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Update on Medical Plasticised PVC

Xiaobin Zhao and James M. Courtney

Smithers Rapra Update

Update on Medical Plasticised PVC

Xiaobin Zhao

James M. Courtney

iSmithers – A Smithers Group Company

Shawbury, Shrewsbury, Shropshire, SY4 4NR, United Kingdom Telephone: +44 (0)1939 250383 Fax: +44 (0)1939 251118

http://www.iSmithers.net

Typeset by Kailash Media Pvt. Ltd.

Printed and bound by Lightning Source Inc.

ISBN: 978-1-84735-208-8

First Published in 2009 by

iSmithersShawbury, Shrewsbury, Shropshire, SY4 4NR, UK

©2009, Smithers Rapra

All rights reserved. Except as permitted under current legislation no part of this publication may be photocopied, reproduced or distributed in any form or by any means or stored in a database or retrieval system, without

the prior permission from the copyright holder.

A catalogue record for this book is available from the British Library.

Every effort has been made to contact copyright holders of any material reproduced within the text and the authors and publishers apologise if

any have been overlooked.

Executive summary ...................................................................... 1

Plasticiser selection ............................................................... 3

1. Brief history of the medical applications of plasticised PVC ..................................................................... 9

2. PVC-P formulation ................................................................. 13

2.1 PVC raw material ......................................................... 13

2.1.1 Suspension polymerisation ...........................13

2.1.2 Emulsion polymerisation ..............................14

2.1.3 Mass or bulk polymerisation ........................14

2.2 Additives ..................................................................... 16

2.2.1 Plasticiser .....................................................16

2.2.2 Other additives .............................................26

2.3 PVC-P formulation ...................................................... 27

2.3.1 Selection of plasticiser ..................................27

2.3.2 PVC-P compounding ....................................31

3. Properties of PVC-P ............................................................... 35

3.1 Mechanical properties .................................................. 35

3.2 Low-temperature properties ......................................... 35

3.3 Electrical properties ...................................................... 36

3.4 Surface properties ......................................................... 36

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Contents

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Medical Plasticised PVC

3.5 Permanence properties .................................................. 36

4. PVC-P as a biomaterial .......................................................... 39

4.1 Introduction ................................................................. 39

4.2 Advantages of PVC-P ................................................... 40

4.3 Disadvantages .............................................................. 42

4.4 PVC-P as a blood-contacting biomaterial ..................... 44

4.5 Other applications of PVC-P as a biomaterial .............. 44

5. Blood compatibility of PVC-P ................................................ 49

5.1 Introduction ................................................................. 49

5.2 Blood-biomaterial interactions ..................................... 49

5.3 Factors influencing blood response to PVC-P ............... 50

5.3.1 PVC formulation ..........................................52

5.3.2 Selection of plasticiser ..................................52

5.3.3 Plasticiser concentration ...............................55

5.3.4 Plasticiser surface level .................................55

5.3.5 Plasticiser surface distribution ......................56

5.3.6 Surface modification .....................................58

5.3.7 Nature of application as devices ...................58

5.3.8 Blood nature and evaluation procedures .......59

5.4 Plasticiser migration and regulation .............................. 59

5.4.1 DEHP migration and extraction ...................59

5.4.2 Toxicity of DEHP .........................................60

5.4.3 Alternatives to DEHP ...................................65

5.4.4 Alternatives to PVC-P as a blood-contacting biomaterial .....................69

5.4.5 New development of PVC-P biomaterials .....70

5.4.6 Summary ......................................................73

6. Modification of PVC-P surface for improved blood

Contents

compatibility ...................................................................... 83

6.1 Physical treatment ........................................................ 84

6.2 Chemical treatment ...................................................... 85

6.3 Biological treatment ..................................................... 87

7. Future perspectives ................................................................. 95

7.1 Environmental and health concerns and regulatory issues. ....................................................................... 95

7.1.1 Sterilisation ..................................................98

7.2 Market needs ................................................................ 99

7.2.1 Market for PVC ...........................................99

7.2.2 Market for PVC medical devices ................100

7.3 Emerging technology .................................................. 102

Abbreviations ........................................................................... 105

Subject Index ............................................................................ 109

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Poly(vinyl chloride), abbreviated to PVC, is the most versatile of all the commodity polymers. It can satisfy a wide range of product function, safety, performance and cost criteria. PVC can be divided into plasticised PVC and unplasticised PVC. The standard designations PVC-U (unplasticised) and PVC-P (plasticised) have now been adopted by the International Union of Pure and Applied Chemistry (IUPAC) for the two forms of PVC [1]. P represents different types of plasticiser. For example, PVC-DEHP is PVC plasticised with 2-di(ethylhexyl) phthalate (DEHP).

PVC-U is a type of rigid material. The use of PVC-U did not become significant until the 1960s, when the processing technology was available. Nowadays, PVC-U is used extensively for the construction market because of its low cost and fire resistance.

PVC alone is of little value and must be compounded with various additives to make a useful plastic and achieve a broad range of properties. One of the most important additives for PVC is the plasticiser. This increases the flexibility, softness and workability of PVC. The process to achieve this transformation of PVC and plasticiser into a homogeneous plasticised compound is called plasticisation and the final product is PVC-P.

When a plasticiser is blended with PVC, a portion of it forms an intimate bond with the PVC, while the remainder is captured in the polymer matrix. There is no covalent bond between PVC and plasticiser but they are very compatible and become an integral part of the matrix. In the case of extra soft PVC-P, the plasticiser content can approach 50% [2].

Executive summary

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In terms of volume, PVC resin is the most widely used polymeric biomaterial for single use, presterilised medical devices [3]. Plasticised PVC-based film, sheet and tubing are used in numerous medical products. Most of them are relevant to blood-contacting applications, as summarised in Figure 1.

Figure 1 Medical applications of PVC-P as blood-contacting biomaterials (CPB= Cardio pulmonary bypass)

From the blood-contacting material point of view, the blood compatibility of plasticised PVC is influenced by the PVC formulation (plasticiser selection and utilisation of other additives or modifiers) and PVC surface modification (alteration of plasticiser surface distribution, plasticiser surface level and other surface properties). The PVC formulation determines the properties of both bulk and surface while the surface modification only influences the surface properties. The relationships between the PVC formulation, the PVC surface modification and blood compatibility are highlighted in Figure 2.

Executive summary

Plasticiser selection

PVC is a very hard and rigid substance, which is also very sensitive to heat. It requires the addition of plasticiser to provide flexibility and a stabiliser to prevent degradation at high temperature. The composition of the PVC-P formulation used in devices for blood collection, storage and delivery is shown in Figure 3 [3].

