothelial
cells. Research on this theme will be of benefit not only in understanding blood-flow-mediated regulation of vascular functions but in elucidating issues that are of importance clinically, such as angiogenesis, vascular remodeling, and atherogenesis, all of which occur in a
blood flow-dependent manner.
Original biomedical engineering methods have been applied in which cultured endothelial cells are exposed to controlled levels of fluid shear stress in a dynamically designed flow
apparatus (Fig. 1) and their responses are analyzed at the cellular and molecular levels.

Faculty and Students
Professor and Chair Joji Ando, M.D., Ph.D. (since 2000)
Lecturers
Masahiro Shibata, Ph.D.
Associates ...............................1
Graduate Students ..................3

Past Research and Major Accomplishments
Our studies have involved experiments on the following:
1. Endothelial cell responses to shear stress
2. Shear stress-mediated regulation of endothelial
gene expression
3. Shear stress signal transduction in endothelial cells
4. In vivo analysis of blood flow effects
And the results are described below.

Fig. 1.

Endothelial cell responses to shear stress
Our studies have demonstrated that endothelial
cells exhibit functional responses to shear stress.
When a cultured endothelial cell monolayer was partially denuded, surrounding cells migrated and proliferated in the denuded area, and covered it. Shearstress enhanced the regenerative functions ofendothelial cells (Microvasc Res 1987, Biorheology,1990), and it increased the production of nitric oxide,a potent vasodilator, in endothelial cells in a dosedependent manner (BBRC 1994). It also increased theexpression of thrombomodulin, an antithrombotic
molecule, in endothelial cells (BBRC 1994). By contrast, shear stress decreased the expression of vascular cell adhesion molecule-1(VCAM-1), which led toinhibition of leukocyte adhesion to endothelial cells(BBRC 1993, Am J Physiol 1994). A collaborative study

A silicon-tube-type flow-loading apparatus.

93manner (BBRC 1991, 1993). Flow-induced Ca 2+
responses generally start at a locus at the cell edge
and propagate throughout the entire cell in the formof a Ca 2+ wave (Fig. 3). The initiation locus corresponds precisely to caveola-rich cell edges (Proc Natl
Acad Sci 1998). We recently found that a subtype of
ATP-gated cation channel, the P2X4 receptor, isexpressed in human vascular endothelial cells andthat P2X4 receptors play a crucial role in the shear
stress-dependent Ca2+ response (Am J Physiol 2000,
Circ Res 2000).

showed that shear stress increases the levels of
adrenomedulin and C-type natriuretic peptide mRNA,
which have vasodilating effects (Hypertension 1997),
and that it augments the expression of low density
lipoprotein receptor (LOX-1) at both the protein andmRNA level (Circ Res 1998).
Shear-stress-mediated regulation of endothelial
gene expression
We have demonstrated that shear stress regulates
endothelial gene expression transcriptionally and/or
posttranscriptionally. It downregulates VCAM-1 genetranscription via the double AP-1 binding element(TGACTCA) in the promoter, which functions as ashear stress-responsive element (Am J Physiol 1997).
Fig.2 shows shear stress-induced changes in
VCAM-1 mRNA levels determined by the reverse
transcriptase PCR method. Shear stress has also beenshown
toincrease
the
level
of
granulocyte/macrophage-colony stimulating factor(GM-CSF) via mRNA stabilization (Circ Res 1988).
Differential display analysis showed that approximately 600 known and unknown transcripts are upor down-regulated in human umbilical vein endothelial cells exposed to a shear stress of 15 dynes/cm2 for
6 h (BBRC 1996), and a cDNA encoding an unknown
G-protein coupled receptor was cloned from theseshear stress-responsive genes (BBRC 1997).
Shear-stress signal transduction in endothelialcells
We were the first to show that Ca2+ signaling plays
an important role in the mechanism by which
endothelial cells recognize the shear stress signal andtransmit it into the cell interior (In Vitro Cell Dev Biol
1988) . Strong shearing forces induced by rubbing
endothelial cells with a balloon cause an increase incytoplasmic Ca2+ concentrations (Biorheology 1994). A
relatively weak shearing force, such as the shear
stress generated by fluid flow, requires the presenceof extracellular ATP to induce a Ca2+ response, and atseveral hundred nanomolar ATP, intracellular Ca2+
concentrations increase in a shear-stress-dependent94

Fig. 3. A flow-induced Ca2+ wave in an endothelial cell.

In vivo analysis of blood flow effects
Blood flow effects on capillary permeability tomacromolecules and angiogenesis have been investigated in vivo by intravital microscopy. We developed
a new intravital slit-laser microscanning method toquantitatively measure permeability to fluoresecentlabeled proteins at the distal end of arterioles, themiddle of capillaries and the proximal end of venules
in rabbit skeletal muscle tissue (Microvasc Res 1995,
1997). Permeability has been shown to increase withblood flow, indicating that shear stress regulates capillary protein permeability (Jpn J Physiol 1991, 1992).
We also investigated the relationship between capillary blood flow and tissue oxygen demand (Microvasc
Res 1985). We observed that increases in blood flow,which were induced by arterio-venous shunt oradministration of a-blocker, augmented the formationand development of new capillaries (Microvasc Res
1998). Our computer simulations have demonstrated
that formation of capillary networks in mammals corresponds well to an optimum model calculated fromthe oxygen supply efficiency in tissues (Microvasc Res
1995). An intravital laser microscope that utilizes aphosphorescence quenching technique was recently
developed to determine both microvascular and interstitial oxygen concentrations (J Appl Physiol 2001).

Current Research
Ongoing research in our laboratory include projects designed to 1) identify molecules that function asa flow sensor or shear-stress sensor in endothelial
cells, 2) analyze endothelial genes that respond toshear stress, 3) investigate effects of shear force on
the differentiation of endothelial progenitor cells, 4)
study the microcirculation.
Flow-sensing molecules: Our recent studies haverevealed that endothelial cells convert information on
shear stress into changes in intracellular Ca2+ concen-

trations, and that P2X4 purinoceptors and their ligand
ATP play an important role in the Ca2+ signaling. To
examine the role of P2X4 receptors as flow-sensors,
P2X4 cDNA was transfected into human embryonickidney (HEK) cells, and cell lines that stably express
P2X4 receptors were established. As shown in Fig. 4,
the control HEK cells did not show any Ca2+ response
to shear stress, whereas HEK cells that stably
expressed P2X4 receptors showed a shear stressdependent Ca2+ response. Thus, ectopic expression of
P2X4 receptors made the HEK cells sensitive to flow,
suggesting that P2X4 receptors function as a flow sensor. More recently, it has been demonstrated that
endothelial cells release ATP in response to shear
stress, and the endogenously released ATP is involvedin the activation of P2X4 receptors. Shear stress-sensing mechanisms are currently being investigated interms of ATP release.

recently observed that shear stress augments proliferation, differentiation, and tube-formation by EPCs.
This means that mechanical forces can manipulate thedifferentiation of EPCs. These techniques are ofpotential use in clinical applications, such as in thedevelopment of tissue-engineered vessels and celltherapy for ischemic vascular diseases.
Microcirculation study: Oxygen-sensing molecules that play an important role in the regulation ofvascular resistance are now being investigated, and an
in vivo optical method has been developed to monitor
pO2 distribution in skeletal muscle arterioles. We
have observed a significant drop in pO2 in the arterioles and a large pO2 gradient in the arteriolar walls,
indicating that the endothelial cells and/or smoothmuscle cells of arterioles may consume much more
oxygen than expected. We are also developing an insitu vascular Ca2+imaging system to explore the cellular mechanism of the effects of flow and hypoxia on
vascular tone.

Future Prospects
We intend to expand our research vascular biomechanics research to research on tissue engineering,atherosclerosis, and the vascular physiome in the near
future.

Fig. 4. P2X4 cDNA transfection makes HEK cells sensitive toshear stress.

Shear-stress-responsive genes: A high throughput
genomic analysis of gene expression using DNA
microarrays has been used to gain a more complete
appreciation of the extent and biologic significance ofendothelial activation by shear stress. Comparison of
the transcriptional activity of approximately 6,000
unique genes has revealed that laminar shear stressup- or down -regulates the expression of approximately 4% of the genes examined in endothelial cells.
Turbulent shear stress, which is closely related to theconditions under which atherosclerosis develops,
changed the expression of about 1.5% of the genes
examined. These genes included many of the genes
known to function in vascular remodeling, such as
genes encoding plasminogen activator, transforming
growth factor and metalloproteinase. Attention is
now focused on the role of these shear stress responsive genes in atherogenesis.
Effects of shear force on cell differentiation:
Endothelial progenitor cells (EPCs) have recently beenfound to circulate in blood vessels, migrate into tissues, and participate in neovascularization, and we

Vascular biomechanics: To elucidate the physiological or pathophysiological significance of shear
stress, shear stress-sensing molecules will be identified and knockout mice will be produced. Novel drugs
that can modulate the shear stress sensors will be
developed and applied to the treatment of vasculardiseases.
Tissue engineering: Techniques for manipulatingcell functions by mechanical forces will be developed
and applied to the preparation of tissue-engineeredblood vessels. A technique that allows reconstitutionof endothelial progenitor cells to a 3-dimensional, capillary-like structure under flow conditions will be used
to produce engineered capillary network tissue. The
capillary module will be expanded to an innovative
tissue engineering approach to produce blood-vesselcontaining engineered tissues, such as liver andmyocardial tissue.
Atherosclerosis research: Athero-prone or -protective genes will be identified among genes that
respond to turbulent shear stress. An in vitro modelof tissue-engineered atheroma will be established byarranging conditions, such as genetic background,
hemodynamics, and lipids related to atheroscelerosis.
The results of these studies may be useful in develop-95ing a novel therapy for atherosclerosis.
Vascular physiome: The term “physiome” isderived from “physio- (life)” and “-ome” (as a whole),
and means the quantitative and integrated descriptionof physiological functions based on information on
the genome, and proteome, and bioinformatics.
Mechanical forces generated in blood vessels regulate
vascular growth and remodeling in the human body.
An integrative description, including modeling, of themechanical force-mediated vascular controlling system will be conducted, and this is called the “vascularphysiome”.

