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Blood Substitutes: Evolution and Future Applications
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Blood Substitutes: Evolution and Future Applications

A special issue of Journal of Functional Biomaterials (ISSN 2079-4983).

Deadline for manuscript submissions: closed (3 July 2017) | Viewed by 43608

Special Issue Editor

Prof. Dr. Hiromi Sakai

E-Mail Website
Guest Editor
Department of Chemistry, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8521, Japan
Interests: artificial oxygen carriers; molecular assembly; liposome; redox and ligand binding of hemoglobin; tissue oxygenation; tissue engineering; microvascular physiology; hemorheology; microhemodynamics

Special Issue Information

Dear Colleagues,

Hemoglobin (Hb) functions as an oxygen-binding protein in blood. The fact that Hb is the most abundant protein in blood reflects that oxygen transport is the most important function of blood to maintain vital activity. Nevertheless, Hb shows cardiovascular, renal, and neurological toxicity once it is released from erythrocytes. When Hb is used as a biomaterial and as a source of making artificial oxygen carriers (blood substitutes), it is necessary to purify Hb extensively to eliminate pathogens, to engineer Hb with chemical modification, bioconjugation, encapsulation or recombinant technology, to eliminate such toxic effects of molecular Hb, and to prepare a fluid with important physicochemical properties such as affinities to endogenous gas molecules, particle size, osmotic pressure, and viscosity to mimic the characteristics of blood. The advantages of artificial oxygen carriers (blood substitutes) are that they have no contamination of pathogens or blood type antigen, and that they have sufficient stability for long-term stockpiling. They were developed originally as a transfusion alternative. However, their different physicochemical properties from those of erythrocytes enable other clinical applications that include the following: oxygen therapeutics for ischemic diseases, cancer, inflammatory disease, and sickle cell disease; and perfusates for transplantation, tissue engineering, and other applications. They are also used as carbon monoxide carriers to prevent diseases related to oxidative stress. Consequently, the research field of blood substitutes continues to expand.

This Special Issue, “Blood Substitutes: Evolution and Future Application”, provides a multidisciplinary forum for original research articles as well as critical reviews and perspectives related to current advances and innovations in the field of blood substitutes from academia and industry.

Prof. Dr. Hiromi Sakai
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Journal of Functional Biomaterials is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Design, synthesis, and physicochemical properties of artificial oxygen carriers and fluids
  • Toxicity of Hb and its mechanisms
  • Purification processes for Hb
  • Safety and efficacy of blood substitutes
  • Impact on microhemodynamics by injection of artificial oxygen carriers
  • Design of preclinical and clinical studies
  • Transfusion alternatives, oxygen therapeutics, CO therapeutics, photosensitizers, and other potential clinical applications

Published Papers (5 papers)

