Multi-compartmental Tumor-on-a-Chip

Breast cancer is the most common invasive cancer among women. There are several chemotherapeutics and radiotherapeutics approaches available but they have certain limitations. Over the past few years, improved understanding of the microenvironment heterogeneity of breast cancer has allowed the development of more effective treatment strategies. However, researchers have still not been able to recapitulate the entire tumor microenvironment to study the tumor progression and invasion. In this direction, the breast tumor-on-chip model has emerged as an alternative system to study the tumor microenvironment and deciphering its role in metastasis. The tumor-on-chip system mimics the exact in vivo condition, by controlling the user defined environmental parameters, mechanical and biological signals generated by neighboring cells. These controlled microenvironmental conditions enable the investigation of the physiological and metabolic changes and cancer-stromal cells interaction which facilitates the formation of tumor microenvironment conditions. In this way, this tumor-on-chip model can be helpful for providing the information related to basic tumor physiology and characteristic features of tumor which helps in tumor migration, and progression. In this way, it will provide a possible therapeutic approach and potentially helps in drug development for cancer therapeutics.

To generate 3D tumor microenvironment the most important thing is to develop appropriate microfluidic chips. These microfluidic chips were fabricated by using PolyDimethylSiloxane (PDMS) material. This microfluidics chip has three channels, one central channel and two side channels. All the three channels in the chip are connected through microchannels, which allows the cell migration and exchange of nutrients and signaling molecules. The culture media, growth nutrients are injected, or removed from the microfluidic chip with passive ways or external active systems through a pressure controller (OB1, Elveflow).
After designing the chips, a 3D tumor microenvironment was created by using collagen Type 1 biomaterial. This collagen biomaterial forms a 3D hydrogel which is hydrophilic and forms a network of polymeric chains at 37 ºC. Followed by, breast cancer cell suspension was mixed with collagen suspension in 1:1 ratio and loaded into the central channel of the chips, then incubated for 30 minutes at 37 ºC for gel polymerization and to ensure the maintenance of the 3D structure. When the gel turned opaque, endothelial cells were seeded into one of the lateral channels to mimic tumor-stromal condition. The second lateral channel was used to perfuse the culture media. Necrotic core formation, glucose consumption, hypoxia generation and interaction of tumor cells with the neighboring endothelial cells and tight junction formation were evaluated.

MTOAC project was presented and disseminated through the following channels:

-Participation in conferences:
1.- Application of Microfluidics in Breast tumor, 3rd World Congress on Cancer, Prague, Czech Republic, September 23-25, 2019
2.- Summer School on Microfluidics: Concepts, applications, evaluations, from 14th October to 18th October, 2019, Sete, France
3.- IFPEN Conference from Laboratory tool to Process Development 13-15 November 2019 at Rueil Malmaison, France
4.- International “Cell Culture Under Flow Meeting” (Ibidi), Munich Germany, February 18-19, 2020
5.- Microfluidics modelling of breast tumor microenvironment for drug screening. EUROoC conference July, 8-9, 2020.

- Published articles and other communication activities:
1.- "Subia Bano and tumor microenvironment / My microfluidic career", on Elvesys' website
2.- Short review about microfluidic Tumor-on-Chip systems for breast cancer research, on Elvesys' website
3.- A review article on breast tumor-on-chip model was published in the “Journal of Controlled Release”, Elsevier. (Bano Subia et al, 2021)

Pharmaceutical industry typically depends upon the traditional tissue culture flask and animal model to investigate the breast cancer etiology and development of new drugs. These models are inexpensive and show high degree of reproducibility but they cannot mimic the actual tissue heterogeneity and dynamic condition of breast tumor microenvironment.
Microfluidics system emerged as an alternative in vitro technology to manipulate the control of liquid at submillimeter scale, can use channel geometry, cell patterning and fluidic flow to recreate a physiological-like microenvironment to investigate the mechanism behind cancer progression and metastasis. It can also be used to predict the drug efficacy under controlled fluidic flow conditions. With the microfluidic chip, the 3D tumor microenvironment is created by using collagen hydrogel to mimic the in vivo environment in which the cancer cell is surrounded by neighboring endothelial cells. The microchip creates concentration gradient and perfusable platform of cell culture to study the tumor microenvironment and tumor-stromal interactions. This helps in better understanding the tumor progression, invasion and may provide a possible therapeutic approach in a controlled microenvironment.

Periodic Reporting for period 1 - MTOAC (Multi-compartmental Tumor-on-a-Chip)

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