[Professors Dong-Woo Cho, Jinah Jang, Kunyoo Shin and Sungjune Jung are leading the world in bioprinting and organoid research]

Efforts to develop artificial organs began in the 1970s with stem cell research and gained speed in the 2000s when it joined with 3D printing technology to create a new sector called the 3D bioprinting technology. 3D bioprinting creates artificial organs such as cornea, liver, skin, and blood vessels by stacking bioink of living cells just like 3D printing.

This technology is not something in the far off future. In 2013, an American bioprinting company Organovo produced an artificial liver in 2013 and in 2016, China’s Levotech succeeded in producing artificial blood vessels from stem cells extracted from the fat layer of monkeys. In the same year, POSTECH received the spotlight for producing artificial muscles for the first time in the world. The move to produce artificial organs through 3D bioprinting is not only accelerating abroad in countries like the U.S. and China, but also in Korea.

POSTECH is a front-runner in artificial organ development using domestic bioprinting technology. Prof. Dong-Woo Cho of POSTECH’s Department of Mechanical Engineering laid the foundation for an unexplored field of 3D bioprinting in Korea, followed by junior researchers like Prof. Jinah Jang. Professors Kunyoo Shin and Sungjune Jung are also pioneering new industries by incorporating bioprinting technology into organoid development. We meet with these experts who are integrating bioprinting in their respective fields to bring innovations and listened to their stories.

◆ Paving the way for artificial organs – Prof. Dong-Woo Cho, a pioneer in 3D bioprinting

Prof. Dong-Woo Cho, who has researched 3D printing for more than 20 years, is the first person in Korea to explore the 3D printing industry by applying 3D printing to the biomedical industry.

While the artificial organ research that began in the mid to late 1970s was for developing substitute devices designed to replace the functions of organs by combining electronics, machinery and materials, Prof. Cho’s research is a technique that creates tissues and organs with actual cells. By printing living cells instead of general materials, he creates three-dimensional structures and cultivates them to produce tissues and organs that can be applied to humans.

The most important aspect in the bioprinting technology is bioink. Bioink are cells are usually collagen or alginic acid mounted in protective hydrogels. But these materials have the disadvantage of not being able to replicate the characteristics of tissues or organs.

Therefore, in order to recreate the cell environment of each tissue or organ, Prof. Cho took the tissues and organs that he wanted to print from pigs then decellularized them into bioink and named them tissue-specific bioink.

Artificial organs should function properly when transplanted in patients and show no fatal side effects such as immune rejection. Because conventional artificial organs are foreign substances that are different from the body, possibilities of various side effects and durability and power supply issues exist. On the other hand, artificial organs made using tissue-derived bioink are made from the actual patient’s cells, and have relatively a few side effects and can grow as part of the patient’s body.

As such, Cho’s tissue-derived bioink has established a new paradigm by taking the potential of 3D bioprinting to the next level. Last August, Chemical Review published a paper discussing the development and application of tissue-derived bioink. Chemical Review is a world leading journal in science and engineering, published by the American Chemical Society. It selects a topic that is of global significance and gives only the world’s top researchers the opportunity to contribute on the subject. Their selection proves the influence that Prof. Cho and POSTECH researchers’ has on the world stage.

The artificial organs applied to patients are limited to bone tissues so far. The ultimate goal of Prof. Cho’s research is to print all organs and tissues, although organs that must have complex structures such as heart, liver and kidney are still in the research stage and require more time to be applied in actual clinical trials.

“When a patient who couldn’t be helped any other way, for example, a patient who had cheekbones removed due to cancer surgery was transplanted a 3D printed structure to make it look like before. I still remember the ecstatic looks on the faces of the patient and the parents,” Prof. Cho recalled his proudest moment.

Developing the world’s first bioink, 3D printing the world’s first artificial muscle, the world’s first artificial cornea transplant, succeeding at producing the artificial nose, bone, and even blood vessels. Prof. Cho’s ventures have become history. This is why his next move is drawing attention.

