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New organ-on-chip models provide new information for targeted treatments in personalised medicine

Xavi Illa, Gemma Gabriel, Mar Alvarez and Rosa Villa, researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit (from CIBER-BBN and the IMB-CNM-CSIC). are co-authors of two reviews that summarise the latest efforts in organ-on-chip technologies to emulate in vitro microfluidic systems. These devices are an opportunity to evolve the fields of biofabrication and sensing technology.

Organ-on-chip (OOC) technology has been an efficient tool in modern research to substitute laboratory mice and simulate tissue and organ-level physiology and function. In particular, these in vitro devices have been extensively applied to model the intestine, enhancing the research community’s knowledge about intestinal physiology and pathophysiology in order to develop targeted therapies for a more precise and personalised treatment of intestinal diseases.

Now, a review published in Biosensors & Bioelectronics signed by researchers of NANBIOSIS ICTS U8 Micro– Nano Technology Unit, collects information about the intestine models and highlights the necessity to integrate sensors into these in vitro models to shine light on the pathological mechanisms of intestinal disorders at their early stage. The detection of a disease at its early state would allow more efficient treatments and a better prognosis, reducing costs and enhancing the quality of life of the patients.

Last years’ research has had a significant impact in these complex microfluidic systems, though there is still a long way to go to increase biosensors capacity in their operations.

“The potential of the OOC technology is enormous. OOC technology may provide a true precision medicine, allowing the use of the patients’ own cells for performing drugs screening before treating the patient“, -explains Mar Álvarez– “To that end, we believe that the integration of sensors into this platforms is mandatory to understand and evaluate the functioning of the organ in real time, providing information that may be used for in-situ decision making”.

Hydrogel microfluidic platforms to improve the predictive capacities of the in vitro models

Another review article published by theese researchers in Applied Materials & Interfaces tackles the progress made in tissue barrier models, as they have a crucial role in regulating organ homeostasis. Current microfluidic systems do not properly mimic cells’ interaction, so recent developments have included biomaterials, such as hydrogels, to emulate these boundaries between tissues and external environment. A hydrogel acts as a microenvironment of the cell and it permits cell culture.

“The hydrogel mimics the real cell microenvironment, providing the mechanical cues needed to reproduce the proper organ physiology and function“, Mar Álvarez adds.

Recent developments in the fields of biofabrication show that hydrogels are able to mimic and change the tissue properties and dynamics, thus enabling an in vivo recreation for its reparation.

Articles of reference

Marrero D, Pujol-Vila F, Vera D, Gabriel G, Illa X,  Elizalde-Torrent A, Alvarez M, Villa R, Gut-on-a-chip: Mimicking and monitoring the human intestine. Biosensors and Bioelectronics. Volume 181, 1 June 2021, 113156. DOI https://doi.org/10.1021/acsami.0c21573

Vera D, García-Díaz M, Torras N, Alvarez M, Villa R, Martínez E. Engineering Tissue Barrier Models on Hydrogel Microfluidic Platforms, CS Appl. Mater. Interfaces 2021, 13, 12, 13920–13933 DOI https://doi.org/10.1016/j.bios.2021.113156

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Organ-on-chip monitoring. Breakthrough technological approximations

Organ-on-chip (OOC) is the term used to define a microfluidic 3D culture model that contains continuously perfused chambers inhabited by living cells. OOC are considered as very promising tools for investigating many aspects of human physiology and pathophysiology as well as drug testing platforms with future progressions to be used for precision medicine.

As the complexity of OOC systems increases, the necessity to integrate relevant assessment methods to provide information about cell physiology, secreted metabolites as well as pharmacodynamics drug responses also increases. Dr. Rosa Villa, who leads NANBIOSIS U8 Nano Technology Unit and the Biomedical Applications Group of the Institute of Microelectronics of Barcelona and CIBER in Bioengineering, Biomaterials and Nanomedicine, works on different engineering approaches to develop physical and chemical sensors that can be integrated into the OOC devices. The group considers that sensors integration is a requirement that must be taken into consideration in an OOC platform giving the necessary assessment of the OOC platforms in a continuous and real-time

An overview of the most relevant works of the Biomonitoring Group and NANBIOSIS Unit 8 have been presented by Mar Alvarez and Gemma Gabriel, researchers of
NANBIOSIS U8 Nano Technology in the conference on Engineering Multicellular Systems organized by EMBL – IBEC that took place in La Pedrera Auditorium, in Barcelona, from 10-12th February 2020.

