Periodic Reporting for period 1 - BIOFRAC (Modelling of fracture in soft biological tissues)
Periodo di rendicontazione: 2023-12-16 al 2025-12-15
Soft biological tissues such as epithelia are essential for maintaining organ integrity, yet their rupture under physiological or therapeutic loading can have devastating consequences. Blood vessel rupture in brain aneurysms is fatal in approximately 40% of cases, while rupture of the retinal pigment epithelium (RPE) contributes to vision loss affecting millions of people worldwide. Despite this major clinical relevance, the fundamental mechanisms governing fracture in soft living tissues remain poorly understood. Their complex microstructure, ability to undergo large deformations, time-dependent behaviour, and active biological processes make fracture prediction extremely challenging. Current experimental approaches cannot fully disentangle the interacting mechanical and biological phenomena occurring simultaneously at the crack tip and in the surrounding tissue, and existing models typically address only isolated aspects of this complexity. As a result, a quantitative link between tissue-scale loading and cellular-scale failure mechanisms is still missing.
The BIOFRAC project was conceived to address this gap by developing a new modelling and experimental framework to understand fracture initiation and propagation in soft biological tissues. The overarching objective was to establish a quantitative link between macroscopic loading conditions and microscale stress and strain patterns that lead to tissue rupture. By doing so, the project aims to improve the mechanistic understanding of tissue failure and to support the development of safer therapeutic strategies and better-informed biomedical interventions.
The project pursued three main objectives. First, it aimed to develop a micromechanical model capable of predicting local stress and strain fields in tissues under large deformations, explicitly accounting for tissue microstructure and time-dependent material behaviour. Second, it sought to identify the spatial and temporal mechanical signatures associated with fracture initiation and early crack propagation. Third, it focused on identifying anatomical and mechanical risk factors for rupture of the retinal pigment epithelium (RPE), a critical tissue whose failure can lead to irreversible vision loss.
The project pathway to impact is based on combining advanced computational modelling with human-relevant experimental systems. By integrating mechanics, applied mathematics, and biological experimentation, BIOFRAC contributes to EU priorities in health, biomedical innovation, and open science. The results are expected to have significant scientific impact by advancing fracture mechanics in soft matter, and societal relevance by improving understanding of tissue failure in disease contexts. Social sciences and humanities perspectives were indirectly integrated through education, outreach, and responsible research practices, supporting accessibility, transparency, and public engagement with EU-funded research.
The BIOFRAC project was conceived to address this gap by developing a new modelling and experimental framework to understand fracture initiation and propagation in soft biological tissues. The overarching objective was to establish a quantitative link between macroscopic loading conditions and microscale stress and strain patterns that lead to tissue rupture. By doing so, the project aims to improve the mechanistic understanding of tissue failure and to support the development of safer therapeutic strategies and better-informed biomedical interventions.
The project pursued three main objectives. First, it aimed to develop a micromechanical model capable of predicting local stress and strain fields in tissues under large deformations, explicitly accounting for tissue microstructure and time-dependent material behaviour. Second, it sought to identify the spatial and temporal mechanical signatures associated with fracture initiation and early crack propagation. Third, it focused on identifying anatomical and mechanical risk factors for rupture of the retinal pigment epithelium (RPE), a critical tissue whose failure can lead to irreversible vision loss.
The project pathway to impact is based on combining advanced computational modelling with human-relevant experimental systems. By integrating mechanics, applied mathematics, and biological experimentation, BIOFRAC contributes to EU priorities in health, biomedical innovation, and open science. The results are expected to have significant scientific impact by advancing fracture mechanics in soft matter, and societal relevance by improving understanding of tissue failure in disease contexts. Social sciences and humanities perspectives were indirectly integrated through education, outreach, and responsible research practices, supporting accessibility, transparency, and public engagement with EU-funded research.
The project work was structured around three interlinked technical work packages.
A new multiscale micromechanical modelling framework was developed to describe soft tissue mechanics under large deformations. To overcome numerical limitations of standard finite element approaches, the problem was reformulated using a dynamic relaxation strategy, which enables stable and efficient solutions for highly nonlinear materials. Time-dependent viscoelastic behaviour was incorporated through a differential constitutive formulation, allowing accurate prediction of stress and strain evolution without prohibitive computational cost. The resulting framework links macroscopic loading to cellular-scale mechanics and explicitly represents tissue microstructure and cell–cell interactions.
