This review highlights the influence of oxygen (O2) availability on cerebral blood flow (CBF). Evidence for reductions in O2 content (CaO2 ) rather than arterial O2 tension (PaO2 ) as the chief ...regulator of cerebral vasodilation, with deoxyhemoglobin as the primary O2 sensor and upstream response effector, is discussed. We review in vitro and in vivo data to summarize the molecular mechanisms underpinning CBF responses during changes in CaO2 . We surmise that 1) during hypoxemic hypoxia in healthy humans (e.g., conditions of acute and chronic exposure to normobaric and hypobaric hypoxia), elevations in CBF compensate for reductions in CaO2 and thus maintain cerebral O2 delivery; 2) evidence from studies implementing iso- and hypervolumic hemodilution, anemia, and polycythemia indicate that CaO2 has an independent influence on CBF; however, the increase in CBF does not fully compensate for the lower CaO2 during hemodilution, and delivery is reduced; and 3) the mechanisms underpinning CBF regulation during changes in O2 content are multifactorial, involving deoxyhemoglobin-mediated release of nitric oxide metabolites and ATP, deoxyhemoglobin nitrite reductase activity, and the downstream interplay of several vasoactive factors including adenosine and epoxyeicosatrienoic acids. The emerging picture supports the role of deoxyhemoglobin (associated with changes in CaO2 ) as the primary biological regulator of CBF. The mechanisms for vasodilation therefore appear more robust during hypoxemic hypoxia than during changes in CaO2 via hemodilution. Clinical implications (e.g., disorders associated with anemia and polycythemia) and future study directions are considered.
Continuous mode delivery of medical oxygen from oxygen concentrators and oxygen cylinders leads to wastage of precious medical oxygen during exhalation and rest phases of the respiratory cycle. Pulse ...mode oxygen delivery can address the stated problem, however, it is required to determine the number of oxygen release pulses and the exact instant of inhalation or exhalation. Herein we report the design and development of an intelligent pulsed mode respiratory device- “RESPIPulse,” which is capable of delivering oxygen bolus by automatically sensing the inhalation and exhalation instances from body mount surface electromyography (sEMG) electrodes without manual intervention or settings. The device comprises a set of miniature single-channel sEMG electrodes, an embedded machine-learning algorithm, a normally open solenoid valve, an airflow sensor, and necessary driving electronics. The solenoid valve opens or closes depending on the muscular inhalation or exhalation effort determined from the sEMG signals, thus preventing the wastage of respiratory oxygen. The sEMG signals are subjected to envelop extraction followed by feature extraction. Performances of k-nearest neighbor (kNN), support vector regression (SVR), and random forests (RF) regressors are initially tested in Python IDE to identify the best learning algorithm that is deployed in the microcontroller for determination of the instances of inhalation and exhalation. Trials are conducted on 20 healthy subjects and 10 dyspnea-affected patients. Based on the computed performance measures and evaluation time, the kNN algorithm estimates the respiratory instances more accurately than the other two algorithms. A significant amount of oxygen savings, ranging between 35.48–82.35%, is obtained using the RESPIPulse device which is much higher than the pulse mode delivery devices employing manual settings exhibiting maximum conservation of 48.2%.
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•Automated pulsed mode oxygen delivery device based on sEMG and airflow is developed.•The device can save up to 82% of medical oxygen.•The device acts as oxygen conservation system.
As the line between excellent and exceptional athletic performance narrows and as the financial remuneration for exceptional performance increases, unscrupulous athletes and their trainers will ...strive to enhance performance regardless of cost. One method of performance enhancement is by the augmentation of the oxygen-carrying capacity of the blood through blood doping. We discuss the science behind erythropoiesis and means by which these processes can be exploited to the potential advantage of the athlete. These include pre-sport transfusion practices as well as supplemental recombinant human erythropoietin (rHuEpo) and the use of newer erythropoietic agents, many of which have not received FDA approval. Finally, we discuss the data behind the efficacy of blood doping in an attempt to discern whether or not the practice actually works to improve athletic and competitive performance.
Most tumors have more severe hypoxia levels than normal tissue; tumor hypoxia is thus a useful target for cancer treatment. Here, we develop an effective oxygen delivery vehicle of ...polydopamine‐nanoparticle‐stabilized oxygen microcapsules by interfacial polymerization. The oxygen microcapsules have excellent biocompatibility. Oxygen could easily diffuse out from the microcapsules, thus increasing and maintaining the microenvironment at an oxygen‐rich state. In vitro cell cultures confirm that oxygen microcapsules could effectively improve the hypoxia microenvironment, showing the lowest fluorescent intensity of hypoxia‐green‐labeled cells. When injected subcutaneously in vivo, oxygen microcapsules could also improve the tumor's hypoxia microenvironment, thus suppressing the growth of tumor. Synergetic therapy using oxygen microcapsules and gemcitabine drugs is an effective way for tumor treatment, showing the best performance in suppressing the tumor's growth.
