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Blood Substitutes: Evolution from Noncarrying to Oxygen- and Gas-Carrying Fluids
Abstract and Figures
The development of oxygen (O2)-carrying blood substitutes has evolved from the goal of replicating blood O2 transport properties to that of preserving microvascular and organ function, reducing the inherent or potential toxicity of the material used to carry O2, and treating pathologies initiated by anemia and hypoxia. Furthermore, the emphasis has shifted from blood replacement fluid to "O2 therapeutics" that restore tissue oxygenation to specific tissues regions. This review covers the different alternatives, potential and limitations of hemoglobin-based O2 carriers (HBOCs) and perfluorocarbon-based O2 carriers (PFCOCs), with emphasis on the physiologic conditions disturbed in the situation that they will be used. It describes how concepts learned from plasma expanders without O2-carrying capacity can be applied to maintain O2 delivery and summarizes the microvascular responses due to HBOCs and PFCOCs. This review also presents alternative applications of HBOCs and PFCOCs namely: 1) How HBOC O2 affinity can be engineered to target O2 delivery to hypoxic tissues; and 2) How the high gas solubility of PFCOCs provides new opportunities for carrying, dissolving, and delivering gases with biological activity. It is concluded that the development of current blood substitutes has amplified their applications horizon by devising therapeutic functions for O2 carriers requiring limited O2 delivery capacity restoration. Conversely, full, blood-like O2-carrying capacity reestablishment awaits the control of O2 carrier toxicity.
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... The last challenge lies in the scarcity of potential blood substitutes. Although perfluorocarbon (PFC) emulsions and acellular hemoglobin-based oxygen carriers (HBOCs) have emerged as two key alternatives, their short half-lives and potential adverse effects on physiological systems limit their clinical application, and this warrants further exploration and refinement (Cabrales and Intaglietta, 2013;Modery-Pawlowski et al., 2013). ...
Blood has an important role in the healthcare system, particularly in blood transfusions and immunotherapy. However, the occurrence of outbreaks of infectious diseases worldwide and seasonal fluctuations, blood shortages are becoming a major challenge. Moreover, the narrow specificity of immune cells hinders the widespread application of immune cell therapy. To address this issue, researchers are actively developing strategies for differentiating induced pluripotent stem cells (iPSCs) into blood cells in vitro. The establishment of iPSCs from terminally differentiated cells such as fibroblasts and blood cells is a straightforward process. However, there is need for further refinement of the protocols for differentiating iPSCs into immune cells and red blood cells to ensure their clinical applicability. This review aims to provide a comprehensive overview of the strategies and challenges facing the generation of iPSC-derived immune cells and red blood cells.
... Due to the oxidative stress linked to resuscitation and cardiovascular events, polymerized Hb solutions with catalase/superoxide dismutase activity were designed [141], with favorable outcomes in a rat model of transient global brain ischemiareperfusion [142]. Although the association of polymerized Hb with antioxidants has become an emerging relevant feature in HBOC development [143], clinical trials developed using these products, summarized in [5], have still displayed critical issues related to vasoactivity and hypertension [144]. Indeed, the issues related to NO are not covered by the interventions aimed solely at modifying the size of the Hb molecule and the antioxidant capacity. ...
The search for a clinically affordable substitute of human blood for transfusion is still an unmet need of modern society. More than 50 years of research on acellular hemoglobin (Hb)-based oxygen carriers (HBOC) have not yet produced a single formulation able to carry oxygen to hemorrhage-challenged tissues without compromising the body’s functions. Of the several bottlenecks encountered, the high reactivity of acellular Hb with circulating nitric oxide (NO) is particularly arduous to overcome because of the NO-scavenging effect, which causes life-threatening side effects as vasoconstriction, inflammation, coagulopathies, and redox imbalance. The purpose of this manuscript is not to add a review of candidate HBOC formulations but to focus on the biochemical and physiological events that underly NO scavenging by acellular Hb. To this purpose, we examine the differential chemistry of the reaction of NO with erythrocyte and acellular Hb, the NO signaling paths in physiological and HBOC-challenged situations, and the protein engineering tools that are predicted to modulate the NO-scavenging effect. A better understanding of two mechanisms linked to the NO reactivity of acellular Hb, the nitrosylated Hb and the nitrite reductase hypotheses, may become essential to focus HBOC research toward clinical targets.
