Agent-Based Model of Therapeutic Adipose-Derived Stromal Cell Trafficking during Ischemia Predicts Ability To Roll on P-Selectin

Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 µm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications

Hybrid Equation/Agent-Based Model of Ischemia-Induced Hyperemia and Pressure Ulcer Formation Predicts Greater Propensity to Ulcerate in Subjects with Spinal Cord Injury

Pressure ulcers are costly and life-threatening complications for people with spinal cord injury (SCI). People with SCI also exhibit differential blood flow properties in non-ulcerated skin. We hypothesized that a computer simulation of the pressure ulcer formation process, informed by data regarding skin blood flow and reactive hyperemia in response to pressure, could provide insights into the pathogenesis and effective treatment of post-SCI pressure ulcers. Agent-Based Models (ABM) are useful in settings such as pressure ulcers, in which spatial realism is important. Ordinary Differential Equation-based (ODE) models are useful when modeling physiological phenomena such as reactive hyperemia. Accordingly, we constructed a hybrid model that combines ODEs related to blood flow along with an ABM of skin injury, inflammation, and ulcer formation. The relationship between pressure and the course of ulcer formation, as well as several other important characteristic patterns of pressure ulcer formation, was demonstrated in this model. The ODE portion of this model was calibrated to data related to blood flow following experimental pressure responses in non-injured human subjects or to data from people with SCI. This model predicted a higher propensity to form ulcers in response to pressure in people with SCI vs. non-injured control subjects, and thus may serve as novel diagnostic platform for post-SCI ulcer formation. © 2013 Solovyev et al

Identifying the Rules of Engagement Enabling Leukocyte Rolling, Activation, and Adhesion

The LFA-1 integrin plays a pivotal role in sustained leukocyte adhesion to the endothelial surface, which is a precondition for leukocyte recruitment into inflammation sites. Strong correlative evidence implicates LFA-1 clustering as being essential for sustained adhesion, and it may also facilitate rebinding events with its ligand ICAM-1. We cannot challenge those hypotheses directly because it is infeasible to measure either process during leukocyte adhesion following rolling. The alternative approach undertaken was to challenge the hypothesized mechanisms by experimenting on validated, working counterparts: simulations in which diffusible, LFA1 objects on the surfaces of quasi-autonomous leukocytes interact with simulated, diffusible, ICAM1 objects on endothelial surfaces during simulated adhesion following rolling. We used object-oriented, agent-based methods to build and execute multi-level, multi-attribute analogues of leukocytes and endothelial surfaces. Validation was achieved across different experimental conditions, in vitro, ex vivo, and in vivo, at both the individual cell and population levels. Because those mechanisms exhibit all of the characteristics of biological mechanisms, they can stand as a concrete, working theory about detailed events occurring at the leukocyte–surface interface during leukocyte rolling and adhesion experiments. We challenged mechanistic hypotheses by conducting experiments in which the consequences of multiple mechanistic events were tracked. We quantified rebinding events between individual components under different conditions, and the role of LFA1 clustering in sustaining leukocyte–surface adhesion and in improving adhesion efficiency. Early during simulations ICAM1 rebinding (to LFA1) but not LFA1 rebinding (to ICAM1) was enhanced by clustering. Later, clustering caused both types of rebinding events to increase. We discovered that clustering was not necessary to achieve adhesion as long as LFA1 and ICAM1 object densities were above a critical level. Importantly, at low densities LFA1 clustering enabled improved efficiency: adhesion exhibited measurable, cell level positive cooperativity

Towards A Novel Unified Framework for Developing Formal, Network and Validated Agent-Based Simulation Models of Complex Adaptive Systems

Literature on the modeling and simulation of complex adaptive systems (cas) has primarily advanced vertically in different scientific domains with scientists developing a variety of domain-specific approaches and applications. However, while cas researchers are inherently interested in an interdisciplinary comparison of models, to the best of our knowledge, there is currently no single unified framework for facilitating the development, comparison, communication and validation of models across different scientific domains. In this thesis, we propose first steps towards such a unified framework using a combination of agent-based and complex network-based modeling approaches and guidelines formulated in the form of a set of four levels of usage, which allow multidisciplinary researchers to adopt a suitable framework level on the basis of available data types, their research study objectives and expected outcomes, thus allowing them to better plan and conduct their respective research case studies. Firstly, the complex network modeling level of the proposed framework entails the development of appropriate complex network models for the case where interaction data of cas components is available, with the aim of detecting emergent patterns in the cas under study. The exploratory agent-based modeling level of the proposed framework allows for the development of proof-of-concept models for the cas system, primarily for purposes of exploring feasibility of further research. Descriptive agent-based modeling level of the proposed framework allows for the use of a formal step-by-step approach for developing agent-based models coupled with a quantitative complex network and pseudocode-based specification of the model, which will, in turn, facilitate interdisciplinary cas model comparison and knowledge transfer. Finally, the validated agent-based modeling level of the proposed framework is concerned with the building of in-simulation verification and validation of agent-based models using a proposed Virtual Overlay Multiagent System approach for use in a systematic team-oriented approach to developing models. The proposed framework is evaluated and validated using seven detailed case study examples selected from various scientific domains including ecology, social sciences and a range of complex adaptive communication networks. The successful case studies demonstrate the potential of the framework in appealing to multidisciplinary researchers as a methodological approach to the modeling and simulation of cas by facilitating effective communication and knowledge transfer across scientific disciplines without the requirement of extensive learning curves

