Spheroid-on-chip – a leap for cancer research and drug development

Recent years have witnessed a growing trend in combining advanced 3D cell culture models like spheroids and organoids with microfluidic on-chip devices. This integration holds significant promise for revolutionizing cancer research and drug development by offering more physiologically relevant models that closely mimic the complex tumor microenvironment. The spheroid-on-chip approach stands out as a particularly valuable tool, bridging the gap between traditional spheroid cultures and in vivo studies (Zhang 2023 et al.). By combining biomechanical stimulation (TME), with the spatially controlled interaction of tumor and its microenvironment, this technology has the potential to greatly enhance the accuracy and relevance of preclinical testing (Zhang 2023 et al.).

The Unique Advantages of Tumor Spheroids

Tumor spheroids are three-dimensional (3D) cell aggregates composed of tumor cells often combined with other cell types form the TME.

Spheroids offer several distinct advantages over conventional 2D monolayer cultures, making them more suitable for drug screening and cancer research. First, while cells in 2D cultures are uniformly exposed to culture medium, nutrients and, oxygen, spheroids exhibit a compact 3D structure that creates gradients in nutrient and oxygen distribution. The gradients then promote differentiation of cell populations within the spheroid: an outer proliferating layer, an intermediate quiescent layer, and a necrotic core (Pinto 2020 et al.), mirroring the architecture of the gene expression patterns of in vivo tumor tissues (Kapałczyńska 2018 et al.).

Second, during drug treatment, drug gradients are naturally created within the spheroid. Such drug gradients are crucial for mimicking the drug exposure of actual tumors, which is a key factor in drug resistance and efficacy.  Indeed, spheroids exhibit resistance to many anticancer drugs and therapies, often linked to a reduced availability of the drug inside the tumor (Moshksayan 2018 et al.).

Taken together, drug responses in spheroids are often more predictive of in vivo outcomes than those observed in 2D culture.

Relevance of combining spheroids with OOC technology

The use of spheroid-on-chip models in preclinical drug development offers several significant advantages, particularly in the area of dosage estimation. Spheroid on chip models integrate tumor spheroids chip that allows modelling the dynamic interaction of tumors with vasculature and other TME components.

Most importantly, SOC systems allow vascular application of drugs, modelling the natural endothelial barrier drugs need to cross when accessing the tumor, allowing a more accurate prediction of drug dosage reaching the tumor. Furthermore, the stretch and strain stress introduced by the perfusion, induces changes in spheroid biology mimicking the in vivo stress tumors are experiencing (Kimberly 2020 et al.).

In summary, the heterogeneous environment within spheroids allows for the development of more realistic drug penetration profiles, thereby reducing the risk of errors in dosage estimation and reducing the length and cost of the pre-clinical phase.

Moreover, by embedding spheroids into gel like matrix structures, spheroid-on-chip models are highly relevant for studying processes like angiogenesis and metastasis, which are critical drivers of cancer progression. Angiogenesis, the formation of new blood vessels, is essential for early-stage tumor growth, while metastasis of later stage tumors to secondary sites is responsible for over 90% of cancer-related deaths (Zhang 2023 et al.).

Conclusion

The integration of spheroids with on-chip devices represents a significant leap forward in cancer research and drug development. By offering more physiologically relevant models that mimic the complex tumor microenvironment, spheroid-on-chip technology has the potential to improve the accuracy of preclinical testing and reduce the high attrition rates of drug candidates in clinical trials. As this technology continues to evolve, it is likely to become an indispensable tool in the fight against cancer, bringing us closer to more effective and personalized therapies.

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