... Under hypoxic microenvironment tumor cells become more resistant to RT, aggressive and ultimately resistant to death through altering gene expression patterns as well as augmenting free radical scavenging [11,12]. In recent years various approaches and research have been put forward to surpass hypoxia drawbacks, from using the oxygen-carrying blood substitute and high-pressure O 2 cylinder, to using elaborate, truthful strategies that proportionated differences in partial oxygen pressure (PO 2 ) between healthy and tumors tissue [22,23]. In order to ameliorate cancer-associated hypoxia, hyperbaric oxygen as a direct method is widely employed, but this method is not convenient and in some cases it may cause complications [24,25]. ...
Radiation therapy (RT) has been established as a very auspicious tool to tackle cancer, but its efficacy has encountered with some challenges. As we all know, in the case of cancer therapy by RT, high doses of radiation are required to fully eradicate tumor cells and shrink them as well. However, this auspicious tool is far from being faultless, as its enhancement in maximally killing tumor cells while minimally causing severe adverse effects to normal cells have always been unresolved clinical problems and challenges. To address these drawbacks, researchers have conducted a lot of research studies, among them, radiosensitizers have shown great potential to improve the bottleneck of RT for cancer therapy. Radiosensitizers are chemical or pharmacologic agents that makes tumor cells more vulnerable to RT by augmenting free radical formation and assisting DNA damage. Over the last decades, many attempts have been devoted to design and fabricate radiosensitizers that are highly efficient in tumor therapy and characterized with low toxicity. In this review, we classified and summarized the emerging strategies as three main types including nanomaterials, macromolecules, and small molecules based on their structure. Additionally, the development states of radiosensitizers, their mechanisms and how to harness their power to improve radiosensitizers sensibility are presented. We also summarize all exciting advances approaches and emerging smart strategies accossiated with the fabrication of radiosensitizers as well as prospects and challenges for clinical translation of these agents in oncotherapy are reviewed.
... Synthetic liquid perfluorochemicals (PFCs; synonym: perfluorocarbons), which dissolve gases according to Henry's Law, have been adopted in medicinal liquid ventilation procedures [1,2] and bioprocess engineering. PFCs have been repeatedly applied as biochemically inert liquid carriers of respiratory gases in many cell culture systems during the past three decades [3][4][5]. ...
Systems of two immiscible liquid phases-aqueous phase (i.e., distilled water (dH2O) or phosphate-buffered saline (PBS)) and liquid perfluorochemical (i.e., perfluorodecalin (PFD))-were subjected to wave-assisted agitation, i.e., oscillatory rocked, in a disposable bag-like container in a ReadyToProcess WAVE TM 25 bioreactor, to recognize oxygen transfer effects and effectivity of the surface aeration. According to the DoE methodology, values of the volumetric liquid-side mass transfer (kLa) coefficient for dH2O, PBS, dH2O-PFD, and PBS-PFD systems were determined for the whole range of operating parameters of the WAVE 25 bioreactor. A significantly higher maximal value of kLa was found for waving dH2O than for dH2O-PFD (i.e., 0.00460 s −1 vs. 0.00331 s −1 , respectively) compared to more equal maximal values of kLa reached for PBS and PBS-PFD (0.00355 s −1 vs. 0.00341 s −1 , respectively). The interface development factor (f) depended on the interfacial area a, and the enhancement factor (E PFD), depending on kLa, was introduced to quantitatively identify the mass transfer effects in the systems of waving two immiscible liquids. The phase of PFD was identified as the reservoir of oxygen. Dimensional correlations were proposed for the prediction of the kLa coefficient, in addition to the f and E PFD factors. The presented correlations, and the set of kLa values, can be directly applied to predict oxygen transfer effects reached under continuous oscillatory rocked systems containing aqueous phase and liquid perfluorochemical.
... Endothelial NO is dispersed in vascular smooth muscle cells where cytosolic guanylate cyclase is activated and increases the production of cyclic guanosine monophosphate, leading to smooth muscle cells relaxation. Loss of endothelium-mediated vasodilator capacity is considered one of the earliest manifestations of cardiovascular damage and precedes the formation of atherosclerotic plaques [13][14][15]. ...
