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There is only one known portal system in the mammalian brain - that of the pituitary gland, first identified in 1933 by Popa and Fielding. Here we describe a second portal pathway in the mouse linking the capillary vessels of the brain’s clock suprachiasmatic nucleus (SCN) to those of the organum vasculosum of the lamina terminalis (OVLT), a circumventricular organ. The localized blood vessels of portal pathways enable small amounts of important secretions to reach their specialized targets in high concentrations without dilution in the general circulatory system. These brain clock portal vessels point to an entirely new route and targets for secreted SCN signals, and potentially restructures our understanding of brain communication pathways., The first known portal system in the mammalian brain was identified in 1933. Here the authors describe a new portal system between the capillary beds of the Suprachiasmatic Nucleus master clock and a circumventricular organ, enabling humoral signals to reach targets without dilution in the systemic circulation.

Human organoids, self-organized and differentiated from homogenous pluripotent stem cells (PSC), replicate the key structural and functional characteristics of their in vivo counterparts. Despite the rapid advancement of organoid technology and its diverse applications, major limitations in achieving truly in vivo like functionality have been the lack of matured structural organization and constraints on tissue size, both of which are direct consequences of lacking a functional vasculature. In the absence of perfusable vessels, a core region within organoids quickly becomes necrotic during development due to increased metabolic demands that cannot be met by diffusion alone. Thus, incorporating functional vasculature in organoid models is indispensable for their growth in excess of several hundred microns and maturaturation beyond the embryonic and fetal phase. Here, we review recent advancements in vascularizing organoids and engineering in vitro capillary beds, and further explore strategies to integrate them on a microfluidic based platform, aiming for establishing perfused vasculature throughout organoids in vitro.

During metastasis, tumour cells navigating the vascular circulatory system—circulating tumour cells (CTCs)—encounter capillary beds, where they start the process of extravasation. Biomechanical constriction forces exerted by the microcirculation compromise the survival of tumour cells within capillaries, but a proportion of CTCs manage to successfully extravasate and colonise distant sites. Despite the profound importance of this step in the progression of metastatic cancers, the factors about this deadly minority of cells remain elusive. Growing evidence suggests that mechanical forces exerted by the capillaries might induce adaptive mechanisms in CTCs, enhancing their survival and metastatic potency. Advances in microfluidics have enabled a better understanding of the cell-survival capabilities adopted in capillary-mimicking constrictions. In this review, we will highlight adaptations developed by CTCs to endure mechanical constraints in the microvasculature and outline how these mechanical forces might trigger dynamic changes towards a more invasive phenotype. A better understanding of the dynamic mechanisms adopted by CTCs within the microcirculation that ultimately lead to metastasis could open up novel therapeutic avenues.

Erythrocytes have a well-defined role in the gaseous exchange of oxygen and carbon dioxide in the mammalian body. The erythrocytes can contain more than half of the free amino acids present in whole blood. Based on measures showing that venous erythrocyte levels of amino acids are much less than arterial erythrocyte levels, it has previously been proposed that erythrocytes also play a role in the delivery of amino acids to tissues in the body. This role has been dismissed because it has been assumed that to act as an amino acid transport vehicle, the erythrocytes should release their entire amino acid content in the capillary beds at the target tissues with kinetic studies showing that this would take too long to achieve. This investigation set out to investigate whether the equine erythrocytes could rapidly take up and release smaller packages of amino acids when exposed to high or low external concentrations of amino acids, because it seemed very unlikely that cells would be able to release all of their amino acids without serious impacts on osmotic balance. Freshly prepared erythrocytes were placed in alternating solutions of high and low amino acid concentrations in PBS to assess the capacities of these cells to rapidly take up and release amino acids depending on the nature of the external environment. It was found that amino acids were rapidly taken up and released in small quantities in each cycle representing 15% of their total load in equine erythrocytes and 16% in human erythrocytes. The capacity for rapid uptake/release of amino acids by equine and human erythrocytes provided evidence to support the theory that mammalian erythrocytes have a significant role in transport of amino acids from the liver to tissues, muscles and organs. Electronic supplementary material The online version of this article (10.1007/s00726-020-02845-0) contains supplementary material, which is available to authorized users.

Arteriovenous malformation (AVM) results from errors in vascular development during embryogenesis; absent capillary beds lead to shunting directly from the arterial to venous circulation. Although it is common in the head and neck region, AVMs located in the parotid gland are quite rare. Here, we report two cases of arteriovenous malformation of the parotid gland that presented to our out-patient setup with swelling in the parotid region and were diagnosed as arteriovenous malformation on histopathological study after surgical resection.

Recent studies suggested that cerebrovascular micro-occlusions, i.e. microstokes, could lead to ischemic tissue infarctions and cognitive deficits. Due to their small size, identifying measurable biomarkers of these microvascular lesions remains a major challenge. This work aims to simulate potential MRI signatures combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). Driving our hypothesis are recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially-oriented, and optical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n = 5) before and after inducing targeted photothrombosis, were analyzed. Computational vascular graphs combined with a 3D Monte-Carlo simulator were used to characterize the magnetic resonance (MR) response, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. We quantified the minimal intravoxel signal loss ratio when applying multiple gradient directions, at varying sequence parameters with and without ASL. With ASL, our results demonstrate a significant difference (p < 0.05) between the signal-ratios computed at baseline and 3 weeks after photothrombosis. The statistical power further increased (p < 0.005) using angiograms measured at week 4. Without ASL, no reliable signal change was found. We found that higher ratios, and accordingly improved significance, were achieved at lower magnetic field strengths (e.g., B0 = 3T) and shorter echo time TE (< 16 ms). Our simulations suggest that microstrokes might be characterized through ASL-DWI sequence, providing necessary insights for posterior experimental validations, and ultimately, future translational trials.

