Pharmacological risk assessment using a bio-digital twin: LIFESAVER
Author
Christa Ivanova
Publication Date
November 23, 2021
Status
Keywords
pharmacological risk assessment
digital twin
pregnancy
drug safety
placental tissue
3D-printed cell structure
environmental pollutants
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LIFESAVER will develop a model to test and assess chemicals and pharmaceuticals safely on their potential to cross placental tissue barriers, thus offering a platform for pharmacological risk assessment during pregnancy.
A bio-digital twin for pharmacological risk assessment: introduction
The health of pregnant women and their unborn children is of utmost importance and needs to be protected at any price.
This paradigm has led to a dilemma in pharmacology, where new drugs cannot be tested during pregnancy. Still, therefore, no drugs can be approved for use by pregnant women, denying them treatment options.
A majority of 90% of approved drugs lack information on efficacy and safety in pregnancy.
The LIFESAVER project aims to solve this dilemma by constructing a bio-digital twin, a platform modeling placental tissue that allows the pharmacological risk assessment of drugs and chemicals during pregnancy.
Pregnant women can suffer from a variety of conditions requiring medical treatment. Untreated, they can pose a threat not only to the mother but also to the unborn child, ultimately resulting in premature birth or complications in the future life.
In addition to medical conditions, pregnant women are continuously exposed to environmental pollutants such as chemicals, human-made endocrine-disrupting hormone contaminations, antibiotic residues, and antibacterial substances, such as cosmetics and food.
Measuring the effects of environmental pollution and pharmacological risk assessment are already challenging tasks. Still, they are impossible to perform on the population of pregnant women who are protected from invasive tests.
A bio-digital twin for pharmacological risk assessment: project description
There is no reliable model for pharmacological risk assessment or chemical compound testing during pregnancy.
Animal models fail to translate to human conditions, and ex-vivo placental tissue is limited (it can be used only for a couple of hours and is seldom available).
It is, therefore, nearly impossible to measure the amount of drugs or chemicals that cross the placenta from the bloodstream of the mother into the bloodstream of the baby.
The LIFESAVER project, coordinated by EnginSoft S.p.A., envisions constructing a platform that models the early placenta using a 3D-printed cell structure.
The platform will incorporate immortalized cell lines printed on a designated scaffold and offer the possibility to exert physical stimuli (mimicking pelvic movement) by peristaltic pressure change.
The cell culture will be supplemented with growth media, and chemical compounds will be tested and controlled using a microfluidic system.
We will design and construct the setup tailored to the project’s specific needs and in close collaboration with the project partners.
Digital output from the experimental results will be analyzed to develop a digital model that will help predict the outcome of pharmacological risk assessment without the need to perform experiments.
You can now visit the official project website at www.lifesaverproject.eu or follow LIFESAVER on social media:
A bio-digital twin for pharmacological risk assessment: results
Related content & results from this project
In the light of the Lifesaver project, we have developed the level sensors, which we integrated into the automated recirculation perfusion system.
In addition, we developed the following packs and instruments:
- Sequential injection device,
- Multiple drug injection instrument,
- Automated sampling instrument,
- Inline hypoxia chamber,
- Neuron culture pack for low-shear stress,
- Lung-on-a-chip pack,
- Blood-vessel on-a-chip pack,
- Kidney-on-a-chip pack,
- Liver-on-a-chip pack,
- Skin-on-a-chip pack,
- Bone-on-a-chip pack,
- Stem cell culture platform,
- A pack for biomechanics and modeling in mechanobiology,
- Smart culture tube rack,
- Cell culture oxygen control pack,
- A microfluidic pack for CO2 control,
- A pack without a CO2 incubator for dynamic cell culture.
In addition, we have published three reviews:
- Organ-on-a-chip technology,
- Different bidirectional and unidirectional recirculation systems,
- Unidirectional flow recirculation using our automated system vs peristaltic pump.
We have also released three application notes:
Funding
This project has received funding from the European Union under H2020-LC-GD-2020-3, grant agreement no. 101036702 (LIFESAVER).
Start date: 1 November 2021
End date: 31 October 2025
Overall budget: €6,136,512.50
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FAQ – Pharmacological risk assessment using a bio-digital twin: LIFESAVER
What is the project of LIFESAVER?
A coordinated approach to model microfluidic feto-maternal models, placental-barrier-on-chip systems, coupled to exposures of fetal-surrogate tissues by using fetal doses substantially earlier than possible in animal or clinical models.
What is the value of the use of microfluidics in terms of pregnancy safety?
Traditional measurements are faced with two moving objectives: dynamic maternal-fetal gradients and time-dependent tissue maturation. Microfluidic chips have enabled us to perfuse fetal and maternal channels independently, control shear stress and oxygen, and subsequently observe the effects of drugs on the placental interface and downstream fetal cells or organoids. Practically, this displays profiles of concentration-time, saturation of the transporter, and metabolite synthesis that is not given by 2D static inserts that are routinely used.
