Role of three-dimensional cell culture in therapeutics and diagnostics: an updated review

Abstract

Drug development and testing are a tedious and expensive process with a high degree of uncertainty in the clinical success and preclinical validation of manufactured therapeutic agents. Currently, to understand the drug action, disease mechanism, and drug testing, most therapeutic drug manufacturers use 2D cell culture models to validate the drug action. However, there are many uncertainties and limitations with the conventional use of 2D (monolayer) cell culture models for drug testing that are primarily attributed due to poor mimicking of cellular mechanisms, disturbance in environmental interaction, and changes in structural morphology. To overcome such odds and difficulties in the preclinical validation of therapeutic medications, newer in vivo drug testing cell culture models with higher screening efficiencies are required. One such promising and advanced cell culture model reported recently is the “three-dimensional cell culture model.” The 3D cell culture models are reported to show evident benefits over conventional 2D cell models. This review article outlines and describes the current advancement in cell culture models, their types, significance in high-throughput screening, limitations, applications in drug toxicity screening, and preclinical testing methodologies to predict in vivo efficacy. Graphical Abstract

Metallothionein-3 is a multifunctional driver that modulates the development of sorafenib-resistant phenotype in hepatocellular carcinoma cells

“…Studying the differences between 2D and 3D cell cultures is crucial for understanding how the 3D culture environment influences cellular behavior. This comparison provides a better representation of physiological processes and enables more accurate investigation of a drug response [ 30 ]. Spheroids were generated using the hanging drop method [ 31 ].…”

Advances in the application of extracellular vesicles derived from three-dimensional culture of stem cells

“…In contrast, synthetic scaffolds possess stronger mechanical properties and better control over scaffold characteristics, allowing adjustments based on specific requirements to address batch variations, but they lack bioactivity [ 91 , 117 ]. Hybrid scaffolds, combining raw materials from both natural and synthetic scaffolds, aim to overcome these limitations of both [ 118 ]. For example, hybrid scaffolds made from synthetic PEG and natural collagen have been demonstrated to have sufficient mechanical strength and higher cell adhesion to further enhance the efficiency of adipogenic differentiation of adipose-derived SCs [ 110 ].…”

Biomimetic Scaffolds—A Novel Approach to Three Dimensional Cell Culture Techniques for Potential Implementation in Tissue Engineering

“…This is due to changes in cell morphology, reduced cell–cell and cell–ECM interactions, and altered gene and protein expression resulting from the lack of a complex microenvironment [ 23 ]. Researchers were compelled to explore 3D culture techniques due to impaired cell polarity, ample access to oxygen and nutrition, and the absence of an external matrix, among other characteristics [ 24 ]. In the early 2000s, it became evident that 3D cultures were an emerging technology [ 25 ].…”

“…Secondly, cadherins localize on the cell surface. Finally, cadherin-cadherin homophilic bindings between nearby cells cause stronger cell-to-cell adhesion and spheroid formation [ 24 , 32 , 33 ].…”

“…Organoids are more complex structures than spheroids and are named as such because they represent the complexity of organs, unlike spheroids, which generally represent only one type of tissue [ 30 ]. Organoids can be derived from various types of stem cells, including embryonic, induced pluripotent, or tissue-specific cells [ 24 ]. Due to their complexity, organoids are valuable models for studying and simulating physiological processes that occur in living organisms’ organs.…”