Although our current knowledge of the pathophysiology of COVID-19 is still fragmentary, the information so far accrued on the tropism and life cycle of its etiological agent SARS-CoV-2, together with the emerging clinical data, suffice to indicate that the severe acute pulmonary syndrome is the main, but not the only manifestation of COVID-19. Necropsy studies are increasingly revealing underlying endothelial vasculopathies in the form of micro-haemorrhages and micro-thrombi. Intertwined with defective antiviral responses, dysregulated coagulation mechanisms, abnormal hyper-inflammatory reactions and responses, COVID-19 is disclosing a wide pathophysiological palette. An additional property in categorising the disease is the combination of tissue (e.g. neuro- and vasculo-tropism) with organ tropism, whereby the virus preferentially attacks certain organs with highly developed capillary beds, such as the lungs gastrointestinal tract, kidney and brain. These multiple clinical presentations confirm that the acute respiratory syndrome as described initially is increasingly unfolding as a more complex nosological entity, a multiorgan syndrome of systemic breadth. The neurological manifestations of COVID-19, the focus of this review, reflect this manifold nature of the disease. Fil: Barrantes, Francisco Jose. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina

Red color is pervasive in local and systemic skin conditions. It is a color that often reflects variations of dermal blood flow and extends beyond the rubor and calor of inflammation. The pathophysiology of red skin involves remote and local chemical mediators that dilate arteriolar smooth muscle and increase blood flow to superficial vessels and capillary beds. Incident light hits hemoglobin, which preferentially absorbs light of shorter wavelengths, such as blue, and reflects warmer colors. Due to its pervasiveness and consistency, red color is a useful descriptive factor in helping narrow a differential diagnosis. Red skin disorders include a variety of conditions involving endocrine mediators, cardiovascular responses, and the disruption of the skin barrier. An understanding of the blood's role in these disorders equips clinicians to generate differential diagnoses through the lens of pathophysiology. Dermatologists can improve management by considering red skin as part of systemic disease rather than as an isolated incident.

The behaviour of circulating tumour cells in the microcirculation remains poorly understood. Growing evidence suggests that biomechanical adaptations and interactions with blood components, i.e. immune cells and platelets within capillary beds, may add more complexity to CTCs journey towards metastasis. Revisiting how these mediators impact the ability of circulating tumour cells to survive and metastasise, will be vital to understand the role of microcirculation and advance our knowledge on metastasis.

Arteriovenous malformations (AVMs) are defined as an abnormal collection of dysplastic blood vessels wherein the arterial blood flows directly into the draining veins without any intervening neural parenchyma or capillary beds. These are usually congenital lesions with a lifelong risk of hemorrhage of about 2–4% per year. These lesions tend to enlarge with age and may progress from low-flow AVMs at birth to medium- or high-flow and high-pressure AVMs in adulthood. Grossly, it appears as a “tangle” of vessels with a well-circumscribed center called nidus. Intracranial AVMs are classified as parenchymal and dural depending, upon the location of AVMs. Intracranial AVMs in pediatric patients might present with congestive heart failure (CHF) in neonates, seizures or hemorrhage, and varying degrees of ischemic symptoms. Anesthetic management in this group of patients is quite challenging as surgical interventions are associated with massive blood loss. The pediatric population has a low cardiopulmonary reserve and poorly tolerates such losses. This chapter describes the anesthetic management of patients with intracranial AVMs posted for various interventions.

Recent studies suggested that cerebrovascular micro-occlusions, i.e. microstokes, could lead to ischemic tissue infarctions and cognitive deficits. Due to their small size, identifying measurable biomarkers of these microvascular lesions remains a major challenge. This work aims to simulate potential MRI signatures combining arterial spin labeling (ASL) and multi-directional diffusion-weighted imaging (DWI). Driving our hypothesis are recent observations demonstrating a radial reorientation of microvasculature around the micro-infarction locus during recovery in mice. Synthetic capillary beds, randomly- and radially-oriented, and optical coherence tomography (OCT) angiograms, acquired in the barrel cortex of mice (n=5) before and after inducing targeted photothrombosis, were analyzed. Computational vascular graphs combined with a 3D Monte-Carlo simulator were used to characterize the magnetic resonance (MR) response, encompassing the effects of magnetic field perturbations caused by deoxyhemoglobin, and the advection and diffusion of the nuclear spins. We quantified the minimal intravoxel signal loss ratio when applying multiple gradient directions, at varying sequence parameters with and without ASL. With ASL, our results demonstrate a significant difference (p