Figure 2 Blood and PVC-P interface

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With respect to the formulation, plasticiser selection is critical in the medical application of PVC-P. DEHP is the most commonly utilised plasticiser, which comprises 30-40% of final polymer weight (mass) [4]. Also, DEHP is the only plasticiser mentioned in any European Pharmacopoeia Monograph. It remains by far the largest tonnage plasticiser used in medical products [1]. It is probably one of the most studied substances in the world and it is estimated that over 3000 scientific papers on its biological activity have appeared [5].

As DEHP is not covalently bound within the PVC-DEHP matrix, it might leach from the material into the contacting physiological medium [6]. The migration problem of DEHP has promoted the research and development of new-generation plasticisers as alternatives to DEHP or polymers as PVC-P alternatives.

Figure 3 PVC-P formulation for medical devices

Executive summary

The new-generation PVC-P include PVC plasticised with triethylhexyl trimellitate (TEHTM) and butyryl trihexylcitrate (BTHC). Both of these have been shown to leach from plastic and into blood components to a lesser extent than DEHP.

The blood compatibility of PVC-P is strongly dependent on the plasticiser selection. PVC-TEHTM was found to be unsuitable for red cell storage because it had no stabilising effect on red cell membranes [7, 8] and reduced in vivo survival time, while PVC-DEHP was shown to confer stability on red cell membranes, reducing haemolysis and increasing in vivo survival [7-9].

PVC-BTHC has been shown to have a stabilising effect on red cell membranes, similar to that of DEHP [10], and has proved to be an excellent platelet storage plastic for high concentrations of machine-derived platelets [11].

The content of plasticiser in the PVC-P formulation also influences the blood compatibility. Bowry [2] compared extra soft (48% DEHP) and standard PVC (39% DEHP) and found an enhanced platelet adhesion and aggregation with extra soft PVC.

Protein adsorption was found to be dependent on the DEHP concentration, either at the PVC surface [12] or in the total formulation [13].

It was also found that plasticiser surface distribution has a pronounced effect on blood compatibility [14].

In brief, in the first three chapters of this book, the history of PVC-P in medical applications is considered and the manufacturing and processing of PVC-P together with the properties are reviewed. The selection of plasticisers is a particular focus. In Chapters 4 and 5, PVC-P as a biomaterial and the blood compatibility of PVC-P are examined systematically, based on the most recent information. In summary, the blood compatibility of PVC-P is influenced by the PVC formulation, mainly in terms of plasticiser selection and level of incorporated plasticiser. The research and development of PVC-P as

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a biomaterial are focused on understanding the relationship between the nature of the PVC-P surface and blood components.

The regulatory requirements and environmental concerns over the leaching of plasticisers and the generating of dioxins during the incineration of PVC-P medical products after use are discussed in detail in Chapter 6. In order to improve the blood compatibility of PVC-P and to minimise the environmental impact during the life cycle of PVC-P medical products, many approaches have been adopted and the development and commercialisation of alternatives to plasticisers and PVC-P encouraged. However, the ratio of benefits to risks is the key when the performance of PVC-P medical devices is assessed and any replacement of PVC-P should fulfil the essential regulatory requirement and have a competitive all-round performance comparable to that of PVC-P (Chapter 7).

References

1. A.S. Wilson, Plasticisers, Principles and Practices, The Institute of Materials, London, UK, 1995.

2. S.K. Bowry, Development of In Vitro Blood Compatibility Assessment Procedures and Evaluation of Selected Biomaterials, University of Strathclyde, 1981. [Ph.D. Thesis]

3. C.R. Blass, Medical Device Technology, 1992, 3, 3, 32.

4. L. Ljunggren, Artificial Organs, 1984, 8, 1, 99.

5. A.A. Van Dooren, Pharmaceutisch Weekblad, Scientific Edition, 1991, 13, 3, 109.

6. R.J. Rubin and P.M. Ness, Transfusion, 1989, 29, 4, 358.

7. T.N. Estep, R.A. Pedersen, T.J. Miller and K.R. Stupar, Blood, 1984, 64, 6, 1270.

Executive summary

8. G. Rock, M. Tocchi, P.R. Ganz and E.S. Tackaberry, Transfusion, 1984, 24, 6, 493.

9. J.P. AuBuchon, T.N. Estep and R.J. Davey, Blood, 1988, 71, 2, 448.

10. D. Buchholz, R. Aster, J. Menitove, L. Kagan, T. Simon, A. Heaton, T. Keegan, G.S. Hedber, W. Davisson and A. Lin, Transfusion, 1989, 29, (Supplement), S9.

11. T.L. Simon, E.R. Sierra, B. Ferdinando and R. Moore, Transfusion, 1991, 31, 4, 335.

12. S.W. Kim, R.V. Petersen and E.S. Lee, Journal of Pharmaceutical Sciences, 1976, 65, 5, 670.

13. Y.I. Kicheva, V.D. Kostov and M. Chichovska, Biomaterials, 1995, 16, 7, 575.

14. X. Zhao, J.M. Courtney, H.Q. Yin, R.H. West and G.D.O Lowe, Journal of Materials Science: Materials in Medicine, 2008, 19, 2, 713.

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1 Brief history of the medical applications of plasticised PVC

Poly(vinyl chloride) (PVC) is produced by polymerisation of vinyl chloride monomer. In 1795, four Dutchmen, Diemann, Trotswyck, Bondt and Laurverenburgh, prepared a substance that was named after them, ‘the oil of the Dutch chemists’ (dichlorethane). In 1835, Henri Regnault produced a gas that burned with a yellow flame with a green mantle (presumably vinyl chloride, the basic material for making PVC). The first recorded use of the name vinyl chloride appeared in 1854, in Kolbe’s Lehrbuch der Organischen Chemie. However, it was Baumann [1], who first reported that on exposing vinyl chloride to sunlight, a white solid with a specific gravity of 1.406, which could be heated at 130 °C without decomposition, was obtained.

In 1912, Klatte reported on a production process for PVC [2], but the production difficulties were enormous, the resulting PVC was brittle, and it degraded when exposed to heat and light.

In the same year, Ostromislensky [3] patented the polymerisation of vinyl chloride and related substances but the high decomposition rate at processing temperatures proved an insurmountable problem for over 15 years [4]. After 1930, when it was discovered how to process PVC using heat stabilisers, commercial interest shifted to this synthetic polymer, and today, PVC is one of the two largest tonnage plastics materials, second only to polyethylene (PE). In 1996, PVC production by manufacturers in Western Europe reached 5209000 t and the total PVC sales by them was about 5,222,000 t. The European market in 2000 was 5.5 million t and growing at around 2% per year. Europe represents about a fifth of the world market. The value of finished PVC products made in Europe is estimated at

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EUR 75,000 million and more than 530,000 people are employed by the sector. [5].

