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1.  Modeling and Simulation of the Effects of Cyclic Loading on Articular Cartilage Lesion Formation 
We present a model of articular cartilage lesion formation to simulate the effects of cyclic loading. This model extends and modifies the reaction-diffusion-delay model by Graham et al. [20] for the spread of a lesion formed though a single traumatic event. Our model represents “implicitly” the effects of loading, meaning through a cyclic sink term in the equations for live cells.
Our model forms the basis for in silico studies of cartilage damage relevant to questions in osteoarthritis, for example, that may not be easily answered through in vivo or in vitro studies.
Computational results are presented that indicate the impact of differing levels of EPO on articular cartilage lesion abatement.
doi:10.1002/cnm.2636
PMCID: PMC4950512  PMID: 24753483
2.  A Validated Model of the Pro- and Anti-Inflammatory Cytokine Balancing Act in Articular Cartilage Lesion Formation 
Traumatic injuries of articular cartilage result in the formation of a cartilage lesion and contribute to cartilage degeneration and the risk of osteoarthritis (OA). A better understanding of the framework for the formation of a cartilage lesion formation would be helpful in therapy development. Toward this end, we present an age and space-structured model of articular cartilage lesion formation after a single blunt impact. This model modifies the reaction-diffusion-delay models in Graham et al. (2012) (single impact) and Wang et al. (2014) (cyclic loading), focusing on the “balancing act” between pro- and anti-inflammatory cytokines. Age structure is introduced to replace the delay terms for cell transitions used in these earlier models; we find age structured models to be more flexible in representing the underlying biological system and more tractable computationally. Numerical results show a successful capture of chondrocyte behavior and chemical activities associated with the cartilage lesion after the initial injury; experimental validation of our computational results is presented. We anticipate that our in silico model of cartilage damage from a single blunt impact can be used to provide information that may not be easily obtained through in in vivo or in vitro studies.
doi:10.3389/fbioe.2015.00025
PMCID: PMC4354422  PMID: 25806365
articular cartilage; structured model; lesion formation and abatement; EPO; IL-6
3.  Corrigendum: “A Validated Model of the Pro- and Anti-Inflammatory Cytokine Balancing Act in Articular Cartilage Lesion Formation” 
doi:10.3389/fbioe.2015.00073
PMCID: PMC4443297  PMID: 26075201
articular cartilage; structured model; lesion formation and abatement; EPO; IL-6
4.  Linking Cellular and Mechanical Processes in Articular Cartilage Lesion Formation: A Mathematical Model 
Post-traumatic osteoarthritis affects almost 20% of the adult US population. An injurious impact applies a significant amount of physical stress on articular cartilage and can initiate a cascade of biochemical reactions that can lead to the development of osteoarthritis. In our effort to understand the underlying biochemical mechanisms of this debilitating disease, we have constructed a multiscale mathematical model of the process with three components: cellular, chemical, and mechanical. The cellular component describes the different chondrocyte states according to the chemicals these cells release. The chemical component models the change in concentrations of those chemicals. The mechanical component contains a simulation of a blunt impact applied onto a cartilage explant and the resulting strains that initiate the biochemical processes. The scales are modeled through a system of partial-differential equations and solved numerically. The results of the model qualitatively capture the results of laboratory experiments of drop-tower impacts on cartilage explants. The model creates a framework for incorporating explicit mechanics, simulated by finite element analysis, into a theoretical biology framework. The effort is a step toward a complete virtual platform for modeling the development of post-traumatic osteoarthritis, which will be used to inform biomedical researchers on possible non-invasive strategies for mitigating the disease.
doi:10.3389/fbioe.2016.00080
PMCID: PMC5086581  PMID: 27843894
articular cartilage; osteoarthritis; mathematical modeling and simulation; age-structured model; reaction-diffusion model; finite element analysis
5.  TOWARDS A NEW SPATIAL REPRESENTATION OF BONE REMODELING 
Irregular bone remodeling is associated with a number of bone diseases such as osteoporosis and multiple myeloma. Computational and mathematical modeling can aid in therapy and treatment as well as understanding fundamental biology. Different approaches to modeling give insight into different aspects of a phenomena so it is useful to have an arsenal of various computational and mathematical models. Here we develop a mathematical representation of bone remodeling that can effectively describe many aspects of the complicated geometries and spatial behavior observed.
There is a sharp interface between bone and marrow regions. Also the surface of bone moves in and out, i.e. in the normal direction, due to remodeling. Based on these observations we employ the use of a level-set function to represent the spatial behavior of remodeling. We elaborate on a temporal model for osteoclast and osteoblast population dynamics to determine the change in bone mass which influences how the interface between bone and marrow changes.
We exhibit simulations based on our computational model that show the motion of the interface between bone and marrow as a consequence of bone remodeling. The simulations show that it is possible to capture spatial behavior of bone remodeling in complicated geometries as they occur in vitro and in vivo.
By employing the level set approach it is possible to develop computational and mathematical representations of the spatial behavior of bone remodeling. By including in this formalism further details, such as more complex cytokine interactions and accurate parameter values, it is possible to obtain simulations of phenomena related to bone remodeling with spatial behavior much as in vitro and in vivo. This makes it possible to perform in silica experiments more closely resembling experimental observations.
