Experts: Ursula Graf-Hausner (graf 3dcellculture), Ralph Müller (ETH Zurich), Michael Raghunath (ZHAW)
By producing complex tissue, 3D bioprinting could revolutionise regenerative medicine and contribute significantly to personalised medicine. For Switzerland, this technology represents a great opportunity, as the country is home to internationally competitive players along the entire value chain.
Picture: iStock
3D bioprinting is one specific application within the broad field of 3D printing. In 3D bioprinting, living human cells are selectively sprayed onto printed structures or embedded in a substrate, bio-ink, and positioned three-dimensionally in a matrix. In this way, small models of various tissues and, as a long-term goal, implantable organs for personalised regenerative medicine can be printed and, theoretically, built up according to requirements. Optimal matrix configuration, with proteins and growth factors, helps to ensure that the living cells develop as desired.
So far, there have only been a few attempts to print highly complex organs or tissues. One successful example in regenerative medicine is the printed trachea, which is currently undergoing the clinical trials necessary for approval and may provide a remedy in the case of injuries. For other organs, development is not yet as advanced. 3D printing primarily offers advantages for the production of organs or structures (such as those found in muscles, hearts and bones) that are subjected to considerable mechanical stress: A rigid structure is a given and can be populated with cells of various types. One problem, however, is that although the cells survive the printing process, they subsequently die due to insufficient blood perfusion. Today, blood perfusion is achieved by means of diffusion, which is inadequate for larger structures. The idea of printing entire functional organs will not become reality for at least 20 years.
Diffusion-based supply is sufficient if the printed constructs, e.g. three-dimensional tissue models, are small. Such organoids, as mini-organs made of human cells are also known, are used in drug development, as well as for drug testing and toxicological studies. Since the studies use human tissue is used, the data obtained are highly reliable. In addition, the number of animal experiments is thus reduced, which is important from a socio-political and ethical point of view. Thanks to 3D bioprinting, personalised studies can be carried out with diseased tissue; the technology is thus paving the way for personalised medicine. Such an approach does not create any regulatory problems, as the removed tissue is not transplanted, but only used for laboratory studies. The high price is an obstacle though. It is likely that applications will be limited to rare diseases. The knowledge gained from studying mini-organs is accelerating both basic and applied research.
Over the next few years, applications will still mainly be limited to in-vitro models, such as tissue models and organoids. Technologies based on 3D printing that also achieve a specific three-dimensional arrangement of cells should make it possible to produce structures that are closer to the physiological state than 3D-printed geometries. One future application in the broad field of 3D bioprinting is the production of laboratory-grown meat (see also Alternative protein sources and Implants from the loudspeaker). Printing can give the final product a fibrous structure, which is almost impossible in normal cell culture.
3D bioprinting is not used as a stand-alone technology and is part of the wider field of biomanufacturing, which is not just about the tissue production process, but also encompasses the upstream production of hardware, optimal tissue supply and the downstream use of analytical methods. Internationally competitive players along the entire value chain are based in Switzerland, including large pharmaceutical companies. This country is also strongly established as a research location in this field. Accordingly, the topic offers great opportunities for Switzerland. Nevertheless, there is a need for coordination at federal level: The players along the entire value chain should be brought together, for instance with the aid of the Innosuisse funding scheme Innovation Booster, or a National Research Programme. This would give research a major lift, enhance international competitiveness and prevent Switzerland from lagging behind.
Although the technology is promising, it is being held back by regulatory requirements. Since animal testing is a regulatory requirement for dose-finding and toxicity studies, the use of 3D-printed models is not worthwhile for industry. The regulatory authorities should be involved in development at an early stage, as they are in the USA, so they can approve the replacement of animal testing with 3D-printed models. What has worked in the cosmetics sector, where societal pressure eventually forced a change in regulations, could also be successful in the context of printed tissue models. It is to be expected that the long-term vision of printing implantable organs will come up against acceptance problems in society, especially if the cells used are genetically modified. The more immediate problem though, is that of the population’s excessively high expectations regarding in vitro systems.
From a scientific point of view, the composition of the bio-ink and matrix is a challenge: The materials must not only be printable, but also constitute a ‘natural’ environment for the printed cells, and be compatible with the body. Regulatory approval considerations must be incorporated right from the start, so that applications do not remain limited to tissue models. The integration of blood vessels into the printed structures is also a problem. However, researchers are confident that the problem of supplying larger structures will be solvable.
A high level of automation, encompassing aspects ranging from cell harvesting to the production of organ models and taking place under sterile conditions, could give the technology a boost. Less space would be required than with current approaches, which rely on animal experiments and the corresponding infrastructure. Prominent Swiss-based players, such as Hamilton Bonaduz AG and Tecan Group Ltd, provide know-how.
At present, the applications are mainly restricted to academia and specialised start-ups. It makes little sense for SMEs to invest in the technology unless they already have in-house experience of cell culturing. It is generally more cost-effective for SMEs to buy in such applications as services. The points of contact are the universities of applied sciences and other universities, although problems with intellectual property (IP) may arise during implementation of projects. Models in which providers operate as firms but remain embedded in academia are of interest: Access to the latest research results is a given, but at the same time, the IP situation is clearly regulated.
One specific example application is described in the article Implants from the loudspeaker.