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Review

1347 KiB  
Review
Potential New Non-Invasive Therapy Using Artificial Oxygen Carriers for Pre-Eclampsia
by Hidenobu Ohta, Maiko Kaga, Heng Li, Hiromi Sakai, Kunihiro Okamura and Nobuo Yaegashi
J. Funct. Biomater. 2017, 8(3), 32; https://doi.org/10.3390/jfb8030032 - 30 Jul 2017
Cited by 10 | Viewed by 6515
Abstract
The molecular mechanisms of pre-eclampsia are being increasingly clarified in animals and humans. With the uncovering of these mechanisms, preventive therapy strategies using chronic infusion of adrenomedullin, vascular endothelial growth factor-121 (VEGF-121), losartan, and sildenafil have been proposed to block narrow spiral artery [...] Read more.
The molecular mechanisms of pre-eclampsia are being increasingly clarified in animals and humans. With the uncovering of these mechanisms, preventive therapy strategies using chronic infusion of adrenomedullin, vascular endothelial growth factor-121 (VEGF-121), losartan, and sildenafil have been proposed to block narrow spiral artery formation in the placenta by suppressing related possible factors for pre-eclampsia. However, although such preventive treatments have been partly successful, they have failed in ameliorating fetal growth restriction and carry the risk of possible side-effects of drugs on pregnant mothers. In this study, we attempted to develop a new symptomatic treatment for pre-eclampsia by directly rescuing placental ischemia with artificial oxygen carriers (hemoglobin vesicles: HbV) since previous data indicate that placental ischemia/hypoxia may alone be sufficient to lead to pre-eclampsia through up-regulation of sFlt-1, one of the main candidate molecules for the cause of pre-eclampsia. Using a rat model, the present study demonstrated that a simple treatment using hemoglobin vesicles for placental ischemia rescues placental and fetal hypoxia, leading to appropriate fetal growth. The present study is the first to demonstrate hemoglobin vesicles successfully decreasing maternal plasma levels of sFlt-1 and ameliorating fetal growth restriction in the pre-eclampsia rat model (p < 0.05, one-way ANOVA). In future, chronic infusion of hemoglobin vesicles could be a potential effective and noninvasive therapy for delaying or even alleviating the need for Caesarean sections in pre-eclampsia. Full article
(This article belongs to the Special Issue Blood Substitutes: Evolution and Future Applications)
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1349 KiB  
Review
Biocompatibility of HbV: Liposome-Encapsulated Hemoglobin Molecules-Liposome Effects on Immune Function
by Hiroshi Azuma, Mitsuhiro Fujihara and Hiromi Sakai
J. Funct. Biomater. 2017, 8(3), 24; https://doi.org/10.3390/jfb8030024 - 28 Jun 2017
Cited by 12 | Viewed by 6191
Abstract
Hemoglobin vesicles (HbVs) are oxygen carriers consisting of Hb molecules and liposome in which human hemoglobin (Hb) molecules are encapsulated. Investigations of HbV biocompatibility have shown that HbVs have no significant effect on either the quality or quantity of blood components such as [...] Read more.
Hemoglobin vesicles (HbVs) are oxygen carriers consisting of Hb molecules and liposome in which human hemoglobin (Hb) molecules are encapsulated. Investigations of HbV biocompatibility have shown that HbVs have no significant effect on either the quality or quantity of blood components such as RBC, WBC, platelets, complements, or coagulation factors, reflecting its excellent biocompatibility. However, their effects on the immune system remain to be evaluated. HbVs might affect the function of macrophages because they accumulate in the reticuloendothelial system. Results show that splenic T cell proliferation is suppressed after injection of not only HbV but also empty liposome into rat, and show that macrophages that internalized liposomal particles are responsible for the suppression. However, the effect is transient. Antibody production is entirely unaffected. Further investigation revealed that those macrophages were similar to myeloid-derived suppressor cells (MDSCs) in terms of morphology, cell surface markers, and the immune-suppression mechanism. Considering that MDSCs appear in various pathological conditions, the appearance of MDSC-like cells might reflect the physiological immune system response against the substantial burden of liposomal microparticles. Therefore, despite the possible induction of immunosuppressive cells, HbVs are an acceptable and promising candidate for use as a blood substitute in a clinical setting. Full article
(This article belongs to the Special Issue Blood Substitutes: Evolution and Future Applications)
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2279 KiB  
Review
Artificial Red Blood Cells as Potential Photosensitizers in Dye Laser Treatment Against Port-Wine Stains
by Naoaki Rikihisa, Shoji Watanabe, Yoshiaki Saito and Hiromi Sakai
J. Funct. Biomater. 2017, 8(2), 14; https://doi.org/10.3390/jfb8020014 - 13 Apr 2017
Cited by 7 | Viewed by 10298
Abstract
We suggest a novel method that uses artificial blood cells (hemoglobin vesicles, Hb-Vs) as photosensitizers in dye laser treatment (at 595-nm wavelength) for port-wine stains (i.e., capillary malformations presenting as red birthmarks) based on the results of animal experiments. As compared with human [...] Read more.
We suggest a novel method that uses artificial blood cells (hemoglobin vesicles, Hb-Vs) as photosensitizers in dye laser treatment (at 595-nm wavelength) for port-wine stains (i.e., capillary malformations presenting as red birthmarks) based on the results of animal experiments. As compared with human red blood cells, Hb-Vs have the same absorbance of 595 nm wavelength light and produce the same level of heat following dye laser irradiation. Small sized Hb-Vs (250 nm) distribute in the plasma phase in blood and tend to flow in the marginal zone of microvessels. Intravenous injections of Hb-Vs caused the dilatation of microvessels, and dye laser treatment with Hb-Vs destroyed the vessel wall effectively. Following the intravenous injection of Hb-Vs, the microvessels contained more Hb that absorbed laser photons and produced heat. This extra Hb tended to flow near the endothelial cells, which were the target of the laser treatment. These attributes of Hb-Vs will potentially contribute to enhancing the efficacy of dye laser treatment for port-wine stains. Hemoglobin is a type of porphyrin. Thus, our proposed treatment may have aspects of photodynamic therapy using porphyrin that leads to a cytotoxicity effect by active oxygen. Full article
(This article belongs to the Special Issue Blood Substitutes: Evolution and Future Applications)
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262 KiB  
Review
Comparison of the Pharmacokinetic Properties of Hemoglobin-Based Oxygen Carriers
by Kazuaki Taguchi, Keishi Yamasaki, Toru Maruyama and Masaki Otagiri
J. Funct. Biomater. 2017, 8(1), 11; https://doi.org/10.3390/jfb8010011 - 18 Mar 2017
Cited by 23 | Viewed by 9479
Abstract
Hemoglobin (Hb) is an ideal material for use in the development of an oxygen carrier in view of its innate biological properties. However, the vascular retention of free Hb is too short to permit a full therapeutic effect because Hb is rapidly cleared [...] Read more.
Hemoglobin (Hb) is an ideal material for use in the development of an oxygen carrier in view of its innate biological properties. However, the vascular retention of free Hb is too short to permit a full therapeutic effect because Hb is rapidly cleared from the kidney via glomerular filtration or from the liver via the haptogloblin-CD 163 pathway when free Hb is administered in the blood circulation. Attempts have been made to develop alternate acellular and cellular types of Hb based oxygen carriers (HBOCs), in which Hb is processed via various routes in order to regulate its pharmacokinetic properties. These HBOCs have been demonstrated to have superior pharmacokinetic properties including a longer half-life than the Hb molecule in preclinical and clinical trials. The present review summarizes and compares the pharmacokinetic properties of acellular and cellular type HBOCs that have been developed through different approaches, such as polymerization, PEGylation, cross-linking, and encapsulation. Full article
(This article belongs to the Special Issue Blood Substitutes: Evolution and Future Applications)
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Graphical abstract