It has been presented a device fabricated for that mimics Retina. In this novel microfluidic device cells are arranged in parallel compartments and are highly interconnected through a grid of microgrooves, which facilitates paracrine signaling and heterotypic cell–cell contact between multiple tissues. In the field of Brain, TEER barrier monitoring is mandatory. An interdigitated electrodes (IDE) configuration where the entire cell culture area contributes equally to the measurement, has been integrated in a custom-made bioreactor. This configuration, besides being more accurate for measuring the TEER, also allows the minimal electrode coverage, so that the optical visualization of the cell culture is maximized. The control and monitoring of dissolved oxygen (DO) is key for most of the OOC. The integration of oxygen sensors in an Liver-On-a-Chip system to achieve in-situ and real-time monitoring of oxygen zonation along the cell culture microfluidic chamber. A miniaturized sensing device compatible with microfluidic technology to measure simultaneously dissolved oxygen, pH, Na+ and K+, able to be connected in the input or output of a cell culture system has been developed for Kidney monitoring.

References

[1]   Yeste J, García-Ramírez M, Illa X, Guimerà A, Hernández C, Simó R, Villa R, “A compartmentalized microfluidic chip with crisscross microgrooves and electrophysiological electrodes for modeling the blood–retinal barrier” Lab on a Chip 18 (2018) 95-105

[2] Yeste J, Martínez-Gimeno L, Illa X, Laborda P, Guimerà A, Sánchez-Marín JP, Villa R, Giménez I “A perfusion chamber for monitoring transepithelial NaCl transport in an in vitro model of the renal tubule “, Biotechnology and Bioengineering 115 (2018) 1604-1613

[3] Moya A, Ortega-Ribera M, Guimerà X, Sowade E, Zea M, Illa X, Ramon E, Villa R, Gracia-Sancho J, Gabriel G., “Online oxygen monitoring using integrated inkjet-printed sensors in a Liver-On-a-Chip system” Lab on a Chip (2018),18, 2023-2035

[4]Moya A, Illa X, Gimenez I, Lazo-Fernandez Y, Villa R, Errachid A, Gabriel G. “Miniaturized multiparametric flexible platform for the simultaneous monitoring of ionic compounds: Application in real urine” Sensors and Actuators B: Chemical 255 (2018) 2861-2870

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Unit 13 of NANBIOSIS participates in a new European project that will boost the Organ-on-Chip technology

The research group coordinating NANBIOSIS Unit 13 is the Spanish group of the European project ORCHID (Organ-On-Chip In Development). The scientists  of Engineering Research Institute (I3A) and CIBER-BBN, Luis Fernández and Iñaki Ochoa, will work on this project whose objective is to accelerate the social and economic impact of the technology known as Organ-on-Chip. This technology based on the use of microfluidic platforms is already facilitating the discovery of drugs, but it can go a step further with applications in personalized medicine and safety pharmacology and that, in addition, offers alternatives to conventional tests in animals. The mechanical properties and research ability of the microfluidic platforms will be tested in NANBIOSIS  unit U13 Tissue and Scaffold Characterization.

 

The project that will take place over two years, is led by the Medical Center of the University of Leiden and the Dutch consortium Organ-on-Chip hDMT and participated by entities and research centers from four other countries, Germany, Belgium, France and the Netherlands. The consortium that has the financial support of the European Union with half a million euros, will work to facilitate and accelerate the development of prototypes, validated cellular systems that mimic sick or healthy human tissue and the implementation of this technology by a broad group of potential users in science, health care and industry. This platform will provide an overview and updates so that users can easily track progress, consult developers directly and identify gaps in current knowledge, which limits implementation. It will also address ethical and regulatory issues, particularly with regard to personalized information, the economic and social impact, the training of researchers and the design of a R & D “roadmap”.

 

Likewise, the construction of an infrastructure is planned so that scientists, policy makers, financiers and end users can join the decision-making processes that will guide future European developments in Organ-on-Chip applications. Among its actions is the establishment of a digital platform that allows the exchange of knowledge between researchers and representatives of private corporations, including insurance companies, pharmaceutical and biotechnology companies, the food industry, health foundations and patient organizations.

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