The commercial success of PVC is strongly linked to the discovery and development of suitable additives, including plasticisers. The first use of a plasticiser was in the 1860s, when Parks and Hyatt used camphor to plasticise cellulose nitrate. Later, in 1882, cellulose nitrate was plasticised to make motion picture film. As early as 1928, two approaches had been attempted to reduce the processing temperature in order to mitigate the instability problem. These were by external plasticisation, using tritolyl phosphate, and internal plasticisation, using vinyl acetate as the comonomer with vinyl chloride. These initiatives led to a rapid expansion in the production and application of plasticised PVC (PVC-P) as a rubber substitute in the early 1930s. The existing rubber processing machinery was modified to compound and fabricate PVC-P and the routine plasticisers for nitrocellulose, such as tricresyl phosphate and dibutyl phthalate, were selected for PVC plasticisation [6].

In 1933, Kyrides [7] patented the use of di-beta-ethylhexyl phthalate for plasticisation of nitrocellulose, acetyl cellulose and other plastics. In this patent, di-2-ethylhexyl phthalate (DEHP) was also covered. Two months later, Semon’s patent on plasticisation of PVC with DEHP was issued [8]. From then, DEHP began its growth and has become the largest volume plasticiser in the PVC industry. In 1934, some ‘nontoxic’ plasticisers appeared and achieved US Food and Drug Administration (FDA) regulation in food packaging, adhesives, coatings and tubing used in food processing [9].

The use of plastic blood processing equipment was pioneered by Carl Walter as early as 1949 [10]. In 1952, Walter and Murphy introduced the use of plastic blood bags to store blood in the presence of acid citrate dextrose (ACD) [11]. In 1955, Strumia and co-workers [12] identified plasticised poly (vinyl chloride) as a blood bag plastic and they were the first to report differences between different plastic formulations, based on the in vitro and in vivo testing of stored blood. Since then, PVC-P as a blood-contacting biomaterial in blood

Brief history of the medical applications of plasticised PVC

11

storage, blood transfusion and other medical uses has been widely applied and intensively investigated.

It was estimated that about 30,000,000 t of PVC were used worldwide in 2004, with an annual growth rate of 4.3%. Medical PVC accounted for 0.5% of the total PVC use, which was approximately 30,000 t in Europe. However, long-accepted biomaterials, such as medical PVC, are now being challenged for medical applications by various alternative materials. DEHP-plasticised PVC-based devices for medical application are now under more stringent scrutiny for regulatory approval.

References

1. E. Baumann, Annalen der Chemie und Pharmacie, 1872, 163, 308.

2. M. Kaufman, The History of PVC, the Chemistry and Industrial Production of Polyvinyl Chloride, MacLaren and Sons Ltd, London, UK, 1969.

3. J. A. Brydson, Plastics Materials, 7th Edition, Butterworth-Heinemann, 1999, p.6.

4. J.A. Brydson, Plastics Materials, 6th Edition, Butterworths, London, UK, 1995.

5. PVC-Polyvinyl Chloride Factsheet, Euro Chlor, http://www.eurochlor.org/upload/documents/document93.pdf


7. L.P. Kyrides, inventor; Monsanto Chemical Company, assignee; British USP 1923938, 1933.

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8. W.L. Semon, inventor; The B.F. Goodrich Company, assignee; US 2188396, 1933.

9. J.K. Sears and J.R. Darby, The Technology of Plasticisers, John Wiley & Sons Inc., New York, NY, USA, 1982.

10. C.W. Walter in Proceedings of the Conference on the Preservation of the Formed Elements and of the Proteins of the Blood, Boston, MA, USA, 1949, 183.

11. C.M. Walter and W.P. Murphy, Surgery, Gynecology and Obstetrics, 1952, 94, 687.

12. M.M. Strumia, L.S. Colwell and K. Ellenberger, Journal of Laboratory and Clinical Medicine, 1955, 46, 225.

2.1 PVC raw material

Poly(vinyl chloride) (PVC) is a thermoplastic formed from the addition polymerisation of vinyl chloride monomer (VCM), which is produced from the reaction of ethylene with chlorine, followed by a pyrolysis processing (Equation 2.1).

nCH2=CH (VCM) (CH2 - CH)n (PVC)

Cl Cl

Equation 2.1 Polymerisation of VCM to PVC

There are three major ways to manufacture PVC raw material:

Suspension polymerisation,

Emulsion polymerisation, and

Mass or bulk polymerisation.

2.1.1 Suspension polymerisation

A mixture of water, VCM, a free radical initiator, such as a peroxydicarbonate, and a protective colloid or suspension agent, usually a water-soluble polymer, such as hydrolysed poly(vinyl acetate), gelatin or dextran, is agitated in a jacketed pressure vessel, capable of withstanding the pressure generated by liquid VCM at the polymerisation temperature [1]. The temperature can be controlled

2 PVC-P formulation

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by hot or cold water in the jacket. After 70-90% conversion of VCM to PVC in a given time, most of the residual VCM (10-20% of the original charge) is recovered by gasification and liquefaction, but because of its carcinogenic nature [2], it is necessary to reduce the monomer content still further. The most satisfactory and common procedure for achieving this is by the use of steam to heat the slurry of PVC particles in water to between 80 and 110 °C, with the steam acting as a carrier for VCM residue, which is later separated from the water in a suitable condenser [3]. In this way, the VCM residue level can be reduced to < 1 ppm.

2.1.2 Emulsion polymerisation

This is similar to suspension polymerisation except that the polymerisation autoclave is linked to either a homogenising mill or emulsifier/initiator injection equipment. The water is removed by evaporation in a spray dryer, instead of using a centrifuge and hot air drying system. In normal emulsion polymerisation, a water-soluble initiator, such as ammonium or potassium persulfate, is employed and the desired latex particle size is obtained by controlling the rate of initiation, the type and amount of emulsifier present, and the agitation rate.

Emulsion polymerisation is used to produce general-purpose polymers for special applications, such as calendered film and thin profile extrusion, where particularly easy processing is required. It is also used for the production of PVC paste, i.e., PVC suspended in plasticiser, which can be used in the fabrication of gloves and fabric coatings.

