"Next-generation biomaterials engineering" refers to the design, creation and evaluation of materials based on mechanisms which result in organism-material interactions that take place between the material and the components making up the organism, such as biological tissues, cells, body fluids and the like. In this proposal, we have accorded the definition of "bioadaptive materials" to materials which can adapt to a diverse range of biological environments and actively control interactions with organisms; our aim is, through the promotion of next-generation biomaterials engineering, to establish a scientific and technological foundation that will enable the creation of bioadaptive materials.

When creating what are known as biomaterials, meaning materials that are to be used in close contact with elements making up living organisms such as biological tissues, cells and body fluids, it is essential to ensure that such materials have "biocompatibility" ―that is to say, the quality of being readily compatible with living organisms. In addition to this, biomaterials need to possess a range of other functions to allow them to control biological phenomena, in line with the growing diversity of medical and healthcare needs and the development of increasingly advanced medical technology and equipment in recent years. For example, there are demands for the creation of materials that could be used to promote the regeneration of tissue by inducing the growth of cells in the sites of internal injuries, and for materials that could enable diagnosis and treatment by creating exchanges of substances and information between the material and the organism in real time. However, many aspects still remain unclear concerning these organism-material interactions and the underlying mechanisms in terms of how biocompatibility actually manifests itself within these diverse and complex biological environments. As a result, many aspects of biomaterial R&D have to depend on empirically-based trial-and-error processes, a fact which forms a roadblock to progress in this domain.

The strategy recommended by this proposal as the key to achieving a breakthrough in this situation is that of moving away from the conventional concept of searching for materials that are adapted to this or that particular biological environment, and instead aiming to create "bioadaptive materials": in other words, to design and create materials with functions that will proactively make use of and actively control the interactions between the material and the organism. This means aiming to set up a scientific and technological foundation which will be able to create materials which possess functions that will be made a reality for the first time by proactive use of the interactions between materials and organisms; in concrete terms, this means materials with functions allowing them to control biological phenomena at an advanced level, or featuring an extremely high level of biocompatibility that is impossible to attain merely by expanding the current ways of doing research in which an all-encompassing search process is carried out. To create bioadaptive materials, it will be essential to work out the design criteria required for creating materials that can control interactions between organisms and materials, based on developing an understanding of the mechanisms behind the interactions, through the promotion of next-generation biomaterials engineering.

To advance the development of next-generation biomaterials engineering in this way, it is vital to have a proper understanding of complex biological environments which undergo changes spatiotemporally, and of the actual substances that will be responsible for the interactions between the material and the organism, and to establish a technological foundation for controlling the chronological and hierarchical biological phenomena which originate from such interactions. Below are the R&D challenges that will need to be tackled in order to do this.

• ①Understanding phenomena which arise as a result of organism-material Interactions

  The interactions between organisms and materials begin at the instant when the material and biological environment come into contact with one another resulting in the formation of an interface. These interactions develop progressively in chronological and hierarchical terms, starting off with phenomena such as hydration and the adsorption of ions and biomolecules which occur in less than a microsecond; minutes or hours later, phenomena such as cell adsorption and propagation develop, followed by phenomena which take place at the level of biological tissues, internal organs and the individual organism. The biological phenomena which require attention for any given biomaterial will vary depending on the material's application and the environments where it is to be used; the key is to clarify in quantitative terms what kind of changes occur chronologically and cross-hierarchically in the background, and to understand and analyze the mechanisms underpinning such changes. It is important to understand complex biological phenomena from medical and biological perspectives, and at the same time to understand the structures, physical properties and functions demonstrated by materials when placed in diverse and complex biological environments from the perspectives of physics, chemistry and material engineering; it is also essential to make efforts to bring together perspectives and knowledge from a number of different domains in order to investigate organism-material interactions.

• ②Developing new technologies and apparatus required for enabling quantitative evaluation and measurement in a diverse range of biological environments

  If we are to develop an understanding of complex biological environments that change spatiotemporally, and of the interactions between materials and such environments, we will need to engage in technological development aimed at measuring and analyzing in chronological and quantitative terms the various phenomena originating from these interactions. Examples of technology which should be developed include technologies which enable existing measurement and analysis technologies to be applied to complex organism-material interfaces, in vivo measurement technologies covering physical and chemical properties such as hardness, pressure, flow of body fluids, temperature and pH at particular locations within the organism in question, three-dimensional dynamic imaging technology enabling minimally-invasive or non-invasive observation within the living body, and information science-based means of analyzing huge volumes of data obtained from various types of measurements and the so-called "omics."

• ③Designing and creating bioadaptive materials

  We will design and create bioadaptive materials that can actively control interactions between the material and the organism, based on an understanding of the chronological and hierarchical phenomena originating from organism-material interactions. Having set out clear definitions of the biological environments that are to be the target and the biological phenomena that need to be controlled, we will then specify the most important parameters for interactions from the organism side and the material side, and establish material systems that will enable control of material properties directly connected with such parameters. The material properties that exert an influence on organism-material interactions cover a broad range of types, and enabling free and complete control over that properties calls for the consideration of a wide variety of materials possessing different characteristics including metals, inorganic materials, polymers and biomolecules, and then combining these as necessary. We will make bioadaptive materials a reality by harnessing the potential of the advanced material design, synthesis and creation technologies and nanotechnology/processing technologies which have been cultivated in Japan to date.

• ④Establishing a foundation for the evaluation of biomaterials that will be required for the practical application

  In order to apply newly-created biomaterials to practical application in medical and healthcare technologies, it is essential to ensure that these materials are fully optimized as products by carrying out evaluations based on the conditions in which materials will actually be used and the purposes they will be used for, and fully guaranteeing safety and efficacy. We will resolve the various challenges associated with the evaluation of biomaterials and establish an evaluation platform by developing simulations of the biological environments in which materials will actually be used and setting out the methods and indicators for evaluations.

Fulfilling these R&D challenges will require partnerships and fusions not only between researchers connected with science and engineering who will be responsible for establishing various material systems and measurement and for quantitative analysis of organism-material interfaces, but also biology researchers who can carry out research using biomolecules, cells and small animals, and medical researchers who are looking for new medical and health technologies and new treatment methods. To ensure that the target of research does not stray from medical and healthcare needs, it is essential that researchers from different domains communicate adequately with one another from the stage of setting out research challenges onwards, particularly researchers connected with material systems and those connected with healthcare systems. We must also ensure that information about the scientific definitions of the biological environments where materials are to be used and about the materials and functions that need to be created is shared among researchers from different domains through such communication. We need to establish schemes which will encourage partnerships and fusions among researchers, and frameworks which enable the long-term promotion of joint research projects involving teams that are formed based on partnerships between different domains and on biomedical-engineering partnerships.

Finally, the difficulty of practical application remains a challenge for biomaterial R&D, and efforts need to be made to resolve this challenge. Currently in Japan, a setup known as the "R&D pipeline" which provides support for the practical application of academic research outcomes in the form of medical care technology exists as part of the Project of Translational & Clinical Research Core Centers at Japan Agency for Medical Research and Development (AMED). It seems likely that practical application of such materials will make progress through the use of this setup; in reality, however, most instances of R&D in biomaterials come to a halt before they can reach this stage. It is vital that we cultivate the seeds of research that we have obtained through the promotion of next-generation biomaterials engineering, and establish the support structures that will allow such seeds to be taken forward into research aimed at developing practical applications.