Research

Graduate School of Medicine

We will scrutinize the needs of the medical field in the medical device development ecosystem, select biocompatible materials based on those needs in collaboration with the Graduate School of Medicine and affiliated hospitals, and study their manufacturing and processing methods. We will then fabricate a prototype and promote its clinical evaluation in cooperation with physicians.

 

1: Development of angiogenesis-promoting technology and research on its clinical application

In the field of regenerative medicine, it has recently been expected to obtain a single cell population from induced pluripotent stem cells (iPS cells) for clinical application by improving the efficiency of differentiation induction and cell separation technology. However, there have been no successful cases of tissue reconstruction after transplantation of a single differentiated cell population into the body, and there have been no cases of connection to the body's circulatory system. In particular, angiogenesis is essential for connection to the body's circulatory system, but due to insufficient angiogenesis, there have been no cases of successful reorganization. In our laboratory, we have prepared "PEG-containing hyaluronic acid gel," in which polyethylene glycol (PEG) is contained in a hyaluronic acid (HA) chemically cross-linked hydrogel and growth factors are distributed and dispersed in the gel, and have found that angiogenesis is promoted by subcutaneous implantation in mice. Therefore, we are clarifying the relationship between the dispersion state of PEG in PEG-containing hyaluronic acid gel in which growth factors are distributed and dispersed and the efficiency of angiogenesis, and are searching for hydrogel specifications that will reliably induce angiogenesis. By doing so, we will clarify the relationship between physical, chemical, and biomedical factors of this gel, which shows an angiogenesis-promoting function, and establish an angiogenesis induction technology to ensure blood flow in subcutaneous transplantation of cells and tissues induced to differentiate from iPS cells.

 

2: Bioartificial Pancreatic Islet Project (Joint research with Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine)

It is reported that there are approximately 150,000 patients with type 1 diabetes in Japan. allogeneic islet transplantation, which was covered by insurance as a treatment for type 1 diabetes, has not yet reached the standard of care due to a lack of donors and the indispensability of immunosuppressive drugs. Overseas, clinical trials have shown that "bio-artificial islet" transplantation, in which islets derived from pigs for medical use are encapsulated in immuno-isolated capsules and transplanted intraperitoneally, has resulted in a low number of insulin withdrawals. To solve this issue, improvement of blood supply to the encapsulated islets is essential. Kobe University aims to establish "bio-artificial islet" transplantation as a novel treatment for all type 1 diabetes patients by applying subcutaneous angiogenesis promotion technology. Islet transplantation is the most effective treatment for type 1 diabetes. However, lack of donors and lifelong use of immunosuppressive drugs are major drawbacks. Encapsulated porcine islet transplantation is expected to solve these two drawbacks. However, there have been problems such as the need to take immunosuppressive drugs for the rest of one's life after transplantation, which can lead to problems such as carcinogenesis and easy infection. This study aims to optimize the encapsulation method and materials for this device. Specifically, taking advantage of the fact that islets are very small tissues (100-300 µm), we encapsulate the entire islet in a micro capsule with the smallest particle size using alginate and implant it with a polymer coating with excellent biocompatibility, thereby isolating it from the host's immune system and preventing the islets from being exposed to low The islets are then encapsulated in a microcapsule with the smallest particle size using alginate and transplanted with a polymer coat with excellent biocompatibility.

 

3: Research on development and practical application of small-caliber artificial blood vessels (Joint research with the Department of Cardiovascular Surgery, Graduate School of Medicine)

Cardiovascular disease (CVD) is the leading cause of death worldwide, with an estimated 23.3 million deaths per year by 2030. One of the treatments for CVD is the use of synthetic vascular prostheses, mainly made of polyester (Dacron) or Teflon (ePTFE), which have shown high patency rates. However, small-caliber artificial vessels with an inner diameter of 6 mm or less have a low patency rate due to thrombus formation and other reasons, and small-caliber artificial vessels with suppressed thrombus formation are needed in clinical practice. Our laboratory is promoting the development of small-caliber artificial blood vessels by focusing on polymer nanofiber processing using the electric field spinning method, which can improve blood compatibility by reproducing the structure of natural extracellular matrix.

