Perfluorocarbon-based Oxygen Carriers Research Articles

Mini review on Artificial Blood Substitutes: Future perspective of Perfluorocarbon based oxygen carriers

The primary cause of death in the battle field and in civilian trauma is haemorrhagic shock. Around 50% combat deaths occur due to haemorrhage, depending on the severity of bleeding medical supervision can be provided like in catastrophic haemorrhage individual death occurs before providing the medical care and it is not a prehospital combat medical management problem during warfare scenario, even to transport wounded personnel to causality centre often takes 45 minutes to one hours. The hazardous nature of the forward combat areas and hostile operational environment frequently prevents medical personnel from quickly reaching the wounded even if the transport distances are small. Moreover, injuries with penetrating battlefield trauma often have only a "platinum 5 minutes." It is very important for military medical personnel to understand their options for treating haemorrhage quickly and efficiently during combat. Early intervention and definitive treatment could save up to 30% of soldier’s who die of action or of wounds. In view of this there is a requirement for the development of synthetic blood substitutes or oxygen therapeutic agents (OTA) in order to maintain the tissue oxygenation. Blood substitutes are the substances which mimic one of the physiological functions of the blood that is transportation of oxygen and carbon dioxide throughout the body. Blood substitutes or OTAs are being clinically tested as artificial oxygen carriers to improve tissue oxygenation and also to reduce allogenic blood transfusions. Two types of blood substitutes are reported so far: 1. Haemoglobin based oxygen carriers (HBOCs) and 2. Perfluorocarbon based oxygen carriers (PFOCs). PFOCs has huge advantages like universal compatibility, no requirement of cold storage, longer shelf life and no risk of infection transmission. These products have their own limitations and they have been withdrawn from international market for clinical use because of their side effects. It is a challenging task to the scientists to develop a safe, stable and biocompatible blood substitute for combat scenarios and also for civilian applications.

Current perspectives of artificial oxygen carriers as red blood cell substitutes: a review of old to cutting-edge technologies using in vitro and in vivo assessments.

BackgroundSeveral circumstances such as accidents, surgery, traumatic hemorrhagic shock, and other causalities cause major blood loss. Allogenic blood transfusion can be resuscitative for such conditions; however, it has numerous ambivalent effects, including supply shortage, needs for more time, cost for blood grouping, the possibility of spreading an infection, and short shelf-life. Hypoxia or ischemia causes heart failure, neurological problems, and organ damage in many patients. To address this emergent medical need for resuscitation and to treat hypoxic conditions as well as to enhance oxygen transportation, researchers aspire to achieve a robust technology aimed to develop safe and feasible red blood cell substitutes for effective oxygen transport.Area coveredThis review article provides an overview of the formulation, storage, shelf-life, clinical application, side effects, and current perspectives of artificial oxygen carriers (AOCs) as red blood cell substitutes. Moreover, the pre-clinical (in vitro and in vivo) assessments for the evaluation of the efficacy and safety of oxygen transport through AOCs are key considerations in this study. With the most significant technologies, hemoglobin- and perfluorocarbon-based oxygen carriers as well as other modern technologies, such as synthetically produced porphyrin-based AOCs and oxygen-carrying micro/nanobubbles, have also been elucidated.Expert opinionBoth hemoglobin- and perfluorocarbon-based oxygen carriers are significant, despite having the latter acting as safeguards; they are cost-effective, facile formulations which penetrate small blood vessels and remove arterial blockages due to their nano-size. They also show better biocompatibility and longer half-life circulation than other similar technologies.

