Organic polymer surfaces for use in medicine: Their formation, modification, characterisation and application

Prog. Polym. Sci., Vol. 15, 715--734, 1990

0079-6700/90 $0.00 + .50 © 1990 Pergamon Press pie

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ORGANIC POLYMER SURFACES FOR USE IN MEDICINE" THEIR FORMATION, MODIFICATION, CHARACTERISATION AND APPLICATION JULIAN H. BRAYBROOK*Tand LAURANCED. HALL

University of Cambridge School of Clinical Medicine, Herchel Smith Laboratory for Medicinal Chemistry, University Forvie Site. Robinson Way. Cambridge, CB2 2PZ, U.K.

CONTENTS

1. Introduction 2. Polymer synthesis and general characteristics 2. I. Polymer types available 2.2. Formation 2.3. Properties 2.4. Common medical applications 3. Modification of polymer surfaces 3.1. Characterisation techniques 4. Polymer compatibility 4.1. Biological characterisation techniques 5. Medical applications 5.1. Plasma extenders 5.2. Artificial organs 5.3. Immobilised enzymes 5.4. Iron-chelating polymers 5.5. Metallobiopolymers 5.6. Controlled release polymers 5.7. Artificial cells 5.8. Microspheres 5.9. Polymeric vesicles 5.10. Polymeric drugs 6. Summary and conclusions References

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1. I N T R O D U C T I O N

The increased demand for polymeric biomaterials and for devices made

therefrom is clearly demonstrated by the numbers utilised, the number of *Author to whom correspondence should be addressed. ~'Present address: Materials Technology Group, Laboratory of the Government Chemist, Queen's Road, Teddington, Middlesex, TWl I 0LY, U.K. 715

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manufacturers involved and by the number of institutions involved with teaching and researching this area. Demand is growing for biomaterial usage in dialysis and immobilisation of enzymes and as artificial cells, organs and prostheses, tissue adhesives and cements, plasma extenders, and controlled drug release agents. Polymers are frequently difficult to characterise accurately and often have variable chain length and molecular weight distribution. Furthermore, there may be problems associated with manufacturing methods, fabrication, sterilisation and component-polymerisation. Nevertheless, the final products are generally relatively light-weight, easily processed and shaped, have good versatility and give a better balance between weight and mechanical, chemical and physical properties than simpler materials. In addition, they may be fabricated with a specific biological function and compatibility. This review will examine the formation, modifications, applications and limitations of some organic polymer surfaces in man. 2. POLYMER SYNTHESIS AND GENERAL CHARACTERISTICS 2. I. Polymer types available Many polymers occur naturally, e.g. collagen, but others are synthesised, e.g. polycarbonate. They may be thermoplastic (softens repeatedly on heating allowing shaping and hardens on cooling), e.g. polystyrene, or thermosetting (softens on heating, but becomes rigid on continued heating), e.g. epoxide resins. The thermal property of each polymer determines the method of formation, purification, and sterilisation and the final polymer properties. A homopolymer is formed by polymerisation of a single monomer. Copolymerisation can be used to balance the properties of the product, whose structure depends on the reactivities of the two different monomers and the polymerisation method employed. Random, alternating, block and graft copolymers can be formed, but batch variations can also occur due to variations in monomer arrangement on the polymer chain, homopolymer contamination and differences in the percentage composition of the product. Terpolymers formed from three monomers are also possible. The desired biostability of the final polymer depends on the intended function, e.g. synthetic heart-valves must have a high biostability along with outstanding mechanical properties, whereas polymers for some drug delivery systems must be biodegradable. Primary polymer bonding is strong and intramolecular, whereas secondary bonding is relatively weak and intermolecular (attractive forces between polymer chains due to dipoles, inductive and dispersion forces, or hydrogen bonding). Cross-linking, introduced by heating, irradiation or chemical reagents, alters the properties. Close polymer alignment promotes crystallinity, e.g. fibres, but large side-groups hinder crystallisation, giving amorphous materials, e.g. atactic polystyrene.

