As teams of scientists around the world work to develop strategies for the treatments and prevention of COVID-19 through therapeutics and vaccination, there is a unique opportunity for 3D bioprinted tissue models to aid the early R&D phases. In this editorial and interview, Hyo-Kyung, Bae (CLECELL, Gyeonggi-do, Republic of Korea) describes how her team are utilizing bioprinting techniques to develop tissue models and how these can be adapted for testing vaccines and therapeutics for COVID-19.
Hyo-Kyung, Bae: biography
Ph.D / Principal Research Engineer, Biomimetic Tissue R&D Department
I am working in the Biomimetic Tissue Research and Development Department at CLECELL. CLECELL is a manufacturer of 3D bioprinters. I am also an animal lover trying to reduce the number of animals used in toxicity test for drugs and cosmetics and have had an interest for a long time in developing artificial tissues and organs with high reliability for test results. With my background in researching cloned embryos using SCNT (Somatic Cell Nuclear Transfer), iPSCs (induced Pluripotent Stem Cells) and MSCs (Mesenchymal Stem Sell), I am currently applying 3D bioprinting techniques on researching and manufacturing human 3D artificial skin tissue.
Scientists all over the world are making all-out efforts to develop a cure and vaccine for the recent outbreak of COVID-19. In vitro testing is used in the initial stage of such research which demands discovery of the candidate substance and evaluating safety and efficacy of the substance.
Currently, U-FAB adopts a 3D bioprinting method which can overcome most of the drawbacks in a 2D cell model. For example, in a 2D model where the growth substrate is bonded to a hard plastic surface to grow, we face the problem of easily losing the characteristic of the cell due to limited cell to cell or external interaction. This is a trait of in vitro culture where only partial exchange of substance is possible. We also face the problem with low reproduction of the actual human body. Compared to this, the 3D structural model allows the cell culture to grow in the same way as within the human body, maintaining single cell properties and similarly copying the complex structures and physiological functions. These strengths help to make this 3D method a worthy prediction model during the initial stage of pharmaceutical development. The reliability of test results from using these tissues is far higher than that of 2D cell model.
Not only that, artificial tissue created from 3D bioprinting techniques can overcome the weakness of the manual creation model where there is continuous lot variation between tissues which is caused by the handling skills of the experimenter.
U-FAB overcomes the weakness of both 2D and manual techniques. So when creating artificial tissue, if you have enough test materials like cells and biomaterial, the multi-channel (15-channel) function of the U-FAB can be used to produce large volume of tissues in a single run. This will contribute to produce a test bed with minimal variation of tissues between lots. Also, we can maximize research efficiency since a single printing process with various bioinks can output multiple test results with varied experimental conditions. In particular, U-FAB allows the researcher to set temperature control (4~50℃) and cell suspension function for individual channel respectively. This decreases cell stress and increases cell viability, leading to high reliability in repeated printing results.
In fact, CLECELL has developed the EpiAirway model in which a human’s bronchial epithelial cell is applied on U-FAB to observe its differentiation into ciliated columnar cells. By using the EpiAirway model which is similar to an in vivo model, we expect that it will provide a test bed for basic research not only for COVID-19, but for other viruses and anti-virus mechanisms as well.
In the present day many researchers in the bio field require the 3D tissue model to research virus diagnosis method and also to swiftly and efficiently develop the optimal vaccine and cure. As a result, 3D bioprinting techniques, with their ability to automate creation, stands out amongst the many different attempts and methods for producing biomimetic tissue. Considering the time and cost for animal testing, clinical trials and approval of cures, our prospect is that U-FAB will be a breakthrough with its precise/accurate printing technology and automated high-volume cell creation capability.
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Could you please tell us a little about your experience bioprinting 3D tissues for therapeutic and/or vaccine development?