Abnormal vasculature is a key feature of hereditary hemorrhagic telangiectasia (HHT) and can also present in the nail fold capillary beds. However, the exact prevalence and the clinical diagnostic value in HHT are still largely unknown. The nail fold can be easily and noninvasively inspected with a capillary microscope. We therefore retrospectively assessed the prevalence and diagnostic value of abnormal nail fold capillaries in all patients who were screened between January 2000 and July 2017 for the presence of HHT and underwent capillary microscopy in St Antonius Hospital, The Netherlands. Capillary microscopy results and clinical characteristics were extracted from medical files and the prevalence of abnormal nail fold capillaries was calculated and the diagnostic value of the Curaçao criteria with and without capillary microscopy results was assessed. Of the 1761 individuals screened, 923 (52%) were diagnosed with a clinical and/or genetic HHT diagnosis. In these patients, capillary microscopy was normal in 23% ( n = 218), enlarged loops were seen in 11% ( n = 99), and giant loops in 66% ( n = 606). The sensitivity and specificity of the Curaçao criteria for the diagnosis of HHT without capillary microscopy results were 96% and 90%, respectively. The addition of the presence of giant loops to the Curaçao criteria led to a small increase in sensitivity to 97% without affecting the specificity. In conclusion, the prevalence of nail fold abnormalities in patients with HHT is high. Capillary microscopy can be a useful, easy, and noninvasive diagnostic tool in HHT.

BACKGROUND AND OBJECTIVE: To describe peripheral retinal vascular abnormalities in the contralateral eyes of patients with unilateral persistent fetal vasculature (PFV). PATIENTS AND METHODS: Retrospective medical record review of fluorescein angiography (FA) findings of patients with unilateral PFV. Width of the temporal peripheral avascular retina in contralateral eyes was measured in disc diameters (DD). Vascular abnormalities were described. RESULTS: In 45 included patients, mean width of temporal peripheral avascular areas in contralateral eyes was 1.87 ± 0.71 DD. Forty-three patients (95.6%) had temporal peripheral avascular areas of 1 DD or greater in contralateral eyes, with 16 having temporal peripheral avascular areas of 2 DD or greater. Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with unilateral PFV. CONCLUSION: PFV patients should undergo careful evaluations of both eyes, preferably with FA, to identify vascular changes that are not visible clinically. [ Ophthalmic Surg Lasers Imaging Retina. 2020;51:506–511.]

The intervertebral disc is part of an anatomic unit that consists of an inner gelatinous nucleus pulposus (NP), an outer annulus fibrosus (AF), and the cartilaginous end plates with their associated capillary beds both cranially and caudally. The central NP is a site of collagen secretion and contains numerous proteoglycans (PG), which facilitate water retention, creating hydrostatic pressure to resist axial compression of the spine. The NP is primarily composed of type II collagen. In contrast, the AF functions to maintain the NP within the center of the disc with low amount of PG and is composed of primarily of type I collagen [1, 2].

The oxygenation state of the blood is a key determinate of physiological state of patient. Several techniques are available for determining the average oxygenation state of the blood in a tissue. However, these techniques cannot resolve relative local volume fractions of reduced/- oxyhemoglobin concentration within the bulk of a highly scattering tissue. Prompt detection of these parameters are important for the clinical diagnosis and effective treatment planning in ICU patients. Therefore, aim of this study is to detect local volume fractions of reduced/- oxyhemoglobin concentrations. The diffuse reflectance spectroscopy can non-invasively measure the various pathophysiological functions by measuring the absorption from blood. Thus, in this study relative local volume fractions of reduced hemoglobin and oxyhemoglobin concentration are measured from the capillary beds close to the upper layer of the lips through the diffuse reflectance spectra.

The cardiovascular system allows the nutrients essential to life to reach all the cells in our body (it is estimated there are more than 37 thousand billion cells!). The fundamental engine of the system is our heart, an organ of extraordinary complexity and efficiency. The heart pumps the blood into the aorta and from there, through successive ramifications, in the bigger and smaller arteries, then in the arterioles and finally in the capillaries. And it is exactly inside the capillary beds that the nutrients are delivered to the cells and the toxic substances – the residues of the cellular reactions – are removed. The waste CO2, for instance, is transported back through the venous system and is eventually released into the pulmonary alveoli where the respiration expels it.

The capillary beds make up a dense network. Capillary diameter is typically the same or even smaller than the size of unstressed erythrocytes. In addition to its role in determining vascular resistance to flow (approximatively 15% of the total resistance), the capillary network is the region of the vascular system that specializes in the transport of substances between the blood and tissues. The distance of diffusion of O2 in tissues implies that the intercapillary distance cannot be greater than 100 μm in any living tissue.

Objective— Vascular endothelial dysfunction is a key component of several major human diseases, but the molecular basis of this complex disorder has been difficult to determine in vivo. Previous attempts to identify key mediators of vascular endothelial dysfunction in experimental models have been limited by the lack of suitable methods for system-wide analyses of vascular bed biology. Here, we aimed to develop a novel method for investigating vascular endothelial dysfunction pathogenesis that enables system-wide analyses of molecular interactions between endothelial glycocalyx, endothelial cells, and smooth muscle cells in murine. Approach and Results— We developed a new technique using whole-body differential perfusion with increasing concentrations of detergent buffer to selectively solubilize distinct layers of vascular bed tissue in rodents. When combined with proteomics techniques, our novel approach of differential systemic decellularization in vivo enabled quantitative profiling of vascular beds throughout the body. Initial perfusion with phosphate buffer was used to obtain the endothelial glycocalyx, followed by subsequent extraction of endothelial cell components, and finally by smooth muscle cell constituents with increasing concentrations of detergent. Differential systemic decellularization in vivo has also been successfully applied to characterize molecular events in the vascular bed pathology of lipopolysaccharide-challenged mice. Conclusions— Together, these data indicate that differential systemic decellularization in vivo permits system-wide molecular characterization of vascular bed proteomes in rodent models and can be used to advance our current understanding of vascular endothelial dysfunction pathogenesis and progression in a wide range of disease settings.