2.1.3 Mass or bulk polymerisation

In mass polymerisation, VCM is polymerised to PVC in the absence of water. The process is divided into prepolymerisation and postpolymerisation. Prepolymerisation produces PVC seeds with an

PVC-P formulation

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adjustable particle size, using high-speed agitation. The final PVC particle type is substantially determined by the nature of the seed. The advantages of mass polymers are their high purity and enhanced clarity and they are intended particularly for the bottle market [4].

The features, which distinguish PVC raw materials one from another and account for the differences in the processability and physical properties of their compounds, are the following:

The molecular weight (MW) of the PVC raw material affects both the processability and the physical properties of the compound. In general, the higher the MW, the greater the difficulty in processing and the higher the physical properties. The MW of most commercial PVC resins lies within the range 30,000-75,000 (average MW). With respect to the surface morphology, the granular PVC resin with a lower surface area presents slow processing characteristics, while the porous emulsion PVC latex, made up of a large number of very small particles, has very good processability, particularly in plasticisation.

Interaction between PVC and the stabiliser system may be affected by the impurities left during the manufacture. For example, in the case of colour, emulsion PVC usually gives compounds which are initially more yellow than those from the granular PVC. In some cases, PVC resin is produced by copolymerisation with other vinyl monomers, such as vinyl acetate and vinylidene chloride. The copolymer component actually acts as an internal plasticiser. The more this component is added, the lower the processing temperatures.

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2.2 Additives

A great variety of additives are used in the PVC formulation to give PVC useful properties, such as colour, resistance to fire, strength and flexibility. Those majoring in importance and/or proportion incorporated are plasticiser, heat stabiliser and fillers.

2.2.1 Plasticiser

Plasticisers are organic compounds added to polymers (especially PVC) to facilitate processing and to increase the flexibility of the final plasticised product by this external modification of the polymer molecule. In rigid PVC, the plasticiser content is very low and some other polymer modifier, such as polyisoprene, will reduce its brittleness. In semi rigid and semi flexible PVC, the plasticiser content is between 10% and 30%, while for the highly flexible PVC, the plasticiser content can be up to 50% (Figure 2.1). The incorporation of plasticisers enables PVC to have versatile applications in the medical field, as shown in Figure 2.2.

Figure 2.1 Flexibility of PVC – relation to the plasticisers

PVC-P formulation

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PVC can be modified chemically, as by copolymerisation with vinyl acetate, to make the product more flexible or to demonstrate better low-temperature properties. This plasticisation process is through the polymer itself and the copolymer component is termed an internal plasticiser.

Plasticisers may be divided into two main groups: primary plasticisers and secondary plasticisers. The former is highly compatible with the resin. As a guide, about 150 phr should be freely compatible in this division [4]. The primary plasticisers can be readily used alone. The secondary plasticisers are less compatible and are usually employed together with primary plasticisers to confer some special properties.

Based on the chemical nature or molecular structure, plasticisers can be categorised as shown in Figure 2.3.

Figure 2.2 Versatile medical applications of PVC with different flexibility

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Figure 2.3 Categories of plasticiser

2.2.1.1 Dialkyl phthalates

Phthalate esters, particularly dialkyl phthalates, have dominated the plasticiser market since the 1930s. Presently, about one million tonnes of plasticisers are used annually in Western Europe. Some 92% of the total is used to plasticise PVC and about 95% of these PVC plasticisers are phthalate esters [5].

PVC-P formulation

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The phthalate plasticisers are esters of ortho-phthalic acid and they are manufactured from phthalic anhydride via a straightforward esterification process with selected alcohols. The great majority of phthalate consumption is of the ‘big three’ general purpose PVC plasticisers, namely:

DEHP (DIOP) – di-2-ethylhexyl phthalate (or dioctyl phthalate),

DINP – di-isononyl phthalate, and

DIDP – di-isodecyl phthalate.

DEHP is almost unique among the phthalates for PVC because of its simple chemical structure (Figure 2.4). For many years, DEHP has been the accepted industrial standard for a general purpose plasticiser for PVC and is the most commonly utilised plasticiser. Its all around performance, e.g., compatibility with PVC, plasticising efficiency, low-temperature properties and low volatility, are so good that it alone has accounted for a fourth of the total plasticiser production [6].

Figure 2.4 Chemical structure of di-2-ethylhexyl phthalate (DEHP) (or dioctyl phthalate - DIOP)

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Various di-isoalkyl phthalates, such as DIDP and DINP, have accounted for another fourth of the market. They helped satisfy the growing need for lower volatility but with some sacrifice in plasticising efficiency. The publication in the European Union Official Journal of the outcomes of the EU risk assessments for di-isononyl phthalate (DINP) and di-isodecyl phthalate (DIDP) marks the end of a 10-year process of extensive scientific evaluation by regulators and provides confirmation of safety for users across Europe (http://www.dinp-facts.com/RA and http://www.didp-facts.com/RA).

The linear dialkyl phthalates account for about another fourth of the total market. For example, diundecyl phthalate (DUP) represents the upper useful limit of chain length for linear phthalate plasticisers. They are manufactured from alcohol with C11 content close to 100%, containing between 50% and 70% of straight chain isomers. DUP has been found capable of increasing the gas permeability of platelet storage bags [7].

2.2.1.2 Trimellitates

Trimellitates, e.g., tri-(2-ethylhexyl)trimellitate (TEHTM) and the mixed esters of almost completely linear heptyl and nonyl alcohols, were developed to provide very low volatility and maintain a good all-round balance of performance, similar to the phthalates. TEHTM is especially used in situations where migration levels lower than those possible with DEHP are required. The TEHTM molecular structure is shown in Figure 2.5.

2.2.1.3 Adipates

The same range of monohydric alcohols used as phthalate feed stocks is available for adipates. The flexible linear molecular structure of adipates gives them the common characteristics of low viscosity and good low-temperature plasticising performance.

PVC-P formulation

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2.2.1.4 Phosphates

Phosphate plasticisers are esters of phosphoric acid. They have a long history of use as plasticisers, dating from the early part of the twentieth century, when tricresyl phosphate was one of the first products to be substituted for camphor in nitrocellulose. They are now mainly used as speciality plasticisers to confer fire resistance on PVC.

2.2.1.5 Citrates

Citrates are esters of citric acid, a raw material manufactured from sugars by enzymatic reactions. Citrates are relatively expensive and while some of them show a useful balance of performance characteristics, they do not display any outstanding technical advantages over phthalate plasticisers. Commercially, the most important citrates are acetyl tributyl citrate (ATBC), Butyryl trihexylcitrate (BTHC) and acetyl tri-2-ethylhexyl citrate (ATEC).

