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Microcirculation (The middle ground.) The 'scale' of the microcirculation Larger than cells and individual elements (e.g. Krogh tissue cylinder). Smaller than organs What it looks like … HUMAN ANATOMY, 3rd. ed., Martini et al., Fig. 22-4, p.567 Microcirculation Issues What is it (structure, mechanism)? What are its important functions? How does it arise, develop, adjust, and repair? What we think it does: Supports metabolism of tissues. Maintains 'appropriate' hydrostatic/oncotic pressure balance. Both of these are transport functions that are either, or both: Gravimetric – transport of substances necessary for material/energy functions Informatic – transport of materials that carry information. Transport Issues – Diffusive Movement Intravascular – unimportant at capillary level. Skalak R,, Bra°nemark P-I. 1969. Deformation of red blood cells in capillaries. Science 164:717–19. Copyright [1969] American Association for the Advancement of Science.) Skalak's early calculation of RBC shape in capillaries Vascular wall Principal discriminant of what passes. Differs from tissue to tissue (e.g. Bloodbrain barrier). Trans-cellular movement, movement at 'tight junctions'. Extravascular space Deterministic models in 'organized' tissues, e.g. Krogh cylinder applied to muscle. What is the functional extravascular space? Which capillaries are open and what is the rate of flow through them? And what to do in 'disorganized' structures? Transport Issues – Convective Movement Starling-Landis hypothesis. Overall balance between oncotic and hydrostatic pressure. Excess of hydrostatic over oncotic pressure at arteriolar end causes outflow. Excess of oncotic over hydrostatic pressure at venous end causes (return) inflow. Extra-capillary flow 'washes' tissue and augments diffusive transport. Starling-Landis components Starling-Landis "In action" Good discussion and slides: http://141.106.8.23/medphy/chout/Lectures/Lecture20&21.pdf Starling-Landis models: Models "work" but have not been clinically useful because their parameters are hard to determine for individual patients and pathologies: Capillary pressure and gradient Tissue pressure Tissue oncotic pressures How does the microcirculation develop? The microcirculation is a stochastic* structure that is difficult to parameterize. Some kind of abstracting model with distributions and defined parameters is always needed to describe its development. In some tissues the stochasticity is limited and deterministic models help. In others? * a process involving a randomly determined sequence of observations each of which is considered as a sample of one element from a probability distribution. Types of models (R. Thomas) What models permit observed behavior? What models impose observed behavior? What interactions and constraints are common to all models? What are the simplest modifications of an existing model to conform it to new facts? Stochastic aspects of the microcirculation Anatomy Spatio-temporal variability Regulation The WBC anomaly Consequences of stochasticity in anatomy and spatio-temporal behavior Flow Transport (convective and diffusive) Fractal Model of Anatomy Branching Models Effect of branching on flow (predicted) Measured regional flow distributions Flow distribution is fractal? How does this tissue develop? ab initio? in response to activity and development of surrounding tissue? [W. Schreiner] in response to injury? Will Genomic Approaches Help? Classical physiology proceeds by induction: conclusions, though supported by the premises, do not necessary follow from them. Genomics-driven physiology proceeds (tries to proceed) by deduction: conclusions follow necessarily from the premises presented so that the conclusions cannot be false if the premises are true. What could happen when the microcirculation becomes disturbed in different places? Happy Easter!