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Graham M. Fraser

BioMedical Sciences
PhD (University of Western Ontario)

Associate Professor of Cardiovascular Sciences

Health Sciences Centre Room 5337
Division of BioMedical Sciences
Faculty of Medicine
Memorial University of Newfoundland
300 Prince Philip Drive
St. John's, NL, CANADA
A1B 3V6
t: 709-864-4313
f:
lab: Lab: 709-864-3386

graham.fraser@med.mun.ca


RESEARCH PROGRAM
 
Mass Transport and the Microcirculation: The nutritive requirements of all body tissues are ultimately provided for by the dynamic distribution of blood flow between microvascular networks.  Under normal physiological conditions this distribution is modulated by metabolic demands of the surrounding tissue in response to changes both within microvessels and the surrounding local microenvironment.  My lab aims to quantify mass transport of oxygen, nutrients, and other biologically active molecules from the vascular compartment into living tissue.  Further, we are working to understand the integrated mechanisms behind blood flow regulation from the arteriolar level, through to capillary networks, and the constituent venous vasculature.   
 
Microvascular Blood Flow:  Fundamentally blood behaves as a non-Newtonian fluid with properties that change depending on hematocrit, shear, the composition of plasma, and the radius of blood vessels.  The unique properties of blood make quantifying blood blow based on classic hydrodynamic laws difficult, particularly as the size of blood vessels transition within the microcirculation.  On larger scales blood flow can be approximated as a homogenous fluid whereas in vessels smaller than 300 microns the two-phase nature of blood (cells and plasma) begins to have a much more significant impact on flow and flow distribution.  In order to properly quantify blood flow in vivo it is necessary to make direct measurements from the vessels of interest.
 
Research Methods: Our primary methodology involves imaging microvascular networks using in vivo video microscopy.  By using high-powered light microscopes we are able to measure vascular geometry, hemodynamics, and oxygen saturation within skeletal muscle microcirculation of living animals.  Using this approach we can quantify mass transport of molecules of interest within the tissue.  We use custom computer programs to process digital video and analyze the hemodynamics within capillaries.  Videos can also be processed to reconstruct three-dimensional network geometries providing a detailed description of capillary and microvascular geometry.  The vascular maps we generate are the most detailed representations of function capillary perfusion within skeletal muscle available.  In vivo measurements from individual vessels are indexed to the corresponding vessels and used as inputs for mathematical models. 
 
The oxygen transport models we use were developed by Dan Goldman at Western University and are based on well-defined physical laws of flow and diffusion.  This ongoing collaboration allows for the calculation of convective and diffusive mass transport of a given molecule of interest between the vasculature and tissue.  We have previously used these models to show how unsteady state in vivo data can be applied to steady state models of oxygen transport.  These models have also been used to show how decreased functional capillary density in sepsis will impact oxygen delivery to tissue.
 
In order to further leverage the utility of intravital microscopy and computational modeling we are currently developing microfluidic devices to precisely manipulate tissue microenvironment in order to isolate specific mechanisms of microvascular regulation.  This allows for the controlled introduction of drugs and probes to micron scale regions of tissue while directly observing the microcirculation using intravital video microscopy. 
 
Disease Models: Currently our research is focusing on inflammatory disease and its impact on blood flow in capillary networks and the resulting defects to oxygen delivery, and glucose/insulin sensitivity in skeletal muscle.  We use rodent models to quantitatively study vascular conditions in health, sepsis, type 2 diabetes, preeclampsia, and hypertension.  My work on preeclampsia is an ongoing collaboration with the group at the University of Alberta (Craig Steinback, Margie Davenport, Jude Morton, and Sandra Davidge) where we are working to quantify the functional changes in capillary blood flow in the RUPP model of preeclampsia.
 
Other Research: I am also interested in cognitive spatial reasoning particularly in how it pertains to learning in anatomy and physiology.  I have developed software to analyze spatial and temporal eye tracking data from spatial reasoning tasks in order to better understand how individuals process visual stimuli.  This work is in collaboration with and Tim Wilson at Western University, and Victoria Roach at Oakland University.
 