◆ Perfecting the 3D bioprinting process. Prof. Jinah Jang, developer of bioink materials

Following in Prof. Dong-Woo Cho’s steps is Prof. Jinah Jang, who is considered as another pillar in the 3D bioprinting industry and one of the most leading figures of 3D bioprinting in Korea.

She thinks that the current role of 3D bioprinting is not to perfectly replace existing organs like liver or pancreas, but to act as a middle step to restore some of their functions to extend their life until the patient can receive the transplants in five to 10 years.

The first thing Prof. Jang did when she began her graduate studies in 2010 as she started the full-fledged bioprinting research through the “Leader Researcher Support Program” with Prof. Dong-Woo Cho, was to work on developing the process for 3D bioprinting.

When setting a goal to target and print a specific organ, such as kidney tissues or cornea, the pig-derived tissue is mixed with human cells making bioprinting possible through a decellularization process that removes the pig cells. Collagen and alginic acid, which are used as conventional bioprinting materials, have a single environment that cells like. But these decellularized materials are a mixture of thousands or hundreds of cells’ favorite environments, so to speak.

Applying these decellularized materials to the human body can fully restore or enhance the functions of tissues or organs so that more types of growth genes can be released continuously from the body over a prolonged period of time. In other words, the research is to create an “environment” so that superior materials can be produced through decellularization that can differentiate into tissues that perform and function better than the conventional bioprinting materials.

“Bioink was previously made of only limited materials and used only in bioprinting. But POSTECH’s research is significant in that it has developed a variety of bioink materials that create an environment where tissues or organs can better adapt and differentiate in humans,” says Prof. Jang.

Since she began studying 3D bioprinting, Prof. Jang has been testing and developing the bioprinting processes, starting with the cartilage, fat and heart, and going through decellularization of most tissues and organs in the human body. She has basically printed all human tissues except fingernails and toenails.

Unfortunately, even though the technology is already being developed, only a few cases have been directly applied to clinical trials due to regulations that are not fully ready. In response, Prof. Jang is working with hospitals, institutions and businesses to prepare for the clinical regulations. “It is important to develop technologies, but it is also meaningful to serve as intermediaries so these developed technologies can actually be applied,” she explains. “We will make detailed plans for commercialization so the technologies can be applied in real life.”

The current bioink printing technology allows to print human tissues the size of a fingernail. Prof. Jang plans to gradually expand the scope to transplant tissues and organs themselves in the future.

She remarked, “If materials that are incorporated with bioink can be allowed in clinical trials, they will be ready for trials within three years from t.” Revealing her aspirations, Prof. Jang commented “For now, we will try to help some functions but ultimately print organs that can replace all functions in the near future.”

◆ Making organoids through 3D bioprinting…Prof. Kunyoo Shin paves the way to an era of patient-tailored treatment and new drug development

Kunyoo Shin is one of the leading organoid experts in the world. He started researching organoids while working at Stanford University and is regarded as a first-generation organoid researcher. Organoids are organ-like structures that debuted about 15 years ago and are created by cultivating or recombining stem cells in three dimensions. They are often called “mini organs” or “organ-likes.” Used for developing artificial organs, the greatest utility of organoids lies in developing new drugs.

Currently, the standard procedure for new drug development is to do clinical trials of various new drug candidate materials after going through animal testing using mice. Mammals and fast-breeding mice are the most suitable subjects for animal testing, but they are quite different from humans in their gene makeup and body structure. This is one of the biggest reasons why the rate of new drug development remains below 5 percent.

Hence, organoids can be an innovative tool to change the paradigm of new drug development. Instead of using mice to test new drug materials, they can be tested on organoids that are grown with actual tissues of a patient.

However, testing tens and thousands of candidate materials requires a lot of work with organoids, which have been carried out manually. To do this, we need a process that can produce a large amount of organoids – and that is where 3D bioprinting comes in.

