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Physiology is an integrative medicine discipline investigating how the structure and function of cell, tissues, and organs explain the behavior of a living organism. By nature computational physiology is emerging as an integrative technology coupling physiological functions such as hemodynamics, respiration, metabolism, autoregulation, biomechanics, neurology, immunology, endocrinology, and others. Because of enormous complexity of the living organism the physiological modeling has been performed using simple network type models for whole body functions, or using higher fidelity (e.g. 3D) models for specific physiological functions, organs, or tissues. Our multiscale approach is unique that it can naturally combine whole body physiological system models with spatial models of specific organs. The whole body hemodynamics can be modeled using CoBi as a compartmental or as quasi 3D arterio-venous network with a number of perfused tissues represented as compartmental/distributed models. Other physiological functions are activated on “top” of the hemodynamic model.
Anatomical/Physiological Body Editor, JCoBi
Physiological models require information of anatomical data (e.g. from medical imaging) and physiological parameters (e.g. from clinical data). We are developing graphical software tools Anatomical/Physiological Editor, JCoBi, generating anatomical human/animal body models for physiological simulations. It will enable image data processing, generation of anatomical geometry of various organs (skeletal, vascular, muscular, nervous, lymphatic, gastrointestinal, respiratory, etc.) at various levels of computational resolution (compartment to 3D mesh).
Hemodynamics
Blood flow can be simulated in CoBi using simple compartmental models, quasi 3D vascular tree, full mesh 3D CFD method, or their combination. Blood vessels are treated as elastic tubes and fully coupled fluid-structures interaction (FSI) problem is solved. Hemodynamics supports other physiological and pharmacological models.
Respiration
Respiration model – trachea, lungs, and pulmonary circulation- in CoBi and Leonardo can be simulated using full 3D model, distributed 1D tree model, or compartmental models. The respiration model includes air and particulates in/out flow in nasal/throat cavity, trachea/bronchial tree, up to the alveoli, alveolar air-blood barrier, and gas exchange between air and pulmonary blood. It is coupled to whole body hemodynamics and metabolism models and can be used to simulate exercise, hypoxia, asthma, inhalation drug delivery, viral infection, blunt or blast injury.
Tissue and Organ Perfusion
CoBi multiscale organ perfusion models range from compartmental (blood, interstitium, cell) models for various organs up to 3D medical image based models of specific organs (brain, liver). For pharmacological (PBPK) simulations we have assembled a database of perfusion data of various organs for humans and animals.
   
Metabolism
Metabolism is simulated using CoBi Biochemistry module. Depending on the required resolution it can me simulated with a simple “minimal model” (VO2, Do2 and O2+ Glucose -> CO2+ H2O + Energy) up to complex multi step cell/mitochondrial biochemistry including range of metabolites. It can be linked to other physiological and pharmacological models (hypoxia, oxidative stress, regulation of vascular tone).
Autoregulation
Local and central cardiovascular autoregulation attempts to keep blood flow constant when blood pressure changes. To simulate the cardiovascular response to perturbations in blood pressure and oxygenation we have implemented in CoBi autoregulation models including baroreflex and chemoreflex control of vascular tone in various organs as well as CNS control of heart and respiration parameters.
Specific Organ Models
Whole body physiological simulations involve several specific organ and tissue models. In CoBi some organs such as heart, lung, brain, and liver have few versions depending on the required resolution. For example heart can be modeled as heart-beat resolved or heart beat average models. Organs which have specific multiresolution implementation include:
Heart Models
Brain Circulation-CSF-Perfusion Models
Liver Models
Gastrointestinal Track (Bolus Peristaltic Transport, Digestion, Absorption)
Skin Model
Other Physiological Functions
CFDRC is working on the implementation of several other models of physiological functions including: nutrition, body energetic balance, circadian rhythms, control of vascular tone, oxidative stress, ischemia, peripheral lymphatics, immunology, water and electrolyte balance, and others.
Pathophysiology, Injury, and Surgical Treatment
Calibrated and validated physiological models provide foundation for more important analysis of disease states. CFDRC is developing several specific “virtual diseases” using whole body physiology coupled to systems biology and pharmacology modules. Most active disease development efforts include:
Link to Bottom-Up Systems Biology, Pharmacology, Biomechanics and Injury
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