Nearly all in vivo cells reside in an extracellular matrix (ECM) consisting of a complex 3D architecture and interact with with neighboring cells via biochemical cues¹. It is therefore logical that a cell culture environment that cannot mimic this structure and organization can have limitations. Cells cultured in flat, 2D environments often exhibit diminished properties such as cellular morphology, viability, differentiation, and proliferation.

The limitations of 2D cell culture can cause roadblocks to research and contribute to poor predictive power of preclinical cell-based drug and toxicity screening assays, ineffective tumor biology modeling, and a reliance on the concomitant use of animal models for preclinical drug development studies, among other issues.

Emerging evidence strongly suggests that 3D cell cultures that establish physiological cell-cell and cell-ECM interactions can mimic the specificity of native tissue, especially in applications such as stem cell culture, cancer research, drug and toxicity screening, and tissue engineering.

When comparing cells in 2D and 3D cultures, one of the primary differences is the dissimilarity of the cell morphology. Because cells adapt to shapes based on the orientation of integrin-mediated adhesions to the ECM, 2D culture attachment occurs on one side of the cell. In contrast, 3D culture attachment occurs around the entire surface of the cell². As a result, cell spreading and attachment takes longer in 3D culture models—in some instances, over the course of several days—which can directly impact cell proliferation, apoptosis, and differentiation^3-6. Some cell types can even regain their physiological form and function when cultured in a 3D environment⁷.

Cellular functionality is also impacted by this adjusted morphology, and cells more closely resemble the properties observed in vivo when cultured in a 3D environment^8,9. As a result, 3D cell culture models can essentially mimic in vivo environments and allow the growth and differentiation of cells that exhibit in vivo-like behaviors and functionality.

In order for 3D cell culture models to enable the accurate prediction of cell behavior, aspects of in vivo cell behavior need to be accurately reproduced—and this is true across various research applications. To do this, 3D cell culture models usually require the use of hydrogel-based matrices or solid scaffolds. Of the various methods available for successful 3D cell culture, naturally derived ECM-based hydrogels are most commonly used.

Hydrogels and ECMs are highly effective matrices for 3D cell culture. Possessing characteristics very similar to natural tissue and commonly derived from natural sources, these gels promote cellular function through their biocompatible and bioactive nature¹⁰. Synthetic hydrogels and solid scaffolds are also effective techniques for 3D cell culture. 

Another approach to 3D cell culture is to use cellular spheroids. 3D spheroid cultures are simple models that can be generated from a wide range of cell types, forming spheroids due to the tendency of adherent cells to aggregate. Spheroids naturally mimic various aspects of solid tissues, which makes for an effective method of tumor research. Differentiation of pluripotent stem cells (PSCs) also typically involves the formation of spherical structures, making spheroids an especially good physiological 3D model.

Learn more about applications and specific techniques to enhance cell culture and assay systems with 3D models.

Whether you are developing your first 3D assay or scaling up an existing 3D model for high throughput, Corning can provide you with reliable cell culture solutions and an extensive support network that’s here for you every step of the way. 

Since the development of the first cell culture flask, Corning has been connected to cell culture innovation. And our dedication to this innovation has not wavered. From the development of Corning^® Matrigel^® Matrix 30 years ago—now the leading 3D matrix available—to breakthrough technologies like our spheroid microplate with Ultra-Low Attachment surface, enabling uniform and reproducible 3D multicellular spheroid formation, it is our goal we to create innovative 3D cell culture solutions that allow you to produce optimal environments for growing cells that exhibit in vivo-like behaviors and functionality—across all aspects of research.

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2.     Baker BM and Chen CS. J. Cell Sci. 125(13):3015-3024 (2012).
3.     Singhvi R, et al. Science 264:696-698 (1994).
4.     Chen CS, et al. Science 276:1425-1428 (1997).
5.     Thomas CH, et al. Proc. Natl. Acad. Sci. USA 99:1972-1977 (2002).
6.     McBeath R, et al. Dev. Cell 6:483-495 (2004).
7.     Benya PD and Shaffer JD. Cell 30:215-224 (1982).
8.     Debnath J and Brugge JS. Nat. Rev. Cancer 5:675-688 (2005).
9.     Nelson CM and Bissell MJ. Annu. Rev. Cell Dev. Biol. 22:287-309 (2006).
10.   Dawson E, et al. Adv. Drug. Deliv. Rev. 60(2):215-228 (2008).