Multiscale Modeling of Tuberculosis Disease and Treatment to Optimize Antibiotic Regimens

Tuberculosis (TB) is one of the world’s deadliest infectious diseases. Caused by the pathogen Mycobacterium tuberculosis (Mtb), the standard regimen for treating TB consists of treatment with multiple antibiotics for at least six months. There are a number of complicating factors that contribute to the need for this long treatment duration and increase the risk of treatment failure. Person-to-person variability in antibiotic absorption and metabolism leads to varying levels of antibiotic plasma concentrations, and consequently lower concentrations at the site of infection. The structure of granulomas, lesions forming in lungs in response to Mtb infection, creates heterogeneous antibiotic distributions that limit antibiotic exposure to Mtb. Microenvironments in the granuloma can shift Mtb to phenotypic states that have higher tolerances to antibiotics. We can use computational modeling to represent and predict how each of these factors impacts antibiotic regimen efficacy and granuloma sterilization. In this thesis, we utilize an agent-based, computational model called GranSim that simulates granuloma formation, function and treatment. We present a method of incorporating sources of heterogeneity and variability in antibiotic pharmacokinetics to simulate treatment. Using GranSim to simulate treatment while accounting for these sources of heterogeneity and variability, we discover that individuals that naturally have low plasma antibiotic concentrations and granulomas with high bacterial burden are at greater risk of failing to sterilize granulomas during antibiotic treatment. Importantly, we find that changes to regimens provide greater improvements in granuloma sterilization times for these individuals. We also present a new pharmacodynamic model that incorporates the synergistic and antagonistic interactions associated with combinations of antibiotics. Using this model, we show that in vivo antibiotic concentrations impact the strength of these interactions, and that accounting for the actual concentrations within granulomas provides greater predictive power to determine the efficacy of a given antibiotic combination. A goal in improving antibiotic treatment for TB is to find regimens that can shorten the time it takes to sterilize granulomas while minimizing the amount of antibiotic required. With the number of potential combinations of antibiotics and dosages, it is prohibitively expensive to exhaustively simulate all combinations to achieve these goals. We present a method of utilizing a surrogate-assisted optimization framework to search for optimal regimens using GranSim and show that this framework is accurate and efficient. Comparing optimal regimens at the granuloma scale shows that there are alternative regimens using the antibiotic combination of isoniazid, rifampin, ethambutol and pyrazinamide that could improve sterilization times for some granulomas in TB treatment. In virtual clinical trials, these alternative regimens do not outperform the regimen of standard doses but could be acceptable alternatives. Focusing on identifying alternative regimens that can improve treatment for high risk patients could help to significantly decrease the global burden for TB. Overall, this thesis presents a computational tool to evaluate antibiotic regimen efficacy while accounting for the complicating factors in TB treatment and improves our ability to predict new regimens that can improve clinical treatment of TB.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/166103/1/cicchese_1.pd

Understanding and Treating Mycobacterium tuberculosis Infection: A Multi-Scale Modeling Approach.

Tuberculosis (TB), caused by the pathogen Mycobacterium tuberculosis (Mtb), remains a significant burden on global health. Central to both host immune responses and antibiotic treatment are structures known as granulomas. In this dissertation we used computational and experimental approaches at a single granuloma level to understand how immune responses to Mtb contribute to both bacterial control and persistence. In addition, we predicted the dynamics of antibiotics in granulomas and designed improved treatment strategies. We built a hybrid multi-scale model of Mtb infection that integrates the cytokines tumor necrosis factor-α (TNF) and interleukin-10 (IL-10). We predicted that a balance of TNF and IL-10 is essential to infection control with minimal host-induced tissue damage. We extended our description of TNF and IL-10 to include simplified models of intracellular signaling driving macrophage polarization, which suggests that the temporal dynamics of macrophage polarization in granulomas are predictive of granuloma outcome. Next, we focused on determining the role of IL-10 in controlling antimicrobial activity. We predicted a transient role for IL-10 in controlling a trade-off between early host immunity antimicrobial responses and tissue damage. This trade-off determines sterilization of granulomas. Lastly, using an experimental model of granuloma formation, we measured significant gradients of TNF in granulomas. xxii We developed a pharmacokinetic and pharmacodynamic model of oral dosing of rifampin and isoniazid used to treat Mtb and incorporated it into our computational model. We predicted that oral antibiotic strategies fail due to sub-optimal exposure in granulomas, which leads to bacterial regrowth between doses. We extended our platform to include a description of inhaled formulations dosed to the lungs with reduced frequencies. We predicted that dosing every two-weeks with an inhaled formulation of isoniazid is feasible with increased sterilization capabilities and reduced toxicity, while an inhaled formulation of rifampin has equivalent sterilization capabilities, but early associated toxicity and infeasible carrier loadings. The keys to understanding immune responses and successful antibiotic treatment of TB lie in the dynamics at the site of infection. Our results help identify the roles of cytokines during Mtb infection, provide new possibilities for immune related therapies, and guide design of better antibiotic strategies.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/108883/1/ncilfone_1.pd