Artificial Red Cells Research Articles

123 ヘモグロビン小胞体混和血液による心筋灌流と心機能評価

123 ヘモグロビン小胞体混和血液による心筋灌流と心機能評価

533 ラット交叉潅流モデルを用いたリポソーム型人工赤血球の局所心筋潅流特性の評価

533 ラット交叉潅流モデルを用いたリポソーム型人工赤血球の局所心筋潅流特性の評価

ARTIFICIAL RED CELLS AS TREATMENT OF ACUTE CEREBRAL INFARCTION

Background: Treatment of cerebral infarction (CI) has been limited to indirect therapies aiming at reduction of edema or oxygen demand. Objectives: Since artificial red cells of Tenuno (Neo Red Cell: NRC) is made much smaller (diameter 0.2 micrometer) than regular red cell, we hypothesize that NRC may deliver oxygen not only to the peripheral area at risk of CI but also infarcted area per se to limit damage or area of infarction. Methods: CI was created by inserting a 2-0 monofilament suture to occlude the middle cerebral artery in SD rats. One minute later, 10 ml of NRC (G1) were infused at a rate of 1 ml/min with the same amount of blood being drawn to avoid volume overload. G1 rats were compared with CI rats with vehicle infusion (G2) and CI rats with no treatment (G3). Severity of edema was compared 24 hours later on T2 weighted images obtained with 0.5T MRI imaging system (Vectra Fast, GEYMS, Japan) by signal strength at cortex, striatum, hyppocampus and pyriform lobe. Results: Signal strength ± standard error were tabulated.TableConclusion: NRC (G1) significantly reduced brain edema as compared to vehicle infusion (G2). Low oncotic pressure of the vehicle and NRC solution appeared to cause non-significant aggravation of edema in G2 and reduced protective effects of NRC in G1 group.

Exploratory design in medical nanotechnology: a mechanical artificial red cell.

Molecular manufacturing promises precise control of matter at the atomic and molecular level, allowing the construction of micron-scale machines comprised of nanometer-scale components. Medical nanomachines will be among the earliest applications. The artificial red blood cell or "respirocyte" proposed here is a bloodborne spherical 1-micron diamondoid 1000-atm pressure vessel with active pumping powered by endogenous serum glucose, able to deliver 236 times more oxygen to the tissues per unit volume than natural red cells and to manage carbonic acidity. An onboard nanocomputer and numerous chemical and pressure sensors enable complex device behaviors remotely reprogrammable by the physician via externally applied acoustic signals.

分子集合を利用した人工血液

For substitution of oxygen transporting ability in blood stream, artificial red cells have been widely developed for recent years. Since the role of the other blood components can be replaced by synthetic molecules (chemical regents), the realization of artificial O2-infusion leads to complement of the artificial blood based on the present transfusion techniques. This review describes the recent topics of the development of artificial red cells, especially on hemoglobin (Hb) based materials and totally synthetic lipidhemes. The Hb vesicles (HbV, cellular type) with appropriate O2-binding ability have several advantages in comparison to the acellular types such as crosslinked Hb. The results of animal tests clearly represented the in vivo oxygen delivery by HbV. On the other hand, molecular assemblies of synthetic lipidhemes act as O2-carrier under physiological conditions, More recently, albumin heme hybrid has also been developed as a new type of the O2-infusion series.

Radiation-induced polymerization of unsaturated phospholipid mixtures for the synthesis of artificial red cells

Radiation induced polymerization of phospholipid containing unsaturated acyl chains was applied to the synthesis of artificial red cells. Vesicles of 1,2-bis-(2,4-octadecadienoyl)-phosphatidylcholine (DODPC) and 1-stearoyl-2-(2,4-octadecadienoyl)-phosphatidylcholine (AODPC) were irradiated by 60Co γ-rays to obtain polymerized bilayer structure of these monomers. It was found that the polymerization of unsaturated groups located at 2-acyl chain of DODPC polymerized faster than those of AODPC. The difference was explained by the packed state of these monomers in the bilayer vesicles. The artificial red cell was obtained by irradiating the mixture of DODPC or AODPC with hemoglobin, cholesterol and palmitic acid sodium salt. The integrity of the irradiated hemoglobin in the vesicle was maintained by keeping the suspended solution at low temperature. On the other hand, oxidation of heme part became remarkable when the vesicle was kept at 37°C. The presence of extra hemoglobin outside the vesicle was found useful to prevent this oxidation.