Prof. Keunyoo Shin explains, “The fusion of organoids and bioprinting is a groundbreaking technology that completely changes the 50-year paradigm of new drug development.” He emphasized, “The next generation of organoids has already begun and in the near future, organoids which have been organ-likes will become mini-organs, which will then become real organs with more research and development.”

Organoids combined with 3D bioprinting further implies innovations in patient-tailored treatments. For example, tumors have genetic differences depending on the person and these are called mutations. Therefore, the concept of customized treatment is to provide different treatment for each of these mutations but the problem is that the number of mutations per patient is too high – at more than 200. Therefore, it is not easy to know which drug should be applied to which mutation.

However, if a patient’s tissues are grown to create large amount of organoids using 3D bioprinting in order to locate the right drug, the era of customized treatment can begin. Prof. Shin states that using this next-generation organoid technology, it is possible to decipher which drug to use within a month or two after diagnosis.

“We can move quicker towards the era of patient-tailored treatment and new drug development using organoids and 3D bioprinting.” He added with confidence, “Pooling the data on the patients’ customized treatments into big data will undoubtedly lead to the day when AI tells us which drug to prescribe when patients visit hospitals.”

◆ Analyzing cancer heterogeneity for the era of patient-tailored treatment. Prof. Sungjune Jung, a trailblazer of an exclusive inkjet bioprinting technology

If Prof. Kunyoo Shin is a master of organoids, Prof. Dong-Woo Cho and Prof. Jinah Jang are pioneers in 3D bioprinting, Prof. Sungjune Jung is a trailblazer of inkjet bioprinting and has a global influence.

Starting with developing inkjet printers at an electronics company, Prof. Jung, who has traveled the lone road of research on printing, is currently conducting research in bioprinting and printed electronics that produce electronic devices and circuits by printing, and bioelectronics and biosensors that reintegrate the two.

For accurate diagnosis of cancer and customized medical treatment, it is paramount to accurately evaluate and utilize genetic heterogeneity between cancer cells. Prof. Jung conducted the pioneering research on producing a bladder cancer model using the inkjet cell printing method and analyzing cancer heterogeneity using the model.

The inkjet-based bioprinting that Prof. Jung has been developing exclusively, controls each cell individually to place it in a desired position quickly and precisely. In addition to cells, various biomaterials such as cell culture fluid or collagen can be discharged together and can be patterned in three dimension on a large scale, attracting much attention from the biotechnology sector.

The inkjet bioprinting which he developed can embed a single cell at the center of a “well” and therefore applicable in research on cancer heterogeneity evaluation, in studying the correlation between cells by making two or more cell types into 2D or 3D patterns, and creating desired artificial tissues.

In particular, he has demonstrated the excellence of inkjet bioprinting by evaluating the effects of different bladder cancer treatments on each organoid by precisely printing cancer cells derived from actual patients, growing them into cancer organoids and quantitatively measuring protein and gene expression to analyze cancer heterogeneity.
Prof. Jung’s research leaves great significance in that he created a bladder cancer model through bioprinting techniques and evaluated and analyzed cancer heterogeneity according to each model, opening new possibilities for precise patient-tailored medical care of the future.

“Inkjet bioprinters have the great advantage of being able to print all kinds of cells and can patternize each and every cell exactly where it needs to be at a very fast pace,” Prof. Jung explained. “More than anything else, they have the advantage of mimicking the characteristics of a real patient’s cancer tissues and allowing various experiments that cannot be tested within the human body.”

Numerous experts in the field – including the pioneer in 3D bioprinting, Prof. Dong-Woo Cho –have gathered to conduct research at POSTECH. One research team cannot solve all the challenges in a given field. Refining the bioprinting technology requires the merging of knowledge and skills from biomedical, tissue, mechanical, materials, and electrical engineering. POSTECH, in particular, has a culture that is suitable for convergent research due to the low barrier between the different departments and many great researchers are working together in one place to create a great deal of synergy. The convergence of science and technology, isn’t this the power of POSTECH that drives innovation?