The main goal of this study was to investigate the cardioprotective properties in terms of effects on cardiodynamics of perfluorocarbon emulsion (PFE) in ex vivo-induced ischemia–reperfusion injury of an isolated rat heart. The first part of the study aimed to determine the dose of 10% perfluoroemulsion (PFE) that would show the best cardioprotective effect in rats on ex vivo-induced ischemia–reperfusion injury of an isolated rat heart. Depending on whether the animals received saline or PFE, the animals were divided into a control or experimental group. They were also grouped depending on the applied dose (8, 12, 16 ml/kg body weight) of saline or PFE. We observed the huge changes in almost all parameters in the PFE groups in comparison with IR group without any pre-treatment. Calculated in percent, dp/dt max was the most changed parameter in group treated with 8 mg/kg, while the dp/dt min, SLVP, DLVP, HR, and CF were the most changed in group treated with 16 mg/kg 10 h before ischemia. The effects of 10% PFE are more pronounced if there is a longer period of time from application to ischemia, i.e., immediate application of PFE before ischemia (1 h) gave the weakest effects on the change of cardiodynamics of isolated rat heart. Therefore, the future of PFE use is in new indications and application methods, and PFE can also be referred to as antihypoxic and antiischemic blood substitute with mild membranotropic effects.
In hospitals, blood transfusions are a common occurrence. Because blood-related products are limited and have a range of adverse side effects, researchers have worked on artificial blood components for nearly 40 years. It is crucial to develop effective and selective alternatives for natural blood products. Artificial blood is a useful idea in transfusion medicine wherein clearly defined compounds perform the functions of oxygen transport and distribution in the body to enhance allogeneic human blood transfusion. Several molecules are created over a long period of time to achieve this goal, and ongoing modifications are performed in the pursuit of the ideal blood substitute. Currently, perfluorocarbons (PFC) or haemoglobin derived from outdated human/bovine blood (Hemoglobin Based Oxygen Carriers; HBOC) are used to manufacture artificial blood. The focus of this review paper is to provide a comprehensive view of different developed products that can be used as blood alternatives.
Hypoxia is a key impediment encountered in the treatment of most solid tumors, leading to immune escape and therapeutic resistance. Perfluorocarbons (PFCs) have a unique electrical structure and are characterized by a high solubility for gases. PFC-based oxygen carriers have been evaluated for their ability to deliver oxygen effectively to hypoxic tissues, and significant clinical translation has been demonstrated. And due to the unique acoustic activity, PFCs have been employed to stabilize the injection of gas microbubbles (MBs) as clinical ultrasonography contrast agents. In contrast, the ultrasound and photothermally activatable PFC phase-shift nanodroplets (P-SNDs) represent a novel alternative to ultrasound imaging and hypoxia improvement. The PFC-based oxygen carriers may be utilized to improve the efficacy of cancer treatments based on synergistic radiotherapy (RT), chemotherapy (CMT), and photodynamic therapy (PDT) to reshape the tumor microenvironment through synergistic immunotherapy (IMT) and to achieve precise tumor diagnosis using acoustic imaging. This review described the characteristics of PFCs to provide an update on the design of PFC delivery systems used for oxygen delivery and ultrasound imaging to facilitate the treatment and diagnosis of tumors. The objective was to contribute to overcoming the obstacles encountered during PFC research and provide the developing prospects.
Purpose:
To determine if intratumoral injections of a liquid oxygen solution is effective at boosting radiation-induced abscopal effects.
Method and materials:
In this study, a liquid oxygen solution, comprising slow-release polymer-shelled oxygen microparticles, was fabricated and injected intratumorally to locally elevate tumor oxygen levels prior to and after treatment with radiation therapy. Changes in tumor volume were monitored. In a subset of studies, CD8 positive cells were depleted, and the experiments repeated. Histological analyses of the tumor tissues were performed to quantify the concentration of infiltrating immune cells.
Results:
Here, we found that daily intratumoral injections of oxygen-filled microparticles significantly retards primary and secondary tumor growth, boosts infiltration of cytotoxic T-cells and improves overall survival when used as an adjuvant to radiotherapy. We also demonstrate that efficacy requires both radiation and oxygen, suggesting that they act synergistically to enhance in situ vaccination and systemic anti-tumor immune responses.
