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wesatimunogo.cf: Blood Substitutes: New Challenges (Advances in Blood Substitutes, V. 2): Robert M. Winslow, Kim D. Vandegriff, Marcos Intaglietta.
Table of contents
- Artificial Blood Substitutes: First Steps on the Long Route to Clinical Utility
- Characteristics of an Ideal Blood Substitute
- Blood Substitutes
Vandegriff , Marcos Intaglietta. This book is not a "proceedings" volume. The contributors were selected because of their expertise in areas deemed by the editors to be critical to the advancement of the field. The course, as in past years, is heavily influenced by feedback from par ticipants, and by research in this and related fields. In addition to the didactic lectures for which these chapters are the foundation , the course also offers the opportunity for presentation of research reports, progress reports from the various companies currently commercializing products, and round table discussions of selected subjects.
Thus, we are grateful to past participants for their helpful comments. Increased population growth, population aging, generation of new infectious agents, and natural disasters are some threatening factors for the current state of blood transfusion. However, it seems that science and technology not only could overcome these challenges but also would turn many human dreams to reality in this regard.
Scientists believe that one of the future evolutionary innovations could be artificial blood substitutes that might pave the way to a new era in transfusion medicine. In this review, recent status and progresses in artificial blood substitutes, focusing on red blood cells substitutes, are summarized. In addition, steps taken toward the development of artificial blood technology and some of their promises and hurdles will be highlighted.
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However, it must be noted that artificial blood is still at the preliminary stages of development, and to fulfill this dream, ie, to routinely transfuse artificial blood into human vessels, we still have to strengthen our knowledge and be patient. Being alive is impossible without blood, the complex liquid containing millions of chemicals and cells.
When William Harvey for the first time described blood circulation, scientists started to think about a proper replacement such as an artificial blood. In fact, production of a liquid that mimics all blood functions is still a dream, although it may come true in future. Some kind of blood substitutes developed over time, including simple liquids such as, urine, beer, and milk and plant resins, 1 with least similarity to the blood constituents, and cells originated from stem cells with maximum similarity to blood.
In addition, low blood supplies especially in developing countries, lower number of donors due to the aging of population and consequently increased demand for blood products, short storage period, and urgent needs for blood supplies during wartime and natural disasters are other important reasons that make the development of a suitable blood substitute indispensable.
Artificial Blood Substitutes: First Steps on the Long Route to Clinical Utility
Understanding the blood behavior at the microcirculation level where blood and tissues come into contact is a key step in the development and application of blood substitutes. In other words, a blood substitute must be designed in a way that it behaves similar to natural blood in microcirculation. Here, we mainly discuss and review the blood substitutes that mimic the oxygen-carrying capability of blood. In addition, potential challenges and obstacles against routine application of artificial blood in human will be discussed. These complications can be divided into noninfectious and infectious and are the most important concerns for the application of RBCs.
Hence, it is essential to develop efficient RBC substitutes capable of active oxygen and carbon dioxide transfer. RBC substitutes or synthetic oxygen transporters studied so far are of mainly two types: Perfluorochemicals PFCs are colorless, inert, and apparently nontoxic liquids with low boiling point temperatures and are insoluble in water and alcohol.
In addition, PFCs dissolve — mL carbon dioxide, which is two to three times higher than the corresponding water capacity. An in vitro study showed that use of PFCs as artificial blood is considerably advantageous in occluded coronary artery to maintain myocardial function. Perflubron and perfluorodecalin have been extensively studied among PFCs.
Other sources for this purpose include cord blood RBCs and animal bovine and recombinant Hb. Transmission of infection is an important concern in the application of Hbs with human or animal origins. In particular, the assessment of transmission risk of infectious agents causing bovine spongiform encephalitis is very important.
Furthermore, Hb can be genetically manipulated by this approach to overcome some side effects associated with these products, for example, the affinity of Hb for NO and O 2 can be changed. The half-life of Hb is equal inside and outside the RBCs; however, outside the RBCs, the natural tetramer molecule of Hb rapidly converts to dimer and monomer Hb species, which cause severe complications such as kidney damage. NO is also involved in relaxation of smooth muscles of blood vessels, and this property is responsible for the vasoactivity of Hb-based products. However, among different modifications of Hb, only nanotechnology-based polyhemoglobin PolyHb and conjugated Hb are effective.
Spontaneous separation of Hb chains is prevented by various modifications. For example, in the cross-linked type, Hb chains are bound by intermolecular covalent bonds, in the polymerized type, they are bound by intermolecular covalent bond, and in the conjugated type, a polymer is bound to the surface of Hb.
As a result, Met-Hb with low oxygen-carrying capacity was produced, showing that such complications can be avoided by attaching reducing agents to Hb surface in this product series. First, acellular HBOCs were cross-linked HBOC in which intramolecular covalent bonds were formed between globin chains in order to prevent their detachment. Diaspirin cross-linked Hb or HemAssist in which human Hb molecule has been intramolecularly cross-linked between alpha chains has been subjected to extensive investigation.
