Society’s interest in "regenerative medicine" has risen dramatically in the wake of ground-breaking research by Professor Shinya Yamanaka, whose development of iPS cells (induced pluripotent stem cells) shook the world. iPS cells are created through an innovative technique by which a cell is reprogrammed to a state in which it has the potential to differentiate into any type of cell throughout the body. It is anticipated that in the near future, there is hope for the ability to freely produce such cells without immunological rejection. I feel that iPS stem cells making the news and awareness of the new medical technology that is "regenerative medicine" among laypeople is cause for celebration, even from the standpoint of a researcher.

On the other hand, though, I do have some concerns. Compared to all the articles written about academic research results involving stem cells and iPS cells, it seems there are very few which contain information on tissue engineering technology and its importance, in that it is necessary for turning those academic results into actual, useable "regenerative medicine".

Generally speaking, before basic and academic research results can be connected to actual clinical medicine, there are many problems that should be solved and various technologies that need to be established. I think it’s safe to say that the greatest hope for results from iPS cell research lies in using cells free from immunological rejection to create internal organs for use in clinical medicine to help those suffering from disease. If we make a goal of realizing "regenerative medicine" as a replacement for transplantation, this raises the technological barriers to a remarkably high level. How can we actually create organs from cells? What kind of technology is required? The fact is that without significant breakthroughs in tissue engineering technology, even "regenerative medicine", much anticipated since the world-famous invention of iPS cells, might turn out to be just a pie in the sky.

Until now, my colleagues and I have been advancing research in tissue engineering technology with the goal of "making organs". At this point, we are working towards research on "biofabrication", which is attracting notice as a new area even in the context of tissue engineering and regenerative medicine. I would like to introduce the current state of research and ways of thinking about this "biofabrication" that we are striving for.

What Is Biofabrication?

The word "biofabrication" comes, of course, from "bio" (as in, biology, life, living organisms) and "fabrication" (as in, forming, manufacturing). Basically, we can say that the goal of research on biofabrication is to use biological materials such as cells, proteins, etc., to manufacture biological products. By "biological products", we mean that our goal is to create cell clusters, cellular structures, and even tissue and organ systems. These could be used in drug screenings such as tests of toxicity or efficacy, or tissue models to be used in pursuit of disease mechanisms. Additionally, future applications would include therapeutic use of tissue models or organ devices; to wit, the outlook for this research is so grand and expansive as to include practical use in such areas as regenerative medicine and bioartificial organs.

So, in order to make such advanced products, we will need advanced fabrication technology. We can work towards manufacturing advanced bioproducts by breaking down previous concepts and technological limits through the introduction of advanced technology for automation, digitization, and roboticization of work such as cell manipulation and cell culture processes that are currently being done manually by engineers and researchers. The challenging struggle to work toward development of this kind of technology is what biofabrication is all about.

The Need for New Technology in Order to Make Organs from Cells

Research on making biological tissue and organs, along with medical treatments, is what we call "tissue engineering/regenerative medicine". In 2007, cultured skin came into use in Japan for treatment of burns; next, cultured corneas and cartilage are standing by to be put to clinical use. It is expected that from this point on, clinical applications of tissue engineering and regenerative medicine will become increasingly mainstream. At this point, however, tissue that can be reliably made with cell cultures is still limited to thin tissue and small amounts of tissue that do not contain any blood vessels. Moreover, these are simple tissues made from only one type of cell which, for the most part, lack structure. In comparison, tissue comprising vital organs such as the heart, the liver, kidneys, and lungs are tissue structures with microscopic features, are composed of many different types of cells, have a structural arrangement, and feature a hemoperfusion mechanism which supplies oxygen and nutrients. Moreover, in order to manifest enough physiological functions to support the body, trillions, even tens of trillions of cells are at work there. To artificially make tissue and organs having such features from cells is absolutely impossible by simply carrying on with heretofore known cell culture techniques. Innovative technology is required.

Printing Technology and Biofabrication

Printing and printer technology works by controlling where the ink is to be applied and coating or adhering the ink onto the paper, thereby rendering images such as letters, pictures, and photographs. We realized, though, that this very technology for printing and printers has great possibilities as a technique for making tissue and organs from cells. The advantages of this are summarized in Table 1.