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2.2. Formation Polymer formation may be achieved by a variety of strategies: (a) by condensation polymerisation where two molecules unite by eliminating a simple molecule. These are stepwise, usually slow, reactions with higher molecular weights being reached only in the final stages. These reactions occur when there is either a monomer containing two different functional groups or two molecules each having more than one functional group. Normally, use of catalysts and high temperatures are restricted as thermally-stable polymers are needed. However, side reactions can occur and catalyst residues can be incorporated into the product, (b) by rearrangement polymerisation where only hydrogen atoms transfer, e.g. as in polyurethane formation; (c) by ring opening of cyclic monomers, the speed of polymerisation being related to the catalyst used, the ring size and the functional group reactivity, and (d) by addition polymerisation when a ring opens or a double bond of the monomer undergoes addition. Generally, these involve fast chain reactions and require asymmetric molecules (except in the case of ethene, tetrafluoroethylene, and some cyclic monomers such as vinylene carbonate and maleic anhydride). Polymerisation may be achieved using thermal or photochemical (free radical propagation) initiation (cationic polymerisation involves carbocation propagation, and anionic, carbanion). The polymers may be atactic, isotactic, or syndiotactic, the tacticity being controlled by the initiator or catalyst. However, these reactions are exothermic and the polymers have a low thermal conductivity. Dilution of the reaction mixture and stirring may help to control the reaction, but elimination of solvent from the product is then important, especially if it is to be used medically. Use of an aqueous medium gives a suspension polymerisation, j and emulsion polymerisation is a variant of this method (though very different kinetically). 2.3. Properties The properties of the final polymer depend on the choice of polymerisation method (residual monomer removal is crucial), polymerisation ingredients, purification techniques, polymer fabrication and sterilisation. Polymerisation ingredients may improve polymerisation and enhance the fabrication and overall properties of the resulting polymer, lnhibitors prevent premature polymerisation and allow safe monomer storage, but their removal is difficult. Initiators, which ~tart the polymerisation process, catalysts, which allow good reaction rates, and chain transfer agents, which control polymer length, may be utilised, but they may become permanently incorporated in the polymer. Anionic, cationic and non-ionic emulsifiers (surfactants) affect blood compatibility unless removed. Plasticisers, as high-boiling point solvents for polymers, give a more flexible product, but may be leached out within the body of a living organism. Curing agents, e.g. peroxides and isocyanates, cross-link

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J.H. BRAYBROOKand L. D. HALL TABLE I. Medical applications of some common polymeric materials Polymer material

Medical applications

Cellulose

Haemodialysis Controlled release devices2-4

Cellulose acetate

Artificial kidney membranes Reverse osmosis Hyperfiltration

Collagen

Haemodialysis

Epoxide resin

Encapsulation

Collodion Albumin

Artificial kidney experiments

Polycarbonate

Skull implants Blood oxygenators Haemodialysis membranes 3'j°'N

Poly(alkyl cyanoacrylates)

Tissue adhesives Controlled release devicesx~2-t6

Polyamides

Short-term microencapsulation Artificial cells

Polyethylene

Hip prostheses Artificial kidney blood ports Splints

Polyelect rolytes/hydrogels

Haemodialysis Blood oxygenation Contact lenses Controlled release devices Implant coatings4'j7

Polyacrylonitriles

Haemodialysis Wound and burn-covering materials

Poly(glycolic acid) and copolymers with poly(lactic acid)

Structures Controlled release devices12'~3~8

Poly(ethylene terephthalate)

Reinforcing implants Promotion of growth of living tissue

Poly(vinyl chloride)

Blood tubing and containers/dispensers Coil-type artificial kidneys

Polyurethanes

Artificial artery and heart materials z'~9'z°

Poly(hydroxyethyl methacrylate)

Breast prostheses Haemoperfusion devices Soft contact lenses Wound and burn-covering materials Controlled release devices4'tT'z2

Poly(methyl methacrylate)

Orthopaedic prostheses Hard contact lenses 2'4'22'z3

Polypropylene

Implantable finger joints Potential blood oxygenation membrane Artificial liver support Controlled release devices3

Polystyrene

Blood compatibility improvement Controlled release devices4-9

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T^aLE I. Medical applications of some common polymeric materials Polymer material

Medical applications

Polysiloxanes

Finger joints Artificial heart valves Arteriovenous shunts for haemodialysis and blood oxygenation membranes

Poly(vinyl alcohol)

Haemodialysis membranes Implantation Hip joint usage Blood oxygenation membrane

Polytetrafluoroethylene (Sometimes used with vitreous carbon)