 

4: Development of a new bile duct stent (in collaboration with the Department of Gastroenterology, Graduate School of Medicine)

Endoscopic retrograde bile duct drainage, in which a tube called a stent is placed in the bile duct, exists as a treatment for bile duct stricture. In particular, plastic bile duct stents are used for temporary treatment, as they are known to remain open for only a few months. However, reocclusion is inevitable, and the main cause is believed to be biliary sludge formed by the interaction of bile with bacteria and other substances. However, the detailed mechanism of its formation has not been clarified. In this study, we will elucidate the actual bile duct stent and the mechanism of obstruction, and promote the development of a new plastic bile duct stent that suppresses this re-occlusion to the utmost limit. The plastic bile duct stent market is worth 175,000 units or 4.55 billion yen per year, and we aim to enter this market.

 

5: Development of Combined Radiation Therapy with Tea Catechin-Coated Gold Nanoparticles (in collaboration with Department of Breast Endocrine Surgery, Graduate School of Medicine)

Radiation therapy is widely used as a treatment for cancer, but its effectiveness is impaired by its damaging effects on the body. Since the radiation field reaches half of the thoracic cavity, a whole-body dose level of 50-60 Gy is required, although attempts have been made to reduce the radiation field by limiting it to the chest wall, and radiation pneumonitis and radiation-related esophagitis are often caused due to the high and limited level of radiation. Therefore, irradiation doses need to be reduced to ensure therapeutic efficacy. We have previously found that gold nanoparticles immobilized with epigallocatechin gallate (EGCG), which is found in green tea, have low toxicity and improved irradiation efficacy (1), and we have also investigated their disposition at the mouse level (2). We have found the conditions that improve the accumulation in tumors, and are aiming to submit a pharmaceutical application by linking this to non-clinical and clinical studies. Devices used（including common equipment）
※Under construction  

Faculty of Engineering

The program is to clarify biomaterial functions from the standpoint of chemistry, from molecular design and synthesis to functional evaluation using cells of materials (biomaterials) that come in contact with the living body and are expected to contribute to the development of advanced medicine (regenerative medicine and drug delivery systems). Based on organic synthesis, macromolecular science, and cell biology, we aim to incorporate food materials and biocompatible materials into biomaterial design with constant awareness of human applications, and to propose a new concept of biomaterials, especially for cancer therapy. In the future, we hope to establish a methodology for prevention and treatment that integrates food science/nutrition and biomaterials.

 

1. Exploring the science of biocompatibility

Water structure and its relationship to hydroxyl groups and etheric oxygen
Focusing on branched molecules (hyperbranched polyglycerol and polyglycerol dendrimer) with no distribution in molecular structure and molecular weight, we will quantitatively change the water structure through different degrees of branching and chemical modifications to clarify the correlation between the water structure and molecular structure parameters. We will then evaluate protein adsorption and cell adhesion, which are indicators of hemocompatibility, and clarify the relationship between water structure and hemocompatibility, thereby providing academic evidence for unique hemocompatible materials. Through these studies, we aim to establish academic principles that integrate biomaterials science and structural physical chemistry of water.  
 

2. Development of materials for cancer treatment

Intracellular anticancer drug synthesis
Recently, the strategy of in vivo synthesis of anticancer drugs has been attracting attention as a new cancer therapy that does not involve administration of anticancer drugs. This strategy is a completely new strategy to synthesize drugs in vivo with pinpoint accuracy by administering non-toxic drug intermediates. Since the accumulation of drug intermediates in normal cells is negligible with this strategy, it is expected to be applied to anticancer drug therapy with reduced side effects. In this study, complexes of vanadium with polyglycerol dendrimer (PGD) and hyperbranched polyglycerol (HPG) have been prepared and evaluated as basic aqueous homogeneous catalysts. If vanadium complexes can be used as aqueous homogeneous catalysts, it is expected that they can be used in a new "targeted drug manufacturing cancer therapy" in which in situ biosynthesis of inexpensive drug intermediates directly into expensive drugs can be achieved.

