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Why do Scientists have High Hopes for 3D Cell Culture for Drug Screening?

“The discovery of new drugs is a monumental struggle with nature." – This quote by renowned chemist Bruce Maryanoff aptly sums up the tedious and expensive drug development process. This ranges from target identification, lead discovery and optimization, preclinical validation, and clinical trials to approval for clinical use.

High-throughput screening (HTS) of small compound libraries to identify lead structures is crucial in the drug development process. Remarkably, much of cell-based HTS is currently still done with two-dimensional (2D) cell culture, though it is known that 2D structures poorly reflect physiological conditions – one reason for the high failure rate in drug discovery [1]. Approaches that rely on animal testing, in turn, bring with them a whole host of other downsides.

Scientists therefore have high hopes for three-dimensional (3D) cell culture. Spheroids and organoids are very useful for more predictive drug screening compared to 2D cultures and animal models. In this article, we tell you why and discuss specific examples.


Why are spheroids and organoids in drug screening so useful?

The extracellular matrix and other microenvironmental factors influence the cell phenotype and drug response. 2D cell culture cannot simulate these factors, but spheroids and organoids can.

In addition, 3D cell cultures for drug screening allow not only organoid but also other organotypic cultures. This is important from a regenerative medicine perspective. With organotypic models, we can explore different organ models by recombining cells that have been previously disaggregated and maintained as cell lines. These models allow the assembly of complex tissues replicating the morphology and cellular interactions of in vivo tissue.


3D cell culture and stem cells: Why are Magnetic 3D Cell Culture Solutions enabling tools?

Stem cells are widely used as a cell source for regenerative medicine and cell therapy applications [2]. Stem cell organoids are understandably a hot topic because the use of human cells is of great importance for many scientific questions.

We can use magnetic 3D (M3D) cell culture with stem cells, with primary cells, with cell lines – the technique facilitates the creation of a desired phenotype for many disease models that researchers are developing. The technology of Greiner Bio-One's M3D Cell Culture Solutions is based on the magnetization of cells using NanoShuttle-PL. The magnetized cells are brought together through the use of magnets via either levitation or biopriting to form both structurally and biologically representative M3D in vitro models. NanoShuttle-PL is composed of iron oxide, poly-L-lysine and gold. These nanoparticles (Ø < 50 nm) attach to the cell membrane by electrostatic attraction during an overnight static incubation period, leading to magnetization of the cells.

The lung model is a good example for 3D cell culture as an enabling tool. Human cells can also be used for the chosen disease model.

Porcine cells are also important for lung model research, where they most closely resemble human cells. In addition, an advantage of porcine cells is that they are easy to obtain in large quantities from slaughterhouse waste, so, researchers don't need to establish an animal protocol.

Representative culture models of the lung are a particularly challenging tissue to recreate in vitro. Tseng et al. used magnetic levitation in conjunction with magnetic nanoparticles to create an organized 3D co-culture of the bronchiole that sequentially layers cells in a manner similar to native tissue architecture [3]. The 3D model was assembled from four human cell types in the bronchiole: endothelial cells, smooth muscle cells, fibroblasts, and epithelial cells. These cell layers were first cultured in 3D by magnetic levitation, and then manipulated into contact with a magnetic pen.

Magnetic levitation is based on the use of a nanoparticle assembly consisting of poly-L-lysine, magnetic iron oxide, and gold nanoparticles that self-assemble into networks based on electrostatic interactions. Cellular adhesion of the biocompatible nanoparticles makes the cell magnetic, allowing for magnetic manipulation [3]. As it relates to the global COVID plight regenerative lung tissue model is highly important and relevant because animal models are not very representative for COVID research.


What are the current methods for 3D cell culture production?

There are several ways to produce 3D cell cultures, which differ in terms of the amount of work required and the quality of the resulting cell cultures.


Scaffold-free 3D culture systems

These are the simplest way to produce spheroid-like cultures, and they come with a drawback: It is difficult to consistently control the formation and shape of spheroids created this way. Large variability in size and shape are a limitation of scaffold-free methods, including non-adherent surface culture systems, hanging drop, and bioreactor techniques.