Reconstructive surgery

linear thermoplastic materials, but again their choice and quantity is important. Reinforcing fillers, e.g. carbon black and silica, impart mechanical strength. Extending fillers, e.g. calcium carbonate, assist processing and decrease product cost. However, their incorporation alters the blood compatibility of the polymer. The same applies to pigments which provide the correct shade necessary for some medical applications, e.g. red stomach tubes. Use of antioxidants minimises deterioration of the polymer by oxidation. Extraction and fractionation purification techniques remove soluble impurities and low molecular weight material whereas filtration and precipitation remove insoluble impurities. Polymer fabrication yields the desired physical form of the polymer. Mould surfaces and release agents can cause contamination and alter the physical properties and chemical structure of the polymer. Purity is ensured by correct ingredient specification. Sterilisation procedures, essential for medical applications, are determined by the polymer's heat sensitivity and chemical structure. They include: (a) dry heat (160-190°C), which is unsuitable for many polymers due to their heat sensitivity, (b) steam autoclaving, which is limited to polymers which do not soften below the normal autoclaving temperature (134°C), (c) gaseous sterilisation using ethene oxide gas, which is suitable for heat-sensitive polymers and whose effectiveness depends on exposure time, temperature, gas concentration and relative humidity, (d) liquid sterilisation using formaldehyde solutions, and (e) irradiation by a radiation source, e.g. 6°Co or high energy electrons. Although 6°Co is powerful, does not induce radioactivity, is highly efficient and has little thermal effect, it is costly and induces cross-linking and degradation, and so has limited use. 2.4. Common medical applications There are many polymers available giving a wide range of medical applications. The more common types of polymer and their respective medical applications are shown in Table 1.

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Silicones as fluids, gums or rubbers (cross-linked gums by free-radical vulcanisation) 24-26may also be employed, their uses and potentially carcinogenic effects having been reviewed elsewhere. 27 3. MODIFICATION OF POLYMER SURFACES The rapidly expanding uses of biomaterials necessitate an understanding of the complex interactions of their surfaces with the surrounding environments. Hence, interest has developed in understanding the nature, distribution and orientation of polymer functional groups 28 and in the modification of surface properties for specific applicationsY Surface modification involves alteration of the surface's chemical and/or physical nature and is such a large area that only some methods are mentioned here. The traditional methods of using additives, coatings and either wet chemical processes or gas-solid interfacial interactions alter the surface as do the modern methods of electric discharge and radioactive source and plasma/ion beam techniques. Typical additives include: (a) Teflon fluoropolymers which improve lubricity, release and anti-corrosion properties, (b) amides which improve lubricity, (c) fluoroacrylates which improve repellency, (d) soaps, salts and humectants which improve anti-static properties, and (e) silicas which improve anti-block properties. Anti-static agents may be anionic, e.g. alkyl(aryl)sulphonates, cationic, e.g. quaternary ammonium salts and amine salts, or non-ionic, e.g. glycerols, humectants and moisture-sensitive compounds. Typical wet-surface chemical reactions for tailored surfaces 3° include: (a) etching which improves adhesion, (b) flaming which improves adhesion, (c) sensitisation/activation which improves metal plating, (d) sulphonation, amination and nitration which improve adhesion, (e) ion exchange and enzyme immobilisation, (f) oxidation and halogenation which improve flame-resistance and anti-static properties, and (g) ceric salt/vinyl grafting which improves permeation. Surface cross-linking may be achieved by chemical treatment with chlorosilane and gaseous fluorine (for polyethylene)31 and by using the CASING technique) t-33 Olsen and Osteraas 34 reported polyethylene modification by reactive sulphur compounds, carbenes and nitrenes) 5 Amino groups have been attached by radio-frequency plasma 36and used for binding blood anti-coagulant and heparin to many types of polymer materials) 7 Also, nitrogen-containing groups have been incorporated in polycarbonates by diamine or polyamine treatment) 8 Courtney 39 has reported surface modification of a copolymer by ethylene oxide, which gives a cyclised structure. Etching using sodium/ ammonia: °-43 sodium-naphthalene-tetrahydrofuran complex solutions, 44-47 chromic acid ~-5° or potassium permanganate 5° dissolves surface impurities and attacks amorphous zones allowing active group incorporation.

