Kadem G. Al-Lamee

Studies in polymer surface functionalization and grafting for biomedical and other applications

Abstract A simple and inexpensive treatment for surface functionalization and grafting carried out under mild aqueous conditions and suitable for prefabricated medical devices, has been developed. The two stages are performed separately; the first is hydroxylation by a peroxy compound, particularly a peroxydisulfate or peroxymonosulfate, in aqueous solution with strong nitrogen purging; and the second is grafting of a vinyl monomer by the conventional ceric ion technique. Types of polymer studied include polypropylene, polystyrene, polyacrylonitrile, polyurethanes, aliphatic polyesters, nylons, aromatic polyesters and polycarbonates. Surface properties of the substrate polymers may be greatly modified by this treatment. To illustrate possible applications for covalent coupling of bioactive molecules to polymers we have attached the blood-anticoagulants heparin and hirudin to the polyester Ecdel and to polystyrene, respectively. The products were highly bioactive.

Studies of a novel membrane for affinity separations: I. Functionalisation and protein coupling

Abstract A study is presented of the potentialities of an electrostatically-spun poly(ether—urethane—urea) as an affinity separation membrane. The spinning process produces a fibrous network with a high internal surface area. A variety of chemical methods has been used for functionalising and activating the membrane. Assessments of the capacities of the activated membranes for covalent coupling of protein A and human immunoglobulin G have given very encouraging data. Non-specific adsorption of both proteins by the inactivated polymer was negligible. Geometric considerations suggest that the limiting factor determining protein coupling is the accessible surface area rather than the number of coupling sites.

Studies in polymer surface modification and grafting for biomedical uses: 2. Application to arterial blood filters and oxygenators

The technique for polymer surface modification described in earlier papers has been applied to two components of an extracorporeal blood circulatory system used in open-heart surgery, with the object of improving their haemocompatibility. The devices were the arterial blood filter composed of nylon membranes and the blood oxygenator consisting of polypropylene microporous hollow fibres. Polyacrylamide and, in some cases, a mixture of polyacrylamide and poly(3-aminopropyl methacrylamide) have been covalently attached to the blood-contacting surfaces. The basic groups of the latter polymers provided a means of coupling heparin to the surface. The extent of heparin coupling was determined by radioactivity measurements with the aid of 35S-labelled heparin. The following determinations were made to assess haemocompatibilities: blood plasma clotting times (PTT); platelet adhesion to the nylon filters; concentrations of lymphocytes and neutrophils in whole blood after exposure to the surfaces. It is concluded that the overall process, which has the merits of cheapness and simplicity in application, has a beneficial effect on haemocompatibility.

Studies of the esterification of dextran: routes to bioactive polymers and graft copolymers

Abstract Problems associated with the esterification of dextran as a means of coupling bioactive molecules or introduction of functionality suitable for graft polymerization are considered. In particular, the importance of eliminating side-reactions which incorporate into dextran unwanted residues, e.g. groups containing nitrogen, is emphasized and practical techniques for minimizing this are described. We have developed a formamide-based solvent suitable for esterification with the aid of dicyclohexyl carbodiimide (DCC) and carbonyl di-imidazole (CDI) as coupling agents. The preferred catalyst is p -pyrrolidinopyridine. CDI has the advantage of enabling dimethylsulphoxide to be used as solvent for dextran and other hydroxylic polymers without inducing oxidation of hydroxyl groups. This coupling agent is flexible and offers a choice of two routes to esterification, each having its merits. We have optimized conditions for coupling by use of butyric acid as model. Esterification of dextran has been employed in the preparation of soluble bioactive macromolecules by coupling the anti-platelet agent (I) and also in the synthesis of graft copolymers via introduction of 2-bromopropionate groups. Crosslinking of dextran and the polymerization of dipyridamole have been effected by use of CDI.

Photolysis of arene chromium tricarbonyls and photoinitiation of polymerization

The photolyses of bzCr(CO)3 and tolCr(CO)3(bz = benzene, tol = toluene) have been studied in hydrocarbon and methyl methacrylate solutions. Scission of carbon monoxide is found to be the main route of photodecomposition in hydrocarbon media (as proposed by some earlier workers), and the resulting fragment arCr(CO)2 decomposes, possibly by a complex mechanism, to yield arene. Addition of CCl4 enhances the rate of arene generation by reaction with arCr(CO)2 and arCr(CO)*3, while in the absence of CCl4, CO suppresses reaction by recombination with arCr(CO)2. In methyl methacrylate solution the rate of arene formation is higher than in hydrocarbon media and is little affected by carbon monoxide, even in the absence of CCl4. We propose that the exciplex [M ·· arCr(CO)3]* is formed in methyl methacrylate (M) solution and may subsequently decompose into ar + MCr(CO)3 or arCr(CO)2 M + CO.Systems containing arCr(CO)3 and halides such as CCl4 are active photoinitiators of free-radical polymerization; the kinetics of the polymerization with ar = benzene and methyl methacrylate as monomer have been studied. Carbon monoxide has a strong inhibitory effect on the reaction. It turns out that at “high”[CCl4](∼0.1 mol dm–3) each molecule of bzCr(CO)3 photolysed yields one initiating radical, the quantum yields of photodecomposition and photoinitiation (λ= 365 nm) being 0.41.A reaction scheme (A) is propsed which is consistent with the available photochemical and polymerization data.

