“…The present understanding of the mature human microcirculation is well established; however, this knowledge is primarily founded on studies involving arteriovenous capillary beds whose primary function is tissue perfusion [15,21]. Unfortunately, much of this valuable body of extensive literature and general conclusions might not be valid for the embryonic great vessels, even though the embryonic great vessel dimensions are still micro-scale.…”
In the developing cardiovascular system, hemodynamic vascular loading is critical for angiogenesis and cardiovascular adaptation. Normal zebrafish embryos with transgenically-labeled endothelial and red blood cells provide an excellent in vivo model for studying the fluid-flow induced vascular loading. To characterize the developmental hemodynamics of early embryonic great-vessel microcirculation in the zebrafish embryo, two complementary studies (experimental and numerical) are presented. Quantitative comparison of the wall shear stress (WSS) at the first aortic arch (AA1) of wild-type zebrafish embryos during two consecutive developmental stages is presented, using time-resolved confocal micro-particle image velocimetry (µPIV). Analysis showed that there was significant WSS difference between 32 and 48 h post-fertilization (hpf) wild-type embryos, which correlates with normal arch morphogenesis. The vascular distensibility of the arch wall at systole and the acceleration/deceleration rates of time-lapse phase-averaged streamwise blood flow curves were also analyzed. To estimate the influence of a novel intermittent red-blood cell (RBC) loading on the endothelium, a numerical two-phase, volume of fluid (VOF) flow model was further developed with realistic in vivo conditions. These studies showed that near-wall effects and cell clustering increased WSS augmentation at a minimum of 15% when the distance of RBC from arch vessel wall was less than 3 µm or when RBC cell-to-cell distance was less than 3 µm. When compared to a smooth wall, the WSS augmentation increased by a factor of ∼1.4 due to the roughness of the wall created by the endothelial cell profile. These results quantitatively highlight the contribution of individual RBC flow patterns on endothelial WSS in great-vessel microcirculation and will benefit the quantitative understanding of mechanotransduction in embryonic great vessel biology, including arteriovenous malformations (AVM). C.-Y. Chen et al. / Embryonic great vessel microcirculation vascular biology. Endothelial cells (EC) act as mechanosensors and translate the WSS loading into biochemical signals, which further control the downstream intracellular responses and modulate the gene/protein expression pathway [9,12,17]. The effects of altered hemodynamics are well established in the literature: the exposure of human aortic endothelial cells to an oscillatory flow (mean time-averaged shear stress 0.10 Pa) leads to an increase in cell proliferation, in contrast to the unidirectional laminar flow condition (mean shear stress > 1 Pa) [5]. Likewise, WSS loading plays a major role in the etiology of a number of cardiovascular diseases [40], such as atherosclerotic lesion development [18] and congenital heart defects. Particularly, the progression of high-flow arteriovenous malformations (AVM), which are associated with the mutations in the actin receptor-like kinase 1 (Alk1) gene, result in autosomal dominant vascular disease and hereditary hemorrhagic telangiectasia type 2 (HHT2) [3]. Recent studies us...
“…The present understanding of the mature human microcirculation is well established; however, this knowledge is primarily founded on studies involving arteriovenous capillary beds whose primary function is tissue perfusion [15,21]. Unfortunately, much of this valuable body of extensive literature and general conclusions might not be valid for the embryonic great vessels, even though the embryonic great vessel dimensions are still micro-scale.…”
In the developing cardiovascular system, hemodynamic vascular loading is critical for angiogenesis and cardiovascular adaptation. Normal zebrafish embryos with transgenically-labeled endothelial and red blood cells provide an excellent in vivo model for studying the fluid-flow induced vascular loading. To characterize the developmental hemodynamics of early embryonic great-vessel microcirculation in the zebrafish embryo, two complementary studies (experimental and numerical) are presented. Quantitative comparison of the wall shear stress (WSS) at the first aortic arch (AA1) of wild-type zebrafish embryos during two consecutive developmental stages is presented, using time-resolved confocal micro-particle image velocimetry (µPIV). Analysis showed that there was significant WSS difference between 32 and 48 h post-fertilization (hpf) wild-type embryos, which correlates with normal arch morphogenesis. The vascular distensibility of the arch wall at systole and the acceleration/deceleration rates of time-lapse phase-averaged streamwise blood flow curves were also analyzed. To estimate the influence of a novel intermittent red-blood cell (RBC) loading on the endothelium, a numerical two-phase, volume of fluid (VOF) flow model was further developed with realistic in vivo conditions. These studies showed that near-wall effects and cell clustering increased WSS augmentation at a minimum of 15% when the distance of RBC from arch vessel wall was less than 3 µm or when RBC cell-to-cell distance was less than 3 µm. When compared to a smooth wall, the WSS augmentation increased by a factor of ∼1.4 due to the roughness of the wall created by the endothelial cell profile. These results quantitatively highlight the contribution of individual RBC flow patterns on endothelial WSS in great-vessel microcirculation and will benefit the quantitative understanding of mechanotransduction in embryonic great vessel biology, including arteriovenous malformations (AVM). C.