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Surface grafting by irradiation and chemicals sl produces a second polymer surface layer on a base polymer, initiation being by high energy radiation (~, rays), low energy radiation (UV) or chemical initiating species. Azrak 52 and Pennings 53 showed orientation of polar groups with environmental influences. Gaines ~ reported siloxane block copolymer surface concentration, Kawakami and Yamashita 55"56the addition of macromer-produced tailored graft copolymers, and Kawakami and coworkers 57surface modification by siloxane graft copolymers. Yamashita ss reported the surface activity of graft copolymers prepared by radical copolymerisation and noted that small amounts of specific graft monomers, e.g. hydroxyethyl methacrylate, improved the wettability of polymethyl methacrylate (PMMA) films by aqueous solutions. Low energy radiation-induced grafting 59~ for adhesive bonding, originally developed for polyethylene, is now applied to fluorocarbon polymers. 62-66The relationship between surface structure and adhesive bond strengths may be informative for synthetic hydrogel preparation on inert polymer surfaces for biomedical applications. 67 Advances have lead to macromolecular engineering and synthesis of many graft, bigraft and block copolymers. 68 Electrical discharge treatment by corona 69and plasma functionalisation 33'4s497° works in air (unlike plasma and high energy irradiation techniques). Fluorene or fluorocarbon surface addition improves release properties and graft vinyl monomer addition decreases polymer permeability. Glow discharge treatments 7~-74 have also been studied. Possibly the most efficient reaction is the use of gas/solid interactions involving "cool" plasma. 7° Oxygen plasma treatmen¢ 3 increases surface oxygen atom density whereas hydrogen plasma treatment decreases it. Tawney 75 has reported imidoalkylene substitution and Klebe 76a Friedel-Crafts alkylation method for polymer surface modification. Electron deficient moieties, e.g. carbene and nitrene, generated by pyrolysis and reacted in the vapour phase with a substrate, have been demonstrated to affect the critical surface tension values. 77 Many polymers have been prepared by standard chemical modifications of polystyrene. TM Phase transfer catalysis is the most efficient method, having modified cross-linked polystyrene in three-phase systems. 79'8° Nucleophilic displacements are involved and this technique has been extended to modification of soluble chloromethylated polystyrenefl 's2 It provides better polymer purity and functional yields, although polystyrene formation with vinyl pendant groups is difficults3 (except when divinylbenzene is used with excess diisopropylamine). 84 Chemical modification of polymer surfaces has been extensively reviewed elsewhere, s~ 3. I. Characterisation techniques

A range of techniques of varying degrees of complexity and sensitivity are required to fully characterise biomaterials. Surface modifications of polymers

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J. H. BRAYBROOKand L. D. HALL

for specific applications have forced investigation of surface morphology and chemical properties by physiochemical and biological characterisation) ~ Surface characterisation is functionally difficult because the number of surface groups is low and because the surface must be distinguished from the bulk material. Major areas of characterisation interest lie in the elemental and molecular properties, the molecular weight distribution, the amount of any isomers, the cross-link density variation, the amount of crystallinity, morphology changes, the amount and nature of molecular segment orientation, the distribution of changing surface free energy, the superficial surface area and the microtopography of the surface. The introduction of surface-sensitive spectroscopy has permitted analysis of polymer surface chemistry c h a n g e s . 31"33'43"48'49'6°'~'87 Auger spectroscopy and electron and ion microprobe techniques have not been successfully applied to polymers due to high energy beam radiation damage of the surfaces, and Mfssbauer spectroscopy is unsuitable due to the nature of organic polymerforming nuclei (except polysiloxanes). X-ray fluoresence and atomic absorption spectroscopy have been used for metal/polymer surfaces and secondary ion mass spectroscopy (SIMS) is promising as there is minimal surface damage, s8'89 Clark and Dilks investigated X-ray photoelectron spectroscopy (ESCA) for bonding structure and polymer reactivity details. 33"9°-95However, the determination of initial surface modification is difficult and so difference spectroscopy has been used. Nevertheless, ESCA provides details of the chemical state and an indication of depth profiling, and has been used, therefore, for many surface modification i n v e s t i g a t i o n s 3°'42'74'93-98 including plasma modification (in inert gases), 33'97'99'1°°valence bond structure changes due to physi- or chemi-sorption on metal surfaces,99 and radiation-induced 65 and siloxane graft copolymer57 modifications of fluorocarbons and PMMAs respectively. Ellipsometry57'ss'~°~-'°4 has been successful, especially for studying the interfacial protein interaction during adsorption and desorption. Other recognised physical techniques are shown in Table 2. TABLE2. Physical techniques available for surface analysis Attenuated total reflectance infra-red (ATR-IR) spectroscopy~'57'1°~'~°3-'°7 Surface enhanced Raman spectroscopy (SERS) los Soft X-ray spectroscopy4~m''°9 Optical and scanning electron microscopy3°'32'57'~'"°-j~2 Contact angle hysteresis J°'s~m'H3''~4 Interference and polarising microscopy~3 Fluorescence spectroscopy'~S Thin wetting, free films and Langmuir-Blodgett monolayers Thermally-stimulated charge decay (TSCD) Thermally-stimulated current (TSC) Transcrystallinity measurements by X-ray diffusion "6