Research Grants
1. Grants-in-Aid for Scientific Research from theJapanese Ministry of Education, Culture, Sports,
Science and Technology
Basic Research (A) 1995-1996 23,000, 000 Yen
2. Grants-in-Aid for Scientific Research from theJapanese Ministry of Education, Culture, Sports,
Science and Technology
Basic Research (A) 1997-1998 21,500, 000 Yen
3. Grants-in-Aid for Scientific Research from theJapanese Ministry of Education, Culture, Sports,
Science and Technology
Basic Research (A) 1999-2000 27, 900, 000 Yen
4. Special Coordination Funds for Promoting Scienceand Technology from the Japanese Ministry of
Education, Culture, Sports, Science and Technology
1998-2002 28, 000, 000 Yen
5. Grants-in-Aid for Scientific Research from theJapanese Ministry of Education, Culture, Sports,
Science and Technology
Basic Research (A) 2001-2002 28, 195, 000 Yen

Select Publications
1. M. Isshiki, J. Ando, K. Yamamoto, T. Fujita, Y. Ying,
R.G.W. Anderson: Sites of Ca2+ wave initiation movewith caveolae to the trailing edge of migrating cells.
J. Cell Sci. 115:475-484, 2002
2. R. Korenaga, K. Yamamoto, N. Ohura, T. Sokabe, A.
Kamiya, and J. Ando: Sp1-mediated downregulationof P2X4 receptor gene transcription in endothelial
cells exposed to shear stress. Am. J. Physiol Heart
Circ. Physiol. 280: H2214-H2221, 2001
3. M. Shibata, S. Ichioka, J. Ando, and A. Kamiya:
Microvascular and interstitial PO2 measurements in
rat skeletal muscle by phophorescence quenching. J.
Appl. Physiol. 91: 321-327, 2001
4. S. Kato, J. Ando, and T. Matsuda: mRNA expression
on shape-engineered endothelial cells: Adhesion
molecules ICAM-1 and VCAM-1. J. Biomed. Mater.
Res. 54:366-372, 2001
5. M. Negishi, D. Lu, Y-Q Zhang, Y. Sawada, T. Sasaki,
T. Kayo, J. Ando, T. Izumi, M. Kurabayashi, I.
Kojima, H. Masuda, and T. Takeuchi: Upregulatory

96

expression of furin and Transforming growth factorb by fluid shear stress in vascular endothelial cells.
Arterioscler Thromb Vasc Biol. 21:785-790, 2001
6. K. Yamamoto, R. Korenaga, A. Kamiya, and J. Ando:
Fluid shear stress activates Ca2+ influx into humanendothelial cells via P2X4 purinoceptors. Circ. Res.
87:385-391, 2000
7. K. Yamamoto, R. Korenaga, A. Kamiya, Z. Qi, M.
Sokabe, and J. Ando: P2X4 receptors mediate ATPinduced calcium influx in human vascular endothelial cells. Am. J. Physiol Heart Circ. Physiol.
279:H285-H292, 2000
8. J. Ando, R. Korenaga, and A. Kamiya: Shear StressDependent Regulation of Endothelial Cell Functions.
In “New Frontier in Vascular Biology; Thrombosis &Hemostasis”, K. Suzuki et al. eds., Eibun Press,
Osaka, pp199-215, 2000
9. J. Ando, R. Korenaga, and A. Kamiya: Flow-induced
endothelial gene regulation. In “Mechanical Forces
and the Endothelium”, P.I. Lelkes ed., Harwood
Academic Publishers, London, pp111-126, 1999
10. M. Nagase, J. Abe, K. Takahashi, J. Ando, S. Hirose,and T. Fujita: Genomic organization and regulationof expression of the lectin-like oxidized low-density
lipoprotein receptor (LOX-1) gene. J. Biol. Chem.
273:33702-33707, 1998
11. T. Murase, N. Kume, R. Korenaga, J. Ando, T.
Sawamura, T. Masaki, and T. Kita: Fluid shear stresstranscriptionally induces lectin-like oxidized LDL
receptor-1 in vascular endothelial cells. Circ. Res.
83:328-333, 1998
12. K. Masatugu, H. Itoh, T-H. Chun, Y. Ogawa, N.
Tamura, J. Yamashita, K. Doi, M. Inoue, Y.
Fukunaga, N. Sawada, T. Saito, R. Korenaga, J. Ando,and K. Nakao: Physiologic shear stress suppresses
endothelin-converting enzyme-1 expression in vascular endothelial cells. J. Cardiovasc. Pharmacol. 31:
S42-S45, 1998
13. M. Isshiki, J. Ando, R. Korenaga, H. Kogo, T.
Fujimoto, T. Fujita, and A. Kamiya: Endothelial Ca2+
waves preferentially originate at specific loci in caveolin-rich cell edges. Proc. Natl. Acad. Sci. U.S.A. 95:
5009-5014, 1998
14. H. Watanabe, R. Takahashi, X-X. Zhang, Y. Goto, H.
Hayashi, J. Ando, M. Isshiki, M. Seto, H. Hidaka, I.
Niki, and R. Ohno: An essential role of myosin lightchain kinase in the regulation of agonist- and fluidflow-stimulated Ca 2+ influx in endothelial cells.
FASEB J 12: 341-348, 1998
15. K. Kosaki, J. Ando, R. Korenaga, T. Kurokawa, and
A. Kamiya: Fluid shear stress increases the production of granulocyte-macrophage colony-stimulating
factor by endothelial cells via mRNA stabilization.
Circ. Res. 81:794-803, 1998
16. S. Ichioka, M. Shibata, K. Kosaki, Y. Sato, K. Harii,
and A. Kamiya: In vivo measurement of morphometric hemodynamic changes in the microcirculation
during angiogenesis under chronic a1-adrenergic
blocker treatment. Microvasc. Res. 55: 165-174, 1998