Quantitative analyses of three-dimensional (3D) micro structures in human lungs can provide detailed information to elucidate pulmonary disease progress. The pulmonary blood vessels, have so far been studied morphologically and functionally from various aspects. However, there are problems with low spatial resolution or limited field of view. In this study, we propose an extraction method for pulmonary blood vessels like to capillary beds. 3D microstructure of vascular systems is visualized by analyzing of high-resolution dual-energy CT images using large-field high-resolution x-ray micro-CT.

Background: Cerebral cavernous malformation is a genetic neurovascular disorder causing aberrant angiogenesis and lesion development within capillary beds. Lesions exhibit impaired endothelial barrier function, causing blood-brain barrier leakage and hemorrhage. Quantitative MRI biomarkers (dynamic contrast-enhanced quantitative permeability (DCEQP) and quantitative susceptibility mapping (QSM)) have been shown to correlate with CCM disease progression as measures of barrier leakage and hemorrhagic iron deposition, and there is interest in utilizing these biomarkers as endpoints in clinical trials. However, their consistencies across multiple platforms and institutions has not yet been rigorously verified. Materials and Methods: Instruments used were a 3T Philips Ingenia at University of Chicago and a 3T Siemens Prisma at Northwestern University. QSM was assessed by five balloons filled with varying concentrations of MultiHance, corresponding to magnetic susceptibilities of 0, 0.1, 0.2, 0.4, and 0.8, surrounded by an agarose gel. Permeability was assessed by the injection of a bolus of MultiHance through a coiled hose inside a water-filled shell, and the consistency of the peak-to-peak ratio of the curves at the input and output was measured. Each biomarker was assessed by accuracy (to expected values, Pearson correlation), precision (between repeated measurements, paired t-test), and reproducibility (between instruments, paired t-test). Results: QSM measured with an accuracy of r 2 = 0.997 on the Philips Achieva and r 2 = 0.999 on the Siemens Prisma. Each scanner had adequate precision between measurements, showing no significant difference by a paired t-test (p = 0.66 Achieva, p = 0.45 Prisma), and the reproducibility between scanners also showed no significant difference (p = 0.89). The peak-to-peak ratio on DCEQP scans was accurate (r 2 = 0.998), precise between measurements (p = 0.54), and repeatable between instruments (p = 0.49). Conclusion: Quantitative imaging biomarkers DCEQP and QSM are accurate, consistent across multiple measurements, and between platforms and will be useful for future clinical trials in CCM.

Arteriovenous malformations (AVMs) are characterized by direct arterial-to-venous shunting, usually through a tangle of vessels called a nidus, without the normal intervening capillary beds, and are thus considered to be high-pressure, high-flow malformations. Clinical sequelae include headaches, seizures, and progressive neurological deficits from vascular steal and rupture. Treatment options include observant with medical management of symptoms, radiosurgery, endovascular embolization, and surgical resection. Often a multimodal treatment is employed. In this chapter we focus on the indications and techniques for surgical resection of AVMs.

Arteriovenous malformations (AVMs) are abnormal communications between arteries and veins that lack intervening capillary beds. They have been described in almost every organ in the body, emerging sporadically or as part of well-described syndromes. Hereditary hemorrhagic telangiectasia (HHT) is a rare, progressive, and lifelong disease characterized by AVMs and recurrent hemorrhaging. In the last 2 decades, significant advances have been made in understanding the pathogenesis of this condition. The accumulation of knowledge has led to a natural evolution of therapy, from open surgery to endovascular procedures, and now to a role for medications in certain AVMs. Here, we review a case of HHT and describe the most up-to-date clinical practice, including diagnosis of HHT, subtypes of HHT, and medical therapy.

Purpose To determine if AVM angioarchitecture characteristics can be predictive and direct specific curative endovascular procedures accurately and consistently to treat high-flow malformations. Materials and methods Angiographic analysis of high-flow vascular malformations determined 4 major angioarchitectures. Type I: Direct arterial/arteriolar to vein/venule connection; e.g., as commonly seen in pulmonary AVF, congenital renal AVF, etc. Type II: Arterial/arteriolar connections to a ‘nidus’ that then have several out-flow veins with no intervening capillary beds in any of the vascular interconnections. Type IIIa: Arterial/arteriolar connections to an aneurysmal vein (‘nidus’ is the vein wall) that drains into a dominant out-flow vein with no intervening capillary bed in these connections. Type IIIb: Same angioarchitecture as Type IIIa, except that there are more than one (several) out-flow veins. Type IV: ‘Infiltrative’ form of AVM whereby innumerable micro-arteriolar branches fistulize through a tissue (e.g., ear) totally infiltrating it, shunting into multiple out-flow veins. Capillary beds also exist in the tissue and are mixed with the innumerable AVFs. Without the capillaries the tissue could not be viable, therefore must be present. Results Type I: Can be effectively treated with mechanical devices; e.g., coils, Amplatzer Plugs, etc. Type II: Can be effectively treated with ethanol embolization. Type IIIa Can be effectively treated by transcatheter ethanol, retrograde vein catheter access or direct puncture access of the aneurysmal vein and treatment with ethanol and coils, or even by coils alone. Type IIIb Can be effectively treated as above, but can be more challenging by the vein route as more veins (not a single out-flow vein) require closure. Type IV: Can be effectively treated by transcatheter or direct puncture of the innumerable microfistulous AVFs by embolization with 50%–50% ethanol non-ionic contrast mixture. Conclusion This never before reported classification system has a direct impact on determining the curative endovascular and direct puncture embolization procedures and also determines the embolic agents that will successfully treat complex AVMS in the body. Disclosures W. Yakes: None.

