Project

Advanced Therapeutic Devices

We are working on minimally invasive therapeutic approaches at the area’s core hospitals and advanced hospitals, employing therapeutic devices that combine existing therapeutic technology with high physical energy (radiation, ultrasound, acoustics, shock waves, heat) control technology.

Research Representative
Noriaki Ohuchi

Noriaki Ohuchi, Graduate School of Medicine
Research on Early Diagnosis and Therapy of Cancer by Nanobio Imaging

Imaging technology is very important for the effective development of diagnosis in early stage and treatment methods for cancer. We have been developing the technologies for X-ray computed tomography (CT) imaging or fluorescence imaging with high accuracy and highly-quantitative sensitivity to clarify the mechanism and develop the diagnostic methods for cancer. The X-ray CT imaging has highly-quantitative sensitivity because X-ray absorption coefficients is proportional to the volume of contrast agents. We have been preparing new gold nanoparticles as contrast agents for X-ray CT and developing a CT imaging method for early diagnosis of cancer with the nanoparticles. Fluorescence imaging also has high quantitative sensitivity because the fluorescence signal intensity is proportional to the intensity of the photon excitation energy. To estimate the expression level of protease-activated receptor 1 (PAR1), which play a critical role in cancer metastasis, in breast cancer tissues, user-friendly immunohistochemistry with high quantitative sensitivity was developed using the fluorescence-labelled anti-PAR1 antibody. The immunohistochemistry showed that PAR1 expression correlated strongly with relapse-free survival in human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients. Therefore, the developed anti-PAR1 antibody is a good candidate as a prognostic biomarker of HER2-negative patients.

Visiting Researcher
Yukinari Kato

Yukinari Kato, Graduate School of Medicine
Development of therapeutic devices using tumor-specific antibodies

Human podoplanin (hPDPN) is a type I sialoglycoprotein, which possesses platelet aggregation-stimulating (PLAG) domains in the N-terminus. Among PLAG domains, O-glycan on Thr52 is critical for the binding with C-type lectin-like receptor-2 (CLEC-2), and is essential for platelet-aggregating activity of hPDPN. In contrast, the glycosylation around PLAG domains remains to be clarified. Recently, we established a cancer-specific monoclonal antibody (CasMab) method, which can produce not only CasMabs but also anti-glycopeptide mAbs (GpMabs) that recognize both glycan and amino acids. In this study, we developed novel anti-hPDPN mAbs for the determination of the O-glycosylation sites. LpMab-2, LpMab-3, LpMab-9, and LpMab-12 were shown to detect sialylated O-glycan using several glycan-deficient hPDPN transfectants. By epitope mapping, LpMab-2, LpMab-3, LpMab-9, and LpMab-12 recognized Thr55, Thr76, Thr25, and Thr52, respectively, indicating that these threonines of hPDPN are O-glycosylated. CasMab method is useful for the determination of O-glycosylation sites of membranous glycoproteins.

Researchers

Tsunemoto Kuriyagawa, Graduate School of Engineering
Development of PJD handpieces used for innovative dental therapy approaches   [from FY2012]

Keiichi Sasaki, Graduate School of Dentistry
Development of Therapeutic Device Based on Radical Disinfection Technique for Treatment of Oral Infectious Diseases   [from FY2012]

Hydroxyl radical, one of the reactive oxygen species, is a strong oxidant. Since the radicals kill bacteria by oxidation (Radical disinfection), they can be used as a disinfectant. When the yield of hydroxyl radicals is controlled, disinfection can be achieved in vivo without harmful side effects because bacteria are killed within short treatment time. In this context, we have developed a novel therapeutic device utilizing photolysis of 3% hydrogen peroxide as a generation system of hydroxyl radicals for the treatment of oral infectious diseases, especially periodontitis. The therapeutic device consists of a main unit and a handpiece. The main unit is equipped with 405 nm laser and feed system of hydrogen peroxide, and the handpiece is equipped with an ultrasound transducer and a scaler tip. Thus, ultrasound scaling for the treatment of periodontitis can be performed together with the radical disinfection technique, which is expected to increase the therapeutic gain. To verify the safety and efficiency of the device, a clinical trial in which 55 patients suffering from moderate or severe periodontitis will enroll has been conducted since July 6, 2015. The clinical trial including data analysis is planned to complete in 2016.