17. Y. Takada, C. Kato, S. Kondo, R. Korenaga, and J.
Ando: Cloning of cDNAs encoding G protein-coupled
receptor expressed in human endothelial cells
exposed to fluid shear stress. Biochem. Biophys. Res.
Commun. 240: 737-741, 1997
18. R. Korenaga, J. Ando, K. Kosaki, M. Isshiki, Y.
Takada, and A. Kamiya: Negative transcriptional regulation of the VCAM-1 gene by fluid shear stress inmurine endothelial cells. Am. J. Physiol. 273: C1506C1515, 1997
19. T. Chun, H. Itoh, Y. Ogawa, N. Tamura, K. Takaya,
T. Igaki, J. Yamashita, K. Doi, M. Inoue, K.
Masatsugu, R. Korenaga, J. Ando, and K. Nakao:
Shear stress augments expression of C-type natriuretic peptide and adrenomedulin. Hypertension
29:1296-1302, 1997
20. M. Miyasaka, H. Kawashima, R. Korenaga, and J.
Ando: Involvement of selectins in atherogenesis: A
primary or secondary event? Atherosclerosis IV:
Recent Advances in Atherosclerosis Research, NewYork Academy of Sciences 811:25-35, 1997
21. J. Ando, H. Tsuboi, R. Korenaga, K. Takahashi, K.
Kosaki, M. Isshiki, T. Tojo, Y. Takada, and A.
Kamiya: Differential display and cloning of shear
stress-responsive messenger RNAs in humanendothelial cells. Biochem. Biophys. Res. Commun.
225: 347-351, 1996
22. Y. Wang, W.S. Shin, H. Kawaguchi, M. Inukai, M.
Kato, A. Sakamoto, Y. Uehara, M. Miyamoto, N.
Shimamoto, R. Korenaga, J. Ando, and T. Toyo-oka:Contribution of sustained Ca2+ elevation for nitricoxide production in endothelial cells and subsequent
modulation of Ca2+ transient in vascular smooth muscle cells in coculture. J. Biol. Chem. 271:5647-5655,
1996
23. J. Ando and A. Kamiya: Flow-dependent regulationof gene expression in vascular endothelial cells. Jpn.
Heart J. 37: 19-32, 1996
24. A. Kamiya and J. Ando: Responses of vascularendothelial cells to fluid shear stress: Mechanism. In“Biomechanics-Functional Adaptation andRemodeling”, K. Hayashi et al. eds., Springer-Verlag,
Tokyo, pp29-56, 1996
25. H. Tsuboi, J. Ando, R. Korenaga, Y. Takada, and A.
Kamiya: Flow stimulates ICAM-1 expression timeand shear stress-dependently in human endothelial
cells. Biochem. Biophys. Res. Commun. 206:988-996,
1995
26. M. Shibata, T. Kawamura, M. Sohirad, and A.
Kamiya: A new fluorescence microscopy for tomographic observation of microcirculation by using dual
beam slit laser illumination. Microvasc. Res. 49: 300314, 1995
27. Y. Takada, F. Shinkai, S. Kondo, S. Yamamoto, H.
Tsuboi, R. Korenaga, and J. Ando: Fluid shear stressincreases the expression of thrombomodulin by cultured human endothelial cells. Biochem. Biophys.
Res. Commun. 205:1345-1352, 1994
28. W. Yang, J. Ando, R. Korenaga, T. Toyo-oka, and A.
Kamiya: Exogenous nitric oxide inhibits proliferationof cultured vascular endothelial cells. Biochem.
Biophys. Res. Commun. 203:1160-1167, 1994
29. J. Ando, H. Tsuboi, R. Korenaga, Y. Takada,
N.Toyama-Sorimachi, M. Miyasaka, and A. Kamiya:
Shear stress inhibits the adhesion of cultured mouseendothelial cells to lymphocytes by down-regulating
VCAM-1 expression. Am. J. Physiol. 267:C679-C687,
1994
30. J. Ando, A. Ohtsuka, Y. Katayama, R. Korenaga, C.
Ishikawa, and A. kamiya: Intracellular calcium
response to directly applied mechanical shearing
force in cultured vascular endothelial cells.
Biorheology 31:57-68, 1994
31. R. Korenaga, J. Ando, H. Tsuboi, W. Yang, I. Sakuma,
T. Toyo-oka, and A. Kamiya: Laminar flow stimulates ATP- and shear stress-dependent nitric oxide
production in cultured bovine endothelial cells.
Biochem. Biophys. Res. Commun. 198:213-219, 1994
32. A. Kamiya and J. Ando: Fluid shear stress and vascular endothelial cell biomechanics. In “Clinical
Biomechanics and Related Research”, Y. Hirasawa,
C.B. Sledge, S.L.-Y. Woo eds., Springer-Verlag Tokyo
pp. 255-271, 1994
33. A. Kamiya, R. Korenaga, and J. Ando: Endothelial cell
responses to fluid shear stress. In”EndotheliumDerived Factors and Vascular Functions”,T. Masakied., Elsevier Science Amsterdam pp. 103-112, 1994
34. J. Ando and A. Kamiya: Blood flow and vascularendothelial cell function. Frontiers Med. Biol. Engng
5:245-264, 1993
35. R. Korenaga, J. Ando, A. Ohtsuka, I. Sakuma, W.
Yang, T. Toyo-oka, and A. Kamiya: Close correlation
between cytoplasmic Ca++ levels and release of an
endothelium-derived relaxing factor from cultured
endothelial cells. Cell Struct. Funct. 18:95-104, 1993
36. A. Ohtsuka, J. Ando, R. Korenaga, A. Kamiya, N.
Toyama-Sorimachi, and M. Miyasaka: The effect offlow on the expression of vascular adhesion molecule-1 by cultured mouse endothelial cells. Biochem.
Biophys. Res. Commun. 193:301-310, 1993
37. J. Ando, A. Ohtsuka, R. Korenaga, T. Kawamura, and
A. Kamiya: Wall shear stress rather than shear rate
regulates cytoplasmic Ca++ responses to flow in vascular endothelial cells. Biochem. Biophys. Res.
Commun. 190:716-723, 1993
38. M. Shibata and A. Kamiya: Blood flow dependenceof local capillary permeability of Cr-EDTA in the rabbit skeletal muscle. Jpn. J. Physiol. 42: 631-639, 1992
39. M. Shibata, M. Yoshida and A. Kamiya:
Measurement of local capillary permeability in skeletal muscle by microscopic clearance method. Jpn. J.
Physiol. 41: 725-734, 1991
40. J. Ando, A. Ohtsuka, R. Korenaga, and A. Kamiya:
Effect of extracellular ATP level on flow-induced Ca++
response in cultured vascular endothelial cells.
Biochem. Biophys. Res. Commun. 179:1192-1199,
1991
41. O. Ono, J. Ando, A. Kamiya, Y. Kuboki, and H.
Yasuda: Flow effects on cultured vascular endothelial

97and smooth muscle cell functions. Cell Struct. Funct.
16:365-374, 1991
42. J. Ando, S. M. Albelda, and E. M. Levine: Culture ofhuman adult endothelial cells in liquid-liquid interfaces: A new approach to the study of cell matrix
interactions. In Vitro Cell Dev. Biol. 27A:525-532,
1991
43. J. Ando, A. Kawarada, M. Shibata, K. Yamakoshi,
and A. Kamiya: Pressure-volume relationships of finger arteries in healthy subjects and patients withcoronary atherosclerosis measured non-invasively byphotoelectric plethysmography. Jpn. Circ. J. 55:567575, 1991
44. J. Ando, S. Araya, Y. Katayama, A. Ohtsuka, A.
Kamiya: Flow-induced calcium response in cultured
vascular endothelial cells. In “The Regulation ofCoronary Blood Flow”, Inoue et al. eds., SpringerVerlag Tokyo pp 230-241, 1991
45. A. Kamiya, J. Ando, M. Shibata, and H. Wakayama:
The efficiency of the vascular -tissue system for oxygen transport in the skeletal muscle. Microvasc. Res.
39:169-185, 1990
46. J. Ando, T. Komatsuda, C. Ishikawa, and A. Kamiya:
Fluid shear stress enhances DNA synthesis in cultured endothelial cells during repair of mechanicaldenudation. Biorheology 27:675-684, 1990
47. J. Ando, T. Komatsuta, and A. Kamiya: Cytoplasmic
calcium response to fluid shear stress in cultured vascular endothelial cells. In Vitro Cell. Dev. Biol.
24:871-877, 1988
48. H. Nomura, C. Ishikawa, T. Komatsuda, J. Ando, and
A. Kamiya: A disk type apparatus for applying fluid
shear stress on cultured endothelial cell. Biorheology
25:461-471, 1988
49. A. Kamiya, J. Ando, M. Shibata, and H. Masuda:
Roles of fluid shear stress in physiological regulationof vascular structure and function. Biorheology
25:271-278, 1988
50. J. Ando, H. Nomura, and A. Kamiya: The effects of
fluid shear stress on the migration and proliferationof cultured endothelial cells. Microvasc. Res. 33:6270, 1987
51. M. Shibata, and A. Kamiya: Microcirculatory
responses to carotid sinus nerve stimilation at various ambient O2 tension in the rabbit tenuissimus
muscle. Microvasc. Res. 30: 333-345, 198598

Department of
Bioimaging and Biomagnetics
Outline and Research Objectives
Our department was established in 1974, with the objective of promoting research on
engineering science in medicine and biology. In April, 1994, Professor Shoogo Ueno joined
the University of Tokyo, replacing retiring Professor Masao Saito as chairman of theDivision of Engineering Science in the Institute of Medical Electronics. In April 1997, ourdivision re-established itself as the Department of Bioimaging and Biomagnetics. Since its
establishment in 1994, the Department of Bioimaging and Biomagnetics has been engaged
in research on engineering science in medicine and biology. Our department specializes inbiomagnetic research, which includes the measurement of biomagnetic fields, magnetic
stimulation of the brain, and the effects of magnetic fields on biological systems.

Faculties and Students
Professor and Chair Shoogo Ueno, Dr. Eng. (1994~)
Associate Professor Keiji Iramina, Dr. Eng.
Lecturer
Masakazu Iwasaka, Dr. Eng.
Postdoctoral Fellow ..............: 1
Graduate Student................: 15
Research Student ..................: 1
Secretary ...............................: 2

Past Research and Major Accomplishments
We have studied the measurement and control ofbiological systems based on biomagnetism. We develop, integrate, and apply new ideas through innovativeinterdisciplinary research approaches. Our research
topics cover wide areas in medical and biological engineering, including technology for measurement, imaging, and modelling in the following fields.
Magnetic stimulation of biological systems
Measurement of biomagnetic fields
Imaging of Electrical Information Based on
Magnetic Resonance Imaging (MRI)
Effects of magnetic and electromagnetic fields on
biological systems and materials(1) Transcranial magnetic stimulation (TMS) has
become an important tool for the study of the functional organization of the human brain. We developed
a method of localized and vectorial magnetic stimulation using a figure eight coil (Fig.1). This method facilitates stimulation of the motor cortex of the humanbrain within a 5 mm resolution. We studied the cortical excitatory and inhibitory systems, using the technique of paired TMS. We observed that TMS initiates
the excitation of both cortical interneurons andpyramidal tract neurons. Once the pyramidal tract
neurons generate a D-wave, the excitation is unaffected by a conditioning stimulus, which has an inhibitory effect on excitability of pyramidal tract neurons.
(2) For the measurement of biomagnetic fields, wedeveloped a SQUID (superconducting quantum interference device) system with high sensitivity that facilitates the measurement of auditory brainstem evokedmagnetic fields.
We studied higher brain functions associated withshort-term memory and mental rotation processes
using MEG. In the functional information related toshort-term memory processes, a DC-like slow wave
was observed in the period between latencies of 900

Fig.1 Basic principles of magnetic stimulation using a figure-eight coil. (a) A figure-eight coil on the head. (b) A single ring coil andan induced current pattern. (c) A figure-eight coil and an induced-current pattern.