When we consider various characteristics of printing technology, we can get a glimpse of the possibility of bringing about a great technological innovation and overcoming the limits of previous technology in tissue engineering for vital organs. Be that as it may, there are no printers anywhere that can print cells. Even if we wait for some time, it is hardly possible that they will appear. I was fortunate enough to be chosen the head the Kanagawa Academy of Science and Technology’s 3-year long "bio-printing" project [1]. We assembled a medical engineering team of specialists in engineering and cellular biology and grappled with the problem of developing devices for printing cells. We were able to make 3-dimensional structures out of cells and gel using the equipment we developed. I would be very happy to have you read the paper we published on the results of that work. [2]

Global Trends

Research on "bio-printing" and "biofabrication" is currently attracting a lot of international attention as a topic within tissue engineering and regenerative medicine. In 2009, the first issue of the international journal Biofabrication was put out by IOP Publishing. And, in 2010, researchers from all over the world gathered together for an international conference on biofabrication. [3] Scientists around the world are spurring on new research into engineering technology for making tissue and organs from cells.

Some key terms related to "biofabrication" would be "cell printing", "bio-printing", "organ printing", "bio-assembly", "bio-rapid prototyping", "tissue/organ fabrication", and "direct tissue engineering". Additionally, since we have models using computers and other instruments, we can include "computer-aided tissue engineering", "bio-CAD/CAM/CAE", "bio-robotics", and "digital biofabrication". Encompassing a larger scope would be the terms "tissue/organ factory" and "in factory tissue engineering". "Can machines make organs?" This is the catchphrase we use at the lab I set up at the University of Toyama. It expresses the essence of biofabrication.

Within printing technology, we have inkjet and dispenser printing, laser transcription technology, and applied laser transcription printing techniques. In the area of 3-D fabrication technology, we have optical prototyping, 3-D printing via laser or inkjet, sheet lamination methods, and solid free forming. In addition, we are getting glimpses of original new technologies in the form of applications of robotics, manipulation, and micro-molding techniques.

Further Developments in Biofabrication

Progress in biofabrication from this point on will enter a period during which harmony and coordination between advanced engineering technology and extensive knowledge of life sciences will be important. It will of course be necessary to have technology for producing large amounts of stem cells and other cells suitable for use in cellular engineering. But, in addition to the research we are doing on technology for arranging cells three dimensionally, we will need to work on the processes by which actual tissue can be cultivated beyond that stage. There is also the urgent business of developing new technologies for biofabrication such as biomaterials to control the pericellular environment and for the controlled release of growth factors in cell management. Add to that technology for observation and evaluation, cultivation and control, preservation of cellular tissue, and other related technologies to support biofabrication, of which there are yet hardly any.

As I stated above, there are extremely high hurdles to overcome for the goal of making organs. These hurdles are many, and it will take a long time. And so, I think we really need to get to work on this research as quickly as possible. The sooner we start, the sooner more barriers can be broken down, and, unmistakably, the sooner we can see clinical applications. I would also add that in terms of overcoming international competition, it’s a matter of "first come, first served", and so time is of the essence.

[1]	Kanagawa Academy of Science and Technology Innovation Center, Current Research Projects, Nakamura "Bio-printing" Project
[2]	University of Toyama, Nakamura’s Laboratory, Home Page
[3]	Biofabrication 2011 in Toyama

Table 1: Advantages of Printer and Printing Technology

Microscopic resolution: Even structures within organs that can’t be seen with the naked eye and cell structures of biological tissue can be printed thanks to a degree of resolution that allows us to control the position of each individual cell.

Color printing: Biological tissue is composed of a variety of cell types and component parts. With color printing, it is possible to separately control a variety of cell types.

Large format printing: Large objects can be printed with microscopic resolution. It may be possible to simultaneously create a hierarchical structure that is comprised of cells, tissue, and organ.

High-speed printing: When creating biological tissue, it is necessary to arrange one hundred million cells just to make one cubic centimeter of tissue. This is realistic considering that a conventional inkjet printer actually uses a hundred million droplets of ink to print one A4 sized sheet of paper.

Digital printing: Digital signals from a computer can be printed as is. A computer’s processing power and digital technology can be freely put to use as it becomes possible to create forms based on organ and tissue data designed on a computer.

Reproducibility: It is possible to repeatedly print the same image. It is anticipated that cell tissue, organs, etc. could be created with the same reproducibility.

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