Masaaki Sato, Frontier Research Institute for Interdisciplinary Sciences
Development of New Generation Stents Suited to a Wide Range of Conditions   [from FY2012]

Stent placement has received a great deal of attention as a minimally invasive procedure for treating vascular stenotic lesions associated with coronary atherosclerosis. However, the long-term placement of stents can lead to the severe problem of in-stent restenosis in blood vessels. In-stent restenosis results from neointimal thickening from the hyperplasia of smooth muscle cells, caused by the stimulus of the force of the stent on the vascular wall. In the present study, a method to design a bare metal stent with mechanical properties suitable for a wide range of conditions is proposed for lowering the risk of in-stent restenosis. In the method, a stent with mechanical properties sufficient to expand the stenotic part in a blood vessel is designed by applying the mechanical properties of the host blood vessel. The designed stent also has a performance to relax force concentration at the stent ends. In addition, we develop a novel technique to coat a stent with biological molecules for improving biocompatibility. In evaluation using vascular endothelial cells, the developed technique produced an excellent result for improving biocompatibility of the stent material. Thus, this study will enable us to provide a suitable stent with a lower risk of in-stent restenosis.

Hiroaki Shimokawa, Graduate School of Medicine
Development of a non-invasive angiogenic therapy with ultrasound for severe ischemic heart disease   [from FY2012]

Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD. We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle. Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced cardiac function. The heart was treated with either sham or LIPUS (32-cycle with 193 mW/cm2 for 20 min) at 3different short axis levels. LIPUS therapy enhanced angiogenesis and improved myocardial ischemia and contractile function. Based on these promising results, we are conducting a clinical trial in patients with severe angina pectoris to evaluate the efficacy and safety of LIPUS therapy in 8 institutes in Japan. These results suggest that LIPUS therapy is promising as a new, non-invasive therapy for IHD and other ischemic cardiovascular disorders.

Hidetoshi Matsuki, Graduate School of Biomedical Engineering
Development of an intelligent implant magnetic hyperthermia system for cancer therapy   [from FY2012]

Teiji Tominaga, Graduate School of Medicine
Development of laser-induced pulsed water jet surgery system   [from FY2012]

The author will summarize the development of pulsed laser-induced liquid jet surgery system, which facilitates to achieve both maximal resection of the lesion and maximal preservation of the function after the surgery. This technology discriminates from other in terms of no heat damage, tissue selectivity, and high affinity to be incorporated into minimally invasive medical device, such as catheter and endoscopy. The device is now in the phase of clinical study for microsurgery, but had three major barriers during this translational research process. The first barrier being technological issue (how to generate high speed small pulsed water jet), the second being regulatory and IP issues, and the third being business issues (how to increase the market size to facilitate working with the industries for commercialization of the device). Through this research period, our aim is to approve for regulatory approval and commercialize as microsurgical device, and expand over to endoscopic application.

Kei Takase, Tohoku University Hospital
Development of transvenous radiofrequency ablation wire for aldosterone producing microadenoma ablation   [from FY2013]

Prevalence rate of primary aldosteronism Primary aldosteronism is increasingly recognized as a cause of secondary hypertension with prevalence rate of approximately 10% in hypertensive populations. Unilateral aldosterone hypersecretion caused by unilateral aldosterone producing adenoma is a curable form of hypertension. We have performed clinical trial of CT-guided radiofrequency ablation for unilateral aldosterone producing adenoma. However, microadenoma or bilateral aldosterone producing adenomas cannot be treated by interventional procedure. We developed flexible radiofrequency ablation wire and microballoon catheter for transvenous treatment of primary aldosteronism. Catheterization into tributaries of adrenal vein was possible introducing our new devices. Although transvenous radiofrequency ablation of adrenal gland was possible, total area of ablation was not thought to be enough to treat hyper-aldosteronism. Ethanol ablation of adrenal gland was also proved to be possible by animal experiment. Enlargement of ablation area should be achieved by improving the devices.

Masafumi Goto, United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine
Development of a novel device for cell transplantation therapy   [from FY2013]

Toshiro Kaneko, Graduate School of Engineering
Development of a Highly-Efficient and Minimally-Invasive Gene Transfection System Using Atmospheric-Pressure Plasma Devices   [from FY2013]

Controlled non-equilibrium (low-temperature) atmospheric-pressure plasma jet (APPJ) is used for gene/drug transfection system and the cell membrane transport induced by the APPJ irradiation is investigated toward developing minimally-invasive and highly-efficient macromolecule transfer tool. The transfer efficiency and cell viability after direct or indirect plasma irradiation under the various conditions were evaluated through a confocal laser scanning microscope. It is clarified that the high transfer efficiency is realized by optimizing the plasma irradiation time and shortening the diffusion distance of APPJ. Furthermore, the transfer efficiency is significantly improved by the cell-solution electrode APPJ, because the distance between the plasma generation area and the cell solution surface becomes almost zero, which could reduce the radial diffusion loss of the plasma irradiated to the cell solution. The enhancement of the cell membrane permeability (i.e., increase of the transfer efficiency) is found to be caused by three factors of the physical effects, short-lived reactive species, and long-lived reactive species. The cell viability is kept high value (>80%) when the plasma irradiation time is less than 30 s.

Knowledge based Medical Device Cluster / Miyagi Area ICR

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