BBI Contributing Writer

TSUKUBA, Japan – What formerly was known as the Japan Medical Engineering Society, which has sponsored the medical engineering annual meeting since 1962, has been renamed the Japanese Society for Medical and Biological Engineering (JSMBE; Tokyo) by adding biology to enlarge the society’s scope of activity. Its membership numbers about 2,700. In April, JSMBE held its annual meeting, titled the 44th annual conference of the Japanese Society for Medical and Biological Engineering. Coinciding with the JSMBE meeting, the 6th Asian-Pacific Conference on Medical and Biological Engineering (APCMBE 2005) was held in conjunction with JSMBE at Tsukuba Science City in Ibaragi Prefecture.

Tsukuba Science City, built some 30 years ago under the auspices of the Ministry of Science and Education, has lacked an upsurge of growth, but that may now come with the badly needed improved access via the introduction of the Tsukuba Express train.

JSMBE was attended by about 800 persons and APCMBE by another 400 for a total of some 1,200 persons, not a small gathering for this kind of event. Both meetings had symposia, with more than 30 organized sessions and some 600 and 300 poster sessions by JSMBE and APCMBE, respectively, meaning that most attendees must have been presenters themselves. Five international companies had booths displaying their products in a separate room. Those companies must have displayed their products without knowing that the exhibition was almost completely ignored by Japanese manufacturers. The ongoing sluggish economy may partly be the reason for ignoring the exhibition, but the main reason must have been the inconvenient location and poor access.

The meeting also had poor participation by Japan’s biomedical industry. That is typically what happens when such a meeting is organized by scientists from the University of Tokyo (so-called Todai), who tend to live an “ivory tower” existence. The emphasis of the meetings was heavily focused on presentations of studies on basic science and interdisciplinary research.

The president of the meeting, Professor Sho-go-Ueno of the department of biomedical engineering in the university’s Graduate School of Medicine, said in the abstracts for the meeting that “a multilateral development will be pursued collaborating among the areas ranging from molecular biology to welfare medicine, while maintaining fusion of fundamental principles of medicine and engineering.” Literally to the letter, the presentations included many different fields. While there were quite a large number of people present in the conference hall, the vastness of the hall made the participants look sparse, and in a way, produced a lifeless atmosphere. Practically all presenters had their laptop computers hooked into PC ports at the podium to read proceedings and show relevant scientific data. The conference progressed remarkably efficiently with all the electronic gadgets.

While quite a few presentations were made from joint studies among different universities, the conference lacked conversations such as among scientists and clinicians and there were no lectures designed for laymen to enlighten the public as a whole. With the meetings being purely focused on academics while the rest of the world is eager to commercialize cutting-edge technologies for early diagnosis and treatment of diseases that in turn reduce healthcare cost, the Todai lived up to their reputation. With the primary interest of physicians and patients being what new findings are and when that knowledge will become available for them, topics that appeared to address possible commercialization were as follows.

One interesting theme at a special session titled “Looking into the Body through Fundus-the Window of the Body,” discussed development of a device for ultra-early stage diagnosis of lifestyle-related diseases. A workshop at which several presentations and a panel discussion took place was organized by a group from the New Energy Development Oranization (NEDO; Tokyo). The objective is to develop a new examination device that helps practitioners and family doctors more easily identify diseases derived from an individual’s lifestyle, including cardiovascular diseases and strokes through close examination of fundus vasculature.

The plan is to encourage companies to submit proposals and grant a subsidy to whatever company produces a prominent plan for the development of such a device in order to accelerate the development cycle. If practitioners and family doctors can identify signs of such diseases, it will certainly help in saving many patients in an earliest possible stage, especially among the aging population, who would otherwise prematurely degrade their quality of life. While Japanese ophthalmic devices are internationally known for their high level of precision, such advanced devices are not necessarily reaching remote locations in the country. The status of specialty medical disciplines such as ophthalmology and dentistry still lags behind.

A presentation titled “The Development of Life Science and Regenerative Medicine using Free Electron Laser” was made by Kunio Awazu, PhD, MD, of the Institute of Free Electron Laser in the Graduate School of Engineering at Osaka University (Osaka, Japan). The free electron laser is capable of continuously scanning oscillation wavelength in addition to being able to excite specific molecular vibration in selective order. As a new ionization method in mass analysis, the facility is aiming at establishing a method of analyzing refractory protein, which was conventionally difficult, by using an ultraviolet laser in the FEL/UV-MALDI method. In his experiments, Awazu succeeded in measuring mass of insoluble proteins with high molecular mass (keratin), which previously was not possible to measure. It also was shown that cholesterol ester can be selectively dissociated by irradiating MIR-FEL at 5.75 wavelength.

As a result of that success, Awazu now is aiming at developing an optical guiding hollow fiber system to deliver the laser beam for treatment of lesion inside a vessel. With a theme of “quality control of cells and tissues by means of lasers,” this research is expected to develop into regenerative medicine using FEL as one of an overall base formation toward collective control of cells and tissues in the innovative academic field chosen by the Ministry of Education, Culture, Sports and Science as Osaka University’s core project in the 21st century.