PMCID: PMC3708700  PMID: 22901065
Bone remodeling; level-set equation; cytokines; osteoclast; osteoblast
6.  The Role of Osteocytes in Targeted Bone Remodeling: A Mathematical Model 
PLoS ONE  2013;8(5):e63884.
Until recently many studies of bone remodeling at the cellular level have focused on the behavior of mature osteoblasts and osteoclasts, and their respective precursor cells, with the role of osteocytes and bone lining cells left largely unexplored. This is particularly true with respect to the mathematical modeling of bone remodeling. However, there is increasing evidence that osteocytes play important roles in the cycle of targeted bone remodeling, in serving as a significant source of RANKL to support osteoclastogenesis, and in secreting the bone formation inhibitor sclerostin. Moreover, there is also increasing interest in sclerostin, an osteocyte-secreted bone formation inhibitor, and its role in regulating local response to changes in the bone microenvironment. Here we develop a cell population model of bone remodeling that includes the role of osteocytes, sclerostin, and allows for the possibility of RANKL expression by osteocyte cell populations. We have aimed to give a simple, yet still tractable, model that remains faithful to the underlying system based on the known literature. This model extends and complements many of the existing mathematical models for bone remodeling, but can be used to explore aspects of the process of bone remodeling that were previously beyond the scope of prior modeling work. Through numerical simulations we demonstrate that our model can be used to explore theoretically many of the qualitative features of the role of osteocytes in bone biology as presented in recent literature.
doi:10.1371/journal.pone.0063884
PMCID: PMC3661588  PMID: 23717504
7.  Reaction-Diffusion-Delay Model for EPO/TNF-α Interaction in articular cartilage lesion abatement 
Biology Direct  2012;7:9.
Background
Injuries to articular cartilage result in the development of lesions that form on the surface of the cartilage. Such lesions are associated with articular cartilage degeneration and osteoarthritis. The typical injury response often causes collateral damage, primarily an effect of inflammation, which results in the spread of lesions beyond the region where the initial injury occurs.
Results and discussion
We present a minimal mathematical model based on known mechanisms to investigate the spread and abatement of such lesions. The first case corresponds to the parameter values listed in Table 1, while the second case has parameter values as in Table 2. In particular we represent the "balancing act" between pro-inflammatory and anti-inflammatory cytokines that is hypothesized to be a principal mechanism in the expansion properties of cartilage damage during the typical injury response. We present preliminary results of in vitro studies that confirm the anti-inflammatory activities of the cytokine erythropoietin (EPO). We assume that the diffusion of cytokines determine the spatial behavior of injury response and lesion expansion so that a reaction diffusion system involving chemical species and chondrocyte cell state population densities is a natural way to represent cartilage injury response. We present computational results using the mathematical model showing that our representation is successful in capturing much of the interesting spatial behavior of injury associated lesion development and abatement in articular cartilage. Further, we discuss the use of this model to study the possibility of using EPO as a therapy for reducing the amount of inflammation induced collateral damage to cartilage during the typical injury response.
Model Parameter Values for Results in Figure 5
Model Parameter Values for Results in Figure 6
Conclusions
The mathematical model presented herein suggests that not only are anti-inflammatory cy-tokines, such as EPO necessary to prevent chondrocytes signaled by pro-inflammatory cytokines from entering apoptosis, they may also influence how chondrocytes respond to signaling by pro-inflammatory cytokines.
Reviewers
This paper has been reviewed by Yang Kuang, James Faeder and Anna Marciniak-Czochra.
doi:10.1186/1745-6150-7-9
PMCID: PMC3356234  PMID: 22353555
8.  A SPATIAL MODEL OF TUMOR-HOST INTERACTION: APPLICATION OF CHEMOTHERAPY 
In this paper we consider chemotherapy in a spatial model of tumor growth. The model, which is of reaction-diffusion type, takes into account the complex interactions between the tumor and surrounding stromal cells by including densities of endothelial cells and the extra-cellular matrix. When no treatment is applied the model reproduces the typical dynamics of early tumor growth. The initially avascular tumor reaches a diffusion limited size of the order of millimeters and initiates angiogenesis through the release of vascular endothelial growth factor (VEGF) secreted by hypoxic cells in the core of the tumor. This stimulates endothelial cells to migrate towards the tumor and establishes a nutrient supply sufficient for sustained invasion. To this model we apply cytostatic treatment in the form of a VEGF-inhibitor, which reduces the proliferation and chemotaxis of endothelial cells. This treatment has the capability to reduce tumor mass, but more importantly, we were able to determine that inhibition of endothelial cell proliferation is the more important of the two cellular functions targeted by the drug. Further, we considered the application of a cytotoxic drug that targets proliferating tumor cells. The drug was treated as a diffusible substance entering the tissue from the blood vessels. Our results show that depending on the characteristics of the drug it can either reduce the tumor mass significantly or in fact accelerate the growth rate of the tumor. This result seems to be due to complicated interplay between the stromal and tumor cell types and highlights the importance of considering chemotherapy in a spatial context.
PMCID: PMC2981353  PMID: 19566124
tumor invasion; hypoxia; chemotherapy; anti-angiogenic therapy; mathematical modeling
9.  A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease 
Biology Direct  2010;5:28.
Background
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
Results
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
Conclusions
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Reviewers
This article was reviewed by Ariosto Silva and Mark P. Little.
doi:10.1186/1745-6150-5-28
PMCID: PMC2867965  PMID: 20406449

Results 1-9 (9)