Scaffold-based 3D culture systems

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.


Bioprinting 3D culture systems

3D bioprinting is the newest tissue engineering technique for the biofabrication and recapitulation of complex biological tissues. In particular, magnetic 3D bioprinting (M3D) is an exciting approach: This system is a xenogenic-free, highly scalable and reproducible 3D culture platform for exocrine glands such as the salivary glands. M3D uses biocompatible magnetic nanoparticles to label cells and print them into a spatially organized 3D structure, depending on the magnetic field used [4].


How is high-throughput screening performed with organoid cultures?

Fernandez-Vega et al. applied the 3D technology to the first large-scale screening in which over 150,000 molecules were screened against primary pancreatic cancer cells using HTS. It is the first demonstration that a screening campaign of this magnitude using clinically relevant, ex vivo 3D pancreatic tumor models obtained directly from biopsy can be performed in the same manner as a conventional drug screening using 2D cell models [5].

Hou et al. describe the utility of 3D magnetic cell culture for large-scale drug screening [6]. The researchers developed an HTS-compatible method to produce organoids in standard 384 consistently- and 1536-well flat-bottomed plates by combining the use of a cell-repellent surface with magnetic force bioprinting technology. They validated this method by studying the effect of well-characterized anticancer agents against four patient-derived pancreatic cancer primary cells associated with KRAS mutations. The technology was tested for compatibility with HTS automation by performing a cytotoxicity pilot screening of ~3,300 approved drugs. The results suggest that this technique can readily be used to support large-scale drug screening using clinically relevant ex vivo 3D tumor models taken directly from patients [6].


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 [1] Langhans SA. Three-Dimensional in Vitro Cell Culture Models in Drug Discovery and Drug Repositioning. Front Pharmacol. 2018 Jan 23;9:6. doi: 10.3389/fphar.2018.00006. PMID: 29410625; PMCID: PMC5787088.
[2] Fang Y, Eglen RM. Three-Dimensional Cell Cultures in Drug Discovery and Development. SLAS Discov. 2017 Jun;22(5):456-472. doi: 10.1177/1087057117696795. Erratum in: SLAS Discov. 2021 Oct;26(9):NP1. PMID: 28520521; PMCID: PMC5448717.
[3] Tseng H, Gage JA, Raphael RM, Moore RH, Killian TC, Grande-Allen KJ, Souza GR. Assembly of a three-dimensional multitype bronchiole coculture model using magnetic levitation. Tissue Eng Part C Methods. 2013 Sep;19(9):665-75. doi: 10.1089/ten.TEC.2012.0157. Epub 2013 Feb 25. PMID: 23301612.
[4] Rodboon T, Yodmuang S, Chaisuparat R, Ferreira JN. Development of high-throughput lacrimal gland organoid platforms for drug discovery in dry eye disease. SLAS Discov. 2022 Apr;27(3):151-158. doi: 10.1016/j.slasd.2021.11.002. Epub 2021 Dec 4. PMID: 35058190.
[5] Fernandez-Vega V, Hou S, Plenker D, Tiriac H, Baillargeon P, Shumate J, Scampavia L, Seldin J, Souza GR, Tuveson DA, Spicer TP. Lead identification using 3D models of pancreatic cancer. SLAS Discov. 2022 Apr;27(3):159-166. doi: 10.1016/j.slasd.2022.03.002. Epub 2022 Mar 17. PMID: 35306207.

[6] Hou S, Tiriac H, Sridharan BP, Scampavia L, Madoux F, Seldin J, Souza GR, Watson D, Tuveson D, Spicer TP. Advanced Development of Primary Pancreatic Organoid Tumor Models for High-Throughput Phenotypic Drug Screening. SLAS Discov. 2018 Jul;23(6):574-584. doi: 10.1177/2472555218766842. Epub 2018 Apr 19. PMID: 29673279; PMCID: PMC6013403.

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