Conclusions:
Our findings demonstrate the potential advantages of intratumoral injections of a liquid oxygen solution as a strategy to boost radiation-induced abscopal effects and warrant future efforts into clinical translation of the injectable liquid oxygen solution.
Sanguinate is a unique polyethylene glycol modified form of bovine hemoglobin that represents the latest generation of hemoglobin-based oxygen carriers. Its structural characteristics and altered hemoglobin-oxygen binding affinity allow it to bypass obstructions in the microcirculation and effectively deliver oxygen to ischemic tissues. Sanguinate is also able to endogenously deliver carbon monoxide, which has been shown to reduce inflammation, oxidative stress, mitigate ischemia-reperfusion injury, and promote vasodilation. Only results from phase I trials using Sanguinate have been published, although several phase II trials have been completed. While these trials suggest a possible risk of myocardial injury there was little evidence that it was due to Sanguinate. Additional larger studies are needed to better define this relationship. It has been successfully used under emergency circumstances in over 100 patients with severe anemia and impaired oxygen delivery where blood transfusion was contraindicated. The additional therapeutic effects (anti-inflammatory, anti-vasoconstrictive, plasma expansion) may make Sanguinate useful in the treatment of disorders in which blood is ineffective, such as stroke, inflammatory diseases, and sepsis. As such, Sanguinate is more effectively termed a resuscitation fluid than blood substitute.
The glomerular filtration of hemoglobin (α2ß2) was studied under conditions in which its dissociation into αß dimers was experimentally altered. Rats receiving hemoglobin treated with the sulfhydryl reagent bis(N-maleimidomethyl) ether (BME) showed a much lower renal excretion and prolonged plasma survival as compared with animals injected with untreated hemoglobin. Plasma disappearance was also prolonged in dogs receiving BME hemoglobin. Gel filtration data indicated that under physiological conditions, BME hemoglobin had impaired subunit dissociation. In addition, BME hemoglobin showed a very high oxygen affinity and a decreased rate of auto-oxidation.
Glomerular filtration was enhanced under conditions which favor the dissociation of hemoglobin into dimers. Cat hemoglobin, which forms subunits much more extensively than canine hemoglobin, was excreted more readily by the rat kidney. The renal uptake of 59Fe hemoglobin injected intra-arterially into rabbits varied inversely with the concentration of the injected dose.
Context.—Infectious disease testing has dramatically improved the safety of blood for transfusion in the United States, especially since the introduction in 1999 of nucleic acid amplification testing. In 2004, methods (primarily culturing) for detecting bacteria in platelets were also added.
Objective.—To provide current risk estimates for the likelihood of viral transmission by test-negative blood components and to illustrate the safety improvements since the introduction of bacterial testing of platelets.
Data Sources.—Published literature from 1999 through 2006 and unpublished American Red Cross data sources.
Conclusions.—The risk of human immunodeficiency virus and hepatitis C virus transmission through blood transfusion since the introduction of nucleic acid amplification testing is approximately 1 in 2 million. Hepatitis B virus risk, for which nucleic acid amplification testing is not performed routinely, remains at 1 in 200 000 to 500 000 using a combination of anti–hepatitis B core and hepatitis B surface antigen testing. Seven cases of transfusion-transmitted West Nile virus have been reported since the introduction of nucleic acid amplification testing in 2003, but none has been reported since system-wide implementation of processes to increase the test sensitivity for use in epidemic areas. The residual risk of receiving a bacterially contaminated platelet component with clinical consequences is estimated at approximately 1 in 75 000, if culture negative and 1 in 33 000 if not tested by culture methods.
The interior surfaces of capillaries are lined with a layer (glycocalyx) of macromolecules bound or adsorbed to the endothelium. Here, a theoretical model is used to analyze the effects of the glycocalyx on hematocrit and resistance to blood flow in capillaries. The glycocalyx is represented as a porous layer that resists penetration by red blood cells. Axisymmetric red blood cell shapes are assumed, and effects of cell membrane shear elasticity are included. Lubrication theory is used to compute the flow of plasma around the cell and within the glycocalyx. The effects of the glycocalyx on tube hematocrit (Fahraeus effect) and on flow resistance are predicted as functions of the width and hydraulic resistivity of the layer. A layer of width 1 μm and resistivity 108 dyn·s/cm4 leads to a relative apparent viscosity of ∼10 in a 6-μm capillary at discharge hematocrit 45% and flow velocity of ∼1 mm/s. This is consistent with experimental observations of increased flow resistance in microvessels in vivo, relative to glass tubes with the same diameters.