Perfluorocarbon-Based Oxygen Carriers and Subnormothermic Lung Machine Perfusion Decrease Production of Pro-Inflammatory Mediators

The quality of marginal donor lungs is clinically assessed with normothermic machine perfusion. Although subnormothermic temperature and perfluorocarbon-based oxygen carriers (PFCOC) have proven favourable for other organ transplants, their beneficial use for ex vivo lung perfusion (EVLP) still requires further investigation. In a rat model, we evaluated on a 4 h EVLP time the effects of PFCOC with either 28 °C or 37 °C perfusion temperatures. During EVLP at 28 °C with PFCOC, we recorded significantly lower lung pulmonary vascular resistance (PVR), higher dynamic compliance (Cdyn), significantly lower potassium and lactate levels, higher lung tissue ATP content, and significantly lower myeloperoxidase tissue activity when compared to the 37 °C EVLP with PFCOC. In the subnormothermic EVLP with or without PFCOC, the pro-inflammatory mediator TNFα, the cytokines IL-6 and IL-7, the chemokines MIP-3α, MIP-1α, MCP-1, GRO/KC as well as GM-CSF, G-CSF and the anti-inflammatory cytokines IL-4 and IL-10 were significantly lower. The 28 °C EVLP improved both Cdyn and PVR and decreased pro-inflammatory cytokines and pCO2 levels compared to the 37 °C EVLP. In addition, the 28 °C EVLP with PFCOC produced a significantly lower level of myeloperoxidase activity in lung tissue. Subnormothermic EVLP with PFCOC significantly improves lung donor physiology and ameliorates lung tissue biochemical and inflammatory parameters.

Artificial Oxygen Carriers—Past, Present, and Future—a Review of the Most Innovative and Clinically Relevant Concepts

Blood transfusions are a daily practice in hospitals. Since these products are limited in availability and have various, harmful side effects, researchers have pursued the goal to develop artificial blood components for about 40 years. Development of oxygen therapeutics and stem cells are more recent goals. Medline (https://www.ncbi.nlm.nih.gov/pubmed/?holding=ideudelib), ClinicalTrials.gov (https://clinicaltrials.gov), EU Clinical Trials Register (https://www.clinicaltrialsregister.eu), and Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au) were searched up to July 2018 using search terms related to artificial blood products in order to identify new and ongoing research over the last 5 years. However, for products that are already well known and important to or relevant in gaining a better understanding of this field of research, the reader is punctually referred to some important articles published over 5 years ago. This review includes not only clinically relevant substances such as heme-oxygenating carriers, perfluorocarbon-based oxygen carriers, stem cells, and organ conservation, but also includes interesting preclinically advanced compounds depicting the pipeline of potential new products. In- depth insights into specific benefits and limitations of each substance, including the biochemical and physiologic background are included. "Fancy" ideas such as iron-based substances, O2 microbubbles, cyclodextranes, or lugworms are also elucidated. To conclude, this systematic up-to-date review includes all actual achievements and ongoing clinical trials in the field of artificial blood products to pursue the dream of artificial oxygen carrier supply. Research is on the right track, but the task is demanding and challenging.

Perfluorocarbon‐Based Oxygen Carriers: Review of Products and Trials

A viable blood substitute is still of great necessity throughout the world. Perfluorocarbon-based oxygen carriers (PFCOCs) are emulsions that take advantage of the high solubility of respiratory gases in perfluorocarbons (PFCs). Despite attractive characteristics, no PFCOC is currently approved for clinical uses. Some PFCOCs have failed due to secondary effects of the surfactants employed, like Fluosol DA, whereas others to adverse cerebrovascular effects on cardiopulmonary bypass, such as Oxygent. Further in-depth, rigorous work is needed to overcome the annotated failures and to obtain a safe PFCOC approved for human use. The aim of this study is to review in detail the most-used PFCOCs, their formulation, and preclinical and clinical trials, and to reflect upon causes of failure and strategies to overcome such failures.

Enhancing oxygen solubility using hemoglobin- and perfluorocarbon-based carriers

The objective of this paper is to review the properties of fluids capable to enhance oxygen transport and transfer and recent developments in this field. This paper reviews and compares two different approaches, which could be used to solve the important problem of oxygen supply in some cell and tissue cultures: 1) hemoglobin-based and 2) perfluorocarbon-based (PFC) oxygen carriers. Several types of modified hemoglobin-based oxygen carriers (HBOCs) and their preparation are reviewed, as well as advances in the field of PFC oxygen carriers. Finally, we highlight the advantages and pitfalls, when reported in the literature, associated with each technique.