Building on this framework, computational methods were established to study fracture initiation and early propagation in soft tissues. Fracture energy and energy release rates were computed using simulations of notched and unnotched samples, combined with functionally graded meshes to resolve highly localised stress fields near crack tips. The implementation was parallelised to enable large-scale simulations. Additional analyses under cyclic loading conditions revealed loading-history-dependent strengthening effects, highlighting the adaptive and time-dependent nature of living tissues.
In parallel, an experimental platform was developed to mechanically characterise Retina Pigment Epithelium tissues. The project focused on the retinal pigment epithelium using monolayers differentiated from patient-derived stem cells, providing a human-relevant model system. A dedicated tensile testing setup was designed to accommodate fragile samples while preserving their structural integrity. Mechanical tests revealed that tissues carrying disease-associated genetic mutations exhibit reduced rupture strength, and that the tested gene-editing strategy did not restore healthy mechanical behaviour under the applied conditions.
A new multiscale micromechanical modelling framework was developed to describe soft tissue mechanics under large deformations. To overcome numerical limitations of standard finite element approaches, the problem was reformulated using a dynamic relaxation strategy, which enables stable and efficient solutions for highly nonlinear materials. Time-dependent viscoelastic behaviour was incorporated through a differential constitutive formulation, allowing accurate prediction of stress and strain evolution without prohibitive computational cost. The resulting framework links macroscopic loading to cellular-scale mechanics and explicitly represents tissue microstructure and cell–cell interactions.
Building on this framework, computational methods were established to study fracture initiation and early propagation in soft tissues. Fracture energy and energy release rates were computed using simulations of notched and unnotched samples, combined with functionally graded meshes to resolve highly localised stress fields near crack tips. The implementation was parallelised to enable large-scale simulations. Additional analyses under cyclic loading conditions revealed loading-history-dependent strengthening effects, highlighting the adaptive and time-dependent nature of living tissues.
In parallel, an experimental platform was developed to mechanically characterise Retina Pigment Epithelium tissues. The project focused on the retinal pigment epithelium using monolayers differentiated from patient-derived stem cells, providing a human-relevant model system. A dedicated tensile testing setup was designed to accommodate fragile samples while preserving their structural integrity. Mechanical tests revealed that tissues carrying disease-associated genetic mutations exhibit reduced rupture strength, and that the tested gene-editing strategy did not restore healthy mechanical behaviour under the applied conditions.
BIOFRAC delivers results that go beyond the current state of the art in both modelling and experimentation. The project produced the first computational framework that directly couples fracture mechanics with nonlinear, time-dependent soft tissue behaviour at the microscale. This represents a substantial advance over existing models, which on simplified assumptions. The identification of local stress and strain patterns associated with fracture initiation provides new mechanistic insight into how and where soft tissues fail. The discovery of history-dependent strengthening under cyclic loading opens new perspectives on tissue adaptation and resilience, with potential implications for understanding repetitive physiological loading and long-term tissue health.
Experimentally, the establishment of a tensile testing protocol for patient-derived epithelial tissues enables direct investigation of human-specific mechanical risk factors. The in-plane mechanical characterisation of basement membranes represents a methodological breakthrough with relevance for a wide range of biological and medical applications.
To ensure further uptake and long-term impact, additional steps are needed, including extended parametric studies of fracture propagation, larger experimental datasets across different tissue types, and integration with disease-specific models. Open-source release of the developed software, further validation, and alignment with standardisation efforts will support reuse by the wider research community. In the longer term, the results provide a foundation for translational research, improved therapeutic strategies, and future innovation in biomedical engineering and mechanobiology.
Experimentally, the establishment of a tensile testing protocol for patient-derived epithelial tissues enables direct investigation of human-specific mechanical risk factors. The in-plane mechanical characterisation of basement membranes represents a methodological breakthrough with relevance for a wide range of biological and medical applications.
To ensure further uptake and long-term impact, additional steps are needed, including extended parametric studies of fracture propagation, larger experimental datasets across different tissue types, and integration with disease-specific models. Open-source release of the developed software, further validation, and alignment with standardisation efforts will support reuse by the wider research community. In the longer term, the results provide a foundation for translational research, improved therapeutic strategies, and future innovation in biomedical engineering and mechanobiology.