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Research concept:

             
    The main objective of our department is to investigate and develop methods, procedures, and technologies which are applicable to basic and clinical medicines as well as basic researches of biology and medicine from the viewpoint of material sciences. The materials to use in the body and to contact biological substances, like proteins and cells, are defined as biomedical materials and biomaterials. In our department, various types of biodegradable and non-biodegradable biomaterials of polymers, metals, ceramics, and their composites, are being designed and created aiming at their clinical applications as well as the development of experimental tools necessary for basic researches of medicine and biology which scientifically support clinical medicine. We are actively proceeding research and development (R & D) of biomaterials to assist reconstructive surgery and apply to drug delivery systems (DDS) for improved therapeutic efficacy. However, it is often difficult for patients to improve their Quality of Life (QOL) only by the therapeutic procedure of reconstructive surgery because the biomaterials applied are of poor biocompatibility and functional substitutability. For organ transplantation, there are several problems to be resolved, such as the lack of donor tissue and organ or the adverse effects of immunosuppressive agents. The two advanced medical therapies currently available are clinically limited in terms of the therapeutic procedure and potential. In these circumstances, a new therapeutic trial, in which disease healing can be achieved based on the natural healing potential of patients themselves, has been increasingly expected. This is termed the therapy of regenerative medicine where the regeneration of tissues and organs is naturally induced to therapeutically treat diseases by artificially manipulating the cell potentials of proliferation and differentiation. The objective of regenerative therapy is to regenerate injured or lost tissues and substitute organ functions by making use of the cell potentials. The regenerative medical therapy is quite different from the reconstructive surgery and organ transplantation from the viewpoint that neither biomaterials and medical devices nor immunosuppressive agents are needed. The basic idea of regenerative therapy is to give cells a local environment which is suitable to promote their proliferation and differentiation, resulting in the cell-based induction of tissue and organ regeneration. It is tissue engineering that is a biomedical technology or methodology to create this environment for the natural induction of tissue regeneration. Generally, there are three factors necessary to induce tissue regeneration, such as cells, the scaffold for cell proliferation and differentiation, and biosignaling molecules of growth factors and the related gene, which are fundamentally 3 components constituting the body tissue. For successful regenerative therapy of tissue and organ, it is indispensable to efficiently combine various biomaterials with the body components. Among biomaterials, biodegradable biomaterials play an important role in this medical applications. Since there are few metals and ceramics with biodegradable nature, polymer materials of biodegradability are generally preferable for this purpose. The combination of polymers with metals or ceramics is effective in preparing material composites of suitable biodegradability. If a biomaterial is degraded to disappear in the body, it is not always necessary to retrieve the material from the body after the function expected is accomplished. In addition, the material should be degraded at the right time profile not to physically impair the natural process of tissue regeneration by the material remaining. Biodegradable biomaterials well-designed are indispensable for the research and development (R&D) of regenerative medical therapy, DDS or basic biology and medicine.  

       Our research goal is to design and create biomaterials from polymers and the composites with metals or ceramics which are practically applicable for regenerative medical therapy, stem cell technology, DDS, and medical therapy of reconstructive surgery and internal medicine. More detailed explanation about every project is described.

Key words; Tissue engineering, DDS,

       Biomaterials(biodegradable, non-biodegradable, and composites)

Figure: Tissue Engineering (jpg.173k)

  

On-going research projects:

  

1) Biomaterials for the Therapy of Regenerative Medicine

    It is well recognized that cells are present in the living tissue interacting with the extracellular matrix (ECM) of natural scaffold for their proliferation, differentiation, and morphogenesis. When the body tissue is largely lost, the ECM itself also disappears. In such a case, only by supplying cells to the defect, we cannot always expect the tissue regeneration at the large defect. One of the possible ways to achieve successful tissue regeneration is to provide a temporary scaffold for the proliferation and differentiation of cells to the defect. We are designing and creating 3-dimensional and porous constructs of biodegradability as this temporary cell scaffold which is an artificial ECM. However, if the number of cells and the amount of biosignaling molecules are not large enough to promote the cell activities, only the supply of a scaffold to the tissue defect will not induce the tissue regeneration. As one trials to break through the situation, it practically possible to make use of growth factors for promoted proliferation and differentiation of cells. It is, however, necessary for in vivo use of growth factors to contrive their administration form because of the in vivo short half-life and instability. One possible answer for that is to use the controlled release of growth factor or the related gene at the tissue site to be regenerated over an extended time period by incorporating the factor or gene into an appropriate carrier. This release technology enables the growth factor to efficiently enhance the biological activity, resulting in promoted cell-induced tissue regeneration. We are designing and preparing the biodegradable carrier of growth factors and genes from gelatin and its derivatives. A new therapy to naturally induce tissue and organ regeneration by the controlled release of various biologically active growth factors has been achieved and the therapeutic potentials have been scientifically demonstrated through animal experiments. Among the tissue regeneration trials, clinical experiments of angiogenic and bone regeneration therapies have been started by the controlled release technology of basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF)-1, and platelet-rich plasma(PRP) to demonstrate the good therapeutic efficacy.
    Generally, in the chronic fibrotic disease, such as diluted cardiomyopathy, liver cirrhsis, lung fibrosis, and chronic nephritis, the damaged portion of organ is often occupied with the fibrous tissue, which often causes organ dysfunction. It is highly possible that if the fibrosis is enzymatically digested by a proper way, the fibrotic site is naturally regenerated and repaired on the basis of the inherent regenerative potential of the surrounding normal tissue and consequently the organ function is regenerated and recovered. The systems of drug targeting and the local release with polymers of an organ affinity are being designed and prepared to achieve the regeneration therapy for chronic disease based on the natural healing potential of patients. Based on the drug administration therapy which has been clinically used in internal medicine, this is called as physical regenerative therapy of internal medicine. This is a therapeutic approach which is different from the conventional regenerative therapy of surgery where cells, the scaffold, and signal molecules or the combinations are surgically applied to a tissue defect for regeneration induction thereat. The two surgical and physical regenerative therapies are conceptually identical from the viewpoint of the positive use of natural healing potential. In addition, the basic idea of regenerative therapy will be combined with interal medical therapy to open a new therapeutic field in the future. For example, the combination with aneurysm catheter therapy has been tried, and consequently the aneurysm occlusion by the regenerated tissue-based organization has been succeeded by the bFGF release system. On the other hand, a new cell culture technology is being developed to enhance the cellular expression level of nucleic acid compounds, such as decoy DNA and small interfering RNA (siRNA), with non-viral gene carriers.