Objective The purpose of this paper was to review the literature regarding the mechanisms leading to degeneration in intervertebral disks and to discuss contributing mechanical and biological factors. Methods The inclusion criteria for the literature review were research studies conducted in the last 3 decades with free full-text available in English. Review articles and articles pertaining to temporomandibular joints and joints of the body other than the intervertebral disk were excluded. The following databases were searched: PubMed, EBSCOhost, and Google Scholar through September 9, 2016. Results A total of 57 articles were used in this review. Intervertebral disk cells require glucose for sustainability and oxygen to synthesize matrix components. Nutrients enter the disk via 2 vascular supply routes: capillary beds of end plates and the peripheral annulus fibrosus. Solute size, shape and charge, compression, and metabolic demand all influence the efficiency of nutrient transport, and alterations of any of these factors may have effects on nutrient transport and, potentially, disk degeneration. Conclusions Progressive nutrient transport disruptions may actively contribute in advancing the phases of degenerative disk disease. Such disruptions include dysfunctional loading and spinal position, lack of motion, high frequency loading, disk injury, aging, smoking, an acidic environment, and a lack of nutrient bioavailability.

This chapter will survey our current knowledge on lymph formation from the extracellular fluid, lymphatic circulation, and overall lymph proteomic composition during physiological and pathological states. Generation of the lymphatic fluid depends on hydrostatic and osmotic pressure gradients operating in the capillary beds. Lymph movement toward the draining node hinges on the pumping activity of the lymphangions and the presence of unidirectional valves. The lymph proteomic composition is generated by a combination of ultrafiltrated plasma proteins with proteins and molecules generated from the metabolic and catabolic activities of each drained anatomical site. Importantly, lymph proteins and peptides contribute to the MHCII-presented peptidome displayed by nodal dendritic cells. Altogether, these analyses have brought new attention to the role of the lymphatic fluid in transporting the «immunological self» and have indicated how physiological and pathological conditions affect lymph composition.

Vascular Biology Small-diameter arteries link main arteries to capillary beds that feed tissues and organs. Persistent constriction of these arteries may generate high blood pressure (hypertension). Khavandi et al. (see also Hill and Braun) found that arterial constriction initiated the production

Therapeutic vascular embolization is a minimally invasive transcatheter procedure by which abnormal vasculature which is either congenital or a result of an acquired pathological process is obliterated, thereby resulting in clinical improvement. It has also been used for occlusion of normal vasculature to palliate neoplasms and ablate tissue. These normal or abnormal vessels either cause excessive bleeding or produce hemodynamic disturbances. This procedure has gained acceptance in terms of safety and efficacy with the advent of more advanced hardware like microcatheters, embolization materials and high resolution digital imaging. The rate of procedural complications is low with expanding operator expertise, making it the first line of treatment in several clinical situations reviewed in the following chapters.

In microvascular transport, where both blood and drug carriers are involved, plasma skimming has a key role on changing hematocrit level and drug carrier concentration in capillary beds after continuous vessel bifurcation in the microvasculature. While there have been numerous studies on modeling the plasma skimming of blood, previous works lacked in consideration of its interaction with drug carriers. In this paper, a generalized plasma skimming model is suggested to predict the redistributions of both the cells and drug carriers at each bifurcation. In order to examine its applicability, this new model was applied on a single bifurcation system to predict the redistribution of red blood cells and drug carriers. Furthermore, this model was tested at microvascular network level under different plasma skimming conditions for predicting the concentration of drug carriers. Based on these results, the applicability of this generalized plasma skimming model is fully discussed and future works along with the model's limitations are summarized.

Research into the effects of surgical ligation of the ductus arteriosus (DA) on regional tissue perfusion is limited. Near-infrared spectroscopy (NIRS) is a non-invasive technique for monitoring regional mixed arteriovenous saturations in capillary beds. Previous data suggest that DA closure may result in impaired cerebral perfusion1 because of alterations in pulmonary mechanics or cardiac function.2 These changes have been implicated in the aetiology of adverse neurodevelopmental outcome in neonates after DA ligation.3 In our neonatal unit, around 20 DA ligations are performed per year. Cerebral NIRS is routinely applied perioperatively using a non-adhesive positioning technique. …

The lumped constant is a proportionality factor for converting a tracer analogue's metabolic rate to that of its mother substance. In a uniform system, it is expressed as the ratio of the tracer analogue's extraction fraction (E⁎) to the extraction fraction of its mother substance (E). Here we show that, in capillary beds perfused by unidirectional blood flow, unequal concentration gradients of the tracer analogue and of the mother substance influence extraction fractions both locally and across the organ and that the direct proportionality of E⁎ and E must be replaced by ln(1−E⁎)/ln(1−E) to yield Λ, i.e. the lumped constant derived from first principles of bi-substrate enzyme and membrane kinetics. In other words, at a given capillary blood flow (F), the ratio of systemic clearances (FE⁎/FE), often used in compartmental kinetic analysis, must be replaced by the ratio of the intrinsic clearances, [−F ln(1−E⁎)]/[−F ln(1−E)]. The conclusion is supported by 2-[18F]fluoro-2-deoxy-d-galactose removal kinetics in pig liver in vivo from previous publications by the dependence of E⁎/E and the independence of Λ, on blood galactose concentration. Moreover, our corrections to the results of compartmental kinetics are quantified for comparing extraction fractions in different regions of interest (e.g. by positron emission tomography) and for calculating Λ using whole-organ E⁎ and E measured by arteriovenous concentration differences.