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723

Electron spin resonance (ESR) of nitroxide-labelled surfaces,t 17 crosspolarisation of carbon atoms by protons in solids and resolved or partially resolved anisotropies can be useful sources of information)is In many systems overlapping occurs although magic-angle spinning improves resolution. "ga~° Its combination with deuterium quadropolar-echo spectroscopy ~2t'~22has been used for nuclear magnetic resonance (NMR) analysis of polymers, j23-t25 The determination of bulk properties, however, is also necessary. This is because assurance of the quality and of the nature of the individual components of the material provides the basis for interpreting the results of surface analyses and parameters correlating to the properties of the material, both in vitro and in vivo. Bulk properties can be determined using similar spectroscopic methods to those for surface property analysis, in addition to durometer readings for hardness, water displacement methods for density, mechanical measurements, solubility, optical birefringence, electrical conductivity and oscillatory response readings, s5 New data analysis methods allowing maximum information to be gained from the data tend to be based upon expert systems n6 and multivariate analysis.L2? Some of the more common biological techniques will be discussed following a brief mention of polymer compatibility. 4. P O L Y M E R

COMPATIBILITY

Biocompatibility, the ability of a material to perform with an appropriate host response in a specific application, ~2g is of primary importance in the long term usage of polymers in medical applications. It should be noted that there cannot ever be a truly biocompatible material and that biocompatibility is a concept which ranges from inertness and no interaction to one of positive interaction. Nevertheless, there has been much research and many articles published which provide a good insight into the area of biocompatibility through the determination and control of the chemical properties, physical properties/surface morphology and accompanying mechanical properties of implanted polymers. 39'n9-~34

4.1. Biological characterisation techniques Several papers have reported the common biological techniques presently used for analysis of interfacial phenomena between polymer and blood components or living tissues. The understanding of these interactions may lead to development of ways to improve biocompatibility, ttg'm'~-~3g However, it should be noted that gap areas exist, e.g. in the analysis of mutagenicity and carcinogenicity. Also, poor surface characterisation and test designs mean that, up to now, in vivo results of implanted polymers generally do not agree well with those obtained in vitro, t29")39

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J.H. BRAYBROOK and L. D. HALL 5. M E D I C A L

APPLICATIONS

Some of the applications of polymers in medicine, mentioned earlier, will now be discussed in more detail. 5.1. Plasma extenders These materials are used to maintain or expand blood volume in cases of trauma and hence should have good biorheological properties and maintain satisfactory osmotic and flow properties in increased blood volume for as long as is required. Molecular weights of 30,000 or more are required although very large molecules are undesirable as erythrocyte aggregation may occur. Poly(vinyl pryrrolidone)s (PVPs) are water-soluble polymers that have been evaluated, and extensively used for this purpose? 7"~4° They have also been designed to delay resorption of penicillin and insulin, etc., and to hasten dye clearance from the reticuioendotheliai system. However, there is a question of their toxicology due to latent hepatic lesions and cancers in rats. Poly(vinyl alcohol)s have similar storage distribution to PVPs, but as polymers they tend to produce anaemia and infiltrate the hypophysis and kidney. Safety testing of water-soluble macromolecules has been conducted, t4~ but the conclusions drawn were unconvincing due to inadequate control. Other polymers considered include the most widely used plasma extenders, dextran j42, gelatin j43 polyaspartamide ~ and other polyacrylamide types. ~45 5.2. Artificial organs A perfect prosthetic device will replace all functions required of it and be completely biocompatible. Progression of kidney disease often leads to severe impairment of kidney function and death. Extracorporeal dialysis is the most common therapy for acute and chronic renal failure. Precise details of the various artificial kidney devices may be found elsewhere. ~'27"~ In these devices, blood and dialysate are circulated on opposite sides of a semi-permeable membrane, e.g. cellophane, which allows lower molecular weight solutes (not blood proteins or formed elements) to pass through. Heparinisation is also required. Originally the films used were fragile and awkward, but now coils and hollow fibres increase the membrane area and add support. Ideally, membranes which separate molecules on the basis of chemical properties and size are required, i.e. block copolymers and cross-linked polymers having the desired hydrophilic/phobic properties. Other ideas regarding artificial cells will be discussed later in this review. Artificial devices for blood oxygenation outside the body (and carbon dioxide removal) have been intensively developed recently. Oxygen is added to and carbon dioxide removed from the blood, the exchange occurring across a

