Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Ellis, Christopher G

2nd Supervisor

Goldman, Daniel

Abstract

The purpose of this thesis was to evaluate the physiology of red blood cell (RBC) distribution in skeletal muscle capillary networks. Because this is the terminal site of oxygen exchange in the microcirculation, characterization of this fundamental process informs an understanding of how microvascular blood flow regulation matches oxygen supply with local tissue demand. Prior studies in this field have focused on small groups of capillaries, and have not linked capillary network structure with functional measurements, nor evaluated the temporal complexity of RBC distribution over physiologically-relevant scales. It is also unclear how the functional units called capillary modules – comprised of parallel capillaries from arteriole to venule – relate together within large capillary networks. In this thesis, we employed multiple methodologies to achieve this goal with preclinical animal models, theoretical simulations, and translational studies in human patients. First, we used intravital videomicroscopy of resting extensor digitorum longus muscle in rats and discovered that skeletal muscle capillary networks are organized into columns of interconnected capillary modules spanning thousands of microns – a structure we called the Capillary Fascicle. We showed that capillary-RBC hemodynamics are heterogeneous within a module and between modules. Next, we evaluated capillary module hemodynamics and demonstrated that RBC flow is independent of module resistance, providing evidence for regulation of driving pressure at the level of the capillary module, that requires pre- and post-capillary mechanisms of control. Using a dual-phase mathematical model of blood flow within artificial capillary module geometries, we showed that RBC flow heterogeneity is an intrinsic property of capillary module structure, and that variations to inflow hematocrit and pressure impact RBC distribution as a consequence of the rheological properties of microvascular blood flow. Finally, we used high-resolution near-infrared spectroscopy to monitor the temporal variability of hemoglobin content in skeletal muscle of patients in the intensive care unit (ICU). We showed that RBC perfusion characteristics are not consistent between patients, and that ICU interventions directly impact microvascular RBC distribution. Together, these studies support a theory of capillary networks as active participants in microvascular blood flow regulation, with structural features of capillary networks contributing to functional characteristics of RBC distribution.

Summary for Lay Audience

Capillaries are the smallest blood vessels in the microcirculation, and red blood cells (RBCs) contain hemoglobin that carries oxygen throughout the body. Oxygen is fundamentally exchanged at the level of the capillary network, making the study of RBC distribution in capillary networks very important for understanding how the microcirculation regulates oxygen delivery. Prior studies of capillary biology has focused on small groups of capillaries (called capillary modules) and have not linked capillary network structure with function, nor described how capillary modules relate within large capillary networks. The purpose of this thesis was to evaluate the physiology of RBC distribution in skeletal muscle capillary networks. We employed a variety of techniques ranging from animal models, to theoretical simulations, and clinical studies with human patients. First, we used microscopy in living rodents to examine RBC flow in resting skeletal muscle. We discovered that capillary networks are organized into columns of interconnected capillary modules– a structure we called the Capillary Fascicle. We also showed that blood flow control is actively adjusted in capillary modules through changes to perfusion pressure. We used mathematical simulations to understand how the structure of the capillary modules and the properties of blood flow in the microcirculation affect RBC distribution. Finally, we used near-infrared spectroscopy (a non-invasive monitoring technology that uses light) to investigate the physiology of RBC distribution in patients in the intensive care unit (ICU). We showed that the patterns of RBC flow in the microcirculation are not consistent between patients, and are impacted by ICU interventions including medications and the ventilator. Together, these results provide a novel and comprehensive description of RBC distribution in skeletal muscle capillary networks, and suggest that capillary networks participate in blood flow regulation and oxygen delivery.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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