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Artificial oxygen carriers have emerged as potential substitutes for red blood cells in situations of major blood loss, including accidents, surgical procedures, trauma, childbirth, stomach ulcers, hemorrhagic shock, and blood vessel ruptures which can lead to sudden reduction in blood volume. The therapeutic delivery of oxygen utilizing artificial oxygen carriers as red blood cell substitutes presents a promising avenue for treating a spectrum of disease models. Apart from that, the recent advancement of artificial oxygen carriers intended to supplant conventional blood transfusions draws significant attention due to the exigencies of warfare and the ongoing challenges posed by the COVID-19 pandemic. However, there is a pressing need to formulate stable, non-toxic, and immunologically inert oxygen carriers. Even though numerous challenges are encountered in the development of artificial oxygen carriers, their applicability extends to various medical treatments, encompassing elective and cardiovascular surgeries, hemorrhagic shock, decompression illness, acute stroke, myocardial infarction, sickle cell crisis, and proficient addressing conditions such as cerebral hypoxia. Therefore, this paper provides an overview of therapeutic oxygen delivery using assorted types of artificial oxygen carriers, including hemoglobin-based, perfluorocarbon-based, stem cell-derived, and oxygen micro/nanobubbles, in the treatment of diverse disease models. Additionally, it discusses the potential side effects and limitations associated with these interventions, while incorporating completed and ongoing research and recent clinical developments. Finally, the prospective solutions and general demands of the perfect artificial oxygen carriers were anticipated to be a reference for subsequent research endeavors. Graphical Abstract

Blood transfusion is a routine yet resource-intensive medical procedure. Increasing global demand, limited donor availability, and logistical and ethical constraints have driven the search for adequate blood substitutes. Hemoglobin-based oxygen carriers (HBOCs) represent a promising class of therapeutics designed to mimic the oxygen transport function of red blood cells while overcoming the challenges of storage, compatibility, and infection risk. Despite decades of research, no HBOC has yet met all criteria for widespread clinical use. This review summarizes recent advances in the design and development of hemoglobin derivatives, with a focus on their biochemical properties, safety profiles, and oxygen delivery capabilities. We also discuss current limitations and translational barriers. The successful implementation of HBOCs could significantly improve transfusion strategies, especially in emergency medicine, military applications, and resource-limited settings. Continued innovation is essential to bring safe and effective oxygen therapeutics into routine clinical practice.

Hemoglobin-based oxygen carriers have been developed to compensate the needs of blood for transfusions. Most of them were based on intracellular hemoglobin extracted from bovine or human blood, but unfortunately, this type of hemoglobin did not pass through the last steps of clinical trials. In this context, HEMARINA discovered a natural extracellular hemoglobin, possessing several advantages avoiding intracellular hemoglobin-related side effects. Many preclinical studies assessed the safety of M101 used in intravenous (IV) injection in rodents. To explore the safety of IV injections of M101 in large mammals, six dogs received each a single injection of liquid M101 according to a dose escalation with a 48 h follow-up. Then, two monkeys received multiple IV injections of the same dose of M101 every hour for seven hours. This study showed that single and multiple IV injections in dogs and monkeys did not cause clinical or histological lesions, nor did they induce immunological reactions. This makes M101 the best candidate to date for human use in emergency situations requiring blood and, in several diseases, causing hypoxia problems.

The blood plays a vital role in the human body and serves as an intermediary between various physiological systems and organs. White blood cells, which are a part of the immune system, defend against infections and regulate the body temperature and pH balance. Blood platelets play a crucial role in clotting, the prevention of excessive bleeding, and the promotion of healing. Blood also serves as a courier system that transports hormones to facilitate communication and synchronization between different organs and systems in the body. The circulatory system, comprised of arteries, veins, and capillaries, plays a crucial role in the efficient transportation and connection of vital nutrients and oxygen. Despite the importance of natural blood, there are often supply shortages, compatibility issues, and medical conditions, which make alternatives such as artificial blood necessary. This is particularly relevant in cancer treatment, which was the focus of our study. In this study, we investigated the potential of artificial blood in cancer therapy, specifically to address tumor hypoxia. We also examined the potential of red blood cell substitutes such as hemoglobin-based oxygen carriers and perfluorocarbons. Additionally, we examined the production of hemoglobin using E. coli and the role of hemoglobin in oncogenesis. Furthermore, we explored the potential use of artificial platelets for cancer treatment. Our study emphasizes the significance of artificial blood in improving cancer treatment outcomes. Graphical Abstract

•Bloodstain pattern analysis is a field of forensic science, and the need for experiments and education is emphasized for bloodstain analyst.•Through the development of appropriate blood substitute that can replace human blood, it can greatly help in the development of forensic science and bloodstain pattern analysis.•In the manufacture of blood substitute, the similarity between physical properties and drip bloodstain characteristics with human blood is very important.•It will be more efficient if various functions are complemented for practical use of blood substitute. Bloodstain pattern analysis, one of the areas of forensic science, is performed to analyze the physical characteristics of bloodstains, including their size, shape, and distribution, to reconstruct a crime scene. A bloodstain pattern analyst should obtain through experiments and education the capabilities to both understand the generation mechanisms of bloodstains and identify the characteristics of the bloodstains. Experiments and education about bloodstain pattern analysis are carried out by using human blood taken from subjects, animal blood (porcine or bovine) supplied from butcheries, and blood substitute products developed in other countries. However, these kinds of blood have many limitations in their application due to various problems. The blood substitute developed in the present study is more similar to human blood than other blood substitute products developed in other countries with regard to the physical properties, including viscosity, viscoelasticity, and surface tension, as well as the drip bloodstain patterns depending on the surface and coordinate characteristics of drip stains impact angle. The blood substitute developed in the present study is more practical, because the materials that are used in its preparation are readily available in the market and do not include chemicals that are harmful to the human body, and the blood substitute has luminol reaction functionality and pattern transfer bloodstain (bloodstain fingerprint, bloodstain footprint, etc.) dyeing functionality.

