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Institute for Frontier Medical Sciences, Kyoto University

Department of Reparative Materials

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Our Reserch

Our research group intends to develop engineered materials that contribute practically and efficiently to the advanced therapeutic interventions for the treatment of diseases and traumatic injuries. These materials are expected to exhibit diverse functions in vitro or in vivo. Fundamental and applied studies are undertaken to realize such biomaterials, taking advantage of organic materials, namely polymeric materials and state-of-the-art techniques for analyzing and handling biomolecules and cells. Research subjects currently undertaken in our department are listed below.

> Publications

Surface chemistry of biomedical materials

The surface plasmon resonance technique

Protein adsorption and complement activation are involved in the initial reactions against man-made materials with living bodies. It is necessary to elucidate these mechanisms in relation to the surface properties so as to rationally design biocompatible surfaces of synthetic implants. Most of information on protein adsorption and complement activation by artificial polymeric materials has been accumulated from studies with polymeric materials. However, polymer surfaces could not be assumed rigid and immobile at equilibrium. The polymer molecules in the vicinity of the surface or interface would exhibit motion and relaxation in response to the different interfacial environments. Thus, it is difficult to prepare model surfaces using polymeric materials for studies of the complement activation. Self-assembled monolayers of alkanethiols formed on a gold thin film provide well-defined model surfaces suitable for studies on interfacial phenomena and intermolecular interactions. The surface plasmon resonance technique can be applied to analyze the interfacial phenomena under water. We have been studying protein adsorption, complement activation, and cell adhesion on well-defined surfaces made of self-assembled monolayers using the surface plasmon resonance technique as well other analysis techniques highly sensitive for interfacial molecular events.

Polymeric materials for cell transplantation therapy

Cell-surface modification

Islets of Langerhans have been transplanted to treat insulin-dependent diabetes patients. Adult pancreatic cells are known to have a poor growth capacity. Islets containing cells from cadaver donors or animals should be employed. In bioartificial pancreas, islets are encapsulated into a semi-permeable membrane and then implanted into the diabetic patients to protect them from immune rejection. The semi-permeable membrane permits permeation of oxygen and nutrient which are necessary for islet survival, but prohibits contact of islet cells with components of the host immune system. We encapsulated islets into agarose-based microbeads and induced normalization of blood glucose levels of diabetic recipient mice by implanting 1000 microencapsulated hamster islets into the peritoneal cavity.

Several research groups showed that transplantation of neural stem cells (NSCs) or NSC-derived progenitors to the site of lesions was effective for structural and functional restoration of the central nervous system. However, clinical applications of NSC further require methodological advances especially for controlling the engraftment, proliferation, migration, and differentiation of NSCs. Our approach is to construct composite biomaterials that consist of extracellular matrix (ECM) components and signaling molecules such as growth factors and cell adhesion molecules. We are employing genetic engineering to design rationally such composite biomaterials.

Cell processing technology for regenerative medicine

キメラ蛋白質を構成要素とするデバイスおよび機能材料の設計

Cells and ECMs are important components for regenerative medicine. In recent years, many research groups have devoted enormous efforts to establish in vitro culture conditions in which stem cells, such as ES cells and tissue-derived stem cells, differentiate into various functional cells. Those cells are expected to be very useful for treatment of various diseases. Many kinds of stromal cells have been used to differentiate stem cells to functional cells. However, most of stromal cells preferentially used are derived from mice. Some authorities who are in charge of regulatory issue have pointed out the difficulty to rule out the possibility that retrovirus incorporated in mouse gene will be activated and transferred to stem cells and functional cells derived from stem cells. One of our research activities is focused on the development of stromal cell free culture systems used for the induction of ES cells to various functional cells. ES cells cultured on the substrate, onto which bioactive molecules isolated from stromal cells, are immobilized effectively differentiated to dopaminergic neurons.

Conventional cell culture substrates are not always suitable for cells used for regenerative medicine. Neurons differentiated from ES cells in vitro are very difficult to be collected from a cell culture flask without deterioration of cell functions, because long axons from neurons are easily damaged during detachment of neural cells from the cell culture substrate. Cell sheets but not single cells are needed in some instance, such as regeneration of a skin and a mucous membrane. We have been examining a film of cellulose derivatives for a cell culture substrate. Cells cultured on it are removed by cellulose-degrading enzyme, cellulase, without damaging cells on the substrate.

Cell chips for high-throughput functional screening

Transfectional array

細胞チップによる蛋白質性材料のハイスループット機能アッセイの一例

Functional characterization of human genes may be one of the most challengeable tasks in the post-genome era. Due to a huge number of novel genes discovered in genomics, high-throughput methods are required to express or silence in parallel thousands of genes in living cells. The objective of our study is to fabricate transfectional arrays through patterning of self-assembled monolayers on a gold substrate and the subsequent site-specific spotting of different expression vectors or short interfering RNAs.

Antibody array

Recent progress in stem cell research provides us with promising options of cell sources for use in tissue engineering. However, insufficient knowledge about specific surface antigens expressed on most of stem cells limits their application in regenerative medicine. To solve this problem, we developed a high-throughput analytical method for typing multiple membrane proteins. Our method is based on solid-phase cytometry using an antibody array prepared on a patterned alkanethiol monolayer.

ECM array

Arrays that display a panel of biologically-active substances on a flat plate are promising due to their potential use in functional screening over multiple samples in a parallel fashion. We developed cell-based arrays that displayed combinatorially various ECM-growth factor composites and used them for parallel and rapid screening biomaterials that serve to maintain NSCs and direct the differentiation of NSCs.