Editorial
10 November 2023
Thomas Ming Swi Chang
Editorial: Innovative medical technology based on artificial cells, including its different configurations
Editors
2
Impact
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Brief Research Report
07 August 2023
M. Hoq
and
T. M. S. Chang
1,986 views
2 citations
Original Research
13 June 2023
Matthew C. Williams
, 2 more and
Felice D’Agnillo
2,129 views
2 citations
Brief Research Report
03 May 2023
Bohdan J. Soltys
, 3 more and
Haotian Zhao
2,543 views
1 citations
Mini Review
14 April 2023
Yuzhu Bian
and
Thomas Ming Swi Chang
This is a mini review on the biotechnological aspects of the most extensively developed hemoglobin-based oxygen carriers The emphasis is on the most recent Polyhemoglobin-catalase-superoxide dismutase-carbonic anhydrase (PolyHb-CAT-SOD-CA), which is a nanobiotechnological complex that is being investigated and scaled up with the potential for clinical use as nanobiotherapeutics. Hemoglobin, a tetramer, is an excellent oxygen carrier. However, in the body it is converted into toxic dimers. Diacid or glutaraldehyde can crosslink hemoglobin into polyhemoglobin (PolyHb) and prevent its breakdown into toxic dimers. This has been developed and tested in clinical trials. A bovine polyhemoglobin has been approved for routine clinical use for surgical procedures in South Africa and Russia. Clinical trials with human PolyHb in hemorrhagic shock were effective but with a very slight increase in non-fatal myocardial ischemia. This could be due to a number of reasons. For those conditions with ischemia-reperfusion, one would need an oxygen carrier with antioxidant properties. One approach to remedy this is with prepared polyhemoglobin-catalase-superoxide dismutase (PolyHb-CAT-SOD). Another reason is an increase in intracellular pCO2. We therefore added an enhanced level of carbonic anhydrase to prepare a PolyHb-CAT-SOD-CA. The result is an oxygen carrier with enhanced Carbonic Anhydrase for CO2 transport and enhanced Catalase and Superoxide Dismutase for antioxidant functions. Detailed efficacy and safety studies have led to the industrial scale up towards clinical trial. In the meantime, oxygen carriers are being investigated around the world for use in ex vivo biotechnological fluid for organ preservation for transplantation, with one already approved in France.
![Plasmid DNA cleavage of wt HbF and the HbFα4 mutant was monitored for 12 h at 37°C in 20 mM phosphate buffer pH 7.2. Without the addition of Hb, no cleavage of the supercoiled (sc) pDNA was observed. In contrast, when Hb was included, the sc form deteriorated and open circular and linear pDNA bands emerged. By increasing the Hb concentrations from 0 µM to 25, 100, 200 and 300 µM (heme) the process was accelerated. The decay of sc pDNA over time was plotted and fitted to a single exponential equation and the data for wt HbF and HbFα4 mutant can be seen in graphs (A) and (B), respectively. Circles represent wt HbF and triangles represent HbFα4 mutant. The obtained rates were then plotted against the Hb concentration and the linear relationship was used to determine the decay constants of pDNA cleavage [graph (C)]. The data point for wt HbF at 300 µM (open circle) in graph (C) is a product of the linear fitting to the other wt HbF data points, due to the lack of detection of the sc DNA band after 1 h of incubation.](https://www.frontiersin.org/_rtmag/_next/image?url=https%3A%2F%2Fwww.frontiersin.org%2Ffiles%2FArticles%2F1133985%2Ffmolb-10-1133985-HTML%2Fimage_m%2Ffmolb-10-1133985-g002.jpg&w=3840&q=75)
Original Research
16 March 2023
Karin Kettisen
, 3 more and
Leif Bülow
4,025 views
3 citations
Original Research
21 February 2023
Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock
Jun Wang
, 7 more and
Raymond C. Koehler
Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Stabilization of PNPH with bound carbon monoxide prevents methemoglobin formation during storage and permits it to serve as an anti-inflammatory carbon monoxide donor. We determined whether small volume transfusion of hyperoncotic PNPH is neuroprotective in a porcine model of traumatic brain injury (TBI) with and without accompanying hemorrhagic shock (HS). TBI was produced by controlled cortical impact over the frontal lobe of anesthetized juvenile pigs. Hemorrhagic shock was induced starting 5 min after TBI by 30 ml/kg blood withdrawal. At 120 min after TBI, pigs were resuscitated with 60 ml/kg lactated Ringer's (LR) or 10 or 20 ml/kg PNPH. Mean arterial pressure recovered to approximately 100 mmHg in all groups. A significant amount of PNPH was retained in the plasma over the first day of