Synthetic Blood

7/31/2019 Synthetic Blood

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Since the 17th century, blood transfusions have beenattempted to offset blood loss from trauma and childbirth, or for therapeutic uses. Until the identificationofiso-agglutinating antibodies, however,transfusions were undesirable with significant early

complications. These early complications sparked interest in using

haemoglobin as an oxygen carrier in plasma. Earlytrials of these solutions proved disastrous as well,with significant immediate complications resulting

from infusions of stroma-free human haemoglobinsolutions These complications were most often acuterenal failure thought to be the result of directhaemoglobin nephro toxicity.


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Blood is a specialized body fluid that deliversnecessary substances to the body's cells (in animals) such as nutrients and oxygen andtransports waste products away from those same cells.

It is composed of blood cells suspended ina liquid called blood plasma. Plasma, whichconstitutes 55% of blood fluid, is mostly water (92% byvolume), and contains proteins, glucose, mineral

ions, hormones, carbon dioxide(plasma being themain medium for excretory producttransportation), platelets and blood cells themselves.

The most abundant cells in vertebrate blood are redblood cells. These contain haemoglobin, an iron-

containing protein, which facilitates transportationof oxygen by reversibly binding to this respiratory gasand greatly increasing its solubility in blood. Incontrast, carbon dioxide is almost entirelytransported extracellularly dissolved in plasma

as bicarbonate ion.


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Blood is circulated around the body through bloodvessels by the pumping action of the heart. Inanimals with lungs, arterial blood carries oxygenfrom inhaled air to the tissues of the body,and venous blood carries carbon dioxide, a wasteproduct of metabolism produced by cells, from thetissues to the lungs to be exhaled.


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The history of blood transfusion can be regarded asthe history of blood substitute as

infusion of any material other than autologousblood, is actually infusion of blood substitute.

Substances like milk, casein derivatives, starch,

saline and Ringers solution had been tried prior tothe first successful human to human transfusion.

Development of a haemoglobin-based blood

substitute was pursued vigorously by the military asa means to have an oxygen-carrying plasmaexpander available for battlefield use. Despiteresearch throughout the Vietnam War, a clinicallyeffective blood substitute was unable to bedeveloped.


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During the era of blood substitute research in the1960s, Dr. Leland Clark began experimenting with a

class of compounds known as per-fluorocarbons.Oxygen has approximately 100 times greatersolubility in per-fluorocarbon solutions than inplasma. As a result, the amount of oxygen dissolvedin plasma may be sufficient to sustain life, withoutthe need for RBC-contained haemoglobin toprovide additional oxygen.

The functions of each blood component and thesubstitution of each are quite familiar,

excepting that of oxygen carrying capacity. Therehas been considerable progress in two major classesof substitutes ,i.e. haemoglobin solutions and per-fluorocarbon (PFC) emulsions.


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Working ofhaemoglobulinmolecules


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Oxygen transport is primarily a function oferythrocyte-contained haemoglobin. Von Stark(1898) was the first to use haemoglobin (Hb)solution in the treatment of a patient sufferingfrom anaemia. A lot of research has subsequentlymodified Hb solution to form purified Hbsolutions.

Initial trials of free haemoglobin solutionsdemonstrated little benefit to patients withunmodified haemoglobin molecules. Presently,

HBOCs represent an interesting class of bloodsubstitutes, which are undergoing advanced clinicaltrials. The therapeutic goal of these compounds isto avoid or reduce blood transfusion in different

surgical and medical situations of acute Hb


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The main advantages include availability in largevolumes, storage for prolonged periods, rapidadministrationand sterilisation by pasteurisation.

Poly-haemoglobin preparations will increase inplasma half-life as their size is enlarged; a limit tothe size is the viscosity and oncotic effects of thelarger haemoglobin molecules. Most preparations

will be retained in the plasma for half-lives of 8-30hours


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Haemoglobin-based oxygen carriers have someadvantages over allogeneic red blood celltransfusions. The lack of iso-agglutinating antigens,

due to the absence of a red cell membrane, obviatesblood typing and screening and eliminates the mostcommon morbidity and mortality of allogeneic andautologous transfusions, mismatching of blood

units and the transfusion recipient. The lack ofcross-matching requirements also allows virtuallyimmediate availability of an oxygen carrier incritical periods of trauma or haemorrhage.

However, there may be issues with administrationof free haemoglobin in potentially septic situations.


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Plasma haemoglobin is not a true blood substitute;haemoglobin can replace only the oxygen transportcapacity of whole blood, without the coagulation orimmunologic aspects which are normally present inblood.

Haemoglobin-based oxygen carriers will not replaceblood, allogeneic whole blood, or allogeneic redblood cells completely. Thus, use of these productsmay be limited to specific applications or withspecialized techniques, such as cardiopulmonarybypass.