This product has been used for various purposes, such as reduction of neurological damage in a mouse model, 29 intraoperative anemia in sheep, 30 cardiopulmonary resuscitation in pigs, 31 and postcardiac bypass surgery to avoid allogeneic blood transfusion. Each PolyHb molecule is composed of 4—5 Hb molecules, and various kinds of PolyHb molecules have been produced so far. However, its administration has been rejected by the United States Food and Drug Administration US FDA due to its adverse effects 5 including hypertension, safety and toxicity issues attributed to vasoactivity, and oxidative stress.
Oxyglobin is another product developed by OPK biotech in which bovine Hb has been used. This product could be stored at room temperature for days and its lyophilized form can be sterilized. PolyHb—fibrinogen is a product showing both oxygen-carrying and blood coagulation properties, which can be used in massive bleedings where the oxygen-carrying capacity is not sufficient by itself.
Their study showed that application of larger polysaccharides led to higher Hb cross-linking and polymerization, and O -methylglucopyranoside is the best polysaccharide to achieve this goal. Due to unique characteristics, low toxicity, and lack of immunogenicity or antigenicity in body, PEG can be the best polymer for conjugation. Hemospan is a PEG-conjugated Hb, which is under clinical trial as an oxygen carrier. This modification has been shown to increase the circulation half-life of the product. This product did not cause vasoconstriction in animal models, and its efficacy to deliver oxygen to hypoxic tissues was demonstrated; MP4 is now under human clinical trials.
In addition to PEG, other polymers have been used to conjugate Hb, including benzene tetracarboxylate dextran, 39 hydroxyethyl starch called HRC , 40 and albumin. The highest Hb activity is seen when it is within RBCs. Therefore, when Hb is going to be used in a cell-free format, it must be subjected to various modifications for increasing its half-life in circulation and preventing related complications in the body.
In fact, recombinant production of Hb makes it easier to be modified specially through site-directed mutagenesis. In s, human Hb was produced in large quantities in transgenic organisms. Since then, investigations for higher quality and more efficient production of recombinant Hb were started. It should be noted that most studies have focused on the production of Hb by E.
There have been several attempts to increase the production yield of recombinant Hb. For example, in a study, E. Then, the produced Hbs Hb minotaur were polymerized using intermolecular disulfide bonds and designated as Hb Polytaur. Animal studies revealed some advantages for this product over the other products of this type. In addition, to increase the production yield of heme for the generation of functional Hb, the strategy of simultaneous heme transporter generation in bacterial membrane can be used, which might increase heme uptake by the bacterial host and subsequently increase the production yield.
Characteristics of an Ideal Blood Substitute
Targeted mutations of Hb might also cause several improvements in its functions outside RBCs. For example, targeted mutations could result in increased oxygen affinity, reduced capacity of Hb to scavenge NO, reduced autooxidation, decreased rate of heme loss, preventing the detachment of subunits, and decreased irreversible denaturation of subunits. This polymerizes using intertetramer disulfide bonds, and the molecular size of this product was shown to be stable in fresh frozen plasma. This mutation causes reduced oxygen affinity, increased cooperativity, and decreased autooxidation of the product.
These are only a few cases of successful efforts for the production of recombinant HBOCs being able to be used as a favorable blood substitute. However, none of the products have received therapeutic licensure in the USA. Other types of Hb-based products as artificial blood are cellular HBOCs, in which Hb is encapsulated in a cell-like structure. In this way, some products with highest similarity to RBCs were produced, which do not cause vasoactivation due to scavenging of NO. A summary of products corresponding to the cellular-based Hb is shown in Table 2.
Encapsulation of Hb by a phospholipid layer liposome-encapsulated Hb [LEH] prolonged its half-life and shelf-life comparing to acellular products. This small size enables their entry into areas of body that are not accessible for RBCs. Hence, they can pass through clots and blockages causing more oxygenation during stroke. In a study, liposome-encapsulated Hbs known as neo red cells were developed, and their efficiency as artificial RBCs was demonstrated in total cardiopulmonary bypass in an animal study, which showed even higher oxygen delivery capacity than RBC.
Modifying the surface of these liposomes, including PEGylation, can result in products with higher half-life, stability, and solubility, as well as lower antigenicity and immunogenicity. Hb vesicle is a PEGylated product with increased serum half-life and decreased recognition by the immune system.
In addition to the removal by reticuloendothelial system, another reason for low serum half-life of LEHs is shear-induced liposome destruction in bloodstream. Hence, to address this issue, an actin matrix was introduced into the aqueous core of the submicron liposomes to increase their mechanical strength.
This strategy caused increased half-life of the product known as LEAcHb. However, the most important problem with their application is rapid clearance by phagocytes either directly or through opsonins. To address this problem, several studies have been conducted. It was demonstrated that surface charge of products used as artificial blood substitutes has a profound effect on their circulation time, where anionized HbPNPs are rapidly cleared from bloodstream and cationized HbPNPs have high circulation half-life.
Other cellular-based biocompatible Hb products with repetitively branched molecular structures are dendrimers. Poly propylene , poly amide amine , and polyether are among synthetic dendrimer products. The shape and size of these products are similar to Hb, and they are able to bind and release oxygen. Summarizing landmark study, quantity four of this crucial seriesfurnishes details at the availability of germplasm assets that breeders can make the most for generating high-yielding oilseed crop kinds. Written through major foreign specialists, this quantity provides the main up to date info on utilising genetic assets to extend the yield of the key seven oilseed vegetation.
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