Figure 2.5 Chemical structure of tri-(2-ethylhexyl)trimellitate (TEHTM)

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The particular attention to citrate owes much to the common knowledge that they are derived from citric acid, a natural product of low toxicity, occurring in citrus fruits and as a human metabolite of carbohydrates. However, in comparison with the extensive toxicological studies of DEHP, the citrate esters have been relatively little investigated [8].

BTHC (Figure 2.6) has received particular attention following its evaluation as a nonphthalate plasticiser or an alternative to DEHP in PVC medical devices, particularly in blood-contacting materials.

Figure 2.6 Chemical structure of Butyryl trihexylcitrate (BTHC)

2.2.1.6 Polymeric plasticisers

Polymeric plasticisers, mainly polyesters, have about 2% of the total plasticiser market and are used in applications where specifications impose limits on levels of migration into solvents, oils and oily media. Figure 2.7 gives the chemical structure of a typical polyester (polyadipate, PA).

Some other types of polymeric plasticiser in current use are shown in Table 2.1.

PVC-P formulation

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Figure 2.7 Chemical structure of polyadipate

Table 2.1 Examples of polymeric plasticisers [8]Trade name Supplier Chemical composition

Elvaloy series Dupont Ethylene/vinyl acetate/carbon monoxide

Elvaloy HP series

Dupont Ethylene/acrylate/carbon monoxide

Baymod L2418 Bayer Ethylene vinyl acetate copolymer (68% vinyl acetate)

Baymod PU Bayer Aliphatic polyester urethane

Chemigum P83 Goodyear Partially crosslinked nitrile elastomer

The molecular weight of adipate polyester (PA), terminated with alcohols, is commonly ca.2000, with a range of ca.800-6000. The high MW results in exceptionally good resistance to extraction, migration and volatile loss. Unlike other polymeric plasticisers or high-MW phthalates (trimellitate) with relatively low plasticising efficiency, PA acts almost segment by segment, which results in a good plasticising efficiency (see Table 2.2).

Certain high-MW ethylene copolymers have been found to plasticise PVC. Typically, this ethylene copolymer is ethylene/vinyl acetate copolymer, containing a high level of vinyl acetate, and

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terpolymers of ethylene, vinyl acetate or an alkyl acrylate, and carbon monoxide (Table 2.1). The strongly polar nature of the carbon monoxide enhances the miscibility with PVC, which reduces the other comonomer content required for miscibility. These ethylene copolymers are soft but essentially nonfluid at ambient temperature [9].

Chlorinated polyethylene (CPE) with 36-48 wt% chlorine is polyblended with PVC as a polymeric plasticiser. Consequently, it can replace part of the PVC resin and part of the conventional plasticiser. Thus, a 50/50 blend of PVC/CPE-36%Cl with 30 phr of a conventional polyester plasticiser may exhibit tensile properties similar to those achieved with 60 phr of polyester with pure PVC [10].

2.2.1.7 Polymerisable plasticisers

The so-called polymerisable plasticisers only act for plasticisation at the processing stage. In their monomeric state, they are liquid and compatible with PVC. During processing to the end product, polymerisation of the monomer occurs, resulting in the formation of a crosslinked interpenetrating network, not involving any reaction with the PVC. This gives the composition reduced flexibility but the enhanced toughness required for specific end uses. Figure 2.8 gives two examples of polymerisable plasticisers.

2.2.1.8 Biochemical plasticisers

In addition to plasticisers derived from the petroleum industry, there is another class of environmentally benign plasticisers, which are derived from vegetable oils. They are named biochemical plasticisers. One of the most significant biochemical plasticisers is epoxidised soybean oil (ESBO), which holds 43% of the vegetable oil-derived plasticiser market. Other vegetable-based plasticisers are esters derived from the reaction of an alcohol with a fatty acid. Fatty

PVC-P formulation

25

acids are the main component of vegetable oils, and sebacic acid, a component of castor oil, is the most commonly used fatty acid for plasticisers formulated for PVC.

Most biochemical plasticisers are suitable for use only as secondary plasticisers. At higher levels, they may not mix properly into the plastic formulation or may cause PVC formulations to become brittle. At current levels of technology, the markets for vegetable oil-derived plasticisers are mature and are likely to experience growth only with the growth of the PVC market. In the future, the vegetable oil-derived plasticisers may acquire improved properties and replace DEHP as primary plasticisers. This may provide a solution to those

Figure 2.8 Two examples of polymerisable plasticisers

26


public concerns about the environment and potential health risks of chemical plasticisers, particularly in the areas of food packaging and medical applications.

2.2.2 Other additives

Additives used in plastics formulation are normally classified according to their specific function, rather than on a chemical basis [11]. In the PVC-P formulation, commonly applied additives other than plasticisers include: heat stabilisers, lubricants, antioxidants, colourants, fillers, flame retardant and smoke suppressers, fungicides, bactericides and pesticides, optical brighteners, surfactants and other surface property modifiers. Here, only stabilisers and some additives affecting the surface properties of PVC-P are reviewed.

Practical stabilisation of PVC has been investigated since the 1930s. Stabilisers are added to protect PVC against thermal decomposition during processing. The commonly applied PVC stabilisers include: inorganic metal salts, such as basic lead carbonate (white lead) and tribasic lead sulfate (TBLS); metal soaps, such as the soaps of lead, barium, cadmium, calcium and magnesium, zinc; metal complexes, such as barium/cadmium, barium/cadmium/zinc and calcium/magnesium/zinc; epoxy compounds and organotin compounds. A good combination, which is nontoxic, specifically designed for food packaging or medical application, is the use of calcium stearate, zinc stearate and their mixture with ESBO. This stabilising system is widely accepted in PVC-P formulation for medical applications.

Lubricants are added to the PVC formulation to avoid excessive sticking on the processing mill, which has a strong influence on the surface properties of PVC-P. The common lubricants for PVC-P formulation are stearic acid, waxes such as paraffin and microcrystalline waxes, low molecular weight polyethylene, natural and modified natural waxes, fatty acid amides, silicones, as well as ‘lubricating type stabilisers’ [12].

PVC-P formulation

27

2.3 PVC-P formulation

2.3.1 Selection of plasticiser

The ease of PVC processing, the physical properties of a PVC formulation and its biorelated performance are dependent to a large degree on the chemical structure and level of incorporation of the plasticiser if the employed PVC resin has already been selected. Molecular mass, polarity and linearity of the plasticiser are the three key molecular properties to determine the final properties of plasticised PVC (PVC-P) [8].