Polydopamine‐nanoparticle‐stabilized oxygen microcapsules are developed. These are capable of alleviating the hypoxia condition of a tumor microenvironment. Synergetic treatment using oxygen microcapsules and gemcitabine drugs is shown to be an effective strategy for enhanced tumor therapy.
The combination of photothermal and photodynamic therapy (PTT/PDT) shows pronounced potential as a prominent therapeutic strategy for tumor treatment. However, the efficacy is limited by insufficient ...tumor-targeted delivery of PTT and PDT reagents and the hypoxic nature of the tumor microenvironment. To overcome these limitations, tumor acidity-responsive lipid membrane-enclosed perfluorooctyl bromide oil droplet nanoparticles (NPs) surface modified with N-acetyl histidine-modified D-α-tocopheryl polyethylene glycol 1000 succinate (PFOB@IMHNPs) were developed, capable of co-delivering oxygen, IR780 (a photothermal agent) and mTHPC (a photodynamic sensitizer) into tumors. Through self-sufficient oxygen transportation in combination with promotion of cellular uptake upon acid-triggered generation of surface positive charge, the PFOB@IMHNPs effectively delivered IR780 and mTHPC and produced singlet oxygen within hypoxic TRAMP-C1 cells following exposure to irradiation at 660 nm. This led to effective killing of hypoxic cancer cells in vitro. Importantly, when irradiation at 808 and 660 nm was carried out, PT/PD combination therapy utilizing PFOB@IMHNPs dramatically suppressed the growth of TRAMP-C1 tumors through effective tumor-targeted cargo delivery and relief of tumor hypoxia. Our results suggest the high potential of the PFOB@IMHNPs developed in this study in clinical application for cancer treatment.
Tumor microenvironment-responsive and oxygen self-sufficient oil droplet nanoparticles for enhanced photothermal/photodynamic combination therapy against hypoxic tumors Display omitted
•Smart oil droplets were developed for photothermal/photodynamic combined therapy.•pH-induced charge conversion on NP surfaces highly enhanced cellular uptake.•Oil droplet NPs carried oxygen and accumulated in tumor significantly.•Oxygen supply modulated tumor hypoxia and enhanced photodynamic therapy.•Functionalized phototherapy oil droplets effectively suppressed tumor growth.
Microbubbles lower the threshold for cavitation of ultrasound and have multiple potential therapeutic applications in the cardiovascular system. One of the first therapeutic applications to enter ...into clinical trials has been microbubble-enhanced sonothrombolysis. Trials were conducted in acute ischemic stroke and clinical trials are currently underway for sonothrombolysis in treatment of acute myocardial infarction. Microbubbles can be targeted to epitopes expressed on endothelial cells and thrombi by incorporating targeting ligands onto the surface of the microbubbles. Targeted microbubbles have applications as molecular imaging contrast agents and also for drug and gene delivery. A number of groups have shown that ultrasound with microbubbles can be used for gene delivery yielding robust gene expression in the target tissue. Work has progressed to primate studies showing delivery of therapeutic genes to generate islet cells in the pancreas to potentially cure diabetes. Microbubbles also hold potential as oxygen therapeutics and have shown promising results as a neuroprotectant in an ischemic stroke model. Regulatory considerations impact the successful clinical development of therapeutic applications of microbubbles with ultrasound. This paper briefly reviews the field and suggests avenues for further development.
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Tissue hypoxia has been proposed as an important factor in the pathophysiology of both chronic kidney disease (CKD) and acute kidney injury (AKI), initiating and propagating a vicious cycle of ...tubular injury, vascular rarefaction, and fibrosis and thus exacerbation of hypoxia. Here, we critically evaluate this proposition by systematically reviewing the literature relevant to the following six questions: (i) Is kidney disease always associated with tissue hypoxia? (ii) Does tissue hypoxia drive signalling cascades that lead to tissue damage and dysfunction? (iii) Does tissue hypoxia per se lead to kidney disease? (iv) Does tissue hypoxia precede pathology? (v) Does tissue hypoxia colocalize with pathology? (vi) Does prevention of tissue hypoxia prevent kidney disease? We conclude that tissue hypoxia is a common feature of both AKI and CKD. Furthermore, at least under in vitro conditions, renal tissue hypoxia drives signalling cascades that lead to tissue damage and dysfunction. Tissue hypoxia itself can lead to renal pathology, independent of other known risk factors for kidney disease. There is also some evidence that tissue hypoxia precedes renal pathology, at least in some forms of kidney disease. However, we have made relatively little progress in determining the spatial relationships between tissue hypoxia and pathological processes (i.e. colocalization) or whether therapies targeted to reduce tissue hypoxia can prevent or delay the progression of renal disease. Thus, the hypothesis that tissue hypoxia is a “common pathway” to both AKI and CKD still remains to be adequately tested.
