Configurable bio-transport system simulator

Data processing: structural design – modeling – simulation – and em – Simulating nonelectrical device or system – Biological or biochemical

Reexamination Certificate

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C703S002000, C703S009000

Reexamination Certificate

active

06381562

ABSTRACT:

FIELD OF INVENTION
This invention relates to a computer-based simulation model for simulating a transport system in an organism. More specifically, the present invention relates to a configurable simulation model that emulates the behavior of a circulatory system.
BACKGROUND OF THE INVENTION
Almost all organisms have systems for channeling or otherwise controlling the movement of mass and/or energy in or around the organism. These systems are referred to herein as “bio-transport systems” (BTS), and include, for example, circulatory systems, digestive (gastrointestinal) systems, pulmonary systems, lymphatic systems, renal systems, and the movement of chemical and biological entities within and among tissues and cells just to name a few.
One bio-transport system of particular interest herein is the circulatory system. The circulatory system channels blood and other entities through vessels and among the various organs to supply nutrients to tissues, to regulate body mechanisms, and to facilitate the flow of materials and interactions necessary in general to keep an organism alive. Additionally, the circulatory system contains a medium, that is, blood, in which various chemical, biological and physical reactions take place. Thus, the circulatory system is a complex system having geometric, physical and chemical/biological properties; flow behavior; internal reactions; and interactions among blood, vessels, connected organs, and the organism in general. The properties, configurations, behaviors, reactions and interactions of a bio-transport system are collectively referred to herein as “bio-transport dynamics” [BTD].
As medicine becomes more quantitative, there is a need for analytic tools to relate more precisely causes to effects in organisms and to more clearly elucidate the mechanisms involved. This requires obtaining bio-transport dynamic data. For example, in the pharmaceutical field, there is a need to evaluate the effects of chemicals in drug studies by computing and displaying the concentration, at different points in the circulatory system and as a function of time, of a chemical injected into the body at a point in time and space, or bio-availability of an orally ingested drug in its journey through the GI tract and the circulatory system to its final destination at an organ or other target within the body. Aside from pharmaceutical applications, there is a need for analyzing bio-transport dynamics for diagnostic purposes, such as, when assigning a quantitative measure to the degree of atherosclerosis present in an individual's specific circulatory system.
Despite the desire to analyze bio-transport dynamics of mass transport systems within organisms, the dynamic nature of these systems makes them inherently difficult to study. Conventional approaches of studying bio-transport dynamics of the circulatory system for example involve obtaining clinical measurements or images of the circulatory system in humans and animals. For example, blood pressure cuffs and direct pressure probes are used to measure flow rates and pressures, and ultrasound and angiography are used to image vessels of the circulatory system. These measurements and images are compared against norms to attempt to qualify an organism's status and to help locate anomalies. Some of these tools are non-invasive but imprecise, such as sphygmomanometer, while others are precise but invasive, and potentially life threatening, such as cardiac catheterization.
Animal testing is another approach for obtaining bio-transport dynamic data that traditionally has allowed for more invasive measurements. Animal testing, however, is under scrutiny. Political and social pressure against animal testing has become very strong and is expected to increase. For example, scientists now must seek approval from the FDA for every primate subjected to experimentation and must account for every rat used. Animal testing is being framed today in a broader ethical context, and is likely to become even more circumscribed in the future.
Given the limitations presented by in-vivo testing, a theoretical approach in analyzing bio-transport dynamics is attractive. There are a number of practical difficulties, however, associated with a pure theoretical analysis of bio-transport dynamics that are not normally encountered outside living organisms. Sir James Lighthill [Lighthill M. J. Mathematical Biofluiddynamics” SIAM Regional Conference Series in Applied Math. 1975] lists four broad categories:
1. Unusual vessel distensability and resultant attenuation of wave propagation;
2. Great range of Reynolds numbers >5000 to <100 with small capillaries <10 microns;
3. Atypical fluid properties; and
4. Branching in lungs and circulatory system [20-30 forkings leading to >100 m branches].
To this list should be added the historic difficulty of obtaining clinical experimental data as mentioned above to compare with theory.
Piecemeal solutions that arise from considering only part of a problem-, or a radical simplification of the problem to obtain an assumption-restricted solution, while useful within the stipulated range of applicability, do not meet current and future clinical/research needs for scope, detail, accuracy and architecture. For example, in Guyton, et. al. “Computer Analysis of Total Circulatory Function and of Cardiac Output Regulation”, Chap. 17, Graphical, Algebraic and Computer Analyses 1973, a mathematical representation of the circulatory system is provided based on the system as a whole. Although such a model provides useful information on the circulatory system in gross terms, no detailed information with regard to spatial dependence of the system is available. In other words, this model can only provide data on bulk values for variables in the circulatory system and not for different components of the system where data tend to vary as suggested by Lighthill.
Therefore, a need exists for an approach that will enable researchers and physicians to experiment and practice with a bio-transport system without the attendant time constraints, risks and difficulties of dealing with a real bio-transport system in a living organism. The present invention fulfills this need among others.
SUMMARY OF INVENTION
The present invention provides an approach for analyzing bio-transport dynamics that overcomes the above-identified problems by simulating, in silico, a bio-transport system of an organism using a configurable simulation model. The configurable simulation model provides a generic framework that is readily customizable to simulate one or more bio-transport dynamics aspects of a user-defined bio-transport system as a function of both time and position within the system. More specifically, the present invention applies finite-element techniques along with first principles and empirical relationships to a bio-transport system to construct mathematical representations of one or more bio-transport dynamics in and around the bio-transport system based on user-characterized elements representing the bio-transport system. By using a finite-element approach, the bio-transport system can be compartmentalized to manage its intricacies and provide sophisticated bio-transport dynamic data not only as a function of time, but also as a function of the spatial position locating each element defined.
By combining a configurable finite element approach with modern techniques in computer programming and current computer architecture, the present invention creates a simulation model that affords the flexibility and scope needed to address many of the complexities outlined by Lighthill by offering one or more of the following functional capabilities:
(1) Configurable to provide detailed solutions as a function time and at least one space dimension (e.g. axial position along the blood vessels);
(2) Configurable to account for both nonlinear effects (e.g. vessel elasticity and/or conditions of state dependency) and non-Newtonian fluid behavior;
(3) Configurable to represent multi-level branching;
(4) Provides a pl

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