-Y. Chen et al. / Embryonic great vessel microcirculation vascular biology. Endothelial cells (EC) act as mechanosensors and translate the WSS loading into biochemical signals, which further control the downstream intracellular responses and modulate the gene/protein expression pathway [9,12,17]. The effects of altered hemodynamics are well established in the literature: the exposure of human aortic endothelial cells to an oscillatory flow (mean time-averaged shear stress 0.10 Pa) leads to an increase in cell proliferation, in contrast to the unidirectional laminar flow condition (mean shear stress > 1 Pa) [5]. Likewise, WSS loading plays a major role in the etiology of a number of cardiovascular diseases [40], such as atherosclerotic lesion development [18] and congenital heart defects. Particularly, the progression of high-flow arteriovenous malformations (AVM), which are associated with the mutations in the actin receptor-like kinase 1 (Alk1) gene, result in autosomal dominant vascular disease and hereditary hemorrhagic telangiectasia type 2 (HHT2) [3]. Recent studies us...
“…The blood vessels in tumors are characterized by unstructured growth with irregular shape and diameters where the blood flow can be static and might change direction with time [61]. The tumor blood vessels often grow in a coiling shape [62].…”
The cerebral microcirculation consists of a complex network of small blood vessels that support nerve cells with oxygen and nutrition. The blood flow and oxygen delivery in the microcirculatory blood vessels are regulated through mechanisms which may be influenced or impaired by disease or brain damage resulting from conditions such as brain tumors, traumatic brain injury or subarachnoid hemorrhage (SAH). Monitoring of parameters relating to the microvascular circulation is therefore needed in the clinical setting. Optical techniques such as diffuse reflectance spectroscopy (DRS) and laser Doppler flowmetry (LDF) are capable of estimating the oxygen saturation (SO2) and tracking the microvascular blood flow (perfusion) using a fiber optic probe. This thesis presents the work carried out to adapt DRS and LDF for monitoring cerebral microcirculation in the human brain.A method for real-time estimation of SO2 in brain tissue was developed based on the P3 approximation of diffuse light transport and quadratic polynomial fit to the measured DRS signal. A custom-made fiberoptic probe was constructed for measurements during tumor surgery and in neurointensive care. Software modules with specific user interface for LDF and DRS were programmed to process, record and present parameters such as perfusion, total backscattered light, heart rate, pulsatility index, blood fraction and SO2 from acquired signals.The systems were evaluated on skin, and experimentally by using optical phantoms with properties mimicking brain tissue. The oxygen pressure (pO2) in the phantoms was regulated to track spectroscopic changes coupled with the level of SO2. Clinical evaluation was performed during intraoperative measurements during tumor surgery (n = 10) and stereotactic deep brain stimulation implantations (n = 20). The LDF and DRS systems were also successfully assessed in the neurointensive care unit for a patient treated for SAH. The cerebral autoregulation was studied by relating the parameters from the optical systems to signals from the standard monitoring equipment in neurointensive care.In summary, the presented work takes DRS and LDF one step further toward clinical use for optical monitoring of cerebral microcirculation.
SammanfattningHjärnans mikrocirkulation består av ett komplext nätverk av små blodkärl som försörjer nervceller med syre och näring. Blodflödet och syretransporten i mikrocirkulationen regleras via olika mekanismer som kan påverkas eller försämras vid sjukdom eller hjärnskada som till exempel vid hjärntumörer, traumatisk hjärnskada eller subaraknoidalblödning (SAH). Diffus reflektansspektroskopi (DRS) och laserdopplerteknik (LDF) kan användas för att uppskatta syremättnaden (SO2) och övervaka det mikrocirkulatoriska blodflödet, också kallat perfusion, med hjälp av en fiberoptisk prob. Den här avhandlingen beskriver arbetet med att anpassa DRS och LDF för att övervaka den cerebrala mikrocirkulationen.En metod för realtidsuppskattning av SO2 i hjärnvävnad utvecklades baserat på P3 approximationen av diffus...
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