99

msec and 1,500 msec during the short-term memorytask. A mental rotation process requires rotation andmatching of a pair of mental images. Dynamic properties of the electrical current distribution in the humanbrain that correspond to the early mental rotation
processes were investigated.
We also focused on the relationship between MEG
and fMRI and we studied the temporal and spatial
responses of both hemodynamic and neuronal activities. Activation of the primary somatosensory cortex
was investigated using MEG and fMRI. It was possible
with fMRI to discriminate between the area of thethumb and the ring finger in the primary somatosensory cortex. In MEG measurement, however, it is difficult to discriminate between two closely locateddipoles, if no initial information is given.
(3) Conventional MRI does not reveal information
about the electrical properties of the body. We developed new methods to visualize neuronal current distribution and electrical-impedance distribution. The
basic principle is to erase the effects of BOLD (blood
oxygenation level dependent) by subtracting MRI signals with different polarities of gradient magnetic
fields. Measurements were made with an echo planar
imaging (EPI) sequence at 1.5 T. MRI mapping of theneuronal currents in the brain during middle finger
and thumb tapping was clearly observed (Fig.2). A
new method for impedance tomography was introduced, based on MRI techniques. The basic idea ofimpedance imaging is to use the shielding effects of
induced eddy currents on spin precession.

(4) We investigated the dynamic behavior of waterin high gradient magnetic fields. A superconducting
magnet that produced 8 T magnetic fields at the center was used. The maximum product of the magnetic
field and the gradient was 400 T2 / m at z = 75 mm,
where the z-axis was directed along the bore axis. A
water chamber, 50 mm wide, 60 mm high, and 700
mm long was filled with distilled water. When thewater chamber was inserted into the bore, we
observed the phenomenon in which the water wasparted, and the bottom of the water chamber was
revealed. We call this phenomenon the Moses Effect.
A simple calculation shows that the magnetic force
acting on 100 ml of water at 20 ºC is 0.288 N or about
1/3 of the earth’s gravity, when exposed to a magnetic
field of 8 T and 50 T/m. Since the magnetic force acting on diamagnetic and paramagnetic materials moves
the materials along magnetic field gradients, any kindof biological cells and materials can be manipulated bymagnetic force. In contrast, when biological materials
such as fibrin and collagen are exposed to uniform
magnetic fields, parallel or perpendicular orientation
to the magnetic field direction is attained. For example, we successfully oriented adherent cells such assmooth muscle and endothelial cells, and osteoblasts
in parallel to the magnetic field direction after 8T
magnetic field exposure (Fig. 3). The magnetic manipulation and alignment of cells and other biologicalmaterials has opened a new horizon in tissue engineering.

(a) fMRI(b) current MRI
Fig.2 (a) fMRI and (b)MRI mapping of the neuronal currents in the brain during middle finger and thumb tapping.

Fig.3 Magnetically oriented (a) Fibrin (b) Collagen (c) Osteoblasts under an 8T static magnetic field.

100Current Research
Our department is conducting interdisciplinary
research in three major areas: imaging and cognitive
neuroscience, cell and tissue engineering, and theassessment of the biological effects of electromagnetic
fields.
Imaging and cognitive neuroscience
Our research focuses on the development of functional brain dynamics imaging with high time resolution and high spatial resolution. The main techniques
employed are TMS (transcranial magnetic stimulation), MEG (magnetoencephalography), EEG (electroencephalography), electric current imaging by MRI,
and impedance imaging by MRI. These techniques arenoninvasive and very useful for studying higher brain
functions of humans such as memory and cognition.
We developed a 2-channel repetitive transcranial
magnetic stimulator and an EEG measurement systemthat combines TMS. We were able to non-invasively
evaluate the cortical reactivity and functional connections between different brain areas. We used TMS toinvestigate memory encoding and retrieval, particularly the role of the dorsolateral prefrontal cortex inassociative memory for visual patterns. TMS disrupts
associative learning for abstract patterns over theright frontal area, which suggests that the participating cortical networks may be lateralized in accordancewith classic concepts of hemispheric specialization.
We compared current density distributions in electroconvulsive therapy (ECT) and TMS using the finite
element method. While the skull significantly affectedcurrent distributions in ECT, TMS efficiently induced
eddy currents in the brain. Our results will support
clinical investigations to determine the electrode andcoil positions that maximize efficacy.
To investigate the safety aspects of TMS on thebrain, functional and anatomical changes in the brain
were investigated. Our initial experimental results
revealed that TMS does not affect the fEPSP (field
excitatory post synaptic potential) of the rat hippocampus.
We introduced a new method of conductivity tensor imaging using diffusion-weighted MRI to obtain
conductivity tensor distribution of the brain.
Diffusion-weighted images were acquired withmotion probing gradients (MPGs) applied in three
directions. Conductivities in each MPG direction were
calculated from the fast component and the fractionof the fast component, and two-dimensional conductivity tensor was estimated. We also proposed a new
method of electrical current imaging based on the frequency shift technique of MRI.
In another study, we investigated a method for tissue characterization using diffusion tensor analysis

and applied external electrical currents.
Magnetophysiology
We studied the ischemic myocardial muscles of rat
using a high-resolution DC-SQUID magnetometer.
The information about the ischemic myocardium
region and changes of function were obtained bycaridiomagnetic imaging.
We also measured the magnetic fields associatedwith end plate potentials induced from neuromuscular junctions of frogs. Biomagnetic measurements ofsynaptic transmission processes by micro SQUID systems are useful for the physiological and pharmacological studies such as stimulus-excitation-contraction
coupling.
Biological effects of electromagnetic fields
We investigated the effects of strong magnetic
fields (8T, 14T) on the structure, organization, andfunction of biological systems and materials, and thepossible medical and therapeutic applications of magnetic fields.
The effects of 14 T strong static magnetic fields onthe functional properties of biological materials, suchas proteins, oxygen molecules, and water were also
investigated. (1) A spectrum profile of hemoglobin
inside red blood cells indicated conformationalchanges depending on the magnetic flux density. (2)Magnetic field exposure initiated platelet aggregation
with the aid of collagen and accelerated the aggregation of platelets and fibrin. (3) Leukemia cell proliferation was decreased by an 8 T magnetic field, as aresult of behavioural changes of dissolved oxygen during exposure. (4) Magnetic fields inhibited bioluminescence of luciferin and luciferease in both in vitro
and in vivo experiments. Possible applications of magnetic fields for the control of biochemical reactions
were suggested.
We explored the possible medical applications ofmagnetically oriented collagen. Magnetically aligned
collagen provides a scaffold for smooth muscle cells(A7r5), osteoblasts (MC3T3), nerve cells (PC12 andSchwann cells), and blood vessels on which to grow,and it directs the growth to a specific direction.
Further experiments, however, demonstrated themagnetic orientation of adherent cells without collagen guidance after long-term exposure to static magnetic fields. Further studies must be carried out toclarify the detailed mechanisms which include thediamagnetic properties of the cells. Our findings maylead to clinically viable treatments of bone fracturesand bone defects as well as medical engineering applications such as nerve regeneration.
With the ever-increasing worldwide use of mobile
phones in recent years, social concerns and anxieties
have been raised about the possible detrimental

101

effects on human health. We investigated the effects
of high frequency electromagnetic field exposure onrats.
We investigated the effects of exposure to thestandard frequency of electromagnetic waves used forcellular phones in Japan (1,439 MHz) on the permeability of the blood brain barrier (BBB), brain morphological changes, body mass fluctuations, and cognitive
functions and memory restoration of male SpragueDawley rats.
Our results suggest that exposure to a TDMA field
at levels much stronger than emitted by cellular
phones do not affect the learning and memory
processes when there are no thermal effects. In our
most recent study, however, we investigated theeffects of 1439 MHz TDMA electromagnetic fields on
sleep disturbance or melatonin synthesis in rats. The
pineal melatonin level decreased with short-term
TDMA exposure, whereas the serum melatonin level
was unchanged. Short-term TDMA exposure may
inhibit pineal melatonin synthesis in this limited
experiment. Further studies are currently underway
to confirm and explain our initial results.

erates or prevents damage to injured rat hippocampal
CA3 cells as well as our study on the magnetic orientation of Schwann cells for nerve regeneration.
Researches on the cellular responses to magnetic
fields will also proceed by analyzing the genetic
responses as well as the morphological changes ofcells under strong static magnetic fields. Magneticallyinduced cytoskeleton displacement in an intact cell
will be observed during both long and short-term
magnetic field exposures. A new technique for the
remote handling of macromolecules in living systems
by electromagnetic forces will also be developed.

Research Grants
1. 2000-2004 Grant-in Aid for Specially Promoted
Research, Ministry of Education, Science, Sports,
Culture and Technology, Japan (No. 12002002.)
386,000,000Yen “Study of Dynamic Brain Function
using Transcranial Magnetic Stimulation and
Neuronal Current Imaging”
2. 1998-2000 Grant-in Aid for Scientific Research (A),Ministry of Education, Science, Sports, Culture andTechnology, Japan (No. 10308037) 35,800,000Yen“Control of living systems by strong magnetic fields”

Future Prospects
In the next 3.5 years, we hope to achieve significant progress in our three major areas of research:
imaging and cognitive neuroscience, cell and tissue
engineering, and the assessment of biological effects
of electromagnetic fields.
By determining how the brain works, from thelevel of neurons to the relationships between complex
neural networks, a myriad of medical, therapeutic andengineering applications will be developed. The combination of neuromagnetic imaging techniques willallow us to understand the dynamic interactions
between individual cells and larger neural networks
that give rise to the patterns of electrical activity associated with higher brain function. We hope to determine where and how signals for various higher cognitive processes arise within the brain using TMS, EEG,
MEG, and MRI. The development of new imaging
methods to better visualize brain activity will also provide a wealth of new information. For example, our
new MR imaging techniques will be helpful for the
early detection of neurological disorders, such as acutecerebral infarctions. Ultimately, we hope the information retrieved will uncover the roots of neurologicaland psychiatric diseases.
By determining the effects of electromagnetic
fields on biological materials and systems and understanding the mechanisms involved, we can develop
many potentially viable cell and tissue engineering
applications. For example, we will continue ourresearch to determine whether repetitive TMS regen-102

