Agent-Based Modelling of Radiation-Induced Lung Injuries

Radiotherapy (RT), which nowadays is integrated in more than 50% of the therapies of new cancer patients, involves the use of ionizing radiation (such as photon beams and ions) as a tool to sterilize cancers. However, the lethal doses to be delivered to the tumours are limited by normal tissue complications. Consequently, constraints must be set on the radiation dose and irradiated volume in order to maintain acceptable toxicity levels. An important role in this context is played by computational models that ultimately provide valuable insights useful for tuning the RT parameters. Their use in the biomedical framework has a well-defined pattern: a theoretical model is initially built on the basis of the available in-vitro and/or in-vivo data and implemented in-silico; the model is then altered until a good match between its output and laboratory data is observed and finally used for predictions in the clinical setting. As yet, however, the tolerance doses for the organs at risk are derived from clinical experience and used as inputs for phenomenological Normal-Tissue Complication Probability (NTCP) models that lack a mechanistic description of the underlying phenomena. This thesis describes the implementation of an Agent-Based Model (ABM) that simulates the onset of Radiation-Induced Lung Injuries (RILI) (namely pneumonitis and fibrosis), complications that can occur in the lungs of patients irradiated in the thoracic region. Although relatively common, the risk factors and progression of the RILI, which eventually lead to respiratory failure and death, haven’t been fully elucidated. Here, the capability of the innovative AB modelling approach to improve patient-specific NTCP estimates while attempting to provide insights on the development of RILI is investigated. With respect to the existing dose-volume histogram-based and tissue-architecture approaches, ABMs can take into account not only the patient-specific geometry and tissue-level parameters, but also spatial information on the dose distribution. As a first step, a 3D model of idiopathic pulmonary fibrosis, which resembles the Radiation-Induced Lung Fibrosis (RILF), was implemented using BioDynaMo, an AB simulation framework. The model, whose agents simulate a partial pulmonary acinus, can replicate previous experimental results and assess the appropriateness of the approach for the purpose. The model was subsequently rescaled to represent an alveolar segment at the cell scale that can be damaged locally by external sources. As a surrogate measure of the RILF severity, the RILF Severity Index (RSI) was introduced, derived by combining the loss in the alveolar volume with the increase in the average concentration of the ExtraCellular Matrix (ECM). The RSI showed qualitative agreement with a similar index obtained using data from computational tomographies and the ECM patterns matched clinical findings. Finally, a pipeline was established that links TOPAS-nBio, a particle transport simulator for biological applications, with BioDynaMo. The alveolar segment structure was rebuilt using TOPAS-nBio and the delivery of realistic dose distributions at the cell scale was simulated. The output was then used as an input for the AB model and the effect of different fractionation schemes and radiation qualities on the outcome explored. In accordance with previous studies, a 5-fractions treatment resulted in a lower RSI with respect to the delivery of the same dose in a single fraction and an increased sensitivity to peaked protons dose distributions with respect to flatter ones from photons irradiation was observed. Overall, the results presented in this thesis prove the capability of the AB models to recapitulate some main radiobiological processes and advise for their potential complementary role in NTCP estimates

Recipes for calibration and validation of agent-based models in cancer biomedicine

Computational models and simulations are not just appealing because of their intrinsic characteristics across spatiotemporal scales, scalability, and predictive power, but also because the set of problems in cancer biomedicine that can be addressed computationally exceeds the set of those amenable to analytical solutions. Agent-based models and simulations are especially interesting candidates among computational modelling strategies in cancer research due to their capabilities to replicate realistic local and global interaction dynamics at a convenient and relevant scale. Yet, the absence of methods to validate the consistency of the results across scales can hinder adoption by turning fine-tuned models into black boxes. This review compiles relevant literature to explore strategies to leverage high-fidelity simulations of multi-scale, or multi-level, cancer models with a focus on validation approached as simulation calibration. We argue that simulation calibration goes beyond parameter optimization by embedding informative priors to generate plausible parameter configurations across multiple dimensions

A 3D Agent-Based Model of Lung Fibrosis

Understanding the pathophysiology of lung fibrosis is of paramount importance to elaborate targeted and effective therapies. As it onsets, the randomly accumulating extracellular matrix (ECM) breaks the symmetry of the branching lung structure. Interestingly, similar pathways have been reported for both idiopathic pulmonary fibrosis and radiation-induced lung fibrosis (RILF). Individuals suffering from the disease, the worldwide incidence of which is growing, have poor prognosis and a short mean survival time. In this context, mathematical and computational models have the potential to shed light on key underlying pathological mechanisms, shorten the time needed for clinical trials, parallelize hypotheses testing, and improve personalized drug development. Agentbased modeling (ABM) has proven to be a reliable and versatile simulation tool, whose features make it a good candidate for recapitulating emergent behaviors in heterogeneous systems, such as those found at multiple scales in the human body. In this paper, we detail the implementation of a 3D agent-based model of lung fibrosis using a novel simulation platform, namely, BioDynaMo, and prove that it can qualitatively and quantitatively reproduce published results. Furthermore, we provide additional insights on late-fibrosis patterns through ECM density distribution histograms. The model recapitulates key intercellular mechanisms, while cell numbers and types are embodied by alveolar segments that act as agents and are spatially arranged by a custom algorithm. Finally, our model may hold potential for future applications in the context of lung disorders, ranging from RILF (by implementing radiation-induced cell damage mechanisms) to COVID-19 and inflammatory diseases (such as asthma or chronic obstructive pulmonary disease)

An Agent-Based Model of Radiation-Induced Lung Fibrosis

Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models

A 3D Agent-Based Model of Lung Fibrosis

Understanding the pathophysiology of lung fibrosis is of paramount importance to elaborate targeted and effective therapies. As it onsets, the randomly accumulating extracellular matrix (ECM) breaks the symmetry of the branching lung structure. Interestingly, similar pathways have been reported for both idiopathic pulmonary fibrosis and radiation-induced lung fibrosis (RILF). Individuals suffering from the disease, the worldwide incidence of which is growing, have poor prognosis and a short mean survival time. In this context, mathematical and computational models have the potential to shed light on key underlying pathological mechanisms, shorten the time needed for clinical trials, parallelize hypotheses testing, and improve personalized drug development. Agent-based modeling (ABM) has proven to be a reliable and versatile simulation tool, whose features make it a good candidate for recapitulating emergent behaviors in heterogeneous systems, such as those found at multiple scales in the human body. In this paper, we detail the implementation of a 3D agent-based model of lung fibrosis using a novel simulation platform, namely, BioDynaMo, and prove that it can qualitatively and quantitatively reproduce published results. Furthermore, we provide additional insights on late-fibrosis patterns through ECM density distribution histograms. The model recapitulates key intercellular mechanisms, while cell numbers and types are embodied by alveolar segments that act as agents and are spatially arranged by a custom algorithm. Finally, our model may hold potential for future applications in the context of lung disorders, ranging from RILF (by implementing radiation-induced cell damage mechanisms) to COVID-19 and inflammatory diseases (such as asthma or chronic obstructive pulmonary disease)

An Agent-Based Model of Radiation-Induced Lung Fibrosis

Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models

An Agent-Based Model of Radiation-Induced Lung Fibrosis

Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models

The comparison between two mathematical contractile elements Integrated to an hiPSC-CM in silico Model

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