Development of Zero-Link Polymers of Hemoglobin, Which do not Extravasate and do not Induce Pressure Increases upon Infusion

Bucci, Enrico; Kwansa, Herman; Koehler, Raymond C.; Matheson, Barbara

doi:10.1080/10731190600974277

Cited by 26 publications

(16 citation statements)

References 13 publications

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“…Its large molecular dimensions are accompanied by increased solution viscosity and the attenuation of Hb’s vasoconstrictive activity and extravasation. 86 This formulation has also shown to be highly resistant to dissociation by comparison to natural acellular polymeric Hbs found in the terrestrial and marine organisms. 85 Furthermore, OxyVita has a comparatively high heme stability.…”

Section: Oxygen Carrying Plasma Expandersmentioning

confidence: 94%

“…83 Hemoglobin from the marine worm Arenicola marina is being developed as an HBOC 84 and has properties similar to the synthesized zero linked polymeric Hb OxiVita 85 developed by Prof. Bucci’s group. 86 …”

Section: Blood Rheology and Plasma Expansionmentioning

confidence: 99%

“…144 This configuration can be obtained by oligomerization of Hb, an approach that was used by Bucci and colleagues. 86 Their intra-molecularly cross-linked bovine Hb is obtained by means of a chemistry referred to as “zero length cross linking” that yields a low O 2 affinity Hb polymer with 36 nm hydrodynamic radius and average molecular weight 17 MDa. 86 …”

Section: Oxygen Carrying Plasma Expandersmentioning

confidence: 99%

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Blood Substitutes

Cabrales¹,

Intaglietta²

2013

ASAIO Journal

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The development of oxygen (O2) carrying blood substitutes has evolved from the goal of replicating blood O2 transports 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 physiological 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 current blood substitutes development has amplified their applications horizon by devising therapeutic functions for oxygen carriers requiring limited O2 delivery capacity restoration. Conversely, full, blood-like O2 carrying capacity re-establishment awaits control of O2 carrier toxicity.

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Section: Oxygen Carrying Plasma Expandersmentioning

confidence: 94%

Section: Blood Rheology and Plasma Expansionmentioning

confidence: 99%

Section: Oxygen Carrying Plasma Expandersmentioning

confidence: 99%

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Blood Substitutes

Cabrales¹,

Intaglietta²

2013

ASAIO Journal

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“…But ligand binding varies widely between the HBOCs (a factor of 10 for P 50 in Table 3). The percent tetramer, a critical factor in HBOC-mediated vasoactivity 25,26 ranges from 1% to 100%. Vasoactivity varies widely with product, with 2 HBOCs claiming no vasoactivity.…”

Section: Lack Of Evidence For Toxic Class-effectmentioning

confidence: 99%

Are Hemoglobin-Based Oxygen Carriers Being Withheld Because of Regulatory Requirement for Equivalence to Packed Red Blood Cells?

Mackenzie

Pitman²,

Hodgson

et al. 2015

American Journal of Therapeutics

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“…Earlier pre-clinical studies carried out utilized these initial preparations which typically contained a heterogeneous distribution of high molecular weight species in the range of 25MDa [22]. …”

Section: Experimental Development/production Of Oxyvita Hemoglobin: Lmentioning

confidence: 99%

Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review

Harrington

Wollocko²

2011

JFB

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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

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Development of Zero-Link Polymers of Hemoglobin, Which do not Extravasate and do not Induce Pressure Increases upon Infusion

Cited by 26 publications

References 13 publications

Blood Substitutes

Blood Substitutes

Are Hemoglobin-Based Oxygen Carriers Being Withheld Because of Regulatory Requirement for Equivalence to Packed Red Blood Cells?

Molecular Design Properties of OxyVita Hemoglobin, a New Generation Therapeutic Oxygen Carrier: A Review

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