The future through Bioprinting

What is Bioprinting?

Have you ever heard of 3D printing? Now, imagine that instead of using plastic, we use biological material to print organs and tissues. To me, this sounds like something taken from a movie scene of a futuristic lab. But this is a technology that has been around for quite some time now.

In 1984, a man called Charles Hull invented stereolithography (STL) for bioprinting 3D objects from digital data [1]. STL is a system for creating a three-dimensional structure, built up layer-by layer using photochemical processes [2]. This invention is said to have symbolized the birth of 3D printing. Since then, in vitro models have evolved from simple two-dimensional structures into more advanced three-dimensional structures such as organoids (miniature version of an organ), micro-tissues and dynamic culture systems [3]. Four years after Charles Hull´s invention, the first bioprinting was demonstrated by micro-positioning cells in a two-dimensional pattern.Today, bioprinting technology is mostly used to model a variety of tissues, organs and diseases [3]. This allows for researchers and doctors to get access to models that could simulate real tissues and organs and interactions between materials and cells, which makes them easier to study.

How to bioprint ?

Now when we have introduced what bioprinting is and understood why this is a revolutionary technology in the field of medicine and potentially also in other fields of science, we can get more into detail. How does bioprinting work? Or, how to bioprint?

Four methods

Firstly, the material that is used for bioprinting is called bioink. Bioink consists of cells surrounded by a supporting material called hydrogel [4]. This bioink is used to form three-dimensional structures in which the cells can grow, divide and migrate.

Next, there are four different methods used in bioprinting [5]. There is the extrusion bioprinting, Inkjet printing, Lithography bioprinting and Cell spheroid-based bioprinting. Extrusion bioprinting is the most common and accessible method. This method uses a pressure-driven extrusion of bioink from a nozzle to print filaments which have been designed by the user. Inkjet printers are quite similar to the extrusion printers, the main difference lies in that the bioink is deposited in the form of droplets instead of in a continuous flow. 

The lithography bioprint method uses light to pattern a cell-filled hydrogel resin into three-dimensional structures. This technique offers a higher resolution than the extrusion technique. In the last method Cell spheroid-based bioprinting, also known as bioassembly, cell aggregates are precisely assembled into cell-dense 3D structures, or structures containing organoids.

Three approaches

Lastly, when designing objects to be bioprinted, there are three different approaches to consider: biomimicry, mini-tissue building blocks and autonomous self-assembly [6]. Biomimicry is about the concept of taking inspiration from nature when seeking solutions to complex human problems. When applying biomimicry to bioprinting, it involves the manufacture of identical reproductions of cellular and extracellular components of tissues and organs. It can be both small parts of a tissue or organ, like branching patterns of blood vessels, or entire organs that are replicated.

Autonomous self-assembly is also an approach that mimics nature, but in this case to specifically replicate biological tissues. The method uses embryonic organ development as a guide when designing the biological systems. This technology however requires an intimate knowledge of the developing mechanisms of embryonic tissues and how to manipulate the environment of the cells to drive embryonic mechanisms in the bioprinted tissues.

A mini-tissue can be defined as the smallest functional component of a tissue or an organ. This concept can be relevant for both of the strategies above as mini-tissues can be fabricated and assembled into larger functional pieces by using self-assembly, rational design or a combination of both.

To print a complex three-dimensional biological structure with functional, mechanical and structural properties, all of the strategies above are likely to be required. In addition to this, further important steps of the bioprinting process includes imaging and design, choice of suitable materials and cells and finally the printing of the tissue construct. When the tissue is constructed, it can be transplanted, or in some cases it undergoes maturation in an in vitroenvironment before the transplantation. It can also be reserved for in vitro examination and analysis.

Possible applications

Regenerative medicine and tissue engineering for possible transplantation [7]

When we think of bio-printing, we immediately imagine printing hearts, lungs, kidneys and even an eye. But printing functional organs is a challenging task. But any tissue that does not require vasculature, such as blood vessels or cartilage, is already an excellent example of success.

