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Multiplexed biosensing and tissue-on-a-chip integrated platform for breast cancer biomarkers monitoring

Periodic Reporting for period 2 - BITFORM (Multiplexed biosensing and tissue-on-a-chip integrated platform for breast cancer biomarkers monitoring)

Reporting period: 2021-10-01 to 2022-09-30

Breast cancer is the most common cancer in women, still, 15% of women affected by breast cancer die each year according to the World Health Organization (WHO). In addition, the number of new cases is increasing every year and, therefore, there is an imperative need to control and mitigate this affection.
For that, novel technologies such as organ-on-a-chip addressed to mimic breast cancer tissues are needed. This will allow us to study how cancer tissue is developed and to better understand the biological, molecular, and physiological mechanisms involved in this disease. Moreover, this organ-on-a-chip approach can help to develop new drugs and elucidate which therapies are more effective on the different cancer organoids (3D self-organized tissues) developed.
In this regard, this project aims to develop a multimodular platform including a (breast cancer ecosystem) BCE-on-a-chip (perfused bioreactor containing an organoid) module connected to a label-free biosensor for continuous monitoring of cell-secreted biomarkers.
In other to enhance the organ-on-a-chip technology, one of the key factors is to be able to monitor hundreds of parameters affecting the tissue construct. For that reason, different characterization and monitoring strategies need to be developed and implemented in the system. One of them is the continuous detection of cell-secreted biomarkers. For that reason, in this project, we are developing a label-free optical biosensor based on R-NPs (resonant nanopillars) for in-line monitoring of the BCE-on-a-chip. There are other label-free sensors performing competitive sensitiveness’ (mirco and nanomolar) able to provide real-time measurements, such as microwave-based resonator devices or SPR. But they depend on complex light coupling which hampers their combination with bioreactors included in an incubator. R-NPs, meet the optical performance to satisfy the real-time monitoring and sensitivity requirements (ng/mL which is in the same order of concentration of target biomarkers such as Interleukin-8. In addition, RNPs multiplexing provides the desired layout for simultaneous biomarker sensing.
Therefore the main objective of this project is to fabricate a multi-modular platform for breast cancer-on-a-chip cell-secreted, monitoring of several biomarkers, by means of RNPs optical biosensors.
The specific objectives are listed below:
1 Implementation of the sensing module for the three biomarkers.
2 Development of the BCE-on a-chip module as well as the corresponding physiological and bubble trapping modules.
3 Microfluidic setup for the connection of the different modules. And platform breadboard.
4 Testing of cancer therapies on the BCE-on-a-chip defined, as well.
On one hand, the platform will allow us to deepen our knowledge of the biomarker’s efficiency in breast cancer monitoring. On the other hand, specific cells from patients can be used for the organoid construct to be studied, and thus patients can receive more accurate treatments. This is called precision medicine and it is considered one of the paradigms of future medicine.
The work developed during this Project (01/10/2019 to 02/07/2023) has been performed according to the time chart presented in part B1 of the proposal. It is summarized below and more extensively described in the project's periodic report.
It has been successfully developed a biosensing module for its integration into the multimodular platform proposed in this project. For that, it was designed and fabricated a fluidic chip capable of holding the optical transducer based on RNPs and coupled to an optical head allowing the fluidic tightness and the optical interrogation (through optical fibers) of the RNPs at the same time. This permitted the detection of one of the cell-secreted breast cancer target biomarkers in this work, IL-8 among them.
Also, a breast cancer ecosystem-on-a-chip has been designed and developed to increase cellular complexity and achieve a more biomimetic breast cancer organoid. For that, it was fabricated and tested, a perfused bioreactor capable of hosting the tumor organoid and keeping it alive for several days. Moreover, a 3D arrangement of the complex tumor microenvironment in the form of cocultured spheroids containing two different cell lines was developed inside the bioreactor, and thus the prototype of the breast cancer-on-a-chip was created in this work.
In parallel, the work also focused on the integration of all the parts in a multimodule platform including a physiological sensor for pH, oxygen, and temperature monitoring. This provides further information on the organoid microenvironment, which is very useful to understand how external factors can affect the organoid.
Lastly, it was tested the effect of the anticancer drug Gemcitabine on the breast cancer cell line MDA-MB-231. It was studied how IL-8 cell secreted biomarker concentration was affected by cell exposition to the drug. Also, a breast cancer mouse explant was introduced in a perfused bioreactor and kept viable for several days to study tissue evolution and for cell media collection for further biomarkers detection.
The aim of this project is to develop in-vitro models of breast cancer capable of reproducing tissues with a high degree of accuracy to in-vivo models.
For the moment we have achieved a breast cancer organoid based on TS (tumor spheroids) directly fabricated in a perfused bioreactor for the cell culture media flowing inside it. This is a novel fabrication approach developed in this project for the first time. This strategy can be used by other research groups working in this field or even startup companies focused on this technology even for other types of organoids. In addition, a fluidic chip for the optical label-free biosensor implementation has been successfully developed and specifically fabricated in this project for continuous biomarker detection.
Expected results are focused on the development of breast cancer organoids based on the MCTS (multicellular tumor spheroids) co-culture and tissue spheroids approach, specifically designed, and fabricated for this project. Also, it is foreseen the multiplexing continuous detection of the cell-secreted biomarkers for the organoid continuous monitoring.
The goal is to use these models to continuously monitor the evolution of the specific type of cancer that has been developed and to be able to predict the response of new anticancer drugs in patients, in a personalized way.
This project can lead to the development of a breakthrough technology for breast cancer models and therapies development. A game changer approach that can be taken advanced by all society, especially due to the accuracy of the technology in pathological tissue development and for the decreased associated costs, by avoiding long and expensive animal and clinical trials.
This was a multidisciplinar ambitious project that presented continuous challenges to overcome with originality, patience, and divergent thinking. I worked hard every day to give the best of myself. I plan to continue working in the area because I really strive to develop a technology that represents a true innovation in the treatment of this disease and to achieve a positive impact on people who suffer from it.
Multimodular platform for cell-secreted biomarkers continuous sensing