Book Reviews

Book reviewed in this article:Artificial Red Cells: Materials, Performances and Clinical Study as Blood Substitutes.Handbook of Blood Transfusion Therapy, 2nd edn.

Development of artificial red cells (ARC) produced by γ-ray induced polymerization of liposomes

Artificial red cells (ARC) are prepared by encapsulating Hb with a polymerizable phospholipid. The polymerization of the vesicles were carried out with the irradiation of γ-rays. The irradiated ARC are physically more stable than any other known liposome type blood substitutes. Because of this stability, they can be easily stored under frozen condition for a long time. No significant changes were observed in vivo study with rats in which ARC were injected intravenously. The oxygen transport capacity of ARC was similar to that of native red blood cells.

多量の酸素を運べるリポソーム

多量の酸素を運べるリポソーム

Structure and Solution Properties of Lipidheme-Microsphere

Triglyceride microsphere emulsified with phospholipid derivative of heme (5,10,15,20-tetrakis[alpha,alpha,alpha,alpha-o-[2,2-dimethyl-20- [2-(trimethylammonioethoxy) phosphonatoxy]eicosanamido]phenyl]porphinatoiron(II); lipidheme) provides a totally synthetic artificial red cell (lipidheme-microsphere; LH-M). Its structure, solution properties and O2 binding ability are described. The particle diameter of the LH-M was ca. 90 nmø elucidated by electron microscopy. Viscosity of the LH-M suspension (approximately 1.5 cP) was much lower than that of human blood and the viscosity of mixed system of LH-M/human blood (1/1(v/v)) was 2.5 cP. Specific gravity, osmotic pressure, and colloid osmotic pressure of the LH-M suspension also satisfied the physiological needs. The LH-M can bind O2 reversibly in response to O2 pressure (P50(O2): 41 torr (pH 7.4, 37 degrees C)). O2 solubility of the LH-M was more than that of human blood caused by its high heme concentration.

人工赤血球"ネオレッドセル(NRC)"の開発

人工赤血球"ネオレッドセル(NRC)"の開発

Modulation of oxygen‐carrying capacity of artificial red cells

AbstractThe oxygen‐carrying capacity of artificial red cells (ARC), which were prepared by encapsulating hemoglobin (Hb) into polymerized lipid vesicles, has been investigated in detail. It was found that the effects of inositol hexaphosphate (IHP) on the oxygen affinity of stromafree Hb and ARC are quite different. By co‐encapsulating IHP at a IHP:Hb molar ratio of 1.0, the oxygen affinity of the encapsulated Hb in ARC was decreased to such an extent that P50 was about 60–65 mmHg, and only about 70–80% of the encapsulated Hb could be oxygenated at an oxygen partial pressure (Po2) of about 100 mmHg. As pyridoxal 5‐phosphate (PLP) and chloride ions were coencapsulated instead of IHP, P50 and the Hill coefficient of the obtained ARC were adjusted to 25–30 mmHg and 2.5–2.8 respectively. The oxygen‐transporting efficiency of PLP‐modulated ARC was similar to or better than that of red blood cells.

Characteristics of artificial red cells. Hemoglobin encapsulated in poly-lipid vesicles.

Artificial red cells (ARC) were prepared by encapsulation of purified human Hb with polymerizable phospholipid, 1,2-bis (2,4-octadecadienoyl)-sn-glycero-3-phosphocholine (DODPC). The polymerized lipid bilayer of the ARC produced great physical stability that could not be achieved using a non-polymerizable lipid for encapsulation. ARC showed no change in particle size or distribution or leakage of Hb after repeated freeze thawing (stability test). ARC have also been studied with regard to biocompatibility. The authors' results showed low acute toxicity (> 8000 mg/kg) and adequate blood compatibility. The result of transfusion tests in dogs showed that ARC had sufficient oxygen transporting capabilities.