CLECELL has focused on research and development of artificial tissue through 3D bioprinting technology. My team has been conducting research on respiratory epithelium models using our proprietary 3D bioprinter – the U-FAB – and through 3D bioprinting technology we have created a respiratory epithelium model. Furthermore, the model is expected to become a test bed for not only SARS-Cov-2, but also for research of mechanisms of various viruses.
What are important characteristics in a 3D tissue structure in the research and development of therapeutics and vaccines against a pandemic virus?
When a virus (e.g., COVID-19) infects a person, antibodies must be produced through the immune system. However, with novel viruses, the body does not possess the necessary data of the virus which makes the body vulnerable. Therefore basic tests to test the efficacy of the new drug and vaccine are carried out using epithelial cells. The epithelial cells are the cells that are first exposed to the virus within the body.
However, in a regular 2D cell model we face the problem of easily losing the characteristic of the cell and also low reproduction of the actual human body. The 3D model retains the characteristic of a single cell and also can similarly copy the complex structure and functional traits of a human body. These strengths help to make this 3D method a worthy prediction model and the reliability of test results is far higher than that of the 2D cell model.
What are the benefits of using 3D bioprinting as a technology for the manufacture of tissue models for COVID-19 therapeutics research and development?
All of the experiment materials used in researches have lot variation from each production. The reliability of the test result can be guaranteed only when the test materials have been produced in a uniform manner. So, minimizing the lot variation plays a very fundamental and key role in reliability of test results.
The tissue models that are commercially sold in the market nowadays produce the tissues using a manual method. This leads to constant lot variation between each production which is caused by the handling skills of the experimenter. However, modeling tissues using 3D bioprinting adopts the multi-channel function which can produce large volume of tissues and also minimizes lot variation between tissues. This supports production of 3D tissues with uniformity and quality. These tissues can be used for researching COVID-19.
What challenges with 3D cell cultures could 3D bioprinting overcome at a time of coronavirus?
In case of CLECELL’s EpiAirway model where the human bronchial epithelial cell is applied, we used 3D tissue model from 3D printing and we were able to observe its differentiation into ciliated columnar cells. By using the EpiAirway model, which is similar to an in vivo, we expect to contribute to researches not only for COVID-19 but for other virus infections and anti-virus mechanisms as well.
How are 3D bioprinted tissues already being used for the testing and development of therapeutics against COVID-19?
An advantage of using 3D tissue models from 3D bioprinting is that the test results can be directly observed from the 3D tissue model. Also, the model maintains the similar structure of an actual body which helps to gain higher reliability from the research. It also has the strength of being similar to in vivo so it is projected to be used in various different kinds of research on COVID-19.
How has the on-demand production of 3D tissue structures affected research during COVID-19 pandemic?
CLECELL is currently in the final stages of developing 3D tissue. We have not yet begun on-demand production, but our ultimate aim is to be able to develop 3D tissue according to the specific demands from the researchers.
Should there be a future wave or even another, different infectious pandemic, how could bioprinting technologies be applied to future, urgent research demands?
We can apply 3D bioprinting on developing disease models that are difficult to replicate on animal models. We can also use patient-derived cells to study 3D-printed tissue models in a short time frame and use it as a patient-specific test bed for pharmaceuticals.
In the face of COVID-19, what do you think the research and medical communities may have learned about 3D printing and bioprinting technologies?
When a severe pandemic sweeps the world, we focus on seeking for the most efficient and effective methods for researching the cure to protect against the disease. Many researchers in the bio field are now utilizing 3D printing technology for research on virus diagnosis and vaccine development. This demonstrates that 3D models have a very important role in the industry.
Where do you see bioprinting in 5—10 years’ time? Has the response to COVID-19 changed your expectations for the technology in any way?
More and more researchers from around the world are taking part in 3D bioprinting, so we believe that this development will continue on to a point where pharmaceutical test bed will completely replace animal disease models. We have already confirmed that our EpiAirway model can offer direct aid for basic research on diseases. We can look forward to its limitless application in various other clinical fields.