Electrospinning is a nonmechanical processing strategy that is used to fabricate tissue-engineering scaffolds composed of submicron diameter, banded fibrils of collagen. In biocompatibility tests these fibers are nonimmunogenic. Fiber diameter can be manipulated over a wide range by regulating the concentration of collagen present in the starting electrospinning solutions. Table 1 illustrates average fiber diameters and pore dimensions achieved under different conditions. Collagen Concentration Fiber Diameter Pore Area 40 mgs/ml TFE 113 ± 51 nm 184 ± 87.6 nm2 60 mgs/ml TFE 304 ± 120 nm 1,311 ± 384 nm2 80 mgs/ml TFE 761 ± 276 nm 4,913 ± 3978 nm2 100 mgs/ml TFE 745 ± 314 nm 5,039 ± 2947 nm2 120 mgs/ml TFE 1,534 ± 448 nm 19,154 ± 20809 nm2 We prepared four 1 cm2 full thickness dermal injuries on the dorsum of the guinea pig. Electrospun scaffolds composed of different fiber diameters were cut to fit the defects, sutured in place and then recovered at 7 and 14 days. Injuries treated with scaffolds composed of electrospun collagen fibers greater than 300 nm in diameter exhibited extensive tongue formation, dense dermal cell infiltration and functional capillary beds. Dermal regeneration was substantially complete by 14 days. Scaffolds prepared with individual fiber diameters of less than 300 nm were well epithelialized but, less densely "populated by dermal fibroblasts and capillaries. Fibrils of electrospun gelatin, a collagen isolate that is heat denatured prior to electrospinning, lack the banded appearance of electrospun collagen. Scaffolds of electrospun gelatin were less densely infiltrated than electrospun collagen at all fiber diameters and pore dimensions, and induced inflammation. We conclude that banded fibrils of electrospun collagen have unique biological activity. Funded in part NIH R01 EB003087. US & International Patents Issued and Pending.

Although heart-lung machines and cardiac assist devices have been used successfully for acute and chronic cardiac support for decades, controversies still remain concerning the benefits of pulsatile and non-pulsatile perfusion. The core of the debate is whether enough energy is generated by the artificial pulse to keep capillary beds open and cell metabolism stabilized during acute or chronic cardiac support. In other words, does artificial pulsatility exist in the microcirculation: small vessels of less than 100 μm in diameter? Many investigators have tried to use different tools and biomarkers to reflect directly or indirectly the state of the microcirculation when comparing the two different perfusion modes during acute and chronic cardiac support. However, the results are controversial. First, direct observation of the state of the microcirculation during acute and chronic cardiac support is limited; and reports concerning direct observation of the microcirculation with different perfusion modes in contemporary literature are rare. Secondly, different investigators have used their own criteria to define pulsatile flow. Therefore, it is necessary to develop more efficient methodologies, enabling direct observation of the microcirculation during acute and chronic cardiac support and also establish common criteria that will precisely quantify the pulsatile flow in terms of energy equivalent pressure (EEP) and surplus hemodynamic energy (SHE) levels. Using these critical parameters may explain how excess energy is created by pulsatile flow and maintains perfusion through the microcirculation by ensuring capillary patency. Perfusion (2007) 22, 115—119.

Continuous Lateral Rotation Therapy (CLRT) is a therapy used in ICUs for early mobilization of ventilated patients. CLRT is believed by some in health care to not be sufficient to allow for capillary re-perfusion, and may lead to tissue damage.To determine if there are differences in skin interface pressures, skin integrity, or perceived discomfort across three positioning scenarios.A Hill-Rom Total Care SpOrt(®) bed was equipped with a pressure mapping device. Ten healthy volunteers were placed in each positioning scenario for 30 minutes; interface pressures were recorded.CLRT alone demonstrated statistically lower interface pressures on ischial tuberosities (p0.05) as compared to the scenarios with static wedge. Higher pressures were noted on the heels in CLRT alone (p0.05). One subject noted pain with CLRT. No erythema or breakdown noted.This feasibility study supports the use of CLRT to decrease pressure on capillary beds and decrease patient discomfort.

Pulmonary arteriovenous malformations (AVMs) are caused by abnormal vascular communications between the pulmonary arteries and pulmonary veins, which lead to the blood bypassing the normal pulmonary capillary beds. Pulmonary AVMs result in right-to-left shunts, resulting in hypoxemia, cyanosis, and dyspnea. Clinical signs and symptoms vary depending on the size, number, and flow of the AVMs. Transcatheter embolization is the treatment of choice for pulmonary AVMs. However, this method can fail if the AVM is large or has multiple complex feeding arteries. Surgical resection is necessary in those kind of cases. Here, we report the case of a patient with a 6-cm pulmonary AVM with multiple feeding arteries that was successfully treated by repeated coil embolization without surgery.