Characteristics of polylipid/Hb vesicles (ARC) (in vitro and in vivo test).

Polylipid/Hb vesicle, which is polymerized phospholipid vesicles (200 nm) encapsulating concentrated Hb solution, has been established by us as an artificial red cell (ARC). ARC can be easily adjusted to physiological conditions (viscosity, density and oncotic pressure etc) as the same of human blood. Our ARC has excellent blood compatibility (no effect on coagulation, no hemolysis and no red cell aggregation). Neither acute toxicity nor damage of internal organs was confirmed. Oxygen transporting capacity was almost the same as human blood, and the half life in blood stream was ca. 13 hrs.

Stability and blood compatibility of polylipid/Hb.

The Polylipid/Hb vesicle is a new artificial red cell (ARC) based on liposome-encapsulated Hb. Advantages are derived from the stabilized liposomal bilayer membranes, obtained by polymerization of 1,2-bis(2,4-octadecadienoyl)-sn-glycero-3-phospho choline (DODPC). Furthermore, blood compatibility in vitro are good.

Synthesis and characterization of artificial red cell (ARC).

An unsaturated lipid made from 2,4-octadecadienoic acid was used as a component of phospholipid vesicles. The vesicles (0.2 micron phi) was prepared by an extrusion method, and the unsaturated lipid was polymerized with gamma-ray. Vesicles constructed from the polylipid show enormous stability during long term storage in frozen state and can be handled easily. Negative effect could not be confirmed in vitro tests. This system satisfies all the physiological conditions, such as oxygen transport ability and solution properties as a blood substitute.

Artificial Red Cells. A Link Between the Membrane Skeleton and Res Detectability?

Factors governing nonspecific reticuloendothelial system (RES)-detectability are largely unknown. Will a liposome that mimics the lipid composition of the outer leaflet of the erythrocyte membrane be invisible to the RES? On both experimental and theoretical grounds we believe the answer is no, in part because 1) sorption of proteins is believed to be important in determining RES uptake, 2) a membrane skeleton is apparently necessary to inhibit protein sorption into erythrocyte membranes and 3) Neohemocytes (a liposome encapsulated hemoglobin product) currently lack a membrane skeleton. Neohemocytes with erythrocyte outer leaflet lipid composition do have extended circulation half-times, but these are at least two orders of magnitude shorter than the circulation half-times of erythrocytes. How might a membrane skeleton modulate RES-detectability? Can avoidance of opsonization result in part from the properties of the membrane skeleton? If so, then how? To explore and quantify such questions we have developed a theoretical, statistical-thermodynamic model of protein binding into membranes. It predicts that the membrane area available for rapid lateral diffusion is critically important in controlling the amount of sorbed protein per unit area, and that a membrane skeleton can reduce a protein's sorption by several orders of magnitude. Based on theoretical results, we offer a speculative model for the detection of non-self lipid bilayers by the RES.

人工赤血球の新展開

人工赤血球の新展開

人工血液と人工赤血球

人工血液と人工赤血球

Blood transfusion: yesterday, today, and tomorrow.

AbstractThe evolution of blood transfusion practice into modern transfusion medicine is reported. The impact of great wars on the technique of blood storage and organization of blood supply is discussed. The progress of immunotechnology and fractionation of plasma contributed greatly to contemporary transfusion medicine and the implementation of blood and plasma component therapy. Three basic indications for use of blood in surgery are summarized: restoration of acute loss of circulating blood volume, improvement of oxygen transport, and delivery and correction of coagulation disorders. Some factors arising from storage lesion of blood (citrate intoxication, 2,3‐DPG depletion, cellular aggregates) are described. The recent research in blood transfusion refers particularly to red cell substitutes. The oxygen‐carrying solutions, perfluorocarbons, stroma‐free hemoglobin, and current research on artificial red cells are discussed. The in vitro culturing, recombinant DNA technology, and the practical application of monoclonal antibodies in clinical practice are emphasized. The advent of great technological advances in transfusion medicine makes it possible to predict several future developments. Blood will be substituted by oxygen carriers, human protein and cells by biotechnological and genetic engineering. The education of tomorrow's surgeons must be adapted to the recent progress and advances of transfusion medicine.