Special Issue "Blood Substitutes"

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

Deadline for manuscript submissions: closed (30 November 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Ken Olsen

Department of Chemistry, Loyola University of Chicago, 1032 W. Sheridan Rd., Chicago, IL 60660, USA
Website | E-Mail
Interests: the development of polymeric hemoglobins as potential blood substitutes; developing cancer-targeted photodynamic therapy agents; understanding protein-ligand interactions through molecular dynamics simulations

Special Issue Information

Dear Colleagues,

The development of hemoglobin-based oxygen carriers (HBOC) as effective alternatives to blood transfusion is clearly a desirable goal. Despite the significant commercial resources that have been expended over the last several decades to achieve this end, no products have received US FDA approval. The basic science is much better understood than it was in the 1980s when the quest began. The requirements for a successful HBOC have been clearly delineated. Various side effects have inhibited further development and regulatory approval. Cardiovascular events are of particular concern, but other aspects needing investigation include the impact of HBOCs on human physiology, the routes and consequences of hemoglobin metabolism and developing new HBOCs with improved characteristics, such as prolonged functional intravascular persistence, greater stability, and a decreased propensity to generate reactive oxygen species. New biomaterials are being developed to address these problems encountered with earlier HBOCs. In some cases these are not hemoglobin-based, but may offer new solutions to the same problems faced by the HBOCs.

Prof. Dr. Ken Olsen
Guest Editor

Submission

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. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as 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 refereed through a 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 quarterly 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 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.


Published Papers (6 papers)

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Research

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Open AccessArticle Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats
J. Funct. Biomater. 2014, 5(4), 246-258; doi:10.3390/jfb5040246
Received: 17 September 2014 / Revised: 7 November 2014 / Accepted: 12 November 2014 / Published: 18 November 2014
Cited by 1 | PDF Full-text (242 KB) | HTML Full-text | XML Full-text
Abstract
The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with
[...] Read more.
The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction. The aim of this study was to assess vasoactive effects of OxyVita C on systemic blood pressures and cerebral pial arteriole diameters. Anesthetized healthy rats received four intravenous (IV) infusions of an increasing dose of OxyVita C (2, 25, 50, 100 mg/kg) and hemodynamic parameters and pial arteriolar diameters were measured pre- and post-infusion. Normal saline was used as a volume-matched control. Systemic blood pressures increased (P ≤ 0.05) with increasing doses of OxyVita C, but not with saline. There was no vasoconstriction in small (<50 µm) and medium-sized (50–100 µm) pial arterioles in the OxyVita C group. In contrast, small and medium-sized pial arterioles vasoconstricted in the control group. Compared to saline, OxyVita C showed no cerebral vasoconstriction after any of the four doses evaluated in this rat model despite increases in blood pressure. Full article
(This article belongs to the Special Issue Blood Substitutes)
Open AccessArticle Monodisperse 130 kDa and 260 kDa Recombinant Human Hemoglobin Polymers as Scaffolds for Protein Engineering of Hemoglobin-Based Oxygen Carriers
J. Funct. Biomater. 2012, 3(1), 61-78; doi:10.3390/jfb3010061
Received: 3 November 2011 / Revised: 29 December 2011 / Accepted: 5 January 2012 / Published: 13 January 2012
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Abstract
A recombinant 130 kDa dihemoglobin which is made up of a single-chain tetra-α globin and four β globins has been expressed as a soluble protein in E. coli. The sequence of the single chain tetra-α is: αI-Gly-αII-(SerGlyGly)5Ser-αIII-Gly-αIV. This dihemoglobin has been purified
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A recombinant 130 kDa dihemoglobin which is made up of a single-chain tetra-α globin and four β globins has been expressed as a soluble protein in E. coli. The sequence of the single chain tetra-α is: αI-Gly-αII-(SerGlyGly)5Ser-αIII-Gly-αIV. This dihemoglobin has been purified and characterized in vitro by size exclusion chromatography, electrospray mass spectroscopy, equilibrium oxygen binding, and analytical ultracentrifugation. The observed values of P50 and nmax for the dihemoglobin are slightly lower than those observed for the recombinant hemoglobin rHb1.1 (a “monohemoglobin” comprised of two β globins and an αI-Gly-αII diα-globin chain). Titration of the deoxy form of dihemoglobin with CO shows that all eight heme centers bind ligand. In vivo, dihemoglobin showed increased circulating halflife and a reduced pressor response in conscious rats when compared to rHb1.1. These observations suggest that dihemoglobin is an oxygen carrying molecule with desirable in vivo properties and provides a platform for an isooncotic hemoglobin solution derived solely from a recombinant source. A 260 kDa tetrahemoglobin has also been produced by chemical crosslinking of a dihemoglobin that contains a Lys16Cys mutation in the C-terminal α-globin subunit. Tetrahemoglobin also shows reduced vasoactivity in conscious rats that is comparable to that observed for dihemoglobin. Full article
(This article belongs to the Special Issue Blood Substitutes)