Select Publications
1. Iramina K, Maeno T, Kowatari Y, and Ueno S: Effectsof transcranial magnetic stimulation on EEG activity.
IEEE Transactions on Magnetics, 38(5): in press,
2002.
2. Huang SF, Iramina K, Yumoto M, and Ueno S:
Visual-evoked magnetic fields associated with geometric and phonetic discrimination. IEEE
Transactions on Magnetics, 38(5): in press, 2002.
3. Kotani H, Kawaguchi H, Shimoaka T, Iwasaka M,
Ueno S, Ozawa H, Nakamura K, and Hoshi K: Strong
static magnetic field stimulates bone formation to adefinite orientation in vitro and in vivo. Journal of
Bone and Mineral Research, 17(10): 1814-1821, 2002.
4. Hong B, Kuwaki T, Kihwan J, Kumada M, Akai M,
and Ueno S: Changes in blood pressure and heart
rate by repetitive transcranial magnetic stimulationin rats. Neuroscience Letters, 329: 57-60, 2002.
5. Sekino M and Ueno S: Comparison of current distributions in electroconvulsive therapy and transcranial
magnetic stimulation. Journal of Applied Physics,
91(10), 8730-8732, 2002.
6. Epstein CM, Sekino M, Yamaguchi K, Kamiya S andUeno S: Asymmetries of prefrontal cortex in humanepisodic memory: Effects of transcranial magnetic
stimulation on learning abstract patterns.
Neuroscience Letters, 320(1-2): 5-8, 2002.
7. Uchida S, Goto K, Tachikawa A, Iramina K, and Ueno
S: Magnetocardiographic imaging for ischemic
myocardial muscles on rats. IEICE Transactions on
Information and Systems, 65-D(1): 30-35, 2002.

8. Niijima S and Ueno S: MEG source estimation using
the fourth order MUSIC method. IEICE Transactions
on Information and Systems, E85-D(1): 167-174,
2002.
9. Iwaki S, Tonoike M, and Ueno S: Visualization of thebrain activity during mental rotation processing
using MUSIC-weighted lead-field synthetic filtering.
IEICE Transactions on Information and Systems,
E85-D(1): 175-183, 2002.
10. Kasai K, Yamada H, Kamio S, Nakagome K, Iwanami
A, Fukuda M, Itoh K, Koshida I, Yumoto M, Iramina
K, Kato, M, and Ueno S: Brain lateralization for mismatch response to across- and within-categorychange of vowels. NeuroReport, 12(11): 2467-2471,
2001.
11. Iramina K, Kamei H, Yumoto M, and Ueno S: Effects
of repetition rate of electric stimulation on MEG and
fMRI signals. IEEE Transactions on Magnetics, 37(4):2918-2920, 2001.
12. Iwasaka M, Yaoita M, Kono T, and Ueno S:
Magnetically disturbed activity of immobilized catalase on an electrode in hydrogen-peroxide buffer.
IEEE Transactions on Magnetics, 37(4): 2941-2943,
2001.
13. Iwasaka M, Miyakoshi J, and Ueno S: Opticalabsorbance of hemoglobin and red blood cell suspensions under magnetic fields. IEEE Transactions on
Magnetics, 37(4): 2906-2908, 2001.
14. Iwasaka M, Miyakoshi J, and Ueno S:
Magnetophoresis of diamagnetic cells and microorganisms in a culture medium. IEEE Transactions on
Magnetics, 37(4): 2644-2646, 2001.
15. Ogiue-Ikeda M., Kotani H, Iwasaka M, Sato Y, andUeno S: Inhibition of leukemia cell growth undermagnetic fields of up to 8T. IEEE Transactions on
Magnetics, 37(4): 2912-2914, 2001.
16. Umeno A, Kotani H, Iwasaka M, and Ueno S:
Quantification of adherent cell orientation and morphology under strong magnetic fields. IEEE
Transactions on Magnetics, 37(4): 2909-2911, 2001.
17. Hayashi R, Imaizumi S, Mori K, Niimi S, Ueno S, andKiritani S: Elicitation of N400m in sentence comprehension due to lexical prosody incongruity.
NeuroReport, 12(8): 1753-1756, 2001.
18. Iwasaka M, Takeuchi M, and Ueno S: Aggregation ofblood platelets in static magnetic fields. IEEE
Transactions on Magnetics, 36(5): 3721-3723, 2000.
19. Uchida S, Iramina K, Goto, K, and Ueno S: A comparison of iterative minimum norm estimation and current dipole estimation for magnetic field measurements from small animals. IEEE Transactions on
Magnetics, 36(5): 3724 -3726, 2000.
20. Tsuda R and Ueno S: Source localization of visually
evoked magnetic fields to stimuli in apparent
motion. IEEE Transactions on Magnetics, 36(5):3727-3729, 2000.
21. Tsurita G, Nagawa H, Ueno S, Watanabe S, and Taki
M: Biological and morphological effects on the brain
after exposure of rats to a 1439 MHz TDMA field.
Bioelectromagnetics, 21: 364-371, 2000.

22. Ichioka S, Minegishi M, Iwasaka M, Shibata M,
Nakatsuka T, Harii K, Kamiya A, and Ueno S: Highintensity static magnetic fields modulate skin microcirculationandtemperatureinvivo .
Bioelectromagnetics, 21: 183-188, 2000.
23. Liu R and Ueno S: Calculating the activating functionof nerve excitation in inhomogeneous volume conductor during magnetic stimulation using the finite
element method. IEEE Transactions on Magnetics,
36(4): 1796-1799, 2000.
24. Kotani H, Iwasaka M, Ueno S, and Curtis A:
Magnetic orientation of collagen and bone mixture.
Journal of Applied Physics, 87(9): 6191-6193, 2000.
25. Uchida S, Iramina K, Goto K, and Ueno S: Current
source imaging for high spatial resolution magnetocardiography in normal and abnormal rat cardiac
muscles. Journal of Applied Physics, 87(9): 62056207, 2000.
26. Tsurita G, Ueno S, Tsuno N, Nagawa H, and Muto T:
Effects of exposure to repetitive pulsed magnetic
stimulation on cell proliferation and expression ofheat shock protein 70 in normal and malignant cells.
Biochemical
andBiophysicalResearch
Communications, 261(3): 689-694, 1999.
27. Iramina K, Kamei H, Uchida S, Kato T, Ugurbil K,
Yumoto M, and Ueno S: Effects of stimulus intensity
on fMRI and MEG somatosensory cortex using electrical stimulation. IEEE Transactions on Magnetics,
35(5): 4106-4108, 1999.
28. Kamei H, Iramina K, Yoshikawa K, and Ueno S:
Neuronal current distribution imaging using magnetic resonance. IEEE Transactions on Magnetics, 35(5):4109-4111, 1999.
29. Yukawa Y, Iriguchi N, and Ueno S: Impedance magnetic resonance imaging with external AC field
added to main static field. IEEE Transactions on
Magnetics, 35(5): 4121-4123, 1999.
30. Uchida S, Iramina K, Goto K, and Ueno S: High-resolution magnetocardiography for the study of dynamic propagation of excitation sites in rat cardiac muscles. IEEE Transactions on Magnetics, 35(5): 41244126, 1999.
31. Nakagawa S and Ueno S: Measurements and source
estimations of extremely low frequency brain magnetic fields in a short-term memory task by a wholehead neurogradiometer. IEEE Transactions on
Magnetics, 35(5): 4130-4132, 1999.
32. Nakagawa S, Ueno S, and Imada T: Changes inparameters pf auditory evoked magnetic fields withclick train patterns. Journal of Applied Physics, 85(8):5708-5710, 1999.
33. Sugase Y, Yamane S, Ueno S, and Kawano K: Global
and fine information coded by single neurons in thetemporal visual cortex. Nature, 400(6747): 869-873,
1999.
34. Iwaki S, Ueno S, Imada T, and Tonoike M: Dynamic
cortical activation in mental image processing
revealed by biomagnetic research. NeuroReport, 10:
1793-1797, 1999.