recovery. At 4 days of recovery in the LR-resuscitated group, the volume of frontal lobe subcortical white matter ipsilateral to the injury was 26.2 ± 7.6% smaller than homotypic contralateral volume, whereas this white matter loss was only 8.6 ± 12.0% with 20-ml/kg PNPH resuscitation. Amyloid precursor protein punctate accumulation, a marker of axonopathy, increased in ipsilateral subcortical white matter by 132 ± 71% after LR resuscitation, whereas the changes after 10 ml/kg (36 ± 41%) and 20 ml/kg (26 ± 15%) PNPH resuscitation were not significantly different from controls. The number of cortical neuron long dendrites enriched in microtubules (length >50 microns) decreased in neocortex by 41 ± 24% after LR resuscitation but was not significantly changed after PNPH resuscitation. The perilesion microglia density increased by 45 ± 24% after LR resuscitation but was unchanged after 20 ml/kg PNPH resuscitation (4 ± 18%). Furthermore, the number with an activated morphology was attenuated by 30 ± 10%. In TBI pigs without HS followed 2 h later by infusion of 10 ml/kg LR or PNPH, PNPH remained neuroprotective. These results in a gyrencephalic brain show that resuscitation from TBI + HS with PNPH protects neocortical gray matter, including dendritic microstructure, and white matter axons and myelin. This neuroprotective effect persists with TBI alone, indicating brain-targeting benefits independent of blood pressure restoration.
Review
09 February 2023
The role of normothermic machine perfusion (NMP) in the preservation of ex-vivo liver before transplantation: A review
Chuanyan Shen
, 2 more and
Hongli Zhu
The discrepancy between the number of patients awaiting liver transplantation and the number of available donors has become a key issue in the transplant setting. There is a limited access to liver transplantation, as a result, it is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. However, there are still many unknown risks associated with the use of ECD, among which preservation before liver transplantation is important in determining whether patients would experience complications survive after liver transplantation. In contrast to traditional static cold preservation of donor livers, normothermic machine perfusion (NMP) may reduce preservation injury, improve graft viability, and potentially ex vivo assessment of graft viability before transplantation. Data seem to suggest that NMP can enhance the preservation of liver transplantation to some extent and improve the early outcome after transplantation. In this review, we provided an overview of NMP and its application in ex vivo liver preservation and pre-transplantation, and we summarized the data from current clinical trials of normothermic liver perfusion.
Review
04 January 2023
Yameng Yu
and
Lailiang Ou
3,172 views
3 citations
Opinion
18 August 2022
Jonathan S. Jahr
Mini Review
28 November 2022
Oxygen reversibly binds to the redox active iron, a transition metal in human Hemoglobin (Hb), which subsequently undergoes oxidation in air. This process is akin to iron rusting in non-biological systems. This results in the formation of non-oxygen carrying methemoglobin (ferric) (Fe3+) and reactive oxygen species (ROS). In circulating red blood cells (RBCs), Hb remains largely in the ferrous functional form (HbF2+) throughout the RBC's lifespan due to the presence of effective enzymatic and non-enzymatic proteins that keep the levels of metHb to a minimum (1%–3%). In biological systems Hb is viewed as a Fenton reagent where oxidative toxicity is attributed to the formation of a highly reactive hydroxyl radical (OH•) generated by the reaction between Hb's iron (Fe2+) and hydrogen peroxide (H2O2). However, recent research on both cellular and acellular Hbs revealed that the protein engages in enzymatic-like activity when challenged with H2O2, resulting in the formation of a highly reactive ferryl heme (Fe4+) that can target other biological molecules before it self-destructs. Accumulating evidence from several in vitro and in vivo studies are summarized in this review to show that Hb's pseudoperoxidase activity is physiologically more dominant than the Fenton reaction and it plays a pivotal role in the pathophysiology of several blood disorders, storage lesions associated with old blood, and in the toxicity associated with the infusion of Hb-derived oxygen therapeutics.
Review
23 December 2022
Hiromi Sakai
, 2 more and
Hiroshi Azuma
4,854 views
10 citations
Original Research
08 December 2022
Archna Dhasmana
, 8 more and
Shafiul Haque
2,956 views
2 citations
Original Research
01 December 2022
Bin Li
, 7 more and
Hongli Zhu
2,258 views
1 citations