3D Cell Culture Unlocks New Research Possibilities
From ancient times to the present, a sharper understanding of reality has always driven artists, explorers, and scientists alike. With advances in 3D cell culture, we are once again a step closer to the truth. And since 3D cell culture can often be performed instead of animal testing you avoid animal suffering.
The key to growth is the introduction of higher dimensions of consciousness into our awareness.
- Laozi
In today's competitive research environment, the wealth of available information cannot be grasped in its entirety, while scientists are under enormous pressure to find solutions to their tasks. No one likes to conduct animal experiments, and yet the use of animal models remains widespread in medical and scientific research for a myriad of questions and tests.
However, there are also good alternatives such as in vitro models, cell cultures, simulation in computer models, mini-organs and multi-organs-on-chips, new imaging, and analytical techniques. In vitro models offer the possibility to study cellular reactions in a closed system where experimental conditions are maintained. In this context, three-dimensional (3D) cell cultures have been increasingly used in pharmacology and scientific research to replace laboratory animals and two-dimensional (2D) cell cultures. The validation of such experiments, substituting animal models, can be done by different methods [1]. In this article, we discuss the opportunity provided by 3D cell cultures to replace animal models.
3D cell culture - what is this?
3D cell culture refers to the cultivation of cells in a three-dimensional microenvironment. Just as cells spatially organize to give form and functions in the body, this is also realized in 3D cell cultures. Thus, they can respond better to physiological signals than in conventional 2D culture. 3D cell cultures are more physiologically relevant and predictive than 2D cultures, show a higher degree of structural complexity and retain a steady state for longer. Cells grow and interact with each other and with the surrounding extracellular scaffold in three dimensions.
So, how are 3D cell cultures produced? There are generally two options – cells can be cultured within a scaffold, or cultured scaffold-free. Common scaffold materials include hydrogels of polymeric materials derived from extracellular matrix proteins (ECM) or agarose. They can also be an inert matrix; spongy membranes containing pores for cell growth. Scaffold-free methods are based on the self-assembly of cells into clusters or spheroids and can be enabled, for example, by magnetic 3D cell culture (M3D) [2], low-adhesion plates, micro-structured surfaces or the "hanging drop" method.
Why should you replace animal models with 3D cell culture?
There are several reasons for replacing animal testing: practical, ethical, financial, and regulatory.
With 3D cell culture you keep your research options open
Starting your study with a 3D cell culture validated against an animal model will help you keep your experimental options open, e.g., if you are starting a PhD thesis or a new research program, or if you want to discover new targets. 3D cell culture is simply more flexible and allows you to adjust your approach as needed.
Animal testing raises ethical questions
Scaffold-based approaches focus on applying cytocompatible, natural, or synthetic biomaterials to support cell proliferation, differentiation and function and allow for nutrient and metabolite exchange. Commercially available natural biomaterials for 3D cell culture provide high biocompatibility, but their undefined degradation rate and the existence of xenogenic components limit their human applications [4]. Such approaches also cannot maintain LG viability, expansion, and differentiation potential beyond 4 passages.
Regulatory pressure to reduce the use of animal models is increasing
The 3Rs principle describes the ethical principles for research with animals and stands for "replace, reduce, refine." Only if the 3Rs principle is implemented are animal experiments approved by the competent authority. An animal experiment may only be carried out if there are no alternative methods. Even then, only a minimal number of animals may be used, and the experiments must be designed to be minimally stressful.
Although animal testing is still widespread, regulators are increasing pressure to reduce the use of animal models, e.g., the European Medicines Agency (EMA) is introducing new measures to minimize animal testing in drug development.
EMA is putting in place special support to developers to replace, reduce and refine animal use for the development, manufacturing, and testing of human and veterinary medicines [3]. The agency is promoting the 3R principles through EMA’s Innovation Task Force (ITF). This action will facilitate the development and implementation of New Approach Methodologies (NAMs) in line with the European Union legislation on the protection of animals used for scientific purposes.
3D cell cultures are significantly cheaper than animal models
Finally, financial reasons speak in favor of replacing animal models with 3D cell cultures in research and in the risk assessment of chemicals and drugs.
Some animal tests take months or years to conduct and analyze (e.g., 4-5 years, in the case of rodent cancer studies), with a cost of hundreds of thousands, sometimes even millions of dollars per substance examined. The inefficiencies and enormous costs associated with animal testing make it impossible for regulators to adequately assess the potential effects of the more than 100,000 chemicals currently in commerce worldwide. Studying the effects of the myriad of combinations of substances is even more difficult [4].
Building and maintaining your own animal facility is very costly and labor intensive. Experimental animals must be kept in appropriately equipped buildings, they must be fed and cared for by qualified personnel and veterinarians. In comparison, non-animal methods are significantly cheaper and less time-consuming. If you are a scientist setting up a new laboratory, you would therefore be well advised to avoid animal experiments if possible.
Why 3D cell culture is booming
3D cell culture can save you time, hassle, and money when developing models for preclinical studies and testing, as well as for researching and developing new therapies. Numerous research papers have shown that 3D cell cultures can accurately predict the efficacy or toxicity of drug treatments. Growing cells in 3D can reveal a realistic drug response, gene expression and cell behavior, capture phenotypic heterogeneity and mimic tumor microenvironments.
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References
[1] Avelino TM, García-Arévalo M, Torres FR, Goncalves Dias MM, Domingues RR, de Carvalho M, Fonseca MC, Rodrigues VKT, Leme AFP, Figueira ACM. Mass spectrometry-based proteomics of 3D cell culture: A useful tool to validate culture of spheroids and organoids. SLAS Discov. 2022 Apr;27(3):167-174. doi: 10.1016/j.slasd.2021.10.013. Epub 2021 Oct 27. PMID: 35058185.
[2] Tseng H, Daquinag AC, Souza GR, Kolonin MG. Three-Dimensional Magnetic Levitation Culture System Simulating White Adipose Tissue. Methods Mol Biol. 2018;1773:147-154. doi: 10.1007/978-1-4939-7799-4_12. PMID: 29687387.
[3] European Medicines Agency, EMA implements new measures to minimise animal testing during medicines development https://www.ema.europa.eu/en/news/ema-implements-new-measures-minimise-animal-testing-during-medicines-development
[4] Costs of Animal and Non-Animal Testing, Humane Society International https://www.hsi.org/news-media/time_and_cost/
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3DCC vs. Animal Models