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HEIndividual fellowship2024–2026

CURIES · Chip URInary Engineered System for modelling bladder biomechanics and disease

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2024-05-10 → 2026-05-09
EU contribution
€230,774
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

Chip URInary Engineered System for modelling bladder biomechanics and disease

Antimicrobial Resistance (AMR) remains a serious healthcare issue in Europe, which currently costs the EU/EEA €11.7 billion every year. The urinary tract is a leading site for chronic bacterial infections, with 1 in 4 women versus 1 in 10 in men having suffered from Urinary Tract Infections (UTI) in their lifetimes. Treatment regimens remain broad and insubstantial. AMR can never be combatted without effective human tissue modelling pipelines upon which to develop more targeted strategies. A gateway towards establishing more targeted pipelines is to advance in vitro systems through organ-on-a-chip technologies. These systems empower a vision to increase complexity within bioengineered tissues, giving fourth dimensions of biophysical events over time to more traditional and static three-dimensional culture systems. An in vitro model of the specialised bladder epithelium (the urothelium), that undergoes cycles of stretch and release to simulate the urinary cycle, has more power as a pipeline for modelling UTI than in a static culture system. Constructing such as system has potential to better understand the connection between chronic UTIs and how the homeostatic biomechanics of the urothelium are targeted in chronic infections. In this project, the aim was to construct a state-of-the-art stem cell derived urothelium-on-a-chip in combination with a unique microfluidic system to impose isotropic stretch with increased pressures. Chip URInary Engineered System for modelling bladder biomechanics and disease (CURIES) was conceived to bridge the gap between current infection models and traditionally static engineered urothelia. Characterisation with omics and live-imaging, seeking molecular and biophysical alterations between stretched and voided states, was established to benchmark for normal human urothelial function. The ultimate goal was to create an infection model within the cycling urothelium to explore how each biophysical state of the urothelium, stretched and voided, becomes altered in infections conditions in infected urothelia. The outcome will likely advance the current understanding of how damaged urothelium acts under infection conditions.

Data: CORDIS, © European Union

Project objective

Urinary tract infections (UTI) are severe bacterial infections of the urinary system. Low understanding of specific bacteria-host interactions and associated disease aetiologies has led to global misuse of antibiotics driving bacterial resistance. However, relevant human modelling platforms that replicate all parameters of a physiological bladder and reciprocate infection conditions are non-existent. During infection bladder stretch-mechanisms are commandeered by opportunistic bacteria to penetrate the impermeable bladder defence, that are then not appropriately cleared by antibiotics regimens. With CURIES, we will develop microfluidic bladder-on-chip systems able to replicate the dynamic biomechanical scenarios and chemically-rich environments of the bladder epithelium; the urothelium. Without appropriate models that recapitulate organ biomechanics the emergence of superpathogens is likely to never be counteracted by targeted therapeutic design, accelerating antibiotic resistance to greater crisis levels. In this MSCA application I aim to combine my bioengineering experience with the world-leading expertise of my host laboratory in epithelial mechanobiology to create dynamic simulations of human bladder-on-a-chip homeostasis and UTI infections. I will perform thorough analyses on the transcriptomic level of changes across the expanse of the urothelium with periodic filling and voiding during pathogenic and non-pathogenic infections. CURIES will have unparalleled relevance for the drug discovery industry. Bringing together such advanced methodologies will yield discoveries in molecular mechanisms impacted by bladder-pathogen interactions and enable computational modelling simulations to serve as predictive tools. By undertaking this work I will develop valuable transferable skills, increase my scientific visibility, and move closer to scientific independence. CURIES will both shape my academic career and positively impact the fight against antibiotic resistance.

Original text from CORDIS.

Participants

  • KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark

Links

Data: CORDIS, © European Union