10335. Ueno S: Biomagnetic approaches to studying thebrain. IEEE Engineering in Medicine and Biology, 18:
108-120, 1999.
36. Ueno S and Iriguchi N: Impedance magnetic resonance imaging: a method for imaging of impedance
distributions based on magnetic resonance imaging.
Journal of Applied Physics, 83(11): 6450-6452, 1998.
37. Iramina K, Hong B, Uchida S, Goto K, and Ueno S:
Measurements of biomagnetic fields using a high-resolution dc superconducting quantum interference
device magnetometer. Journal of Applied Physics,
83(11): 6465-6467, 1998.
38. Iwaki S and Ueno S: Weighted minimum-norm
source estimation of magnetoencephalography utilizing the temporal information of the measured data.
Journal of Applied Physics, 83(11): 6441-6443, 1998.
39. Iwasaka M and Ueno S: Structure of water molecules
under 14T magnetic field. Journal of Applied Physics,
83(11): 6459-6461, 1998.
40. Mihara H, Iriguchi N, and Ueno S: A method of rf
inhomogeneity correction in MR imaging. MR
Materials in Physics, Biology and Medicine, 7: 115120, 1998.
41. Iwasaka M, Takeuchi M, Ueno S, and Tsuda H:
Polymerization and dissolution of fibrin underhomogenous magnetic field at 14T. Journal ofApplied Physics, 83(11): 6453-6455, 1998.
42. Iwasaka M and Ueno S: Bioluminescence under static
magnetic fields. Journal of Applied Physics, 83(11):6465-6458, 1998.
43. Ichioka S, Iwasaka M, Shibata M, Harii A, Kamiya A,
and Ueno S: Biological effects of static magnetic
fields on the microcirculatory blood flow in vivo: apreliminary report. Medical and BiologicalEngineering & Computing, 36: 91-95, 1998.
44. Kobayashi M, Hyodo A, Kurokawa T, and Ueno S:
The first component of polyphasic motor evoked
potentials is resistant to suppression by paired transcranial magnetic stimulation in humans. Journal of
the Neurological Sciences, 159: 166-169, 1998.
45. Iramina K, Yumoto M, Kamei H, and Ueno S:
Measurement of somatosensory evoked responseusing functional MR images and MEG. IEEE
Transactions on Magnetics, 33(5): 4260-4262, 1997.
46. Iwaki S and Ueno S: A high-speed estimation ofinternal electrical sources in the human brain from
the MEG measurement using subspace scanningwith multiple scanning resolutions. IEEE
Transactions on Magnetics, 33(5): 4272-4274, 1997.
47. Kobayashi M, Ueno S, and Kurokawa T: Importanceof soft tissue inhomogeneity in magnetic peripheral
nerve
stimulation
mechanism.
Electroencephalography
andClinical
Neurophysiology, 105: 406-413, 1997.
48. Iramina K and Ueno S: Source estimation of spontaneous MEG activity and auditory evoked responses
in normal subjects during sleep. Brain Topography,
8(3): 297-301, 1996.
49. Fujiki M, Isono M, Hori S, and Ueno S: Corticospinal
direct response to transcranial magnetic stimulation

104

in humans. Electroencephalography and Clinical
Neurophysiology, 101: 48-57, 1996.
50. Iwasaka M, Ueno S, and Tsuda H: Measurement ofclottability of fibrin polymers using magnetic orientation. Journal of Applied Physics, 79(8): 4708-4710,
1996.

Department of Biosystem
Construction & Control
Outline and Research Objective
This department was established in 1964 as Division of Clinical Medicine in Institute ofMedical Electronics for research and development of the advanced diagnostic and therapeutic instruments for the clinical medicine and their related technologies. The education to
train the leaders of biomedical engineer and clinical engineer is its another important role.
The first The name of the department and institute has been changed as shown above sinceApril 1, 1997 with the structural reform of Faculty of Medicine.
This department has been cooperating with Division of Artificial Biomechanism,Research Center for Advanced Science and Technology (RCAST) presided by Associate Prof.
Chinzei and Division of advanced Biomedical Engineering & Life Science, Center for
Cooperative Research (CCR) presided by Prof. Mabuchi in the recent 10 years. Both laboratories, 10 Km distant, are connected with a personal microwave television system for all-day
long to exchange many information, to have a periodical research meeting and to monitor
the artificial heart animals from each other.
Our research fields are artificial heart, artificial valve, biomaterials, medical laser, medical
thermography, measurement instruments and sensors, and micromachine.

Faculties and Students
Professor and Chair Kou Imachi, Ph. D.(1993 -)Associate Professors Yusuke Abe, M. D., Ph. D.
Lecturer
Takashi Isoyama, Ph. D.
Associate .................................1
Technical Assistant ................1
Graduate Students ..................2
Guest Researchers...................6
Secretary .................................1
Professor Emeritus Kazuhiko Atsumi, M. D., Ph. D.,
Iwao Fujimasa, M. D., Ph. D.

Past Research and Major Accomplishments
Professor Imachi joined to Institute of Medical
Electronics in 1970 as a student of Graduate School of
Medicine, University of Tokyo, after he got the master’s degree of mechanical engineering at Kyoto
University and spent 2 years at Hitachi Chemical Co.
Ltd. as a chemical plant research engineer. Since thattime he has been studying biomedical engineeringand he became Associate in 1972, Associate professor
in 1987 and Professor in 1993. The past research andmajor accomplishments performed by him and his
group are shown in the following;
1. Artificial heart
The artificial heart(AH) study is world famous
research project having a long history since 1959.
Almost all the research fields such as driving mechanism, blood pump, artificial valve, materials, measure-ment & control method, circulatory physiology andpathophysiology have been developed and studied.
They are summarized in Figure1.
Our peculiar policy for AH research is shown in
Table 1. According to the policy, we have been
approaching to an implantable total AH(TAH) withquite different way from other groups and haveobtained many accomplishments summarized inTable 2. Among these accomplishments, trying 4
types of TAH, development of jellyfish valve, deviceof 1 / R control method, 3 times of the world longest
survival record under TAH goat, proposal of many
pathophysiological hypothesis, and invention ofundulation pump are the most unique and remarkable
outputs.
2. Biomaterials
Concerning the biomaterials, the mechanism ofthrombus formation and calcification on the medical
polymer surfaces, especially in the artificial heart
blood pump and on polymer valve have been studied.
The evaluation of biocompatibility of many biomaterials was also important task.
3. Medical laser
Medical laser research in this laboratory was started in 1965. Ruby laser, CO 2 laser, Nd-YAG laser,
excimer laser, argon laser, semiconductor laser havebeen studied. Laser scalpel, laser coagulator, laser
endoscopes for percutaneous intradiscal laser
nucleotomy, for colonary laser angioplasty and for
percutaneous mitral valvotomy, were developed. As

105

Table 1 The policy of AH research in our laboratory
Never copy the foreign countries project (respect the other person’s originality)
Don’t be captured by the existing laws and theories(there is no common sense in interdisciplinary field research)
Don’t cling to your background
Have always hypothesis
Don’t change the system until it runs into a stone wall
Don’t change more than 2 parameters at once
Try to make all the things by yourself (Speed is the most important)
Don’t hesitate to publish the negative data (truth is hidden in the negative data)

Table2 Accomplishments in AH research in this laboratory
Four types of TAH,: FTAH(1963-1980), HTAH(1977-1982), TRAH(1981-1996) and ITAH(1996-)
FTAH: TAH with fibrillated natural heart
HTAH: Hybrid TAH, Natural heart is beating but trunks of PA and Ao is occluded
TRAH: Total replacement AH, NH is resected and 2 pumps are placed on the chest wall
ITAH: Implantable TAH, All the components except energy source are implantedHome made artificial valves
OED(Oblique elliptical seat door type) valve 1971 - 1978
Jellyfish valve: polymer membrane valve(1987 - )Control method
Fixed cardiac output
Fixed cardiac output with electrical stimulation
1 / R control
World longest survival record with TAH in goat
1980: 288 days with HTAH
1984: 344 days with TRAH
1995: 532 days with TRAH under 1 / R control
Hypothesis
Hyper cardiac output syndrome: 1973 - 1975
Cardiac receptor hypothesis:: 1982 - 1895
Calcification mechanism hypothesis: 1995 - 2000
Blood pump & materials
Critical surface roughness to promote thrombus for mation(3 mm): 1970
Surface coating of segmented polyurethane on PVC: 1973 Multi-material test method of blood compatibility: 1984 - 1990
Clinical device development
Pneumatic driven ventricular assist device in cooperation with Aisin Seiki & Nippon Zeon Co. Ltd.:1990 -106for the basic research, the influence of various kindsof lasers on living tissue, laser therapy for tumor andcancer, laser neurotomy, bactericidal effect of laser
were investigated.
4. Medical thermography
Research of medical thermography in this laboratory was started in 1965. Since that time, many kindsof infrared thermography for clinical use has beendeveloped in cooperation with Fujitsu, Nihon-denshi,NEC, Nihonkoden Co.Ltd, etc.. As the basic and application researches, theoretical model construction toestimate subcutaneous blood flow from thermogram,digital processing of thermogram, dynamic thermography, standardization of clinical daignosis, thermotome, thermo-myotome, etc were studied.
5. Measurement instruments and sensors
Portable electro-magnetic flow(EMF) meter, EMF
flow probe for AH, blood lactate measurement instrument, remote monitoring system of AH animals
through microwave TV, implantable CCD probe toobserve microcirculation were developed.
6. Micromachine
Micromachine research was started in 1987. The
word “micromachine” was made in this laboratorywhen we began to start a society for the study of
micro-mechanical system in 1988. Artificial muscle
moved by vibrating energy, regenerative nerve electrode, micro-laser endoscope were studied and developed

Current Research
1. Artificial heart
Since 1996, AH project in this laboratory is
focused on the development of implantable TAH in
which the all components except outer battery andenergy transmission system are implanted into thebody and expected as the substitution of the hearttransplantation. Undulation pump TAH(UPTAH)
which is the most compact TAH in the world wasinvented(Fig. 2). Another merit of UPTAH is that it
can produce any kinds of flow patterns such as
pusatile flow, continuous flow and pulsatile flow on
the continuous flow, etc.. At the present stage, 6 goatssurvived over 1 month including 63 days as thelongest. Now all the components such as blood pump,driving unit, control system, measurement systemand energy transmission system are being made morecompact and increased in durability and reliability.
The influences of nonpulsatile flow on microcirculation and organ function are being in research. A new

Fig.2 Assembled UPTAH

project to develop an implantable ventricular assist
device for clinical use for the bridge to heart transplantation has been ready to start using the undulation pump. According to our calcifiction hypothesis,
the jellyfish valve is improved design to reduce thecreep fatigue. The new designed valve proved almost
10 years durability in-vitro acceleration fatigue testor.
2. Other researches
In the laser research, handy type laser blood coagulator aiming to use in the surgical field, is being
developed and evaluated in the animal experiments.
The imaging of arterial blood flow distribution in theskin and organs using a high speed thermography is
studying. CCD probe to observe microcirculation
chronically is being made compact including focus.
Regenerative nerve electrode to control artificialorgans through nervous signals is improving its tissuecompatibility.
3. New research
Tissue engineering research has started in thisyear. As the first step, valve membrane of jellyfish
valve is trying to make using endothelial cell culture.