2) Biomaterials for Stem Cells Technology and Basic Researches of Medicine and Biology

   There are two approaches to realize regeneration medical therapy. One is the tissue engineering-based therapeutic approach described above. The other is the transplantation therapy of cells which have a potential to induce tissue regeneration. For the latter approach, it is of prime importance to efficiently obtain and prepare cells with a high potential of proliferation and differentiation, such as stem cells, precursors, and blastic cells. In this department, the technology and methodology of cell culture with various biomaterials and bioreactors have been explored to efficiently isolate, proliferate, and differentiate stem cells, precursors, and blastic cells. A series of this study not only aims at the preparation of cells suitable for the therapy of regenerative medicine, but also research and development (R&D) of materials, technologies, and methodologies for basic medicine and biology. They are also applicable for the research of drugs discovery to evaluate their metabolism and toxicity. In addition, non-viral vectors for plasmid DNA and siRNA have been investigated to design the DDS system for gene transfection which can biologically analyze the functions of stem cells and genetically engineer cells to activate the biological functions for cell therapy. For example, a new system for the controlled release of plasmid DNA inside cells has been developed to succeed in enhancing the level of gene transfection and the consequent gene expression as high as or higher than that of viral vector system. In addition, a new technology of cell culturing on plasmid DNA-coated substrates has been designed and enhanced the level of gene expression as well as prolonged the expressed period. This reverse transfection system (SubFection: substrate-mediated transfection) was effective in the gene transfection for stem and matured cells which have not been readily transfected by the conventional method. This can be applied for the cell internalization of low-molecular weight compounds, peptides, proteins, and nucleic acids (siRNA and decoy DNA). We cannot only enhance the biological activities of plasmid DNA and siRNA with the non-viral vectors for stem cells, but also modify their biological functions and differentiation fate.

3) Biomaterials for DDS

   Generally there are few drugs which have a specific selectivity for the site of action. Therefore, the high-dose administration of drugs is necessary to achieve their in vivo therapeutic efficacy, while this often causes the adverse effects of drugs. DDS is a biomaterial-technology which allows a drug to act at the right time the right site of action at the necessary concentration. The objective of DDS includes the controlled release of drug, the prolongation of drug life-time, the acceleration of drug permeation and absorption, and the drug targeting. Various biomaterials are inevitably required to achieve every DDS objective. In this department, various research projects of DDS for drug and gene therapies have been being carried out from the viewpoint of polymer material sciences. Our definition of “drug” is not limited only to therapeutic substances, but the drug includes every substance which has a certain biological activity and function, such as diagnostic and preventive drugs, cosmetics, and health care substances etc. The DDS technology and methodology can be also applied for preventive and diagnostic substances to enhance the in vivo efficacy of vaccination and diagnosis, such as magnetic resonance imaging (MRI), ultrasound diagnosis or molecular imaging. We are developing DDS technology and methodology which are applicable to the research and development of cosmetics and health care sciences. The basic idea of DDS is to efficiently enhance the biological functions of a certain substance by the combination with biomaterials. DDS is defined as an universal technology or methodology which can apply to every research field of natural sciences.

4) Biomaterials for Surgical and Physical Therapies

   This department is partly originated from the division of Molecular Design and Biomaterials of the former Research Center for Biomedical Engineering where the medical applications of polymer materials have been investigated extensively. Among the research activities, we continue to molecularly design and create biomaterials mainly from biodegradable polymers aiming at the development of assistant materials in surgical and physical therapies.

   From the viewpoint of biomaterial sciences, we are actively proceeding comprehensive biological and medical researches on the scaffold for the cell proliferation and differentiation, the DDS of growth factors and the related genes, and the material-based technology or methodology to use stem, precursor, and blast cells or in addition, their medical applications. Through several R&D collaborations with medical, dental, and veterinary schools as well as private companies, we are planning to apply our basic research results to realize the regeneration induction therapy of various tissues and organs, such as the skin, fat, bone, cartilage, nerve, hair, blood vessels, periodontium, myocardium, and kidney. DDS technologies are also being investigated for their applications of therapeutic, prophylactic, and diagnostic medicines. Some biomaterials are necessary and applicable to further develop the basic researches of medicine and biology.

  De novo formation of adipose tissue in the mouse subcutis 6 weeks after implantation of a collagen sponge incorporating preadipocytes and gelatin microspheres incorporating bFGF (Magnification x 100, H.E. staining) The bFGF dose was 10 mg/site. 

  Histological observation of the skull defect of crab-eating monkey 21 weeks after treatment with bFGF-incorporating gelatin hydrogel (water content, 85wt%) and bFGF solution (100mg/defect)




Original papers

2011, 2010, 2009, 2008, 2007, 2006, 2005, 2004, 2003, 2002, 2001, 2000, 1999, 1998, 1997-


 

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