Chemicals with a MW below 300 are likely to be too volatile for use in PVC and values above 800 (except some polymeric plasticisers) suggest low compatibility, difficult processing and low efficiency, but better extraction resistance. If the chemical structure is predominantly cyclic or branched, the material will show poor low-temperature performance.

Table 2.2 gives typical physical properties of Shore A74 PVC compounds, which indicate that there is a reduction in plasticising efficiencies by TEHTM and PA in comparison with DEHP. A higher level of these DEHP alternative plasticisers is needed in order to achieve the same hardness and flexibility characteristics, while PA exhibits excellent extraction resistance to some extractants [13].

For applications involving particular toxic risks in food contact, medical products or children’s toys, the selection is based on a small group of approved plasticisers, listed in Tables 2.3 and 2.4.

28


Tab

le 2

.2 D

ata

on p

last

icis

ers

and

typi

cal p

hysi

cal p

rope

rtie

s of

the

ir p

last

icis

ed P

VC

com

poun

d (S

hore

A 7

4)

DE

HP

TE

HT

MPA

MW

390

547

2000

app

rox.

Vis

cosi

ty (

Pa-s

at

20 °

C)

0.08

0.3

5 ap

prox

.

Den

sity

(kg

/m3 )

0.98

30.

986

1.07

5

Ref

ract

ive

inde

x1.

487

1.48

51.

467

Liq

uid

appe

aran

ceC

olou

rles

sC

olou

rles

s to

ver

y pa

le

yello

w

Col

ourl

ess

to v

ery

pale

yel

low

Rel

ativ

e co

st

1.0

3.2

3.5

Plas

tici

ser

(%)

31.7

35.8

33.8

Den

sity

(kg

/m3 )

1.23

1.22

1.26

Tens

ile s

tren

gth

(MN

/m2 )

19.0

18.9

19.3

Elo

ngat

ion

at b

reak

(%

)35

540

036

5

Col

d fle

x (°

C )

–20

–20

–10

PVC-P formulation

29

Table 2.3 List of plasticisers acceptable in food-contact applications

Plasticiser Max. level of use (% w/w)

General food type

Countries

DBP 40 Any UK

DIDP 40 Any UK

DEHP 40 Aqueous UK

DEHP 28 Fatty UK

DIOP 40 Non-fatty UK, USA

BBP 33 Any UK, USA

DBS 40 Any UK, USA

DEHA 40 Any UK, USA

DEHS 30 Any UK, USA

ESBO 11 Any USA, Europe

ATBC 38 Any USA, Europe

DACM New developed Any USA

Table 2.4 List of plasticisers acceptable in medical applications

Plasticisers Comments

DEHP Only plasticiser listed in European Pharmacopoeia IV, 1.2.1.1 and 1.2.1.2

TEHTM Some use in medical applications with better resistance to migration

BTHC Medical applications, e.g., Baxter licence blood bags

PA Some medical applications with plasticiser non-migration requirement

ESBO Medical applications as a secondary plasticiser

Historically, the main plasticiser for PVC food packaging film has been di-2-ethylhexyl adipate (DEHA), used in conjunction with a

30


proportion of epoxy soyabean oil [8], while DEHP is the widely accepted and the most commonly used in medical-grade PVC formulations. Because of the concern over migration problems of DEHP, TEHTM and PA have been used as alternatives to DEHP in haemodialysis tubing and blood storage containers [13].

N-Butyryl trihexylcitrate (BTHC), a form of citrate plasticiser, was first introduced by Hull and Mathur to medical-grade PVC formulations [14]. The data on BTHC are shown in Table 2.5, which is based on the BTHC manufacturer’s data sheet from Morflex, Inc., Greensboro, NC 27403, USA.

Table 2.5 Data on BTHCProduct name Citroflex B-6

Chemical name n-Butyryl trihexylcitrate (BTHC)

Molecular weight 514

Molecular formula C28H50O8

Appearance Clear, oily liquid

Odour Mild, characteristic

Freezing point –55 °C

Specific gravity 0.991 (g/cm3) ( 25 °C)

Evaporation rate units? < 1 ( Butyl acetate = 1)

Toxic effects:

Oral-mouse LD50: > 48 g/kg

Oral-rat LD50: > 20 g/kg

Source: Morflex, Inc., Greensboro, NC 27403, USA

2.3.2 PVC-P compounding

The process of preparation of a PVC-P compound is defined as compounding, which involves a mixing procedure with a melting process. PVC-P compounding can be achieved using dry blending via compounding machines, such as two-roll mills, internal mixers,

PVC-P formulation

31

single-screw and twin-screw compounding machines.

Two-roll mills are extensively used in laboratories to examine the compounding behaviour of different components of PVC formulations, and for the preparation of specimens. Owing to the rather low output rates and high labour usage of compounding, they are now rarely employed for production purposes [1].

Batch hot melting and mixing of PVC composition can be achieved in an internal mixer, which contains a well-designed mixing chamber with a heating system. The advantage of using internal mixers is the possibility not only of a reduction in labour because of the provision of an automatic control system, but also a more uniform repetition from batch to batch.

Continuous compounding of PVC composition has been developed, based on the modification of extruders with screws designed to ensure that adequate homogenisation is achieved. Usually, the single-screw extruder is inadequate to homogenise any PVC dry blend in a single pass, unless an additional homogenisation process is introduced, with a suitable adaptation and modification. In an extruder with two or more screws, there exists the possibility of increasing homogenisation of PVC composition. The whole operation of mixing and compounding, and also of extrusion to the finished product, can be carried out continuously.

PVC composition can be dissolved in a suitable organic solvent to achieve a homogeneous solution as a coating material. The solution can also be cast as a film. The structures and physical properties of films are strongly dependent on the nature of the solvent employed, evaporation rate of solvent and residue of solvent, but are mainly dependent on the compatibility between PVC, plasticiser and other ingredients.

According to the PVC processing, the PVC compound can be further processed into a final product, such as a flexible sheet, film or tubing by injection moulding, extrusion or calendering [1].

32


References

1. G. Matthews, PVC, Production, Properties and Uses, The Institute of Materials, London, UK, 1996.

2. A. Whelan and J.L. Craft, Developments in PVC Production and Processing, Applied Science Publishers, London, UK, 1977.

3. R.H. Burgess, Manufacture and Processing of PVC, Applied Science Publishers, London, UK, 1982.

4. W.S. Penn, W.V. Titow and B.J. Lanham, PVC Technology, 3rd Edition, Applied Science Publishers, London, UK, 1971.

5. ECPI, Information on phthalate esters used in plasticised PVC, http://www.ecpi.org; http://www.plasticisers.org

6. J.K. Seats and N.W. Touchette in Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Edition, John Wiley & Sons, New York, NY, USA, 1982, p.111.