Review

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Open AccessReview Effects of Hemoglobin-Based Oxygen Carriers on Blood Coagulation
J. Funct. Biomater. 2014, 5(4), 288-295; doi:10.3390/jfb5040288
Received: 24 August 2014 / Revised: 19 November 2014 / Accepted: 25 November 2014 / Published: 12 December 2014
Cited by 1 | PDF Full-text (191 KB) | HTML Full-text | XML Full-text
Abstract
For many decades, Hemoglobin-based oxygen carriers (HBOCs) have been central in the development of resuscitation agents that might provide oxygen delivery in addition to simple volume expansion. Since 80% of the world population lives in areas where fresh blood products are not available,
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For many decades, Hemoglobin-based oxygen carriers (HBOCs) have been central in the development of resuscitation agents that might provide oxygen delivery in addition to simple volume expansion. Since 80% of the world population lives in areas where fresh blood products are not available, the application of these new solutions may prove to be highly beneficial (Kim and Greenburg 2006). Many improvements have been made to earlier generation HBOCs, but various concerns still remain, including coagulopathy, nitric oxide scavenging, platelet interference and decreased calcium concentration secondary to volume expansion (Jahr et al. 2013). This review will summarize the current challenges faced in developing HBOCs that may be used clinically, in order to guide future research efforts in the field. Full article
(This article belongs to the Special Issue Blood Substitutes)
Open AccessReview Replacing the Transfusion of 1–2 Units of Blood with Plasma Expanders that Increase Oxygen Delivery Capacity: Evidence from Experimental Studies
J. Funct. Biomater. 2014, 5(4), 232-245; doi:10.3390/jfb5040232
Received: 13 August 2014 / Revised: 17 September 2014 / Accepted: 15 October 2014 / Published: 27 October 2014
Cited by 2 | PDF Full-text (223 KB) | HTML Full-text | XML Full-text
Abstract
At least a third of the blood supply in the world is used to transfuse 1–2 units of packed red blood cells for each intervention and most clinical trials of blood substitutes have been carried out at this level of oxygen carrying capacity
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At least a third of the blood supply in the world is used to transfuse 1–2 units of packed red blood cells for each intervention and most clinical trials of blood substitutes have been carried out at this level of oxygen carrying capacity (OCC) restoration. However, the increase of oxygenation achieved is marginal or none at all for molecular hemoglobin (Hb) products, due to their lingering vasoactivity. This has provided the impetus for the development of “oxygen therapeutics” using Hb-based molecules that have high oxygen affinity and target delivery of oxygen to anoxic areas. However it is still unclear how these oxygen carriers counteract or mitigate the functional effects of anemia due to obstruction, vasoconstriction and under-perfusion. Indeed, they are administered as a low dosage/low volume therapeutic Hb (subsequently further diluted in the circulatory pool) and hence induce extremely small OCC changes. Hyperviscous plasma expanders provide an alternative to oxygen therapeutics by increasing the oxygen delivery capacity (ODC); in anemia they induce supra-perfusion and increase tissue perfusion (flow) by as much as 50%. Polyethylene glycol conjugate albumin (PEG-Alb) accomplishes this by enhancing the shear thinning behavior of diluted blood, which increases microvascular endothelial shear stress, causes vasodilation and lowering peripheral vascular resistance thus facilitating cardiac function. Induction of supra-perfusion takes advantage of the fact that ODC is the product of OCC and blood flow and hence can be maintained by increasing either or both. Animal studies suggest that this approach may save a considerable fraction of the blood supply. It has an additional benefit of enhancing tissue clearance of toxic metabolites. Full article
(This article belongs to the Special Issue Blood Substitutes)
Open AccessReview Biophysical Properties of Lumbricus terrestris Erythrocruorin and Its Potential Use as a Red Blood Cell Substitute
J. Funct. Biomater. 2012, 3(1), 49-60; doi:10.3390/jfb3010049
Received: 21 October 2011 / Revised: 9 December 2011 / Accepted: 24 December 2011 / Published: 6 January 2012
Cited by 5 | PDF Full-text (295 KB) | HTML Full-text | XML Full-text
Abstract
Previous generations of hemoglobin (Hb)-based oxygen carriers (HBOCs) have been plagued by key biophysical limitations that result in severe side-effects once transfused in vivo, including protein instability, high heme oxidation rates, and nitric oxide (NO) scavenging. All of these problems emerge after
[...] Read more.
Previous generations of hemoglobin (Hb)-based oxygen carriers (HBOCs) have been plagued by key biophysical limitations that result in severe side-effects once transfused in vivo, including protein instability, high heme oxidation rates, and nitric oxide (NO) scavenging. All of these problems emerge after mammalian Hbs are removed from red blood cells (RBCs) and used for HBOC synthesis/formulation. Therefore, extracellular Hbs (erythrocruorins) from organisms which lack RBCs might serve as better HBOCs. This review focuses on the erythrocruorin of Lumbricus terrestris (LtEc), which has been shown to be extremely stable, resistant to oxidation, and may interact with NO differently than mammalian Hbs. All of these beneficial properties show that LtEc is a promising new HBOC which warrants further investigation. Full article
(This article belongs to the Special Issue Blood Substitutes)
Figures