Birds have evolved a high-performance cardiovascular system to meet the rigorous demands of running, flying, swimming, or diving in a variety of environments, some of them extreme. Sustained high levels of activity in these environments place severe demands on the cardiovascular system to provide adequate delivery of oxygen to working vascular beds and to provide efficient removal of metabolic products. Furthermore, birds are endothermic organisms and the cardiovascular system plays a major role in conserving or removing body heat. The descriptions of the component parts of the circulatory system in this chapter illustrate that these transport requirements are met in a variety of ways in birds inhabiting particular environmental niches. This chapter describes the morphological and functional aspects of the avian heart, circulatory hemodynamics, and the vascular tree. A common thread running through this discussion is that the component parts of the circulation must function in an integrated fashion to ensure tissue oxygen delivery matches tissue demands. This is accomplished through the integrative control of circulation by autoregulatory, humoral, and neural mechanisms. Since the last edition of this book, a significant number of studies have examined the development of cardiovascular control in avian embryos which has expanded our understanding of this system throughout ontogeny. Finally, this chapter examines how the cardiovascular system functions within a complex animal, interacting in complex environments.

ARTERIOVENOUS MALFORMATIONS ARE a heterogeneous group of intra-axial central nervous system vascular lesions consisting of tangles of abnormal arteriovenous connections without intervening capillary beds. The heterogeneity of arteriovenous malformations is described by the Spetzler-Martin grading scale, a scale that also forms the basis for clinical decision making. The microsurgical treatment of appropriately selected supratentorial arteriovenous malformations is based on the tenets of circumferential isolation and transection of arterial feeders, preservation of vessels en passant and surrounding functional neural tissue, and skeletonization and transection of venous drainage.

The construction of tissue-engineered devices for medical applications is now possible in vitro using cell culture and bioreactors. Although methods of incorporating them back into the host are available, current constructs depend purely on diffusion which limits their potential. The absence of a vascular network capable of distributing oxygen and other nutrients within the tissue-engineered device is a major limiting factor in creating vascularised artificial tissues. Though bio-hybrid prostheses such as vascular bypass grafts and skin substitutes have already been developed and are being used clinically, the absence of a capillary bed linking the two systems remains the missing link. In this review, the different approaches currently being or that have been applied to vascularise tissues are identified and discussed.

Accurate characterization of capillary geometry is of the utmost importance for physiological tissue studies such as oxygen transport. We show that 3D microscopy can be used to measure tissue capillary geometry both in normal and disease states. We imaged fluorescently labeled gut mucosa capillary beds of three control rats and three rats 4 hours after i.p. injection of 9 mg/kg endotoxin. We used serial optical sectioning microscopy coupled with deconvolution to reconstruct 3D capillary geometry. Theoretical point spread functions accounting for depth into the specimen resulted in better reconstructions than experimentally measured point spread functions. We next derived the distribution of the shortest distances to the nearest capillary from all extravascular tissue voxels. In normal rats the shortest-distance distributions were remarkably constant despite widely varying capillary geometry. Furthermore, the mean of the shortest-distance distributions increased significantly for endotoxemic rats (4.8 ± 0.4 μm) compared to controls (4.3 ± 0.3 μm, P < 0.05). Hence, serial sectioning microscopy provides an accurate venue for measuring physiologically relevant 3D capillary structure. Microsc. Res. Tech. 61:428–437, 2003. © 2003 Wiley-Liss, Inc.

That smooth muscles dilate and contract rhythmically has been known for a long time and the phenomenon has been studied for nearly as long. However, the causes and effects of smooth muscle oscillation (termed vasomotion) are far from clear. It is thought that vasomotion aids the delivery of oxygen to tissues surrounding capillary beds. On the other hand, unregulated vasomotion might participate in the development and maintenance of pathophysiological states. Nilsson and Aalkjaer review what is known about vasomotion and its consequences.

Cortical blood flow was probed via the motion of red blood cells (RBCs) in individual capillaries that lay as much as 600 μm below the pia matter of primary somatosensory cortex in rat. The flow was quite variable, with a speed of 0.8±0.5 mm/s (mean±S.D.) and a flux of 60±40 RBC/s, averaged over all capillaries and over time. The fluctuations in the flow were dominated by a spectral band near 0.1 Hz. This band coincides with the spectral band of fluctuations previously seen across whole capillary beds with optical [Neuroimage 4 (1996) 183] and f MRI [Mag. Reson. Med. 37 (1997) 511] imaging techniques. Time-locked increases in the flow of red blood cells (RBCs) within individual capillaries were observed in response to stimulation of multiple vibrissae at natural levels of deflection. The magnitude of the stimulus-evoked change in speed was, at most, equal to 20% of the basal speed. This change is comparable to the level of the fluctuations in speed seen in single capillaries. Thus, changes in flow evoked by natural stimuli are largely masked by basal fluctuations. In toto, the results of our study suggest that fluctuations at the level of the microvasculature limit the sensitivity of brain imaging techniques, at least at low frequencies.