7. T. Shimizu, K. Koukelsu and Y. Morishima, Transfusion, 1989, 29, 4, 292.


9. G.H. Hoffman and D.E. Wilmington, inventors; E. I. DuPont de Nemours and Company, assignee; US 5464903, 1995.

10. Effects of CPE on Properties of Plasticised PVC, Technical Data Sheet GF-01806176, Dow Chemical Co, Midland, MI, USA, 1975.

11. L. Mascia, The Role of Additives in Plastics, Edward Arnold, London, UK, 1974.

PVC-P formulation

33

12. J.K. Sears and J.R. Darby, The Technology of Plasticisers, John Wiley & Sons Inc., New York, NY, USA, 1982.

13. C.R. Blass in Progress in Biomedical Polymer, Eds., C.G. Gebelein and R.L. Dunn, Plenum Press, New York, NY, USA, 1990, 315.

14. E.H. Hull and K.K. Mathur, Modern Plastics, 1984, 61, 66.

34


3.1 Mechanical properties

Generally, plasticised poly(vinyl chloride) (PVC-P) differs from unplasticised PVC (PVC-U) most markedly in flexibility or rigidity, with a much lower tensile strength and much higher elongation at break (%). Table 3.1 shows the range of mechanical properties of PVC-P compared with those of PVC-U [1].

Table 3.1 A comparison of the mechanical properties of PVC-P and PVC-U [1]

Properties ASTM test method

PVC-P PVC-U

Tensile strength (MPa) D638, D651 10-24 34-62

Elongation at break (%) D638 200-450 2.0-40.0

Tensile modulus 1013 (MPa) D638 — 2.4-4.0

Compressive strength (MPa) D695 6-12 55-90

Flexural yield strength (MPa) D790 — 69-110

The tensile strength and modulus decrease and elongation at break increases with increase in plasticiser content, which also depends on the particular plasticiser [2].

3.2 Low-temperature properties

Low-temperature properties, in terms of cold flex temperature, are also affected by the selection of plasticiser and the concentration incorporated. Normally, linear plasticisers, such as adipates, have

3 Properties of PVC-P

35

36


good low-temperature properties, while the high molecular weight polyesters show poor flexibility at low temperatures.

3.3 Electrical properties

Insulating properties, in terms of volume resistivity (VR), are strongly influenced by plasticiser content, type and temperature. The increase of a particular plasticiser concentration reduces the VR markedly and tri-(2-ethylhexyl) trimellitate (TEHTM)-plasticised PVC seems to have a higher VR than that of di-2-ethylhexly phthalate (DEHP)-plasticised PVC [2].

3.4 Surface properties

Plasticisation normally lowers the critical surface tension ( c) of PVC. With c for pure PVC at about 0.038-0.039 N/m, the c for PVC-DBP (10-20 phr) falls to 0.024 N/m. However, when the surface was etched by solvents, such as detergent or dimethylformamide (DMF), the c of various plasticised PVC increased about 0.01 N/m or more, suggesting that the plasticiser, lubricant or stabiliser was removed and rigid PVC remained [3].

Surface friction is another important property, related to wear and abrasion resistance. It is influenced by the deformation properties of PVC-P, which in turn are influenced by plasticisers and other additives [4]. As the concentration of plasticiser increases, the amount of deformation for a given load increases and the coefficient of friction also increases [5]. For this reason, tack and blocking actions increase with increasing plasticiser content.

3.5 Permanence properties

Volatility is the first permanence property that needs to be considered for the application of PVC-P. The mobility of a plasticiser, which enables it to soften, flexibilise and toughen PVC, also permits it to

Properties of PVC-P

37

leave the PVC and go into other media, which are in contact. The degree of migration will clearly depend on the type of plasticiser and the type of material with which the PVC-P is in contact.

In general, small molecules migrate faster than large ones, linear molecules migrate faster than bulky, branched ones and highly solvating ones that produce an open gel structure migrate faster than those that are ‘frozen in’ to isolated pockets [6]. For the contacted materials, the resistance to migration increases according to the order: polyethylene > rubber polyisoprene > cellulose nitrate, which depends on the compatibility between the plasticisers and these materials.

Plasticisers may be extracted from PVC-P by liquid media, such as solvents, lipid, blood and detergent. The extraction may theoretically be controlled by the rate of loss from the surface or by the rate of diffusion inside the PVC, but the true extraction process is much more complex because of the nature of the extractant [6]. When a diffusing liquid has no solvent action on a polymer supermolecular structure, coefficients of diffusion are independent of concentration of the liquid in the polymer. However, if the liquid does show some solvent or swelling action on the polymer, the diffusion coefficient may vary widely with solvent concentration [7].

Alcohol and alcohol-water blends can extract plasticiser from PVC. The extraction by 50% ethanol in water is much more sensitive to plasticiser concentration than extraction by pure water and the extraction should be more severe with increasing concentration of alcohol [6].

It is found that DEHP can diffuse to the surface faster than it can be ‘solubilised’ into blood, but the polyester (polymeric plasticiser) can be ‘solubilised’ faster than it can diffuse to the surface from inside the PVC sheet. Therefore, the extraction of DEHP is surface controlled, while extraction of the polyester is diffusion controlled [6].

The problems concerning migration and extraction of plasticiser into

38


blood or the human body during medical applications and approaches for overcoming these problems are discussed in Chapter 5.4.

References

1. W.S. Penn, W.V. Titow and B.J. Lanham, PVC Technology, 3rd Edition, Applied Science Publishers, London, UK, 1971.


3. Y. Nakamura, M. Kunio, S. Kazumi and T. Kosaku, Journal of Applied Polymer Science, 1972, 16, 2727.

4. D.K. Owens, Journal of Applied Polymer Science, 1964, 8, 1465.

5. J.B. Decoste, SPE Journal, 1969, 25, 10, 67.

6. J.K. Sears and J.R. Darby, The Technology of Plasticisers, John Wiley & Sons Inc, New York, NY, USA, 1982.

7. R.L. Laurence and J.C. Slattery, Journal of Polymer Science: Polymer Chemistry Edition, 1967, 1, 5, 1327.

4.1 Introduction

Semi-rigid poly(vinyl chloride) (PVC) or PVC-rubber blended materials have been used to make medical disposables, such as containers, connectors, trays, blister packaging and drip chambers. Flexible, soft plasticised PVC (PVC-P) is the most widely applied biomaterial for medical applications. The earliest medical application of PVC-P was to replace the traditional metal and glass materials for the packaging of pharmaceutical products, such as blood components, sterilised sugars and electrolytes for intravenous infusion and peritoneal dialysis during World War II. As the increasing need for flexible, disposable, biocompatible plastics for medical devices evolved over 50 years, PVC-P became by far the most commonly used polymer in the medical plastics industry. In 1990, its estimated market share was around 25% of all the polymeric materials used in medical devices [1]. By 1995, it was estimated that PVC represented 37% of all medical plastics used in the USA, with worldwide percentages believed to be even higher [2]. In 2004, about 40,000 t of plasticised PVC was used in the medical field in Europe and there is an annual growth rate of 4.3% [3].

