To date, to predict human toxicity, animal studies remain the gold standard for the preclinical test of the efficiency of drugs. Unfortunately, the existing preclinical models are not reliable enough and are poorly predictive. As a matter of fact, because of variable responses and unexpected toxicity in humans, approximately 40% of the newly developed drugs fail clinical trials even after accomplishing preclinical evaluation with animal models. [1]
In an attempt to overcome the limitations of low-throughput animal models, two-dimensional (2D)-based cell culture is a simple and high-throughput method that has been employed as a screening platform for potential drug candidates. However, these 2D monolayer cell culture systems lack a 3D tissue microenvironment and sometimes fail to exhibit the cell development process seen in the physiological environment in vivo due to the simplicity of the systems. [2,3]
Efforts to address the limitation of 2D culture led to the development of 3D cell culture models, in which cells are grown and organized in 3D structures. One example is the culture of cells within extracellular matrix-derived hydrogels that mimic tissue and organ-specific microarchitecture. [4,5]
Despite the great advances, 3D cell culture still fails to reconstitute features of living organs that are critical for their function, including tissue-tissue interfaces (e.g. between epithelium and vascular endothelium), biophysical and biochemical microenvironment. [4,6]
Recent advances in the microfluidics-based Organ-on-a-Chip (OOC) technique have been promising in drug development and personalized medicine as a potential model to replace animal testing [7].
Organ-on a Chip is a microfluidic device fabricated with a silicon-based organic polymer - polydimethylsiloxane (PDMS) - using the standard soft lithography technique.
Stereolitography (SLA) is a light-based technique in which the light source (a laser or UV or visible LEDs) is used to cure a light-sensitive resin or hydrogel. More specifically, masked SLA involves using an LCD screen to create a mask that delimits the passage of light into certain shapes. This technology works through an LED matrix that illuminates the LCD screen, creating the resin's curing pattern, allowing the creation of a microfluidic system.
Organ-on-a-Chip is a very promising technology that can be an alternative to the use of animal models for drug testing. It does not strive to reproduce the whole tissues or organs at the original scale for clinical replacement of their human counterparts but to mimic in a reductionist way the organ's main functions[9, 10]. Externally controlled microfluidics can simulate the blood flow in organs, recreating dynamic nutrient distribution in addition to mechanical cues, like shear stress, in the artificial tissues and can be “custom-designed” to better mimic tissue-specific function.
Numerous single-organ chips have already been developed such as liver, kidney, lung, and gut [6,12,13] to reproduce disease models and analyze drug reactions. These single-organ chip assays can help identify critical biological mechanisms as well as test drug efficiency and toxicity in target organs at the preclinical development stage, thus providing a reliable reference for clinical trials.
As oncology is one of the most important targets of drug discovery, many advances in this area were made. It is known that the tumor microenvironment is very important for tumor progression and it has an important impact on drug efficacy. By integrating cancer organotypic culture with microfluidic devices, “cancer-on-a-chip” systems allow recreation of the tumor microenvironment. Therefore, cancer organoid models that faithfully reflect the phenotypes specific to an individual patient could be used to predict patient response to drug therapies. [14]
OOC is accelerating innovation in the life sciences and could provide high-throughput platforms for drug development, thus potentially bridging the gap between 2D cell culture and animal models by providing an unlimited supply of organs to study normal and diseased physiology. There is a lack of standardization among different devices intended for the same application, leading to distinct performances. Therefore, it becomes difficult to compare and judge what specifications best match the context-of-use requirements. Thus, a proper qualification might contribute to their acceptance in regulatory contexts of use.
The ultimate goal of OOC is to integrate numerous organs into a single chip, and to build a more complex multi-organ chip model, finally achieving a “Human-on-a-chip” but this theory still remains distant.
References:
1. Van Norman GA (2019) Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach? JACC Basic Transl Sci 4 (7), 845–854
2. Modeling Physiological Events in 2D vs. 3D Cell Culture
Kayla Duval*, Hannah Grover*, Li-Hsin Han*, Yongchao Mou, Adrian F. Pegoraro, … See all authors
14 JUN 2017https://doi.org/10.1152/physiol.00036.2016
4. From Three-Dimensional Cell Culture to Organs-on-Chips
Dongeun Huh,1 Geraldine A. Hamilton,1 and Donald E. Ingber1,2,3,
5-3D Printing of Pharmaceutical Application: Drug Screening and Drug Delivery
Ge Gao,1,† Minjun Ahn,2,† Won-Woo Cho,2 Byoung-Soo Kim,3,* and Dong-Woo Cho2,*
6-Organ-on-a-Chip: A new paradigm for drug development
Chao Ma,1,2 Yansong Peng,2 Hongtong Li,1 and Weiqiang Chen1,2,3,*
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11. Organ on Chip Technology to Model Cancer Growth and Metastasis Giorgia Imparato e al, Bioengineering 2022, 9, 28. https://doi.org/10.3390/ bioengineering9010028
13. Organ‑on‑a‑chip: recent breakthroughs and future prospects Qirui Wu1 , Jinfeng Liu1 , Xiaohong Wang1 , Lingyan Feng1 , Jinbo Wu1 , Xiaoli Zhu2 , Weijia Wen1, and Xiuqing Gong1*
14. Organ-on-a-Chip for Cancer and Immune Organs Modeling. Dr. Wujin Sun et al. Adv Healthc Mater. 2019 February ; 8(4): e1801363. doi:10.1002/adhm.201801363.