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We investigated microcirculatory perfusion disturbances following cardiopulmonary bypass in the early postoperative period and whether the course of these disturbances mirrored restoration of ...endothelial glycocalyx integrity. We performed sublingual sidestream dark field imaging of the microcirculation during the first three postoperative days in patients who had undergone on‐pump coronary artery bypass graft surgery. We calculated the perfused vessel density, proportion of perfused vessels and perfused boundary region. Plasma was obtained to measure heparan sulphate and syndecan‐1 levels as glycocalyx shedding markers. We recruited 17 patients; the mean (SD) duration of non‐pulsatile cardiopulmonary bypass was 103 (18) min, following which 491 (29) ml autologous blood was transfused through cell salvage. Cardiopulmonary bypass immediately decreased both microcirculatory perfused vessel density; 11 (3) vs. 16 (4) mm.mm−2, p = 0.052 and the proportion of perfused vessels; 92 (5) vs. 69 (9) %, p < 0.0001. The proportion of perfused vessels did not increase after transfusion of autologous salvaged blood following cardiopulmonary bypass; 72 (7) %, p = 0.19 or during the first three postoperative days; 71 (5) %, p < 0.0001. The perfused boundary region increased after cardiopulmonary bypass; 2.2 (0.3) vs. 1.9 (0.3) μm, p = 0.037 and during the first three postoperative days; 2.4 (0.3) vs. 1.9 (0.3) μm, p = 0.003. Increased plasma heparan sulphate levels were inversely associated with the proportion of perfused vessels during cardiopulmonary bypass; R = −0.49, p = 0.02. Plasma syndecan‐1 levels were inversely associated with the proportion of perfused vessels during the entire study period; R = −0.51, p < 0.0001. Our study shows that cardiopulmonary bypass‐induced acute microcirculatory perfusion disturbances persist in the first three postoperative days, and are associated with prolonged endothelial glycocalyx shedding. This suggests prolonged impairment and delayed recovery of both microcirculatory perfusion and function after on‐pump cardiac surgery.
Tumor hypoxia is believed to be a factor limiting successful outcomes of oxygen-consuming cancer therapy, thereby reducing patient survival. A key strategy to overcome tumor hypoxia is to increase ...the prevalence of oxygen at the tumor site. Oxygen-containing microbubbles/nanobubbles have been developed to supply oxygen and enhance the effects of therapies such as radiotherapy and photodynamic therapy. However, the application of these bubbles is constrained by their poor stability, requiring major workarounds to increase their half-lives. In this study, we explore the potential of biogenic gas vesicles (GVs) as a new kind of oxygen carrier to alleviate tumor hypoxia. GVs, which are naturally formed, gas-filled, protein-shelled compartments, were modified on the surface of their protein shells by a layer of liposome. A substantial improvement of oxygen concentration was observed in hypoxic solution, in hypoxic cells, as well as in subcutaneous tumors when lipid-GVs(O2) were added/tail-injected. Significant enhancement of tumor cell apoptosis and necrosis was also observed during photodynamic therapy (PDT) in the presence of lipid-GVs(O2) both in vitro and in vivo. Lipid-GVs(O2) alone induced no obvious change in cell viability in vitro or any apparent pathological abnormalities after mice were tail-injected with them. In all, lipid-GVs exhibited promising performance for intravenous gas delivery, enhanced PDT efficacy and low toxicity, a quality that may be applied to alleviate hypoxia in cancers, as well as hypoxia-related clinical treatments.
The development of stable oxygen-filled micro/nanobubbles capable of delivering oxygen to tumor sites is a major hurdle to enhancing the efficacy of cancer therapy. Currently, micro/nanobubbles are limited by their instability when oxygen is encapsulated, creating a large pressure gradient and surface tension. To improve stability, we modified the surfaces of GVs, a biogenic stable nanoscale hollow structure, as a new class of oxygen carriers. Lipid-coated GVs were found to be stable in solution and effective O2 carriers. This will overcome the limitations of coalescence, short circulation time of synthetic bubbles during application. Our surface-modified GVs demonstrated low toxicity in vitro cell in vivo, while also being able to overcome hypoxia-associated therapy resistance when combined with photodynamic therapy.
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