746 KiB  
Review
Overview of Potential Clinical Applications of Hemoglobin Vesicles (HbV) as Artificial Red Cells, Evidenced by Preclinical Studies of the Academic Research Consortium
by Hiromi Sakai
J. Funct. Biomater. 2017, 8(1), 10; https://doi.org/10.3390/jfb8010010 - 15 Mar 2017
Cited by 41 | Viewed by 10478
Abstract
Hemoglobin (Hb) is the most abundant protein in whole blood. This fact implies that the oxygen binding and releasing function of Hb is the most vital for sustaining life. All Hb is compartmentalized in red blood cells (RBCs) with corpuscular Hb concentration of [...] Read more.
Hemoglobin (Hb) is the most abundant protein in whole blood. This fact implies that the oxygen binding and releasing function of Hb is the most vital for sustaining life. All Hb is compartmentalized in red blood cells (RBCs) with corpuscular Hb concentration of about 35 g/dL, covered with a thin biomembrane. In spite of its abundance, Hb sometimes shows toxicity once it is leaked from RBCs. The shielding effect of the RBC membrane is physiologically important. Based on this structural importance, we have studied artificial red cells (Hb vesicles, HbV) as artificial oxygen carriers, which encapsulate a purified and concentrated Hb solution in phospholipid vesicles, mimicking the cellular structure of RBCs. Our academic research consortium has clarified the safety and efficacy of this HbV, aiming at clinical applications. Because of some superior characteristics to those of RBCs, HbV has the potential for use not only as a transfusion alternative but also for oxygen and carbon monoxide therapeutics, perfusate for transplant organs, and photosensitizer. In this review paper, such potential applications are summarized. Full article
(This article belongs to the Special Issue Blood Substitutes: Evolution and Future Applications)
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