What is the working principle of a placental-barrier-on-chip?
It is based on the concept of two microchannels, with an opaque membrane or a hydrogel embedded with trophoblasts (synaptized in certain areas) separating the two channels. The flow rate is set to 0.5-2 dyn/cm2 on the maternal side and to a lower value on the fetal side to reflect capillary conditions. Tight-junction integrity (i.e., TEER, or fluorescent dextran leakage), transporter activity (P-gp/BCRP), and endocrine (hCG, sFlt-1) are monitored as a compound is perfused on the maternal side and sampled on both sides.
What are the questions that the platform can answer about drug developers?
Four high-value readouts:
- Kinetics of the transplacental transfer (effective Papp, Ktrans, and fetal/maternal exposure ratios versus time).
- Passive diffusion (vs transporter-mediated) versus protein-binding effects mechanisms.
- Indications of fetal hazard (oxidative stress, apoptosis, cardiotoxic or neurotoxic indicators of fetal models) that are linked to each other.
- Risks associated with interaction (transporter effects of polypharmacy caused by changes in metabolism under realistic maternal plasma proteins).
Is this a mechanism that can substitute for animal research?
Not entirely. It bridges the gap in return: candidate molecules and doses of interest are ranked early and, in a human-relevant manner, bypass in vivo work. Chips are good in days to weeks phenomena – barrier transport, acute toxicity, endocrine disruption. Complementary models for long-horizon developmental endpoints are yet to be developed, but on-chip data are likely to narrow the dose-selection process and reduce the number of in vivo arms.
What are the data outputs that are usually delivered?
In a typical study, the results include: permeability coefficients with confidence intervals, maternal/fetal concentration-time curves (to be sampled every 15-60 minutes), transporter inhibition studies, cytokine/endocrine screening, and multimodal imaging. In teratogenic-risk screens, endpoints range from transcriptomics of fetal-like organoids (e.g., cardiomyocyte beat rate variability, neuronal network firing rates) to morphology scores.
What is the number of practical run compounds/conditions that can be tested?
The 12-36 conditions are realistic with the use of cartridge arrays or multi-lane chips, with 3-4 technical replicates per condition per week. The number of cells consumed is in the thousands, not millions, for each condition, which makes the primary human material viable. Automated fractionation and fraction collectors reduce the amount of manual time after dialing in the assay.
Is it able to deal with actual biological matrices (plasma, protein binding, metabolites)?
Yes. Physiological albumin and α-1-acid glycoprotein can be used as maternal perfusates to prevent false-positive transfer and help bind antibodies. Phase-I/II metabolism may be assessed by either the addition of hepatic microsomes or linkage to a micro-liver again, which is especially helpful to determine whether a metabolite and not a parent crosses the placental interface.
What is the normal interaction of MIC in Horizon Europe on this issue?
Two modes.
Model of research: jointly design the barrier structure, establish transporter/endocrine activity, and get on our feet with the analytics pipeline (fraction collection, LC-MS, multiplex immunoassays).
Mode of translation: we design, automate the design, implant sensors, and assemble mini-sets of prototypes to study test locations. MIC is also a French microfluidics SME; we co-write the proposal, risk registers, and even package exploitation plans. In recent calls, consortia that include a specialized SME such as ours have approximately doubled their success rates compared to official program baselines, principally because of credible implementation and manufacturability stories.
What is an end-to-end timeline of what is needed during kick-off to decisions?
Baseline qualification (TEER/marker panels) can be completed in just 1-2 weeks once the cell sources have been obtained; dose-ranging transfer and acute toxicity require another 1-2 weeks, and data consolidation can be finished in 3-5 business days. To scale up to customized multi-tissue couplings (e.g., a placenta-to-fetal heart), one must allow the organoids to mature and validate the coupling, and repeat this cycle.
What is the perception of regulators of the data from these systems?
A growing number of regulatory agencies are using organ-on-chip data as supporting evidence. Human-relevant transfer and hazard data are not yet a formal alternative to pivotal studies, although they can provide useful support for PBPK modeling and justify safer starting doses or exclusion criteria in an indication related to pregnancy.
What should the partners prepare before making a start?
Agreement first: reference compound collection (e.g., one high-, one moderate-, one low-transfer drug), acceptance of barrier integrity, sample rhythm, analytic (LC-MS methods, LLOQ), cell sourcing and QC, and power. Cross-site comparisons are convenient because clear metadata templates exist for flow rates, shear, oxygen, passage numbers, etc., and the speeding up of publications.
What are the technical areas of greatest MIC added value?
In the last mile: bridging the gap between biology and solid hardware and SOPs. We focus on fixed gradients, sensorized cartridges, automated flow control, and data pipelines that enable frictionless comparisons of results across sites and consortia. And we craft prototypical objects of the things a team can actually ship, run, and iterate on, rather than figures.