We solved the Laplace equation for the radius of an arterial gas embolism (AGE), during and after breath-hold diving. We used a simple three-region diffusion model for the AGE, and applied our results to two types of breath-hold dives: single, very deep competitive-level dives and repetitive shallower breath-hold dives similar to those carried out by indigenous commercial pearl divers in the South Pacific. Because of the effect of surface tension, AGEs tend to dissolve in arterial blood when arteries remote from supersaturated tissue. However if, before fully dissolving, they reach the capillary beds that perfuse the brain and the inner ear, they may become inflated with inert gas that is transferred into them from these contiguous temporarily supersaturated tissues. By using simple kinetic models of cerebral and inner ear tissue, the nitrogen tissue partial pressures during and after the dive(s) were determined. These were used to theoretically calculate AGE growth and dissolution curves for AGEs lodged in capillaries of the brain and inner ear. From these curves it was found that both cerebral and inner ear decompression sickness are expected to occur occasionally in single competitive-level dives. It was also determined from these curves that for the commercial repetitive dives considered, the duration of the surface interval (the time interval separating individual repetitive dives from one another) was a key determinant, as to whether inner ear and/or cerebral decompression sickness arose. Our predictions both for single competitive-level and repetitive commercial breath-hold diving were consistent with what is known about the incidence of cerebral and inner ear decompression sickness in these forms of diving.

The feasibility of targeting nanosizegold drug carriersby using a ferromagnetic wire implanted in capillary beds is studied theoretically. An external uniform magnetic field is applied transversely to the wire to produce high gradient magnetic field which produce magnetic force acting on the carriers in the vicinity of wire surface. The study of gold drug carriers' motion in capillary beds under the influences of magnetic force and blood flow is simplified by neglecting the effect of capillaries' walls. Equations of motion of the carriers are formulated and are solved numerically to obtain carriers' trajectories. By analyzing carriers' trajectories, the feasibility of capturing gold drug carriers near wire surface can be examined and the capture efficacy can be estimated for various parameters suchas the strength of applied uniform magnetic field, the radius of gold drug carrier and the radius of the wire. The results show the feasibility of targeting gold drug carriers in capillary beds by using the implant. Information from this study are useful for developing techniques for magnetic targeting of gold drug which are now used for cancer and tumor therapies.

Research into mechanisms of haematogenous metastasis has largely become genetic in focus, attempting to understand the molecular basis of ‘seed–soil’ relationships. Preceding this biological mechanism is the physical process of dissemination of circulating tumour cells (CTCs) in the circulation. Patterns of metastatic spread have been previously quantified using the metastatic efficiency index, a measure quantifying metastatic incidence for a given primary-target organ pair and the relative blood flow between them. We extend this concept to take into account the reduction in CTCs which occurs in organ capillary beds connected by a realistic vascular network topology. Application to a dataset of metastatic incidence reveals that metastatic patterns depend strongly on assumptions about the existence and location of micrometastatic disease which governs CTC dynamics on the network, something which has heretofore not been considered – an oversight which precludes our ability to predict metastatic patterns in individual patients.

This prospective study of 120 autopsy collected human hearts correlates the "Right Ventricle/Left Ventricle" free walls mass ratio and the ventricular mass fraction supplied by the right coronary ("Right Coronary/Ventricular Weight"). Different coloured gel injected through both coronary artery's capillary beds allowed ventricular myocardium separation to obtain the weights. In hearts without hypertrophy, mean +/- standard deviation of the "Right Ventricle/Left Ventricle" mass ratio was 0.54 +/- 0.09 for males and 0.62 +/- 0.23 for females; "Right Coronary/Ventricular Weight" mass ratios were 0.39 +/- 0.08 and 0.39 +/- 0.04, respectively. Mean +/- standard deviation of the "Right Ventricle/Left Ventricle" and "Right Coronary/Ventricular Weight" ratios were 0.37 +/- 0.05 and 0.36 +/- 0.10, respectively in hearts with "Left Ventricle Hypertrophy"; 0.56 +/- 0.07 and 0.38 +/- 0.11 in hearts "Without Hypertrophy"; 0.54 +/- 0.08 and 0.39 +/- 0.08 in hearts with "Biventricular Hypertrophy"; 0.89 +/- 0.16 and 0.49 +/- 0.06 in hearts with "Right Ventricle Hypertrophy". Means and variances are narrower for the "Right Coronary/Ventricular Weight" than that observed for the "Right Ventricle/Left Ventricle" mass ratio. It is due to the special double coronary arrangement in which every artery irrigates both ventricles. These results suggest that the usual pattern of the human coronary arteries' anatomy acts as a buffer for the ventricular mass distribution to be irrigated by both arteries in hypertrophy.

Arteriovenous malformations (AVMs) represent the most commonly encountered symptomatic vascular malformations of the central nervous system (CNS) identified at either surgery or necropsy. AVMs are hamartomatous lesions of the brain characterized by elongated and enlarged feeding arteries that directly communicate with draining veins and are without intervening resistance vessels or capillary beds.

Indocyanine green (ICG) has been demonstrated to be a reliable indicator for the estimation of plasma volume in man. Since this dye is bound to plasma protein when administered intravenously, overestimation of the plasma volume would occur during the presence of protein leak from plasma. However, to our knowledge, up to now no report has described whether or not plasma volume determined by the indocyanine green dilution method (PVICG) is clinically significantly overestimated under such conditions. We report two burned patients who temporally had an unusual large PVICG even though other clinical variables did not support the presence of hypervolemia. From the case described it can be concluded that a possible overestimation of PVICG occurs when the vascular permeability for proteins is increased.