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725

gas-permeable membrane or blood/gas interface. The design, operation and performance criteria have been described fully elsewhere. ~'zT"t4° An artificial heart must completely replace the circulatory function, whereas a heart-assist device only has to relieve the natural heart, partially and usually temporarily, t'27'~47 Polymers utilised for the manufacture of artificial hearts include Dacron, Dacron velour, polyurethane and poly(vinyl chloride) and those for assist devices include similar polymers as well as polyurethane copolymers, polycarbonates and Silastic and epoxy resins. Caged balls, caged discs or tilting discs as prosthetic heart valves show a lateral blood flow and so polymer cusp valves have been useful, even if awkward. However, knitted Teflon and Silastic cusp valves tend to fracture on calcification and promote fibrous reaction and haemolysis. Hence hollow stellite balls are now favoured in place of these ball valves which have appeared to cause thromboemboli, obstructions, infection, detachment, degradation and anaemia. Other artificial organs include the pancreas which may be formed by microencapsulation of Islet cells in a novel membrane, e.g. an agarose-poly(acrylic acid) complex. 148

5.3. lmmobilised enzymes Much interest has grown in the use of immobilisation in industrial and metabolic processes and analytical chemistry. ~49 Five general immobilisation methods have been developed: (a) microencapsulation, (b) covalent bonding, (c) entrapment in hydrogeis or fibres, (d) adsorption to surfaces, and (e) crosslinking, the enzymes thereby being stabilised and still maintaining their biological activity.~5° Suzuki and Kanube have developed an electrochemical membrane preparation from fibrous proteins, such as collagen, without loss of activity. ~29The enzyme-collagen membrane has a low immunogenic effect and can find application as an enzyme sensor, e.g. lipase--collagen membrane sensor for determination of human serum natural lipids. Bioelect~-ochemical sensors give a good, cheap assaying method, the reactor activity can be altered by varying the amount of column-immobilised enzymes and the enzymatic catalysis rate can be regulated by varying the buffer's flow rate. Such sensors are promising for the determination of biological fluid phospholipids and have been used for determination of both the presence and quantity of hydrogen peroxide, uric acid, glucose, cholesterol, monoamines, sucrose, alcohol and lactic acid. ~z9Bacteriacollagen membranes can be applied to microbial electrode sensors, e.g. cephalosporin and nicotinic acid sensors, and similar bacteria-containing microbial electrode sensors have been developed for determination of glucose, assimilable sugars, acetic acid, ethanol, cell populations, vitamin B~, and amino acids and estimation of biochemical oxygen demand. ~29 Immobilised urokinase on a

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J . H . BRAYBROOK and L. D. H A L L

collagen membrane has been used to lyse a fibrin clot formed during blood dialysis. 5.4. Iron-chelating polymers Polymer frameworks for holding hydroxamic acid or catechol groups in close proximity to one another have been synthesised to mimic naturally occurring siderochromes for use in iron chelation therapy. 6~ Poly(N-methacryloyl/~alanine hydroxamic acid) (PI 1) is effective and about equal to the standard drug desferfioxamine. The eleven atom spacing between hydroxamic groups appears to be the optimum for intramolecular iron chelation and good iron complex solubility. P3 is also active, but rather toxic, probably due to the insoluble intermolecular cross-linked complexes. A catechol group-containing polymer is able to remove iron weakly and improvement may well be possible with better control of the catechol group spacing.

5.5. Metallobiopolymers The administration of heavy metal salts is the standard treatment for a variety of disorders and diseases. ~51 However, because of the toxicity, side effects and ineffectiveness of the free metal ions, metal ion complexes have been investigated. Copper and cobalt have been complexed by an acrylic acid--divinylbenzene copolymer for mycotic infections, ~$2tin and organoarsenic polymers have been used for fungal and bacterial infections, and heteropolymolybdates for anticoagulant and lipolytic properties. TM Microspheres have been used also for introducing metal ions. ~52'~53 Recently, paramagnetic and ferromagnetic functionalised polymers have been proposed as potential magnetic resonance imaging contrast agents which may improve the resolution of the gastrointestinal tract and surrounding tissues.I ~-~57

5.6. Controlled release polymers Controlled release technology has wide applications and may well provide a safer and more efficient means of delivery of a variety of potentially useful materials. There has been much research and many review articles published which report the fabrication of such polymeric systems,24'61'1~166 the mechanisms and factors affecting their release kinetics 167'~ and their potential applications. 3'4'~2.~a'~7"~62'l~'m69-~75However, there has been a move away from the comprehensive description available of controlled release processes and development of more drug delivery devices towards the fundamental determination of the inherent key processes of drug absorption through barriers, m

