Environmental toxicology assessment: ALTERNATIVE
Author
Christa Ivanova, PhD
Publication Date
September 29, 2021
Status
Keywords
Environmental toxicology
chemical compounds
Organ-on-a-chip
cardiac tissue model
pesticide residues
pharmacovigilance legislation
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A cardiac tissue model for environmental toxicology assessment: introduction
Environmental toxicology studies the effects of biological, physical, and chemical hazards on living organisms.
During project ALTERNATIVE, cardiac cells in a 3-dimensional microfluidic tissue-on-chip system will be exposed to different chemicals, and the toxicity thereof will be determined.
Every day, we are exposed to a variety of potentially toxic chemicals present in our surrounding environment.
For example, these can be pesticide residues in our food or residues and degradation products of various types of drugs (antibiotics, parasiticides, antimycotics, and anti-cancer drugs).
They are found in different environmental compartments, including surface water, groundwater, soil, air, and biota, and have been recognized in the pharmacovigilance legislation in the EU as an emerging environmental issue.
Environmental toxicology is the field of science that analyses the effects of these compounds on living organisms.
Environmental toxicology plays a role in many aspects of our lives. Recently, an increase in cardiovascular diseases has been observed, with ischaemic heart disease and stroke representing, in 2019, the top-ranked causes of death among mature and aged populations.
One hypothesis is that this increase is related to exposure to environmental toxic chemicals.
Multiple chemical components have been shown to have cardiotoxic properties, for example, cleaning products, plastic food containers, primary and secondary tobacco smoke, and fuel combustion. A combination of these chemicals with pharmaceuticals could even worsen the effects.
Therefore, a standardized model for environmental toxicology assessment is needed and will be developed during the ALTERNATIVE project.
A cardiac tissue model for environmental toxicology assessment: project description
Related content & results from this project
In light of the Alternative project, we have developed the following packs and instruments:
- Automated recirculation perfusion system,
- Check valve recirculation pack,
- Automated cell culture platform,
- A pack for parallel cell culture,
- A stem cell culture platform,
- Cell culture tubes for perfusion,
- Unidirectional cellular perfusion instrument,
- Automated microfluidic cell culture platform,
- Blood vessel on-a-chip pack,
- Kidney-on-a-chip pack,
- Liver-on-a-chip,
- Lung-on-a-chip pack,
- Skin-on-a-chip pack,
- Neuron culture pack for low shear stress,
- A microfluidic pack for CO2 control,
- A pack without a CO2 incubator for dynamic cell culture.
- Organ-on-a-chip technology,
- Different bidirectional and unidirectional recirculation systems,
- Unidirectional flow recirculation using our automated system vs peristaltic pump.
We also released two application notes:
Funding
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FAQ – Environmental toxicology assessment: ALTERNATIVE
What is ALTERNATIVE attempting to accomplish?
Develop a standardized, human-relevant cardiac tissue-on-chip that can be perfused and monitored in real time, and apply it to understand the effects of environmental chemicals (and their interactions with drugs) on the heart.
Why the heart as an object of environmental toxicology?
Ischaemic heart disease and stroke have taken the number one position in the death lists in the mature and ageing population in Europe. An emerging theory is that chronic, low-dose exposure to daily chemicals (residues of pesticides, plasticizers, by-products of combustion) interacting with drugs and lifestyle predisposes the precariousness. With a cardiac model, we can quantify that risk at the tissue level.
Why should this model differ from a normal cell culture?
It is 3D, perfused, and lasted long cell culture. In contrast to immobile wells, microfluidic channels preserve flows and gradients, creating a simulated capillary-like environment. That de-stabilizes electrophysiology/metabolism, minimizes nutrient-depletion artefacts, and permits repeated-dose/mixture testing with realistic exposure profiles.
What will the chip measure as such?
Basic outputs include viability and contractility (beat rate and variability), barrier/leakage or edema-like, stress and apoptosis, and concentration-time curves of added compounds. Other readouts, such as calcium transients, mitochondrial potential, transcriptomics, and metabolite fingerprinting, can be added when necessary.
Does this substitute for animal tests?
Not entirely. The use of animal models has not been abandoned, although they may produce inaccurate cardiac responses in humans. The objective of ALTERNATIVE is to provide more predictive in vitro standards for humans and to minimize the use of animals, particularly in early environmental risk ranking and in mixtures, as well as in mechanism hunting.
What are the chemicals that are in scope?
Precisely the ones that you come across daily: pesticide leftovers in foods, breakdowns or the remains of antibiotics, antiparasitics, antifungals, anti-cancer medications, and your everyday household and industrial chemicals (cleaning substances, plastic food-contact materials, by-products of combustion). It can also work with drug-chemical interaction studies, which are not easily deconvoluted in vivo.
What does it mean for practice to be standardized?
Using standardized SOPs: cell sources and passage windows, flow and shear parameters, exposure protocols (acute vs. repeated), match criteria on the above-mentioned tissue functionalities, and mutually used metadata templates. That can be used for multi-site comparisons and, most importantly, for reproducibility across labs in a consortium.
What tools and parts of the work came out?
A collection of long-term culture and reconstructed microfluidic packs and instruments, including check-valve recirculation, unidirectional and automated recirculation (and even without a CO2 incubator), a suite of microfluidic packs and instruments biocompatible with classical condition: couple or benchmark a pack to other microfluidics, such as organ-on-chip (vessel, kidney, liver, lung, skin, neuron) or liver necrosis-on-chip (initiating tissue necrosis). They both reduce setup time and ease cross-lab transfers considerably.
How can MIC contribute to a Horizon Europe team in this matter?
The microfluidics SME that transforms biological data into stable gradients, sensorized cartridges, automated flow control, and scalable data pipelines is MIC. The addition of a specialized SME such as MIC to a recent consortium has increased the hits of the proposal by 2 over official baselines, with much of this increase being due to the reviewer’s feeling that they can rely on a credible implementation, manufacturability, and well-defined exploitation paths. We also jointly write proposals and write prototypes that you can make, ship, and run.
What does an average team appear like?
Two tracks. Research mode: Co-design chip geometry, prove cell functionality in flow, and establish acceptance criteria on exposures; analytics (e.g., fraction collection to LC-MS) are locked in early. Translation mode: replace the cartridge, automatize perfusion/valving, capture the SOPs, and run a small series across multiple sites to make results comparable and auditable.
What are the primary weaknesses to plan for?
Gestational models or life-stage modeling are not considered here (this project focuses on adult-like cardiac tissue). The chronic effects that take months to affect are difficult to measure; the repeated-dose procedures are useful but not ideal. And, as with any in vitro system, there should be appropriate integration of absolute risk extrapolation into the population using PBPK modelling and epidemiology.
Why is a European SME, such as MIC, involved, as opposed to an entirely academic arrangement?
Due to the valuation, automation, and design that SMEs organize. The involvement of MIC in a consortium generally speeds up prototyping, de-risks schedules, and makes a lot of sense for exploitation, which, beyond the technical advantages, earns points in Excellence and Implementation. Given our engineering focus, the assay can be reproducible, scalable, and publication-ready.