Albumin-derived perfluorocarbon-based artificial oxygen carriers: A physico-chemical characterization and first in vivo evaluation of biocompatibility

Wrobeln, Anna; Laudien, Julia; Groß-Heitfeld, Christoph; Linders, Jürgen; Mayer, Christian; Wilde, Benjamin; Knoll, Tanja; Naglav, Dominik; Kirsch, Michael; Ferenz, Katja Bettina

doi:10.1016/j.ejpb.2017.02.015

Cited by 40 publications

(60 citation statements)

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“…In vitro experiments, perfusion of isolated Langendorff hearts as well as in vivo toxicities studies showed promising results for the applicability of albumin-derived perfluorocarbon-based capsules as blood substitutes and dispelled concerns on capsule aggregation in vivo 13,15 . Still, physiological in vivo "proof of concept" was missing.…”

Section: Discussionmentioning

confidence: 99%

Albumin-derived perfluorocarbon-based artificial oxygen carriers can avoid hypoxic tissue damage in massive hemodilution

Wrobeln

Jägers

Quinting

et al. 2020

Sci Rep

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Artificial blood for clinical use is not yet available therefore, we previously developed artificial oxygen carriers (capsules) and showed their functionality in vitro and biocompatibility in vivo. Herein, we assessed the functionality of the capsules in vivo in a normovolemic hemodilution rat-model. We stepwise exchanged the blood of male Wistar-rats with medium either in the presence of capsules (treatment) or in their absence (control). We investigated tissue hypoxia thoroughly through online biomonitoring, determination of enzyme activity and pancreatic hormones in plasma, histochemical and immunohistochemical staining of small intestine, heart, liver and spleen as well as in situ hybridization of kidneys. After hemodilution, treated animals show higher arterial blood pressure and have a stable body temperature. Additionally, they show a more stable pH, a higher oxygen partial pressure (pO 2), and a lower carbon dioxide partial pressure (pCO 2). Interestingly, blood-glucose-levels drop severely in treated animals, presumably due to glucose consumption. Creatine kinase values in these animals are increased and isoenzyme analysis indicates the spleen as origin. Moreover, the small intestine of treated animals show reduced hypoxic injury compared to controls and the kidneys have reduced expression of the hypoxia-inducible erythropoietin mRNA. In conclusion, our capsules can prevent hypoxic tissue damage. The results provide a proof of concept for capsules as adequate erythrocyte substitute. The need to develop synthetic products for blood replacement has become more and more important during the last decades. On the one hand, the demographic change leads to increasing requirements for blood, and on the other hand, simultaneously the willingness for blood donation declines 1. Blood with its various characteristics fulfils many functions, recent developments of synthetic blood substitutes focus on its most important function: the transport of physiological gases, in particular of oxygen. Additional key requirements for artificial blood substitutes are optimal size, sterility, biocompatibility, and the ability to be stored without loss of functionality. Moreover, artificial oxygen carriers (AOCs) should have a long intravascular circulation time and universal usage independent of the blood group characteristics 2,3. There are two main approaches to realize the transport of essential gases. The first is the use of the physiological oxygen carrier hemoglobin (hemoglobin-based artificial oxygen carriers, HBOCs); a concept realized e.g. in the prominent product hemopure, that gained pharmaceutical approval in South Africa and Mexico. Further HBOCs (e.g. sanguinate) are currently tested in clinical trials 4. So far, most of the products showed severe side effects so that the manufacturing had to be stopped 5. The second is the work with synthetic materials like perfluorocarbons [perfluorocarbon-based artificial oxygen carriers (PFOCs)]. Depending on the actual partial pressure, PFOCs are able to solve gases physically 6...