RECENT PUBLICATIONS
 
Roach VA, Fraser GM, Kryklywy J, Mitchell D, Wilson TD. Guiding Low Spatial Ability Individuals Through Visual Salience Cueing: The Dual Importance of Where and When to Look. Anatomical Sciences Education, 10(6):528-537, 2017
 
Arpino JM, Nong Z, Li F, Yin H, Ghonaim N, Milkovich S, Balint B, O’Neil C, Fraser GM, Goldman D, Ellis CG, Pickering JG. 4D Microvascular Analysis Reveals That Regenerative Angiogenesis in Ischemic Muscle Produces a Flawed Microcirculation.  Circulation Research, 2017 http://doi.org/10.1161/CIRCRESAHA.116.310535
 
Roach VA, Fraser GM, Kryklywy JH, Mitchell DGV, Wilson TD. Time Limits in Testing: An analysis of eye movements, and visual attention in spatial problem solving. Anatomical Sciences Education, 2017 http://doi.org/10.1002/ase.1695
 
Sové RJ, Goldman, D, Fraser GM. A Computational Model of the Effect of Capillary Density Variability on Oxygen Transport, Glucose Uptake, and Insulin Sensitivity in Prediabetes. Microcirculation, 2016 (Accepted)
 
Sové, RJ, Fraser GM, Goldman D, Ellis EG. Finite Element Model of Oxygen Transport for the Design of Geometrically Complex Microfluidic Devices Used in Biological Studies. PLoS One, 11(11), e0166289. http://doi.org/10.1371/journal.pone.0166289.t001, 2016
 
Roach VA, Fraser GM, Kryklywy J, Mitchell D, Wilson TD. Different perspectives: spatial ability influences where individuals look on a timed spatial test. Anatomical Science Education 10(3), 224–234. http://doi.org/10.1002/ase.1654, 2016
 
Roach VA, Fraser GM, Kryklywy JH, Mitchell DGV, Wilson TD. The eye of the beholder: Can patterns in eye movement reveal aptitudes for spatial reasoning? Anatomical Sciences Education, 9(4), 357–366. http://doi.org/10.1002/ase.1583, 2016
 
Fraser GM, Morton JS, Schmidt SM, Bourque SL, Davidge ST, Davenport MH, Steinback CD. Reduced uterine perfusion pressure (RUPP) decreases functional capillary density in skeletal muscle. AJP: Heart and Circulatory Physiology, ajpheart.00641, 2015
 
Fraser, GM, Sharpe MD, Goldman D, Ellis CG. Impact of Incremental Perfusion Loss on Oxygen Transport in a Capillary Network Mathematical Model. Microcirculation. doi:10.1111/micc.12202, 2015
 
Ghonaim NW, Fraser GM, Ellis CG, Yang J, Goldman D.  Modeling steady state SO2-dependent changes in capillary ATP concentration using novel O2 micro-delivery methods. Frontiers in physiology, 4, 260–260. 2013
 
Fraser GM, Goldman D, Ellis CG. Comparison of Generated Parallel Capillary Arrays to Three-Dimensional Reconstructed Capillary Networks in Modeling Oxygen Transport in Discrete Microvascular Volumes. Microcirculation 10.1111/micc.12075, 2013
 
Fraser GM, Milkovich S, Goldman D, Ellis CG. Mapping 3-D functional capillary geometry in rat skeletal muscle in vivo. Am J Physiol Heart Circ Physiol 302: H654–H664, 2012
 
Fraser GM, Milkovich S, Goldman D, Ellis CG. Microvascular Flow Modeling using In Vivo Hemodynamic Measurements in Reconstructed 3D Capillary Networks. Microcirculation 19: 510–520, 2012
 
Goldman D, Fraser GM, Ellis CG, Sprague RS, Ellsworth ML, Stephenson AH. Toward a multiscale description of microvascular flow regulation: O2-dependent release of ATP from human erythrocytes and the distribution of ATP in capillary networks. Front Physiol vol. 3 pp. 246, 2012