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5.7. Artificial cells Theoretically, many diseases can be treated by parenteral administration of enzymes, e.g. inborn errors of metabolism, hyperuricaemia, gout and inflammatory diseases. However, antibodies develop to intravenously injected enzymes and their long-term usage is not possible. Davis has attached monomethoxypolyethylene glycol (PEG) strands to selected enzymes. ~29Initial covalent attachment to bovine serum albumin and bovine liver catalase using a coupling agent has been successful in improving non-immunogenicity, no antibody accumulation being observed on repeated injections. However, sometimes, enzyme deactivation was observed on coupling. Different enzyme sources can be used in cases where PEG attachment does not eliminate immunogenicity. Enzyme replacement therapy by artificial cells (semi-permeable membraned microcapsules) has been demonstrated experimentally. Each artificial cell has an ultra-thin, cellular-dimensioned, semi-permeable membrane which envelops a solution, suspension or granule of enzyme, cell extracts, cells or other m a t e r i a l s . 129"177'17s This membrane, having a very large surface/volume ratio, separates the contents from the external environment thereby preventing external protein, antibody or cell entry, but allowing permeant substrates to equilibrate rapidly and come into contact with enclosed enzymes or proteins. Also, multienzyme systems, cofactor or regenerating enzyme systems, proteins, magnetic materials, multicompartmental systems, etc., can all be enclosed. Synthetic polymer membrane systems have been used, as have biological and biodegradable membranes, and many different contents have been investigated. Artificial cells containing enzymes and proteins have been used for red blood cell substitutes, 129"ITs'j79model enzyme systems for experimental therapy, ~29'~65't77'~78 enzyme replacement for hereditary enzyme-deficiency conditions, ~29 enzyme therapy using asparaginase for substrate-dependent tumours, ~29'~ specific removal of antigens or antibodies ~:9 and for artificial organs for organ failure, e.g. artificial kidneys, livers and detoxifiers. ~29"~Ts'~s2 A novel approach to artificial organ construction came from Chang and his laboratory with semi-permeable microcapsules as artificial cells which form a miniaturised artificial organ. ~77"~Ts'~8°'~s~ Enzymes, exchange resins, activated charcoal and other materials have been used to retain or convert metabolites entering these microcapsules. An albumin/cellulose, nitrate-coated, activated charcoal (ACAC) microcapsule artificial organ has been developed for chronic renal failure, acute intoxication and liver f a i l u r e , lzg'177,178'lao'lsz Biomedical applications of artificial cells containing microencapsulated enzymes have been demonstrated using simple, single enzyme systems. However, most metabolic functions require multienzyme systems with cofactor requirements, e.g. for the conversion of urea and ammonia into amino acids using sequential enzymatic reactions with microencapsulated multienzyme. Micro,encapsulated urease, glutamate dehydrogenase and glucose-6-phosphate dehydrogenase appear to

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convert urea via ammonia to glutamate, and glucose dehydrogenase can be added to recycle the cofactors.

5.8. Microspheres This form of fabricated polymer has been used in studies of biological systems and biological moieties. The coupling of monoclonal antibodies to polystyrene beads containing iron can be used in selective extraction of cancerous cells using magnetism. The technique, pioneered by Kemshead, 183has been used successfully for removing neuroblastoma cells from bone marrow. Molday has synthesised magnetic microspheres by Co irradiation of iron oxide colloidal particles in the presence of hydrophilic/phobic methacrylate monomers, but there were problems in the synthesis and purification and in the aggregation and nonspecific binding? ~ Kronick synthesised similar magnetic particles (though they were large and irregular) and ferromagnetic iron dextran particles by reacting ferrous and ferric chlorides with dextran polymers under alkaline conditions) 85 These improved particles were stable against aggregation, showed little nonspecific cell binding and possessed a large magnetic moment. Molday and MacKenzie have discussed the application of these reagents in cell separation, cell membranes and receptors and in drug carrier/targeting studies and the surface hydroxyl groups have been found to covalently couple proteins. Polymeric microspheres conjugated to antibodies and lectins have been used as cell surface markers for detection and localisation of antigens and lectin receptors using scanning electron microscopy. Molday has described ironcontaining polymeric microspheres tagged with fluorescent dyes and chemically coupled to antibodies or lectins, the magnetic and fluorescent properties having been used to separate red blood cells and lymphoid cells and to detect immunoglobulin receptors. The sphere sizes can be controlled by using their magnetic pores as part of a redox polymerisation system. Magnetic hydrogel microspheres have also been formed easily.4"~7'~ Recently, gamma scintigraphy j86and magnetic resonance relaxation studies ~87 have been proposed as potential techniques for studying transport, targeting and release from polymers.