IntroductionHaemoglobin vesicles (HbVs) (product name, NMU-HbVs [Nara Medical University-Haemoglobin Vesicles]), which contain purified human haemoglobin encapsulated within liposomes, have been developed as a potential alternative to blood transfusions in emergency situations. A previous phase I study examined doses up to 100 mL in 11 healthy volunteers. Here, we describe the protocol for a phase Ib study, wherein we will evaluate the safety and pharmacokinetics of NMU-HbV in healthy Japanese adults.Methods and analysisThis single-centre, open-label, dose-escalation study will enrol 16 healthy volunteers divided into four cohorts. Planned doses are 100 mL for cohorts 1 and 2, 200 mL for cohort 3 and 400 mL for cohort 4, with infusion rates gradually increasing to a maximum of 5.0 mL/min. The primary endpoint will be safety, which will be assessed as the incidence of adverse events within 14 days and significant clinical changes within 72 hours after administration. Safety evaluations will include subjective symptoms, vital signs, electrocardiograms and laboratory test results compared with the baseline. The secondary endpoint will be pharmacokinetics, which will be assessed as changes in NMU-HbV concentration immediately after infusion until day 4 to determine the maximum blood concentration, time to reach the maximum blood concentration, area under the blood concentration-time curve and elimination half-life. This study will provide data on the safety and pharmacokinetic profiles of NMU-HbV at doses up to 400 mL. The findings are expected to support the further development of NMU-HbV as a viable alternative to emergency transfusions.Ethics and disseminationThe study protocol was approved by the Institutional Review Board of Nara Medical University on 10 December 2024. Dissemination plans include publishing in peer-reviewed scientific journals and presentation at international conferences.Trial registration numberJapan Registry of Clinical Trials (jRCT2051240249). Registered on 27 January 2025 (https://jrct.mhlw.go.jp/en-latest-detail/jRCT2051240249).

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF. Plasma samples were available for 241 patients with IPF (140 derivation and 101 validation). In the derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of matrix metalloproteinase (MMP)-7, MMP-1, and surfactant protein D were assessed by ELISA. In the validation cohort concentrations of intercellular adhesion molecule (ICAM)-1, IL-8, and vascular cell adhesion molecule (VCAM)-1 were assessed by bead-based multiplex assay, and S100A12 and MMP-7 by ELISA. Associations of biomarkers with mortality, transplant-free survival, and disease progression were tested in the derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested. High concentrations of MMP-7, ICAM-1, IL-8, VCAM-1, and S100A12 predicted poor overall survival, poor transplant-free survival, and poor progression-free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant-free survival; MMP-7, ICAM-1, and IL-8 of overall survival; and ICAM-1 of poor progression-free survival. The personal clinical and molecular mortality prediction index derived in the derivation cohort was highly predictive of mortality in the validation cohort. Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

A hemoglobin (Hb) wrapped covalently by human serum albumins (HSAs), a core–shell structured hemoglobin-albumin cluster designated as “HemoAct”, is an O 2 -carrier designed for use as a red blood cell (RBC) substitute. This report describes the blood compatibility, hemodynamic response and pharmacokinetic properties of HemoAct and then explains its preclinical safety. Viscosity and blood cell counting measurements revealed that HemoAct has good compatibility with whole blood. Intravenous administration of HemoAct into anesthetized rats elicited no unfavorable increase in systemic blood pressure by vasoconstriction. The half-life of 125 I-labeled HemoAct in circulating blood is markedly longer than that of HSA. Serum biochemical tests conducted 7 days after HemoAct infusion yielded equivalent values to those observed in the control group with HSA. Histopathologic inspections of the vital organs revealed no marked abnormality in their tissues. All results indicate that HemoAct has sufficient preclinical safety as an alternative material for RBC transfusion.

The topical use of platelet concentrates is recent and its efficiency remains controversial. Several techniques for platelet concentrates are available; however, their applications have been confusing because each method leads to a different product with different biology and potential uses. Here, we present classification of the different platelet concentrates into four categories, depending on their leucocyte and fibrin content: pure platelet-rich plasma (P-PRP), such as cell separator PRP, Vivostat PRF or Anitua's PRGF; leucocyte- and platelet-rich plasma (L-PRP), such as Curasan, Regen, Plateltex, SmartPReP, PCCS, Magellan or GPS PRP; pure plaletet-rich fibrin (P-PRF), such as Fibrinet; and leucocyte- and platelet-rich fibrin (L-PRF), such as Choukroun's PRF. This classification should help to elucidate successes and failures that have occurred so far, as well as providing an objective approach for the further development of these techniques.

Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.