Awazu said that this technology already is being implemented in the field of dentistry. He and his team have succeeded in hardening dentin exposed by decayed enamelum to the hardness similar to that of the enamelum by irradiating a laser beam upon the dentin, thereby restoring hardness not easily eroded by caries. A tooth consists of a dental pulp in the center where blood vessels and nerve fibers cluster and is covered by dentin and then coated by enamelum. Hydroxiapatite, a chemical compound of phosphoric acid and calcium, has a relatively high crystallization characteristic in enameline, while the crystallization of hydroxiapatite in dentin is irregular, rendering the soft tissue vulnerable to caries. The exposure of dentin, therefore, can lead to serious carious tooth problems that can lead to the loss of many teeth all at the same time.

Using a free-electron laser whose wavelength can be freely changed, the team irradiated an extracted tooth with the laser in various different wavelengths. Crystallization of hydroxiapatite in dentin has improved by instantaneous heating by the laser when laser beam in the 9 um band is irradiated and it was confirmed that a material closely resembling to enameline was created. The material also showed that it attained resistance to caries similar to enameline and proved to be effective in preventing carious tooth. The technology has a boundless market in the treatment of periodontitis, which is difficult to cure, and to control its prognosis. The 9 um wavelength is that of existing carbon dioxide gas lasers and therefore the development of the dedicated device should be relatively easy.

Ryo Sudo, PhD, and Professor Kazuo Tanisita of the Center for Life Science and Technology at Keio University (Yokohama, Japan), in collaboration with Professor Toshihiro Mitaka of the department of pathophysiology in the Cancer Research Institute at Sapporo Medical University (Sapporo, Japan), et al., reported their joint study titled “Reconstruction of Ductular Structure by Rat Biliary Epithelial Cells.” The researchers discovered that biliary epithelial cells isolated from a rat’s liver forms small ductular structure between cells. Upon removing liver cells from a biliary duct harvested from an adult rat, the billiary duct was broken into small pieces, dispersed using collagenase and hyaluronidase, and then centrifuged to isolate biliary epithelial cells.

A sandwich culture was made beginning with the fourth day of the culture by overlaying collagen gel into a multilayer. The colony of biliary epithelial cell ceases to expand in the area once the sandwich culture begins, and from the second day of the sandwich culture, small tubule structures begin to form. Observing the cross-section of the colony with a transmission electron microscope, the cells formed a lumen with development of microvilli. There also was a tight binding between cells, and formation of basal membrane was observed.

Performing immunostaining on cells that form the small tubule structure using cytokeratin 19 (CK19), which is the marker for the biliary epithelial cell, cells were confirmed as CK19-positive. From those results, it was found that CK19-positive cell isolated from liver produced a tubular structure resembling a natural biliary duct by using sandwich culture performed in vitro. The researchers also found that the tubular structure was flexible and expandable.

The same group of researchers also made a presentation at APCMBE titled “Reconstruction of 3-D Liver-like Structures by Stacking Cell Layers Cultured on Microporous Membranes,” purportedly for a different end objective from that of the other presentation. One of the researchers, Ryo Sudo, PhD, specializes in tissue engineering at the department of system design engineering at Keio University, and is pursuing reconstruction of liver and vessel.

In order to achieve 3-D culture of hepatocytes, hepatocytes/hepatic progenitor cells needs to be proliferated in vitro. Small hepatocytes, which are one of the hepatocytes/hepatic progenitor cells active in proliferation/differentiation capacity present in the liver in vivo, which also is not differentiated, were chosen. The first step is to two-dimensionally proliferate small hepatocytes on microporous permeable membranes to produce cell sheets, and then to stack up the membranes to multilayers, thereby 3-D tissues were created. Bilayer cells were observed in the boundary between upper and lower porous membranes with a space which appeared to represent bile canaliculi between the upper and the lower cell-layers where development of microvillie, secretion of albumin and tight junction, which appears to represent adhesion (tight junction and desmosomes) were observed by a transmission electron microscope.

Studies on building multi-layer structure of tissues including blood vessels and bile duct are essential in order to reconstruct a total hepatic tissue, and it is the objective of the researchers to reconstruct 3-D tubular structures using small hepatic cells in the human liver. Because the liver is an assembly of hepatic lobule in modular structure, it is assumed that partial replacement of modules may be possible. Such an artificial tissue may be used as an implant for substituting dysfunctional liver, or for drug metabolism tests. The artificial tissues may also be frozen for preservation.

Another study Sudo is pursuing is the regulation of blood vessel formation, based on the fact that cells burrow into gel to form tubular structure by applying stimulation from growth factor. Combining ideas of science and technology with medicine and biology, this research and development is in line with combination products being pursued in the western world.

Aiming at commercialization from the beginning of the multidisciplinary research, Sudo pursues studies in many facets by avoiding any resembling process upon searching existing patents in the process of studies. Such flexibility on the part of researchers typically seen among those in the private universities appears to brighten the outlook toward the future. About 200,000 hepatocirrhosis patients are estimated to exist in Japan, of which some 16,000 are reported to die annually. In addition to those, about 1.4 million hepatitis B and as many as 2 million hepatitis C patients are estimated to exist in Japan. In all aspects of organ transplant, the lack of donors is acutely serious.

Because the liver plays an extremely complex function, the development of an artificial liver replacing organ transplantation is difficult. If substituting the function of the liver by using hepatic cells themselves should become possible, the cost of treatment for hepatic disease may become low compared to organ transplant, providing many hepatic patients with improved quality of life while resulting into a large saving of national health expenditures.

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