Open AccessReview Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review
J. Funct. Biomater. 2011, 2(4), 414-424; doi:10.3390/jfb2040414
Received: 3 November 2011 / Revised: 3 December 2011 / Accepted: 13 December 2011 / Published: 16 December 2011
Cited by 2 | PDF Full-text (269 KB) | HTML Full-text | XML Full-text
Abstract
OxyVita Hb is a new generation hemoglobin based oxygen carrier (HBOC) produced through modification of a zero-linked polymerization mechanism using activators which incorporate cross-linked bovine tetramer hemoglobin into “super-polymeric” macromolecules (Average molecular weight = 17 MDa) for the purpose of oxygen delivery when
[...] Read more.
OxyVita Hb is a new generation hemoglobin based oxygen carrier (HBOC) produced through modification of a zero-linked polymerization mechanism using activators which incorporate cross-linked bovine tetramer hemoglobin into “super-polymeric” macromolecules (Average molecular weight = 17 MDa) for the purpose of oxygen delivery when whole blood or packed red cells are not available. This molecular design approach was generated in order to address several fundamental biochemical and physiological weaknesses of previous generations of HBOCs. Observation during pre-clinical and clinical studies provided evidence that these early generation acellular HBOCs were directly associated with loss of retention within the circulatory system, extravasation across endothelial tissue membranes due to their small molecular size leading to arterial and venous vasoconstriction with coupled increases in mean arterial pressure (MAP). The inherent increase in molecular size and structural stability of the OxyVita Hb is a direct response to addressing these serious weaknesses that have occurred during the evolution of HBOC development within the past two decades. The nature of the zero-linked synthetic route eliminates any chemical linkers remaining in the product, eliminating side reaction concerns, such as reversibility and decomposition due to weak chemical bonds, dependency on temperature and pressure, and residual toxicity. Full article
(This article belongs to the Special Issue Blood Substitutes)

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