Oxygen Therapeutics: Pursuit of an Alternative to the Donor Red Blood Cell

There is no true substitute for the many functions of human red blood cells, and synthetic products will not replace the need for blood donation in the foreseeable future. Hemoglobin-based oxygen carriers have many characteristics that would serve as a useful adjunct to red cells in clinical settings. Over time, these technologies have the potential to dramatically reshape the practice of transfusion medicine. To review the characteristics and potential utility of hemoglobin-based oxygen carriers and perfluorocarbon-based oxygen carriers. Several hemoglobin-based oxygen carriers are under study in phase III clinical trials. Novel uses for synthetic oxygen therapeutics are emphasized. All published reports with the key words oxygen therapeutics, blood substitutes, and red cell substitutes from 1933 until March 2006 were searched through Medline. Significant findings were synthesized. Recognition of the true impact of red cell substitutes is still several years away. The most compelling products, hemoglobin-based oxygen carriers, have potential use in trauma, providing immediate oxygen-carrying support in the face of alloantibodies or autoantibodies, and in other clinical situations in which long-term survival of red cells is not essential. In the interim, efforts should be focused on enhancing the current blood supply system while supporting ongoing and planned blood substitute research efforts, including trials assessing novel clinical indications for these products.

Oxygen Therapeutics: Pursuit of an Alternative to the Donor Red Blood Cell

Abstract Context.—There is no true substitute for the many functions of human red blood cells, and synthetic products will not replace the need for blood donation in the foreseeable future. Hemoglobin-based oxygen carriers have many characteristics that would serve as a useful adjunct to red cells in clinical settings. Over time, these technologies have the potential to dramatically reshape the practice of transfusion medicine. Objective.—To review the characteristics and potential utility of hemoglobin-based oxygen carriers and perfluorocarbon-based oxygen carriers. Several hemoglobin-based oxygen carriers are under study in phase III clinical trials. Novel uses for synthetic oxygen therapeutics are emphasized. Data Sources.—All published reports with the key words oxygen therapeutics, blood substitutes, and red cell substitutes from 1933 until March 2006 were searched through Medline. Significant findings were synthesized. Conclusions.—Recognition of the true impact of red cell substitutes is still seve...

Toward 21st Century Blood Component Replacement Therapeutics: Artificial Oxygen Carriers, Platelet Substitutes, Recombinant Clotting Factors, and Others

In this brief overview, recent progress and current status of blood substitute research and development is summarized. Current blood substitute development efforts are focused on red blood cell substitutes but substitutes for platelets and other blood components are also in progress. Red cell substitutes currently in various stages of development are semi-synthetic or synthetic oxygen carriers that include "stealth" or "masked" red cells, hemoglobin-based oxygen carriers and perfluorocarbon-based oxygen carriers. Artificial platelets (or platelet substitutes) are in early stages of development and include human platelet fragments or particles of synthetic/semi-synthetic materials or recombinant human serum albumin coupled with platelet surface receptor fragments. Of note, some recombinant clotting factors (Factors VII, VIII, IX) have already been successfully developed and licensed for treatment of hemophilia. In addition, some future approaches and prospects of blood component replacement therapeutics are discussed.

Artificial oxygen carriers as red blood cell substitutes: a selected review and current status.

Two distinct approaches are being explored in red blood cell substitute (RCS) development: hemoglobin-based oxygen carriers (HBOCs) and perfluorocarbon-based oxygen carriers (PFBOCs). HBOCs are based on intra- and/or intermolecularly "engineered" human or animal hemoglobins (Hbs), optimized for O2 delivery and longer intravascular circulation. Some are currently being evaluated in Phase II/III clinical studies. PFBOCs are aqueous emulsions of perfluorocarbon derivatives that dissolve relatively large amounts of O2. A PFBOC based on a 60% (wt/vol) emulsion of perfluorooctyl bromide has been evaluated in Phase II/III clinical trials. Although current PFBOC products generally require patients to breathe O2 enriched air, they render certain advantages since they are totally synthetic. This article provides a short review of the basic principles, approaches, and current status of RCS development. Results of preclinical and clinical studies including recent Phase II/III clinical studies are discussed.