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Section: Discussionmentioning

confidence: 99%

Albumin-derived perfluorocarbon-based artificial oxygen carriers can avoid hypoxic tissue damage in massive hemodilution

Wrobeln

Jägers

Quinting

et al. 2020

Sci Rep

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“…Liver damage parameters (aspartate transaminase and alanine transaminase) increase transiently [ 6 , 59 , 68 ], although the storage of the inherently inert PFC does not cause organ damage per se, except for the formation of foamy cells from primary Kupffer cells (Fig. 2A ) [ 84 , 105 ]. The increase of plasma transaminase activity seems to be linked to oxidative stress caused by the O 2 release from the PFC droplet that occurs inside the macrophages (Fig.…”

Section: Pfc-based Oxygen Carriers: Droplets Under Attackmentioning

confidence: 99%

“…5% human serum albumin 0.2 μm Coughing, hypertension [ 12 ] A-AOCs 17% PFD. 5% human serum albumin 0.35 μm Results of clinical studies are not yet available [ 105 ] …”

Section: Pfc-based Oxygen Carriers: Peculiarities and Fields Of Applimentioning

confidence: 99%

“…The above-mentioned universal gas dissolubility opens another path off the beaten tracks for PFOCs. The inertness towards oxidation permits the transportation of excess carbon monoxide (CO) from the blood to the lung, and the acceleration of the recovery of CO-venomed haemoglobin [ 47 , 105 , 108 ]. In addition, the washout of nitrogen associated with decompression sickness was proven efficient in terms of avoiding embolism in rabbit, pig and rat models [ 10 , 57 , 63 , 109 ].…”

Section: Pfc-based Oxygen Carriers: Peculiarities and Fields Of Applimentioning

confidence: 99%

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Perfluorocarbon-based oxygen carriers: from physics to physiology

Jägers

Wrobeln

Ferenz

2020

Pflugers Arch - Eur J Physiol

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138

108

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Developing biocompatible, synthetic oxygen carriers is a consistently challenging task that researchers have been pursuing for decades. Perfluorocarbons (PFC) are fascinating compounds with a huge capacity to dissolve gases, where the respiratory gases are of special interest for current investigations. Although largely chemically and biologically inert, pure PFCs are not suitable for injection into the vascular system. Extensive research created stable PFC nano-emulsions that avoid (i) fast clearance from the blood and (ii) long organ retention time, which leads to undesired transient side effects. PFC-based oxygen carriers (PFOCs) show a variety of application fields, which are worthwhile to investigate. To understand the difficulties that challenge researchers in creating formulations for clinical applications, this review provides the physical background of PFCs’ properties and then illuminates the reasons for instabilities of PFC emulsions. By linking the unique properties of PFCs and PFOCs to physiology, it elaborates on the response, processing and dysregulation, which the body experiences through intravascular PFOCs. Thereby the reader will receive a scientific and easily comprehensible overview why PFOCs are precious tools for so many diverse application areas from cancer therapeutics to blood substitutes up to organ preservation and diving disease.

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“…Albumin-derived perfluorodecalin-filled nanocapsules showed promising results in a first in vivo toxicity study (Wrobeln et al, 2017a) and protected a Langendorff heart (rat) during massive ischemia (Wrobeln et al, 2017b). Similarly, a novel PFC emulsion increased myocardial O 2 delivery, improved cardiac function, and generated a more physiologic redox state in a Langendorff heart (rabbit) compared with perfusion without the PFC emulsion (Kuzmiak-Glancy et al, 2018).…”

Section: In the Pipeline/preclinical Developmentmentioning

confidence: 99%

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

Ferenz

Steinbicker

2019

J Pharmacol Exp Ther

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Albumin-derived perfluorocarbon-based artificial oxygen carriers: A physico-chemical characterization and first in vivo evaluation of biocompatibility

Cited by 40 publications

References 57 publications

Albumin-derived perfluorocarbon-based artificial oxygen carriers can avoid hypoxic tissue damage in massive hemodilution

Albumin-derived perfluorocarbon-based artificial oxygen carriers can avoid hypoxic tissue damage in massive hemodilution

Perfluorocarbon-based oxygen carriers: from physics to physiology

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

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