Future Prospects
The following researches are scheduled as the
future projects and a part of them is already ready tostart.
Development of a permanent use artificial heart tobe able to substitute the heart transplantation. A
rotary type undulation pump which moves magnetically suspended is begun to design.
Complete the regenerative nerve electrode andfind a control algorithm of artificial organs throughnervous signals.
Development distributed artificial heart system inwhich the artificial blood pumps are connected toeach organs and tissues. Basic study to connect asmall AH to a kidney has already started.

107Regenerative medicine to make a whole organs
from ES cells will be started aiming to how to shortening the growing time utilizing a biomedical engineering technologies.

Research Grants in these 5 Years
1. The Program for Promotion of Fundamental Studies
in Health Science of the Organization for
Pharmaceutical Safety and Research(OPSR) “ Thecomprehensive basic research on the development ofJapanese original implantable total artificial heart”,
Head Investigator: K. Imachi, 170,460,000yen, 1996
– 20002. Grant-in-Aid for Scientific Research (B)(2):” A study
on long-term and continuous observation and analysis of microcirculation under artificial circulation”,
Top Head Investigator: K. Imachi, 16,000,000yen,
1999 – 2000
3. Grant-in-Aid for Scientific Research (A)(2): “Development of a simplified pulsatile left ventricularassist device”, Head Investigator: K. Imachi,
17,200,000yen, 1999 – 2000
4. Grant-in-Aid for Scientific Research (A)(2):”Researchand development of implantable artificial heart forpermanent use”, Head Investigator: Y. Abe,
42,600,000yen, 2000 – 2002
5. Grant-in-Aid for Scientific Research (S):“Comprehensive research for the influence of flow
state of artificial heart on the living body by observation of microcirculation”, Head Investigator: K.
Imachi, 87,900,000yen, 2002 – 2006

Select Publications
1. K. Atsumi, Y. Sakurai, I. Fujimasa, K. Imachi, T.
Nishisaka, I. Mano, H. Ohmichi, J. Mori, N. Iwai and
A. Kouno: Hemodynamic analysis on prolonged survival cases (30 days and 20 days) of artificial total
heart replacement, Trans. Am. Soc. Artif. Intern.
Organs, 21,545-554, 1975.
2. I. Mano, I. Fujimasa, K. Imachi, T. Nishisaka, H.
Ohmichi, J. Mori, N. Iwai, K. Atsumi, Y. Sakurai andI. Kino: Pathophysiological studies of the animals
replaced with the artificial heart. Part II. Concerning
liver,, gastrointestinal tract, kidney, and general discussion, Japanese Heart Journal, 17(3),326-337, 1976.
3. K. Imachi, I. Fujimasa. T. Nishisaka, H. Ohmichi, N.
Iwai, A. Koun, H. Miyake, and K. Atsumi:How toprevent thrombus formation in the artificial heart,
Artificial Organs, 2(Suppl)
4. I. Fujimasa, K. Imachi, H. Ohmichi, S. Takasugi, T.
Nsisaka, N. Iwai, A. Kuno, H. Miyake and K. Atsumi:
A circulatory dynamic model for artificial heart control, Artificial Organs, 2(Suppl.), 214-216, 1978.
5. H. Ohmichi, K. Imachi, I. Fujimasa, T. Nisisaka, N.
Iwai, A. Kouno and K. Atsumi: Hemodynamic andblood gas analysis in total artificial heart replaced
animal during treadmill exercise, Artificial Organs,2(Suppl.) 230-233, 1978.

108

6. K. Atsumi, I. Fujimasa, K. Imachi, N. Satoh, H.
Miyake, N. Takido, N. Iwai and A. Kouno: New
hybrid method of total artificial heart replacementwith natural beating by coronary circulatory preservation, Proceedings of 6th European Society for
Artificial Organs, A1-A6, 1979.
7. K. Imachi, I. Fujimasa, H. Miyake, N. Takido, M.
Nakajima, K. Motomura, A. Kouno, T. Ono, and K.
Atsumi:Evaliation of antithrombogenicity, durability
and biocompatibility of an artificial heart system for
more than 100 days, Artificial Organs, 5(Suppl), 423429, 1981.
8. K. Imachi, I. Fujimasa, H. Miyake, N. Takido, M.
Nakajima, A. Kouno, T. Ono, Y. Mori, S. Nagaoka, S.
Kawase, T. Kikuchi, and K. Atsumi: Evaluation ofpolyurethane sac type blood pump after 232 and 288
days total artificial heart pumping without anticoagulant, Trans Am. Soc. Artif. Intern Organs, 27, 118122, 1981
9. K. Atsumi, I. Fujimasa, K. Imachi, H. Myake, N.
Takido, M. Nakajima, A. Kouno, T. Ono, S. Yuasa, Y.
Mori, S. Nagaoka, S. Kawase and T. Kikuchi: Threegoats survived for 288 days, 243 days and 232 days
with hybrid total artificial heart, Trans. Am. Soc.
Artif. Intern. Organs 27, 77- 82 (1981)
10. A. Ihara, K. Motomura, M. Nakajima, K. Imachi, I.
Fujimasa, and K. Atsumi: Comparative study on
Medical laser system and their evaluation criteria,
LASER-TOKYO’81(K. Atsumi et al Ed.), The Jap Soc
for Laser Med, Tokyo, 22-25, 1981.
11. K. Atsumi, I. Fujimasa, K. Imachi, A. Miyamoto, N.
Takido, M. Nakajima S. Tsukagosi and N. Inou:
Development and evaluation on cardiac ventricularassist device for clinical use, Proceedings of ESAO, 9,231- 234, 1982.
12. Fujimasa, K, Imachi, H. Miyake, M. Iwatani and K.
Atsumi: Thermo-blood flowmetry, microprocessor
processed thermograms, Lecture Notes in Medical
Informatics(Lindberg & Leihertz Ed.), SpringerVerlag, 222-227, 1982.
13. K. Imachi, I. Fujimasa, M. Nakajima, A. Miyamoto,
N. Takido, N. Inou., S. Tsukagoshi, K. Mabuchi, K.
Motomura, A. Kouno, T. Ono, and K. Atsumi:
Evaluation of the metabolic state in a total artificial
heart circulatory system, Progress in Artificial
Organs-1983(Atsumi K et al Ed.), 252-256, ISAO
Press, Cleveland, 1984
14. K. Imachi, I. Fujimasa, M. Nakajima, K. Mabuchi, S.
Tsukagoshi, K. Mtomura, A. Miyamoto, N. Takido,
N. Inou, A. Kouno, T. Ono, and K. Atsumi: Overall
analysis of the causes of pathophysiological problems in total artificial heart in animals by cardiac
receptor hypothesis, Trans. Am. Soc. Artif. Intern.
Organs, 30, 591-596, 1984
15. K. Atsumi, I. Fujimasa, K. Imachi and N. Nakajima:
How can the total artificial heart patient be mobileand enjoy his life with an air driven system?, Trans.
Am. Soc. Artif. Intern. Organs, 30, 86-90, 1984
16. N. Inou, I. Fujimasa, K. Imachi, A. Miyamoto, M.
Nakajima, N. Takido, K. Mabuchi, S. Tsukagoshi, A.

Kouno and K. Atsumi: Quantitative approach todetermine the application time of the left ventricularassist device, Artificial Organs, 8(4), 458-469, 1984
17. Fujimasa, K. Imachi, Y. Kajiyama, K. Atsumi: Cardiac
muscle thermo- graphy, Recent Advances in Medical
Thermology(Francic, Ring & Phillips Ed.), Plenum
Publishing, 375-378, 1984
18. K. Atsumi, I. Fujimasa, K. Imachi, M. Nakajima, S.
Tsukagoshi, K. Mabuchi K. Motomura, A. Kouno, T.
Ono, A. Miyamoto, N.Takido and N. Inou: Longterm heart substitution with an artificial heart ingoats, asaio J., 8(3) 155-165,1985
19. Fujimasa, K. Imachi, M. Nakajima, K. Mabuchi, S.
Tsukagoshim A. Kouno T. Ono, N. Takido, K.
Motomura, T. Chinzei, Y. Abe, and K. Atsumi:
Pathophysiological study of a total artificial heartgoat survived for 344 days, Progress in Artificial
Organs-1985(Y. Nose Ed.),ISAO Press, Cleveland,345-353, 1986
20. Y. Abe, M. Nakajima, Y. Orime, K. Maeda, H. Hata,
S. Hosaka, K. Mabuchi T. Chinzei, M. Asano, I.
Fujimasa, K. Imachi, A. Kouno, T. Ono, and K.
Atsumi: Design of contact end of laser probe for contact irradiation laser angioplasty, Nd-YAG laser inMedicine and Surgery(Y. Oguro et al Ed) Professional
Postgraduate Service K.K.,329-332, 1986
21. K. Imachi, I. Fujimasa, K. Mabuchi, T. Chinzei, Y.
Abe, K. Maeda, K. Imanishi, A. Kouno, T. Ono, andK. Atsumi: A newly designed jellyfish valve for an
artificial heart blood pump, Trans. Am. Soc. Artif.
Intern. Organs, 34(3), 726-728, 1988
22. K. Maeda, T. Chinzei, K. Imachi, K. Mabuchi, Y. Abe,T. Yonezawa K. Imanishi, I. Fujimasa, and K.
Atsumi:Predictive control by physical activity rate ofa total artificial heart during exercise, Trans Am Soc
Artif Inter Organs, 34(3),480-484, 1988
23. K. Mabuchi, M. Nakajima, K. Imachi, I. Fujimasa, Y.
Abe, T. Chinzei K. Maeda, K. Imanishi, M. Asano, T.
Yonezawa, and K. Atsumi: Is atrial natriuretic
polypeptide a cause of pathophysiology in total artificial heart animals?, Trans Am Soc Artif Intern
Organs,34(3),463-465, 1988
24. Y. Abe, T. Chinzei, I. Fujimasa, K. Imachi, K.
Mabuchi, K. Maeda, M. Asano A. Kouno, T. Ono,and K. Atsumi: Development of transcutaneous energy transmission system for totally implantable artificial heart, Artificial Heart 2(T. Akutsu Ed.),SpringerVerlag, Tokyo, 257-261, 1988
25. T. Yonezawa, T. Onomura, Y. Abe, K. Mabuchi, T.
Chinzei, K. Imachi, and K. Atsumi: Comparative
study on excimer,CO2 and Nd-YAG laser for biological tissue cutting, Laser Optoelectronics in
Medicine(R. Waidlich & W.Waidlich Ed), SpringerVerlag,31-34, 1988
26. Y. Abe, T. Chinzei, K. Imanishi, T. Yonezawa, S.
Niwa, K. Yotsuya, I. Sogawa, T. Uemiya, S.
Kanazawa, I. Fujimasa, K. Imachi, M. Suzukawa, K.
Mabuchi, M. Asano, Y. Tago, A. Kouno, T. Ono, andK. Atsumi: Laser angioplasty with excimer laser-animal experiment, SPIE,1066,115-122, 1989

