Chemistry of the Clinic - Blood
This part will have a look how chemistry can be applied in healthcare and in this part will have a look for materials that have contact with blood and use in cardiovascular (heart and the blood vessels). As an introduction, the world healthcare market is approximately £4000 billion and globally, the pharmaceutical market is estimated to be £200 billion. Besides that, the world medical device markets have been estimated to be around £120 billion and regenerative medicine is estimated worth £1 000 billion by 2020.
In cardiovascular, more than 1000 devices are interacting with blood everyday and this is the key way in which the body might reject an implant. Then, clotting can be formed that this can be very serious as it might lead to thrombosis and death. The devices that contact with blood such as wound dressings, catheters, artificial valves and veins, bone replacement implants, drug reservoirs, dialysis instruments, and blood bags. Therefore, to begin with we will have a look what blood is and what it does.
In general, there are 2 main components of blood, plasma and the cells. Basically, plasma is an aqueous solution which contains 95% of water, fats, fatty acids, salts and proteins. In plasma, there are a lot of types of plasma such as albumin, fibrinogen, prothrombin, compliment, vonWilebrand factor, and immunoglobulins. Meanwhile, the cells consist of red blood cells for transport oxygen, platelets for clotting, an white blood cells that produce antibodies.
Firstly is albumin which has main roles to maintain osmotic pressure and transport lipids. In pure water, cells die because essential molecules flow from inside the cell. However, when water containing salts and biomolecules (e.g. albumin) at same concentration as in cell, the ions and biomolecules are in equilibrium. Hence, the net flow is 0. Secondly is fibrinogen which has main role in clotting and this is the main problem of biocompability. The clotting process is shown below as the clotting cascade.
Fibrinogen is cleaved by thrombin to form fibrin which is fibre clot and this fibrin clot is stabilised by factor XIIa trans glutaminase to form fibrin stable clot. Before that, prothrombin is a precursor molecule of thrombin and thrombin is synthesised by helps from factor Xa and Va and platelets to provides calcium ions. Therefore, to have good biocompability the materials should prevent fibrinogen adsorption.
Besides that, the third proteins is compliment which is a mixture of approximately 20 proteins. Compliment contributes to acute inflammation and immune response which in biomaterial term is a bad thing. It is also responsible for elimination of foreign bodies. When compliment is activated, it will adsorbs to material and forms clot as well antibodies is produced. This activation is related closely to surface charge of compliment and protein which mainly positive charge. After that, vonWillebrand factor is a large glycoprotein which has role in hemostatis, i.e. prevent coagulation in normal closed system. Lastly is immunoglobulins which consist of 4 chains that form Y-shape.
The part at the end of immunoglobulins has a function to bind to a material and mark the target. Then, phagocytic cell recognise it and destroy it.
The cells in blood contain red blood cells that has a function to transport oxygen. The red blood cells consist of 4 protein chains and a iron-containing haem group. Moreover, when oxygen binds into haem group, there is changing in protein conformation.
In the presence of CO, oxygen has lower binding affinity than CO, so CO binds into haem group. This can lead into CO poisoning cases. Meanwhile, the haem group has cooperative binding with oxygen which means it increases binding affinity once one molecule has bound. Besides oxygen, red blood cells also transport CO2 and it binds at different sites. CO2 binds more strongly in the absence of O2, which is known as Haldane effect.
Moreover, CO2 reacts with water catalysed by carbonic anhydrase to form carbonic acid. This makes venus blood (blood in vein) has a lower pH and at high CO2 levels haemoglobin binds H+ and CO2. The shape of proteins changes when H+ is bound and this aids the release of O2. At decreased concentration of H+ i.e. low concentration of CO2, e.g. in the lungs, the protein shaoe returns to the form that binds O2 to a higher degree.
From those characteristics of blood, materials that in contact with blood should fulfil certain requirements. Firstly is non thrombus formation which means low fibrinogen adsoprtion and low platelet adhesion. Secondly is non compliment activation which means minimal immune response. Nowadays, commercially the most important non-thrombogenic and non-immunogenic materials are polyurethanes. The urethane or carbamate group formed by reaction of an alcohol and an isocyanate.