5.9. Polymeric vesicles Intact and selective delivery to desired targets is an important aim nowadays. Liposomes have been extensively explored as potential drug carriers, ~'~s9 but they have tended to be unstable and lack discrimination. Polymeric vesicles may overcome these problems. 190The enhanced activity of such vesicle-incorporated adenosine triphosphate (ATP)-synthetase is very relevant as ATP-synthetase consists of hydrophilic/phobic regions, the former being in the bilayer and the

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729

latter being exposed to the aqueous environment. Phospholipid and polymeric surfactant vesicles can be used to reactivate enzymes. Cell-specific recognition and tumour cell destruction by membrane-destroying agents may provide a use in cancer chemotherapy. However, the vesicles would have to survive attack. Release of the agent would have to be by a trigger-mediated opening mechanism, e.g. pH, temperature, irradiation or enzymes. Biopolymers in reverse micelles, in a hydrocarbon solution, ~9~may indicate protein interaction with water and membrane-like surfaces. The enzymecontaining reverse micelles can accept and transform water-insoluble, hydrocarbonsoluble substrates, e.g. lipoxygenase. The structures may exist in vivo in biological membranes, may be useful in a chromatographic separation technique for biopolymers, e.g. protein and nucleic acid separation, and may be used as drug delivery systems. 5. I O. Polymeric drugs

Research on polymeric drugs has rapidly accelerated only recently, because it was thought unlikely that synthetic polymers could possess any drug action. ~92"~3Incorporation into polymers reduces the toxicity of small-molecule drugs, 192slows their diffusion, and allows more interfacial adsorption. Polymeric drugs consist of a polymeric backbone with drug attached by a spacer unit and of emulsifying, solubilising and/or lipid transport groups. When introduced into a living system, the polymeric drugs elicit the desired physiological response locally and more effectively than their small-molecule counterparts. The diseases treatable by polymeric antimicrobial drugs are caused by bacteria, fungi, rickettsiae and a few viruses. "Anaflex", a poly(urea-coformaldehyde), has been employed in boil treatment, leg ulcers, infected wounds and sores, acne, gynaecological discharges, diaper rash, urinary dermatitis and fungal infections in humans. Despite the lack of widespread polymer usage as antimicrobial drugs, many macromolecules have shown, in vitro, antimicrobiai activities. ~gz'tg~Polymeric antimicrobial drugs have a sustained release, are easy to handle, may be targeted, have many potential interactions sites with the bacterial cell walls and viruses, are nonabsorbable, have a modified activity in comparison with the incorporated small-molecule drug and have reduced toxicity and side effects. There are many polymeric drugs for potential cancer chemotherapy, ~*'~89"~92"~93 including the pyran copolymer (a I : 2 copolymer of divinyl ether and maleic anhydride which was previously withdrawn but is now again available) and platinum (II) analogues. 6~ Targeting of polymeric drugs has been achieved by coupling with monocional antibodies. More comprehensive details are provided in the reviews and books on polymeric antibacterial, antifungal, antiviral and antitumour drugs published by Donaruma.~.~st. ~95

730

J.H. BRAYBROOKand L. D. HALL 6. S U M M A R Y A N D C O N C L U S I O N S

P o l y m e r s h a v e b e e n s h o w n to p l a y a n i m p o r t a n t role in a v a r i e t y o f m e d i c a l a p p l i c a t i o n s where suitable bit)compatibility has b e e n attained. H o w e v e r , further research m u s t be d i r e c t e d t o w a r d s m o r e fully u n d e r s t a n d i n g the m e c h a n i s m s a n d effects o f the i n t e r a c t i o n s b e t w e e n p o l y m e r s a n d b i o l o g i c a l systems b e f o r e it b e c o m e s m o r e p o s s i b l e to m a n u f a c t u r e i m p r o v e d p o l y m e r i c systems h a v i n g o p t i m u m u t i l i s a t i o n in a n u m b e r o f specific a p p l i c a t i o n s . T h i s will h a v e to i n v o l v e focussed a n d c o o r d i n a t e d research o f a m u l t i d i s c i p l i n a r y n a t u r e .

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