What Are Organoids and Spheroids?
Biomedical research is undergoing a significant shift towards more physiologically relevant models for studying human biology and disease. Traditional two-dimensional (2D) cell cultures, while useful, often fail to replicate the complex structure and functionality of human tissues. These limitations, as well as the FDA’s recently announced plan to phase out animal testing requirements for drug development in favor of New Approach Methodologies (NAMs), have spurred the development and reinforced the adoption of three-dimensional (3D) cell culture systems such as organoids and spheroids.
These 3D cell culture models generally provide a much closer approximation of true human in vivo conditions than 2D cell culture and animal models, making them invaluable tools for drug development, disease modeling, and personalized medicine. Allow us to provide a basic overview of organoids and spheroids, as well as their similarities, differences, applications, and implications for the future of drug discovery.
What Are Organoids?
Organoids are miniature, self-organizing 3D structures derived from stem cells or primary tissues that can simulate the structure and function of real organs. They are typically cultured in extracellular matrix scaffolds (often hydrogels like Matrigel or synthetic alternatives), which provide the necessary support for cell growth and differentiation. Organoids can be generated from various tissues, including the brain, liver, lung, retina, intestine, and kidney, and they contain multiple cell types found in the corresponding organ. This cellular diversity allows organoids to closely mimic the physiological environment of the original tissue.
The practical applications of organoids are incredibly diverse. They are used in drug screening to assess efficacy and toxicity, in disease modeling to study pathogenesis, and in regenerative medicine to explore tissue development and repair mechanisms. Furthermore, organoids have been vital to personalized medicine by enabling the testing of patient-specific therapies to identify the most effective treatment options.
What Are Spheroids?
Spheroids are free-floating, 3D cell aggregates formed from cell suspensions that spontaneously assemble into spherical structures, with or without an extracellular scaffold matrix. Unlike organoids, spheroids are simpler in structure and often only consist of a single cell type or limited number of cell types. They are typically cultured in non-adherent conditions that promote cell aggregation, such as ultra-low attachment (ULA) plates, hanging drop systems, liquid overlay, spinner or pellet culture, rotating wall vessels, microfluidics, or via magnetic levitation.
Despite their relative simplicity, spheroids are valuable models for studying cellular behaviors like proliferation, migration, and drug response via cell health assays. This makes them particularly useful in drug development, as well as cancer research, where they serve as models for tumor growth and metastasis. Spheroids can also be utilized in high-throughput screening assays due to their ease of formation and scalability.
Organoids vs. Spheroids
Organoids and spheroids are both 3D cell culture models and offer more physiologically relevant alternatives than traditional 2D cell cultures. However, they differ significantly in their formation, complexity, and applications. While both models have their strengths, the choice between organoids and spheroids depends on the specific research objectives and the level of complexity required.
1. Complexity and Structure
Organoids and spheroids are quite different in terms of relative complexity. Organoids are far more complex, as they contain multiple cell types and exhibit tissue-specific architecture. Spheroids are simpler, often composed of a single cell type, and lack the intricate structures seen in organoids.
Organoids exhibit a high degree of complexity, often developing organized structures that resemble the original tissue. This complexity arises from the self-organizing properties of stem cells, which can differentiate into various lineages and form functional biological tissues. For example, intestinal organoids can develop villus-like structures and exhibit absorptive and secretory functions like the human intestine. Organoids provide a more detailed and accurate representation of tissue architecture, making them suitable for studies requiring complex models, such as disease modeling and personalized medicine.
Spheroids are much simpler in structure. They typically consist of a mass of cells without the distinct layers or compartments seen in organoids. While they can form from various cell types and may exhibit some degree of cellular heterogeneity, spheroids inherently lack the intricate organization and functionality of organoids, limiting their ability to fully mimic the functionality of true human tissues. While spheroid models may be considered reductionist compared to organoids, their ease of generation makes them more practical for high-throughput protocols and drug screening.
2. Cellular Composition
Organoids are composed of multiple cell types that are spatially organized to mimic the original tissue. This multicellular composition arises from the differentiation of stem or progenitor cells under specific culture conditions. The presence of various cell types within organoids allows for more accurate modeling of tissue-specific functions and interactions. For instance, brain organoids can contain neurons, glial cells, and other supporting cells, providing a more comprehensive model of neural development and disease.
Spheroids, in contrast, often consist of a single cell type or a limited number of cell types. This simplicity can be quite advantageous for certain applications, such as studying basic cellular behaviors or conducting high-throughput drug screening despite not fully capturing the complexity of true human tissues.
3. Applications
Both organoids and spheroids can be found in various biomedical research applications. The choice to use organoids or spheroids generally depends on the specific research question and the level of complexity required. In some cases, combining both models can provide complementary insights into biological processes and therapeutic responses. In general, organoids are suited for long-term culture, genetic manipulation, and modeling organ-specific diseases. Spheroids are advantageous for cell health assays, rapid drug screening, and studying basic cellular behaviors.
Spheroids are widely utilized in cancer research due to their ability to mimic aspects of tumor growth and the tumor microenvironment. They are particularly useful for evaluating drug efficacy and resistance, as they can replicate the 3D architecture of tumors and the gradients of nutrients and oxygen found within them. Additionally, spheroids are have the potential to be more common in high-throughput screening, making them valuable tools for drug discovery.
Organoids, however, offer a more advanced model for studying human biology and disease. Their complex structure and cellular composition make them ideal for modeling organ-specific diseases, such as cystic fibrosis in lung organoids or colorectal cancer in intestinal organoids. Organoids also facilitate personalized medicine approaches, as patient-derived organoids can be used to test drug responses and tailor individual treatments.
While 2D cell culture is still the most popular approach, spheroids can provide value for applications requiring simplicity and rapid scalability. Organoids offer a more detailed and physiologically relevant model for studying complex biological systems and diseases, though they tend to be relatively costly and time-consuming to produce and maintain.
The Future of Drug Discovery
The integration of organoids and spheroids into more drug discovery pipelines marks a significant advancement in modern preclinical research. These 3D models offer several advantages over traditional 2D cultures, including more accurate prediction of drug responses and better representation of human tissue physiology. This shift in mindset and protocol has the potential to save billions of dollars wasted in clinical drug development, ultimately ensuring safer, more effective drugs get to patients faster. Given the FDA’s recent guidance and the increased scrutiny on academic research and pharmaceutical regulatory frameworks, these innovative technologies are poised to play a pivotal role in advancing drug discovery, kickstarting precision medicine, and improving patient outcomes both now and in the near future.
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