However, polyurethanes can be synthesised from diisocynate with diol or diamine.
In some cases, polyurethane has a segmented of polyether or polyester to give flexibility as the benzene ring in polyurethanes give the rigidity of the polymer.
Therefore, polyurethanes are segmented with hard blocks from short diamine or diol ordered and soft segments such as polyether. These segmented polyurethanes give its rubbery characterisic, good fatigue resistance, good blood contacting properties from PEG (polyethylene glycol - polyether) soft segment., and biostable. Despite some issues with oxidation long term, polyurethane is the best of all rubbers for implant (best overall bioperformance), and one of the example is used in pacemaker.
Moreover, polyester polyurethanes are susceptible to hydrolysis. Besides that, polyethers cannot be hydrolysed but can be oxidised, and aliphatic polyurethanes degrade at hard segment also have been used for tissue engineering.
Besides polyurethanes, there is another route to anti-fouling materials such as flexible grafted chains (PEG) and water swollen hydrogel-chains plasticized and mobile. Both of them adsorb platelets or protein to reduce chain mobility.
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| Synthetic materials in the body |
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| Blood components |
In general, there are 2 main components of blood, plasma and the cells. Basically, plasma is an aqueous solution which contains 95% of water, fats, fatty acids, salts and proteins. In plasma, there are a lot of types of plasma such as albumin, fibrinogen, prothrombin, compliment, vonWilebrand factor, and immunoglobulins. Meanwhile, the cells consist of red blood cells for transport oxygen, platelets for clotting, an white blood cells that produce antibodies.
Firstly is albumin which has main roles to maintain osmotic pressure and transport lipids. In pure water, cells die because essential molecules flow from inside the cell. However, when water containing salts and biomolecules (e.g. albumin) at same concentration as in cell, the ions and biomolecules are in equilibrium. Hence, the net flow is 0. Secondly is fibrinogen which has main role in clotting and this is the main problem of biocompability. The clotting process is shown below as the clotting cascade.
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| The clotting cascade |
Besides that, the third proteins is compliment which is a mixture of approximately 20 proteins. Compliment contributes to acute inflammation and immune response which in biomaterial term is a bad thing. It is also responsible for elimination of foreign bodies. When compliment is activated, it will adsorbs to material and forms clot as well antibodies is produced. This activation is related closely to surface charge of compliment and protein which mainly positive charge. After that, vonWillebrand factor is a large glycoprotein which has role in hemostatis, i.e. prevent coagulation in normal closed system. Lastly is immunoglobulins which consist of 4 chains that form Y-shape.
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| Immunoglobulins |
The cells in blood contain red blood cells that has a function to transport oxygen. The red blood cells consist of 4 protein chains and a iron-containing haem group. Moreover, when oxygen binds into haem group, there is changing in protein conformation.
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| Protein chains of haemoglobin (left) and the haem group (right) |
From those characteristics of blood, materials that in contact with blood should fulfil certain requirements. Firstly is non thrombus formation which means low fibrinogen adsoprtion and low platelet adhesion. Secondly is non compliment activation which means minimal immune response. Nowadays, commercially the most important non-thrombogenic and non-immunogenic materials are polyurethanes. The urethane or carbamate group formed by reaction of an alcohol and an isocyanate.
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| Urethane synthesis |
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| Polyurethanes synthesis |
Therefore, polyurethanes are segmented with hard blocks from short diamine or diol ordered and soft segments such as polyether. These segmented polyurethanes give its rubbery characterisic, good fatigue resistance, good blood contacting properties from PEG (polyethylene glycol - polyether) soft segment., and biostable. Despite some issues with oxidation long term, polyurethane is the best of all rubbers for implant (best overall bioperformance), and one of the example is used in pacemaker.
Besides polyurethanes, there is another route to anti-fouling materials such as flexible grafted chains (PEG) and water swollen hydrogel-chains plasticized and mobile. Both of them adsorb platelets or protein to reduce chain mobility.
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