27. T. Yonezawa, T. Onomura, R. Kosaka, Y. Miyaji, S.
Tanaka, H. Watanabe, Y. Abe, K. Imachi,ò K.
Atsumi, T. Chinzei, K. Mabuchi, and I. Fujimasa: The
system and procedures of percutaneous intradiscal
laser nucleotomy, SPINE, 15(11), 1175-1185(, 1990
28. K. Imachi, T. Chinzei, Y. Abe, K. Mabuchi, K.
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29. K. Imachi, K. Mabuchi, T. Chinzei, Y. Abe, K.
Imanishi, T. Yonezawa, A. Kouno, T. Ono, H.
Nozawa, T. Isoyama, K. Atsumi, and I. Fujimasa:
Fabrication of a jellyfish valve for use in an artificial
heart, ASAIO Journal, 38(3), 237-242, 1992
30. K. Imachi, T. Chinzei, Y. Abe, T. Isoyama, K.
Mabuchi, K. Imanishi, T. Ono, A. Kouno, M.
Kusakabe, K. Atsumi and I. Fujimasa: A new apparatus for chronic observation of microcirculation in-situ
to evaluate an artificial organ performance. ASAIO
Journal, 40(3) M757-761, 1994
31. K. Imachi, Y.Abe, T.Chinzei, K.Mabuchi, K.Imanishi,
T.Isoyama, A.Kouno, T.ono and I.Fujimasa: Factors
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32. Y. Abe, T. Chinzei, K. Imachi, K. Mabuchi, K.
Imanishi, T. Isoyama, H. Matsuura, G. Senih, H.
Nozawa, A. Kouno, T. Ono, K. Atsumi, and I.
Fujimasa: Can total artificial heart (TAH) animals
control their TAH by themselves?- One year survivalof a TAH goat with a new automatic control method.
ASAIO J, 40(3) M506-M509, 1994.
33. T. Isoyama., K. Imachi, Y. Abe, T. Chinzei, K.
Imanishi, K. Mabuchi, H. Matuura, I. Fujimasa: New
Version of flow transformed pulsatile total artificial
heart having no electrical switching valve. Artificial
Organs, 19(7), 694-696, 1995.
34. K. Imachi: Implant science of artificial organs: Design
for success. Artificial Organs, 21(11), 1211-1216,
1997.
35. R. Kosaka, T. Onomura, T. Yonezawa, Y. Ichimura,and K. Imachi: Percutaneous laser nucleotomy for
lumbar disc herniation: Preliminary report of early
results and MRI findings, J Orthop Sci, 1, 102-112,
1996.
36. Y. Abe, T. Chinzei, K. Mabuchi, T. Isoyama, K. Baba,
H. Matsuura, A. Kouno, T. Ono, S. Mochizuki, Y.
Sun, K. Imanishi, K. Atsumi, I. Fujimasa and K.
Imachi: Over 500 days’ survival of a goat with a total
artificial heart with 1 / R control. In Heart
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Koyanagi), Springer-Verlag, Tokyo, 34-38, 1998.
37. K. Mabuchi, Y. Abe, S. Shimizu, K. Imachi, T.
Chinzei, H. Matsuura, T. Isoyama, K. Baba, K.
Imanishi, S. Mochizuki, Y. Sun, T. Tago, A. Kouno,
T. Ono, and I. Fujimasa: Pathological study of a goatthat survived for 532 days with a total artificial heart109

using the 1 / R control method. In Heart
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Koyanagi), Springer-Verlag, Tokyo, 313-317, 1998.
38. Y. Abe, T. Chinzei, K. Mabuchi, A. J. Snyder, T.
Isoyama, K. Imanishi, T. Yonezawa, H. Matsuura, A.
Kouno, T. Ono, K. Atsumi, I. Fujimasa, and K.
Imachi: Physiological control of a total artificial
heart-Conductance and arterial pressure based control, J. Appl. Physiol., 84(3), 868-876, 1998.
39. Y. Abe, T. Chinzei, T. Ono, S. Mochizuki, I. Saito, P.
Guba, T. Karita, Y. P. Sun, A. Kouno, T. Isoyama, K.
Baba, and K. Imachi: Implantation of the undulation
pump total artificial heart in the goat, Artificial
Organs, 23(10), 932-938, 1999.
40. K. Imachi, T. Chinzei, Y. Abe, T. Isoyama, S.
Mochizuki, I. Saito, T. Ono, T. Karita, H. Matsuura,
A. Kouno, K. Mabuchi, I. Fuhimasa, and K. Atsumi:
Implantable total artificial heart - History and present status at the University of Tokyo, J. of Artificial
Organs, 2(1): 13-23,
41. T. Karita, K. Imachi, T. Taguchi, M. Akashi, K. Sato,and J. Tanaka: In vitro calcification model Part -1:
Apatite formation on segmented polyurethane containing silicone using an alternate soaking process. J
of Bioactive and Compatible Polymers, 15, 72-84,
2000
42. S. Mochizuki, Y. Abe, T. Chinzei, T. Isoyama, T.
Ono, I. Saito, P. Guba, T. Karita, Y. P. Sun, A. Kouno,
T. Suzuki, K. Baba, K. Mabuchi, and K. Imachi:
Results of animal experiments using an undulation
pump total artificial heart: Analysis of 10 day and 19
day survival, ASAIO Journal, 46(4): 500-504, 2000
43. K. Imachi, T. Chinzei, Y. Abe, K. Mabuchi, H.
Matsuura, T. Karita, K. Iwasaki, S. Mochizuki, Y-P
Son, I. Saito, A. Kouno, and T. Ono: A new hypothesis on the mechanism of calcification formed on a
blood contacted polymer surface. J. of Artificial
Organs, 4(1), 74-82, 2001.
44. Y. Abe, T. Chinzei, T. Isoyama, T. Ono, S.
Mochizuki, I. Saito, K. Iwasaki, M. Ishimaru, T.
Karita, A. Kouno, K. Baba, and K. Imachi: One monthsurvival with undulation pump total artificial heart
in a goat, Artificial Organs, 25(1): 69-71, 2001.
45. Y. Abe, T. Chinzei, T. Isoyama, T. Ono, S.
Mochizuki, I. Saito, K. Iwasaki, M. Ishimaru, A.
Baba, A. Kouno, T. Karita, K. Baba, and K. Imachi:
Progress in the development of the undulation pumptotal artificial heart, J. of Congestive Heart Failure
and Circulatory Support, 1(4), 167-170, 2001, and In
Heart Replacement-Artificial Heart 7(ed. T. Akutsu,
H. Koyanagi), ISIS Medical Media Ltd. England, 167170, 2001.
46. Saito, Y. Abe, T. Chinzei, T. Ono, T. Isoyama, S.
Mochizuki, K. Iwasaki, A. Baba, A. Kouno, T. Karita,
M. Ishimaru, A. Baba, and K. Imachi: Miniature
undulation pump for the study of renal circulation, J.
of Congestive Heart Failure and Circulatory Support,
1(4), 321-325, 2001, and In Heart ReplacementArtificial Heart 7(ed. T. Akutsu, H. Koyanagi), ISIS
Medical Media Ltd. England, 321-325, 2001.

110

47. Y. Abe, T. Chinzei, T. Isoyama, T. Ono, T. Ozeki, I.
Saito, A. Kouno, and K. Imachi: Principle of therotary undulation pump, J Artif Organs, 5(2), 84-90,
2002.
48. K. Iwasaki, M. Umezu, K. Iwasaki, Y.Abe, T.Chinzei,
T.Isoyama, I.Saito, M. Ishimaru, K. Imachi: The
improved jellyfish valve: Durability, enhancementwith sufficient blood compatibility, ASAIO Journal,
48: 532 - 537, 2002.