Abnormalities of nitric oxide (NO) and oxygen radical synthesis and of oxygen consumption have been described in the spontaneously hypertensive rat (SHR) and may contribute to the pathogenesis of hypertension. NO plays a role in the regulation of renal oxygen consumption in normal kidney, so the response of renal cortical oxygen consumption to stimulators of NO production before and after the addition of the superoxide scavenging agent tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) was studied. Baseline cortical oxygen consumption was similar in SHR and Wistar-Kyoto (WKY) rats (SHR: 600 +/- 55 nmol O-2/min per g, WKY: 611 +/- 51 nmol O-2/min per g, P > 0.05). Addition of bradykinin, enalaprilat, and amlodipine decreased oxygen consumption significantly less in SHR than WKY (SHR: bradykinin - 13.9 - 1.9%, enalaprilat - 15.3 +/- 1.6%, amlodipine - 11.9 +/- 0.7%; WKY: bradykinin -22.8 +/- 1.0%, enalaprilat -24.1 +/- 2.0%, amlodipine -20.7 +/- 2.3%; P < 0.05), consistent with less NO effect in SHR. Addition of tempol reversed the defects in responsiveness to enalaprilat and amlodipine, suggesting that inactivation of NO by superoxide contributes to decreased NO availability. The response to an NO donor was similar in both groups and was unaffected by the addition of tempo]. These results demonstrate that NO availability in the kidney is decreased in SHR, resulting in increased oxygen consumption. This effect is due to enhanced production of superoxide in SHR. By lowering intrarenal oxygen levels, reduced NO may contribute to susceptibility to injury and renal fibrosis. Increasing NO production, decreasing oxidant stress, or both might prevent these changes by improving renal oxygenation.
The glomerular filtration of hemoglobin (α2β2) was studied under conditions in which its dissociation into αβ dimers was experimentally altered. Rats receiving hemoglobin treated with the sulfhydryl reagent bis(N-maleimidomethyl) ether (BME) showed a much lower renal excretion and prolonged plasma survival as compared with animals injected with untreated hemoglobin. Plasma disappearance was also prolonged in dogs receiving BME hemoglobin. Gel filtration data indicated that under physiological conditions, BME hemoglobin had impaired subunit dissociation. In addition, BME hemoglobin showed a very high oxygen affinity and a decreased rate of auto-oxidation. Glomerular filtration was enhanced under conditions which favor the dissociation of hemoglobin into dimers. Cat hemoglobin, which forms subunits much more extensively than canine hemoglobin, was excreted more readily by the rat kidney. The renal uptake of 59Fe hemoglobin injected intra-arterially into rabbits varied inversely with the concentration of the injected dose.
Nitrate and nitrite have been considered stable inactive end products of nitric oxide (NO). While several recent studies now imply that nitrite can be reduced to bioactive NO again, the more stable anion nitrate is still considered to be biologically inert. Nitrate is concentrated in saliva, where a part of it is reduced to nitrite by bacterial nitrate reductases. We tested if ingestion of inorganic nitrate would affect the salivary and systemic levels of nitrite and S-nitrosothiols, both considered to be circulating storage pools for NO. Levels of nitrate, nitrite, and S-nitrosothiols were measured in plasma, saliva, and urine before and after ingestion of sodium nitrate (10 mg/kg). Nitrate levels increased greatly in saliva, plasma, and urine after the nitrate load. Salivary S-nitrosothiols also increased, but plasma levels remained unchanged. A 4-fold increase in plasma nitrite was observed after nitrate ingestion. If, however, the test persons avoided swallowing after the nitrate load, the increase in plasma nitrite was prevented, thereby illustrating its salivary origin. We show that nitrate is a substrate for systemic generation of nitrite. There are several pathways to further reduce this nitrite to NO. These results challenge the dogma that nitrate is biologically inert and instead suggest that a complete reverse pathway for generation of NO from nitrate exists.