Artificial oxygen carriers.

The clinical availability of artificial oxygen carriers (AOCs) would result in profound alterations in transfusion medical practice. Rapid progress in the scientific and technological development of AOCs has advanced to a critical stage at which safe and effective alternatives to the transfusion of red blood cells are emerging. Haemoglobin- and perfluorocarbon-based oxygen carriers are under current clinical investigation. Artificial oxygen-carrying solutions, by virtue of their acellular structure, can be used to transport oxygen to ischaemic tissues that cannot otherwise be reached by cellular blood components. Organs awaiting transplantation can be preserved for a long time after perfusion with AOCs and tumour susceptibility to chemo- and radiotherapy is increased. The use of AOCs is therefore not confined to their use as red blood cell substitutes, but may find a wide spectrum of interdisciplinary applications.

Blood substitutes: evolution and future applications

The development of oxygen-carrying blood substitutes has progressed significantly in the last decade with phase I and phase II clinical trials of both hemoglobin-based and perfluorocarbon-based oxygen carriers nearing completion. As these products approach clinical use it is important for the laboratory medicine community to be aware of their effects on routine laboratory testing and the settings in which they might be used. Here we review the forces driving the development of oxygen-carrying blood substitutes, the clinical settings in which they might be used, the major categories of oxygen carriers in clinical trials, and the challenges faced by these products as they approach clinical use.

Oxygen-Carrying Blood Substitutes

Transfusion of human blood components still has major drawbacks, such as transfusion-transmitted diseases, requirements for blood type analysis and cross-match testing, availability and supply, storage and preservation time. The rapid progress in science and technology has advanced to a critical stage where safe and effective alternatives to the transfusion of red blood cells emerge. Although some toxicity issues remain, substantial improvements in the area of artificial oxygen carriers have been made in the past years. To date hemoglobin- and perfluorocarbon-based oxygen carriers are under clinical investigation. In addition to their use as red blood cell substitutes other clinical applications of artificial oxygen carriers should be considered. Due to their physiological properties (especially acellular oxygen transport) artificial oxygen-carrying solutions can be used to provide oxygen to ischemic tissues which cannot be reached by cellular blood components. Longer preservation times of organs awaiting transplantation have been described after perfusion with artificial oxygen carriers as well as an increase in tumor susceptibility to chemo- and radiotherapy. Therefore, artificial oxygen carriers are not only confined to their use as red blood cell substitutes, but will find a wide and divergent spectrum of interdisciplinary applications. Since blood transfusion is a big business and enormous amounts of capital have been invested in the search of artificial oxygen carriers, it can be assumed that substitutes of red blood cells will be available during the next years. However, since there is no anticipated substitute for all fractions of human blood, there will be an ongoing requirement for human blood components, such as fresh frozen plasma, platelets, and others.

Section Review: Cardiovascular & Renal: Blood substitutes in development

‘Blood substitutes’ are products designed to be used when blood is either unavailable or in short supply. Three major classes of products are being developed and tested, including haemoglobin-based oxygen carriers, perfluorocarbon-based oxygen carriers, and liposome-encapsulated haemoglobin. Other novel products are in very early stages of development. None of the products perform all the functions of blood; neither do they persist in the circulation as long as human red blood cells. However, they all carry and transport oxygen to tissues and can support life temporarily until patients can either regenerate their own red cells or can be transfused with banked blood. In the past, the main obstacle to the development of blood substitutes has been in understanding their side-effects. Having overcome the most significant toxicities of each class of products, rather minor problems persist, but these will probably not prevent clinical acceptance and regulatory approval. An important consequence of the extensive...