Biomaterialization of food materials
Although chemotherapy of tumors with anticancer drugs is a useful method, serious side effects related to undesirable delivery to normal tissues remain a major challenge. Therefore, as a potential alternative to anticancer drugs, there are great expectations for micronutrients that can show beneficial effects on normal cells and tissues while also exhibiting anticancer activity. In particular, α-tocopheryl succinate (α-tocopheryl succinate; αTOS), a vitamin E derivative, is known to induce cell death by inhibiting redox reactions in mitochondria. However, the method of delivering αTOS to tumors at high concentrations has not been established, and it is important to find the conditions for tumor delivery. Our laboratory has prepared amphiphilic nanoparticles by combining polymerizable and hydrophilic monomers of αTOS and is promoting research to establish chemotherapy without the use of anticancer drugs (1). We aim to optimize the anti-tumor effect of anti-cancer drug-free nanoparticles by finding the specifications of nanoparticles to be taken into tumors and by elucidating tumor accumulation and cancer cell death mechanisms through animal experiments.
Design of effective photosensitizer carriers for photodynamic therapy
Photodynamic therapy (PDT) is attracting attention as a minimally invasive cancer therapy. Oxygen (SO) or reactive oxygen species (ROS) produced by PS is used to induce cancer cell death. However, P malignancies are known to cause hypoxia due to their distance from blood vessels, which is a major factor in the decreased production of ROS.
Therefore, we have focused on the property of zinc(II) phthalocyanine tetrasulfonic acid (ZnAPC), discovered by Dr. Daisuke Miyoshi and Dr. Keiko Kawauchi of the Department of Frontier Sciences at Konan University, to cause cell death even in hypoxic cells (Kawauchi, K., et.al. Nature Communications, 2018, 9, 1-12). However, ZnAPC lacks in vivo circulation, hindering its application as a PS for PDT, and we are developing novel carriers to increase the in vivo circulation of ZnAPC and selectively deliver ZnAPC to tumors.

 

3. Exploiting the Properties of Cyclodextrins to Develop Materials and Functions

Biodegradable cyclic polymer gel
Polymeric materials, ranging from hard plastics to gel-like materials, have been made highly functional in a wide range of fields, including food containers, industrial products, and medical products necessary for our daily lives, through technological innovations that provide various elasticity, mechanical strength, and self-healing properties. In recent years, the importance of biodegradability has been reaffirmed as a countermeasure to environmental issues such as marine microplastics, which are ultimately degraded into components that are harmless to the ecosystem. However, the problem is that the strength of polymers tends to weaken when biodegradability is attempted to be added, and conversely, there is a trade-off relationship whereby strengthening the polymer makes it difficult to biodegrade. In our laboratory, we have succeeded in creating a new polymer material that has not only elasticity, mechanical strength, and self-healing properties, but also the ability to dissolve in water by replacing conventional covalent bonds (stable chemical bonds) with physically weak "hydrogen bonds" at "moving cross-linking points," which are characteristic of polymer materials in which the chemical bonding sites between polymers (cross-linking points) move freely (cyclic polymer gel) (1). This is the first time that a new material has been successfully developed with hydrogen bonding (1,2). Furthermore, by chemically adjusting the degree of hydrogen bonding, it was found that the pattern of degradation/dissolution in water can be changed arbitrarily, providing a guideline for the development of new biodegradable/dissolvable gels. We are trying to produce not only gels but also films.
Dendritic glycerol-modified cyclodextrin
Our laboratory is exploring the potential of hyperbranched polyglycerol (HPG) and polyglycerol dendrimers (PGD), which are highly hydrophilic and biocompatible, as biofunctional materials (1). We are investigating 1) solubilization of vitamin E (2), 2) boron cluster-loaded neutron capture therapy (BNCT) (3), and 3) construction of supramolecular assemblies (4) using these as host molecules.  
 

4. Self-healing and biodegradable gels by combining polysaccharides

We have investigated the conditions for the preparation of polysaccharide-based hydrogels that can self-heal by simply mixing polyol polysaccharides and medium molecules (1), and clarified the cellular response of gels with different nonlinear elastic properties (2,3). Meanwhile, the possibility of "supramolecular hydrogels that reproduce the mechanical properties of extracellular matrices" has also been investigated. We found that a reversible covalent cross-link between a polyrotaxane and a linear water-soluble polysaccharide, which exhibits high strength, biodegradability, and self-healing properties and does not inhibit cell growth, is not only biodegradable but also has self-healing properties and does not inhibit cell growth despite its high strength (4). Devices used（including common equipment）
※Under construction