Creating heart valves is another important application of tissue engineering, since damaged heart valves lack the ability to regenerate, so they must be replaced with mechanical or biological substitutes. Bioprinting is a viable method to produce anatomically accurate aortic valve geometry to tackle the coarctation of the aorta for example. 

There is, however, still much research to be done before a mechanically stable three-dimensional structure connected to the vascular system.In a similar perspective, experiments were carried out using direct deposition of stem cells on open wounds to allow regeneration of the epidermal layer leading to another success.

As an example, BIOLIFE4D [8] has achieved the bioprinting of a miniature human heart by reprogramming a patient’s own white blood cells into Induced pluripotent stem cells, and then differentiating these iPS cells into the different types of heart cells needed to bioprint individual heart components.

Pharmaceutical research in the field of drugs 

A 3D printed human tissue model can be used as scaffolds for drug delivery research, as well as drug screening studies. Tissue models made from 3D bioprinting can be used to test the effectiveness of the wide array of molecules in drug design as they closely mimic the native tissue and can be created in a high-throughput manner by fabrication in micro networks.

In addition to being able to control the size of the tissues and their microarchitecture, bioprinted tissues can be manufactured in high volumes, cultivated concurrently, and pose little risk of cross-contamination. Indeed, as a direct example of application, it has been possible to test drug metabolism using bio printed liver models.

Research in a larger way   

Consider the case of cancer. Due to their lack of three-dimensional interactions with neighboring cells and substrates, two-dimensional tumor models do not represent a physiologically relevant environment. Therefore, bioprinting provides a means of understanding cellular interactions in three dimensions and making clinically relevant observations.
We could even think bigger: the possibility of printing a skin tissue that mimics it nearly to perfection could be useful in various fields such as cosmetics to test products before marketing.

Advantages and limits

The latest technologies always sound futuristic and innovative with several advantages, but they also have their own set of disadvantages.
Indeed, this possible solution to the hundreds of thousands of patients waiting for a transplant but also to tissue repair would be a revolution against the current shortage. This approach would even prevent possible cell rejections. And it is not only a benefit for humans because it would also allow to decrease tests made on animals, not to mention the important scientific mobilization for research that it already generates.

But there is still a long way to go. The idealistic picture is somewhat tainted by the very high costs of this technique with a possible insurance coverage that remains very low, limiting therefore the accessibility. Being in the test phase makes it difficult to project possible undesirable effects on patients. It is nevertheless a very precise and meticulous science that seeks to mimic the very complex functioning of the human body and its constituents, which is no easy task.

Bioprinting in the future

Today, bioprinting is still in the research stage. Despite the few grey areas of this concept, it remains a promising and revolutionary solution for a better future and offers new perspectives to researchers and professionals who are working hand in hand to meet this large-scale challenge. Would this be an excellent step towards 4D printing?

References

[1] Zeming Gu, Jianzhong Fu, Hui Lin, Yong He, 2020 https://doi.org/10.1016/j.ajps.2019.11.003

[2] Charles W. Hull, 1986 US4575330A – Apparatus for production of three-dimensional objects by stereolithography – Google Patents

[3] Yi Xiang, Kathleen Miller, Jiaao Guan, Wisarut Kiratitanaporn, Min Tang & Shaochen Chen, 2022 https://doi.org/10.1007/s00204-021-03212-y

[4] Immuno Diagnostic, 2020 Bioprinting – the future of research: how to get started – Immuno Diagnostic

[5] Andrew C.Daly, Margaret E.Prendergast, Alex J.Hughes, Jason A.Burdick, 2021 https://doi.org/10.1016/j.cell.2020.12.002

[6] Sean V Murphy & Anthony Atala, 2014 https://doi.org/10.1038/nbt.2958

[7] Madhuri Dey & Ibrahim T. Ozbolat, 2020 https://www.nature.com/articles/s41598-020-70086-y

[8] BIOLIFE4D, 2022 https://biolife4d.com/about/