Organ-on-a-chip for early molecular diagnostic of Schizophrenia: SZ-test
Author
Christa Ivanova, PhD
Publication Date
January 09, 2017
Status
Keywords
neuropsychiatric disorder
Organ-on-chip
schizophrenia
molecular diagnostics
early detection
blood-based biomarkers
precision diagnostics
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Schizophrenia is a severe mental disorder affecting more than 24 million people in the world. The latest advances in microfluidics could allow a better understanding of this disease and develop diagnostic methods.
Microfluidic tools for early diagnostic of schizophrenia: introduction
There is currently no medical test to confirm schizophrenia and no cure. Available treatments are often inefficient and may cause severe side effects.
Molecular mechanisms at the origin of schizophrenia are not fully understood yet, making difficult the development of effective treatments.
This project aims to decipher schizophrenia at a molecular level and to identify new relevant biomarkers to elaborate performant diagnostic tools, allowing early-stage detection and better disease management.
Microfluidic tools for early diagnostic of schizophrenia: our role
In this consortium of 9 partners, we bring our expertise on cell culture in microfluidics devices, particularly for designing.
Elveflow pressure controller and flow multiplexer will allow one to tune the environment of the cells very precisely and be as close as possible to the in-vivo reality.
This cellular model on-a-chip will be a basis for the study of schizophrenia and the development of early diagnostic tools.
This work should be further developed in the future since the consortium applied for two other European fundings.
References
- Chi, Meiying, et al. “A microfluidic cell culture device (μFCCD) to culture epithelial cells with physiological and morphological properties that mimic those of the human intestine.” Biomedical microdevices 17 (2015): 1-10.
- Kim, Hyun Jung, and Donald E. Ingber. “Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.” Integrative Biology 5.9 (2013): 1130-1140.
- Maurer, Michelle, et al. “A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies.” Biomaterials 220 (2019): 119396.
- Kim, Hyun Jung, et al. “Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow.” Lab on a Chip 12.12 (2012): 2165-2174.
- De Gregorio, Vincenza, et al. “Intestine‐on‐chip device increases ECM remodeling inducing faster epithelial cell differentiation.” Biotechnology and Bioengineering 117.2 (2020): 556-566.
- Bein, Amir, et al. “Microfluidic organ-on-a-chip models of human intestine.” Cellular and molecular gastroenterology and hepatology 5.4 (2018): 659-668.
- Jalili-Firoozinezhad, Sasan, et al. “A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip.” Nature biomedical engineering 3.7 (2019): 520-531.
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FAQ – Organ-on-a-chip for early molecular diagnostic of Schizophrenia: SZ-test
What is the issue that SZ-test is addressing?
No confirmatory clinical test today exists in schizophrenia and the treatments are not yet perfect. SZ-test has made an attempt to shift the field to objective, early-stage molecular diagnostics through the creation of an in-vitro organ-on-a-chip system that assists in uncovering strong biomarkers as opposed to utilizing symptom scales. The push is justified in its own right: schizophrenia is a disease that has more than 24 million victims globally.
What was actually constructed in the consortium?
The microfluidic cell-culture platform, which uses a pressure-driven flow system, multiplexed routing, and exposes human cells to precise and programmable micro-environmental cues, and records readouts that can be used to discover biomarkers. This is in an effort to recreate disease-relevant cues in the presence of flow and in order to measure subtle molecular signatures which in the case of non-flow wells typically become obscured.
What is the benefit of organ-on-a-chip in research of diagnostics as compared to classical plates?
Using microfluidics allows you to control shear stress, gradient formation and dosing combinations on much stricter tolerances. That is control that enhances the signal-to-noise ratio of candidate biomarkers (transcriptomic, secreted protein, metabolic). In brief: a reduced number of confounders, enhanced repeatability and conditions more related to human physiology, precisely what you require before progressing an early diagnostic test.
What is the biological question that is answered by this platform?
Three which are significant to an early test:
• Which are the molecular pathways that are regularly disturbed in conditions of disease mimicking?
• What secreted factors can be measured in relatively minimally invasive samples?
• What is the re-modeling of the readout with time-dependent exposures (drug, stressor, cytokine)?
The design renders longitudinal sampling possible without interfering with the culture.
What was the role of MIC in particular?
MIC was in the lead on microfluidic engineering: cell culture in flow, chip and routing architecture, and automation. It relied on pressure controllers and a flow multiplexer to program complex media-switching and sampling sequences, rendering the biological protocol push-button reproducible across biological labs.
What is the daily accomplishment of the control of the experiment?
Using pressure-induced perfusion of written sequences (e.g., baseline – stimulus pulse – recovery) and on-chip sampling positions. This allows teams to pre-store histories of exposures and time-stamps, which is important in case you wish to get candidate biomarkers that recapitulate inter-site and inter-patient-derived lines.
What type of biomarkers are practical in this case?
Usually a multi-analyte panel: discovery transcriptional signatures and a validation-reduced set of secreted proteins or metabolites (those that are stable enough to do early screening). Since the platform is meant to be used in flow-through collection, it is ideally suited to downstream LC-MS, multiplex ELISA or targeted qPCR pipelines.
What is this in the state of the art in gut/brain based microphysiological models?
A decade of advancement demonstrating that flow, peristalsis-like strain, and co-culture can unlock epithelial and immune phenotypes absent in monoculture is in line with the project, the lessons of which have been so far learned in intestine-on-chip studies and now translated to neuro-psychiatric research to provide more realistic readouts.
What is the expeditious way to actionable data when we have to work together?
Begin with a small decision-grade prototype: constant flow rate, two to three exposure conditions, and a small readout package (e.g., 20-40 gene panel and 8-12 secreted proteins). Lock in the protocol and widen to multi-chip runs. MIC will usually provide the calibrated hardware scripts, sampling SOPs as well as analysis templates so that your team can work on biology and not plumbing.
We are preparing a Horizon Europe tender. In what areas can MIC bring the greatest value?
Beyond the chip: automation, microfabrication, and valorization (transforming bespoke rigs into toolkits that can be shared), hands-on proposal design, work plan, risk mitigation, interoperable data. In our practice, with the involvement of a specialized SME such as MIC, the proposal success rates approximate twice those of official baselines, since evaluators reward plausible implementation and impact pathways.
Is it possible to work on additional projects since SZ-test is finished?
Yes. The methods, device layouts and flow-control scripts can be transferred although the funded action is closed. Two other European funding applications were also sought by the consortium, and this implies that the network and protocols have already been set to be expanded with new partners.