Grafting and Attachment of Antiplatelet Agents to Poly(Ether-Urethanes)

Segmented poly(ether-urethanes) have been shown to be particularly suitable for a wide range of biomedical applications on account of their good elastomeric and other mechanical properties and their relative compatibility with blood. Consequently several commercial poly(ether-urethanes) have been exploited for the manufacture of prostheses such as artificial hearts and arteries and extracorporeal circulatory systems.1,2 Attainment of the highest possible degree of haemocompatibility of the polymers is essential in certain applications such as small-boar arterial prostheses of internal diameter 4 mm or less. The work we now describe was undertaken as part of the development of such a prosthesis and required chemical modification of commercial poly(ether-urethanes) rather than the investigation of new types with potentially improved properties.

Modification of polymers for cardiovascular applications—some routes to bioactive hydrophilic polymers

This paper is concerned with the activation of platelets by polymers, a key-process in the behaviour of prosthetic devices in contact with blood.Platelets are activated by contact with many different types of polymer surfaces, which must therefore be regarded as thrombogenic. Two procedures for reducing thrombogenicity are discussed: (i) the chemical attachment of inhibitors of platelet aggregation and (ii) gross modification of the nature of the surface, e.g. by making it more hydrophilic. For purposes of (i) the potent prostaglandin analogue BW 245C has been used, while for (ii) grafting of poly(ethylene glycol) (PEG) has been explored. Both methods give greatly reduced platelet adhesion inin vitro tests.The second part of the paper deals with the properties of adducts of inhibitors of platelet aggregation (BW 245C, dipyridamole) with water-soluble macromolecules [poly(N-vinyl pyrrolidone), PEG, dextran]. Adducts have been synthesized with terminal and side-chain coupling. On adduction the two inhibitors mentioned show opposite types of behaviour: the molar activity of BW 245C is dramatically reduced, but that of dipyridamole is significantly increased. Remarkable synergistic effects have been recorded for BW 245C adducts. These observations are interpreted in terms of differences in stereochemistry in the drug-receptor interactions.Appropriate chemical techniques for coupling are outlined, attention being drawn to the special uses of haloalkyl- and haloacyl-isocyanates and 2-isocyanatoethyl methacrylate as reagents.

Influence of molecular structure on the synergistic action of theophylline or dipyridamole derivatives in the prostaglandin-type inhibition of platelet aggregation

Approximately 30 new derivatives of theophylline and dipyridamole have been prepared and examined as potentiators of the inhibition of platelet aggregation induced by the prostaglandin analogue BW 245C. Potentiating activity has been found to be sensitive to molecular size and also to the presence of specific groups. Polymeric adducts based on dextran, poly(ethylene glycol) or poly(N-vinyl pyrrolidone), and aliphatic esters with alkyl chain-lengths greater than 7 are inactive in potentiation. Derivatives containing carboxyl groups are also inactive. Potentiation is discussed in terms of platelet membrane penetration and extra- and intra-cellular processes. The latter are invoked to account for the enhanced potentiation shown by dipyridamole and derivatives when aggregation is induced by PAF-acether rather than ADP. One derivative of particular interest is the adduct of theophylline with 1,2,5,6-diisopropylidene-D-glucose, containing a furanose ring. This is a more active potentiator than theophylline itself, possibly owing to its molecular resemblance to cAMP. On conversion to the pyranose form all activity is removed.

Synthetic polymer membranes with molecular recognition

The synthesis is described of a macroporous electrostatically-spun poly(ether urethane) membrane, functionalised to show molecular recognition of uracil derivatives.

Photolysis of arene chromium tricarbonyls and photoinitiation of polymerization. Part 3.—Benzene chromium tricarbonyl in styrene

Irradiation of a styrene solution of benzene chromium tricarbonyl with light of λ= 365 nm produces strong absorption in the region 327–450 nm, with a maximum near 360 nm. This spectral change is enhanced by the presence of carbon monoxide. Reasons are given for believing that photolysis involves an exciplex intermediate and yields a complex (II), bzCr(CO)2 st, and perhaps a second complex (III), Cr(CO)5st, in both of which styrene is coordinated to chromium through the vinyl group. Both complexes react with carbon tetrachloride, the reactions being accelerated by illumination.During irradiation in the presence of CCl4 polymerization of styrene occurs; the dependence of the rate on [CCl4] is of the familiar type and the polymerization follows conventional kinetics for a simple free-radical reaction. A very unusual feature, not hitherto observed in a metal carbonyl/halide system, is an increase in the rate of polymerization brought about by the presence of carbon monoxide. It is shown that there is correspondence between rates of initiation and concentrations of complexes (II) and (III); the influence of CO is attributed to its effect in increasing these concentrations. On turning off the light there is a prolonged after-effect. It is concluded that, except in the earliest stages, a major portion of the radical generation arises from photochemical and thermal reactions of (II) and (III) with carbon tetrachloride. The quantum yields of photoinitiation (ca. 5 × 10–2) are low.The major differences between the systems having methyl methacrylate and styrene as solvent appear to arise from the formation of much more strongly absorbing, and more stable, complexes in the latter.