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Their main known disadvantages are, reducedcirculation half-life, haemodynamic andgastrointestinal perturbations, probably related to

nitric oxide (NO) scavenging, free radical induction,and alterations of biochemical and haematologicalparameters (increase in liver enzyme levels, plateletaggregation).


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For per-fluorocarbon emulsions, newer molecules,coupled with advances in emulsification

technology, has produced solutions with greatpotential for clinical applications. Novel methods ofcross linking and chemical modification have madehaemoglobin solutions a viable alternative as

temporary oxygen carriers. After the initial excitement regarding Fluosol,

subsequent small studies demonstrated no benefit

from Fluosol infusions in patients with profoundanemia.With colloid solutions as a comparator,Fluosol did not improve indirect measures ofoxygenation. However, Fluosol continued to be

available for infusion as an oxygen carrier during-


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New emulsions have been developed which utilizeemulsifying agents similar to the primarycompound. In particular, perflubron

(perfluorooctyl bromide) has been developed as astable emulsion safe for intravenous infusion by theaddition of small amounts of perfluorodecylbromide as an emulsifying agent; the emulsion is

then buffered with egg yolk phospholipids. Theresulting emulsion has a calculated oxygen carryingcapacity which is approximately three fold theamount of oxygen carrying capacity of the earlier

Fluosol solutions.


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As Perflubron oxygen carrying capacity is directly

related to the oxygen partial pressure. Therefore perflubron oxygen delivery is

predictable; direct diffusion of oxygen is themechanism by which oxygen is off-loaded to

peripheral tissues.


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Transport of oxygen as soluble gas in plasma is

radically different from hemoglobin-based oxygentransport.

Administration of perflubron can increasedissolved oxygen to approximately 10-15% of thetotal arterial oxygen content, an increase from thenorm of two to three fold, depending on the partialpressure of oxygen inspired. This can also be

understood by considering the figure.:


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Per-fluorocarbons are inert biologically.The retention ofper-fluorocarbons does pose an additional problem withrespect to dosage. Per-fluorocarbons relatively disappearin the plasma, with a half life of approximately 3-4 hours inthe plasma phase.

At present, this limitation of dosing is theoretical, as noclinical data exist to distinguish whether per-fluorocarbonre-dosing results in serious adverse effects; future studiesand newer generation emulsions will address this issue andlead to newer results.


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Current blood substitutes have been demonstrated

to be safe when administered in small quantities to

volunteers. Both perfluorocarbon and hemoglobinbased oxygen carriers have undergone clinical trialsdesigned to determine the safety of thesecompounds when given to otherwise healthy

patients. These preliminary studies have shown thata clinically useful dose of a blood substitute can beinfused to patients.

The short plasma half-life of these compounds

limits the usefulness of blood substitutes to shortperiods of time. Ultimately, the blood substitute

will be removed or metabolized, and decreasedoxygen carrying capacity will reappear as the plasma

oxygen carrying capacity diminishes.


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Thus, if no longer acting agents are available, it islikely that these blood substitutes will merely delayan allogeneic transfusion, rather than avoiding

exposure, when used in place of conventionalallogeneic red blood cell transfusions.

In order to effectively use these compounds, special

techniques should be considered. One techniquewhich theoretically should optimize bloodsubstitute utility is acute normovolemichemodilution. Aggressive harvesting of potentially

several units of autologous fresh whole blood ispossible when the solution to replace the harvestedblood is capable of transporting oxygen.


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Coupling of blood substitutes with acutenormovolemic hemodilution has been successful in

small clinical trials; whether this mode of usingblood substitutes will result in substantial clinicaland economic benefits await larger clinical trials.


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The final goal of any transfusion service is to createa transfusion system with no side effects and withmore effective medical care. The current system ofhomologous blood, although is marked by manyproblems, like allosensitisation and transfusiontransmittable diseases, is working well with low

cost, acceptable efficacy and relatively less side-effects.

Even so, the technologies of the future promise togenerate an effective blood substitute, which will

definitely have an impact on transfusion medicineand the transfusion services. Presently, the prospectof using artificial blood is difficult to envisionowing to problems of short half life, prolonged

tissue retention, potential toxicity, and issues of


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This may cause a temporary shift of focus fromcompletely replacing blood cells, to that of usingthis as

a supplement to homologous transfusion. However,in prehospital or battlefield emergencies , or incountries where supply of safe blood is affected bypotential threat of

HIV infection, the role of blood substitutes willundoubtedly be of immense value. And it isabsolutely certain that a new system of bloodservice with synthetic blood and blood substitutes,

including artificial oxygen carriers andrecombinant plasma components, will bedeveloped in the near future, which will define anew dimension to transfusion medicine.

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