According to Webster’s New Collegiate Dictionary, a biomaterial is defined as ‘a material used for or suitable for use in prostheses that come in direct contact with living tissues’. Briefly, a biomaterial can be defined as a nonviable material used in a medical device intended to interact with a biological system [4]. In more detail, a biomaterial is a substance, which is used in prostheses or in medical devices designed for contact with the living body for the intended method of application and for the intended period [5].

4 PVC-P as a biomaterial

39

40


Synthetic polymers form the most diverse class of biomaterials. As an ideal biomaterial, a synthetic polymer needs to meet the following criteria [6]:

a pure material,

form without being degraded or adversely changed,

mechanical properties for performing its function,

The following sections discuss how PVC-P meets these basic requirements as a biomaterial and where its drawbacks are.

4.2 Advantages of PVC-P

PVC-P-based film, sheet and tubing are used in numerous medical products. The typical requirements for tubing as the intravenous (IV) set, for example, include clarity, flexibility, kink resistance, toughness, scratch resistance, ease of bonding with common solvents or adhesives and suitability for gamma, ethylene oxide (EO) or electron-beam sterilisation. As a biomaterial, PVC-P has achieved its prominent role in the medical plastics industry by virtue of a unique combination of desirable properties.

PVC can be used to produce a variety of medical products, ranging from rigid components to flexible sheeting. The type and amount of plasticiser used determine the compound’s glass transition temperature (Tg), which in turn defines its flexibility and low-temperature properties, and thereby establishes its versatility. Flexible or rigid PVC can be easily processed to shaped end products. They can be readily assembled by solvent bonding or sealed using heat or radio frequency. As a biomaterial for medical products, PVC-P

PVC-P as a biomaterial

41

can be sterilised by most commonly employed sterilisation methods, such as steam, ethylene oxide or gamma radiation. PVC-P can have a Tg as low as –40 °C and still be suitable for steam sterilisation at 121 °C. PVC-P has excellent biocompatibility, very low toxicity and chemical stability. Additional characteristics that make PVC attractive include its low cost, high transparency, wide range of gas permeability, thermoplastic elastomer-like material properties, fire resistance and good insulation properties. Medical products made from PVC have passed many critical toxicological, biological and physiological tests according to national or international standards. In summary, PVC-P is one of the best medical materials in terms of cost and function. No other single material has such broad advantages (Figure 4.1).

In terms of life management of medical PVC, the environmental advantages of PVC use in medical devices are (www.ecvm.org):

conversion,

recovery, or safely disposed of in landfill.

4.3 Disadvantages

According to the criteria that an ideal biomaterial should meet, as previously considered, a polymer should be sufficiently pure without any influence of biocompatibility due to any unintentional additives, such as monomer residues, low molecular weight polymers and other reaction residues, and intentional additives, such as plasticisers, stabilisers, lubricants and fillers. For PVC-P, however, it is the additives that make PVC versatile and useful, while at the same time they are continuously receiving criticism [7].

The most commonly cited shortcomings involve toxic effluents such as vinyl chloride monomer (VCM) produced during manufacture

42


and the generation of hydrogen chloride (HCl) during incineration. Other concerns related to PVC-P depend largely on the type and amount of plasticisers used.

Plasticisers have been found to leach into medical solutions [8], the human body during long-term dialysis [9, 10], stored human blood [11] and foodstuffs [12]. PVC-P pharmaceutical packaging bags have been found to cause drug loss during storage periods. For example, drugs such as diazepam, isosorbide dinitrate, nitroglycerin and warfarin sodium can be adsorbed by PVC-P with 55%, 23%, 51% and 24% loss, respectively, during a 24 h study period [13]. Kowaluk and co-workers [14] have studied the interaction between 46 injectable drugs and PVC-P infusion bags. They found that the drug loss is due to a diffusion-controlled sorption process.

With regard to the leaching of the plasticiser di-2-ethylhexyl

Figure 4.1 Advantages of PVC-P in medical applications


43

phthalate (DEHP), the most commonly applied plasticiser for medical applications, however, there are many divided opinions. It appears that no proof has been found that DEHP is toxic or is a carcinogenic initiator, while its beneficial effect on red blood cell survival is a valued property.

4.4 PVC-P as a blood-contacting biomaterial

The advantages of PVC-P have led to the wide application of PVC-P in single-use, presterilised and disposable blood-contacting devices. Generally, blood-contacting devices are categorised in the ISO10993-4 standard into ‘external communicating devices’ and ‘implant devices’ [15]. For PVC-P, the major applications are in the first area as external communicating devices, as shown in Figure 4.2.

The blood products collected and packaged using PVC-P include whole blood, red blood cells and platelet concentrates. PVC-DEHP is currently the most widely used packaging material for the storage of whole blood, while for red blood cells and platelets, PVC- butyryl tri-n-hexyl citrate (BTHC) has been shown to be capable of maintaining them under optimum conditions [16].

Blood tubing made of PVC-P is widely used in blood extracorporeal circulating devices, such as haemodialysis equipment and lung-heart bypass sets. Medical tubing made of polyurethane and silicone have been utilised, but both are relatively expensive. CellTran developed a ‘living bandage’ using plasticised PVC as a base to carry cells for treatment of chronic wounds.

44


Figure 4.2 Applications of PVC-P as a blood-contacting biomaterial


45

4.5 Other applications of PVC-P as a biomaterial

The applications of PVC-P as a biomaterial other than for blood-contacting use are summarised in Table 4.1.

Table 4.1 Applications of PVC-P as a non-blood-contacting biomaterial

Pharmaceutical solution packaging or delivery sets

Intravenous solution pack, IV sets Peritoneal dialysis solution packs Endotracheal tubes Connectors

Medical disposables Gloves, syringes Drainage tubing or bags Urinary bags and tubing Other surgical products

Medical building products Waterproof mattress sheets Wall-coverings, floor-coverings Electrical systems Appliances and furnishings Oxygen tents

Tissue-contacting biomaterials Burn dressings [17] Artificial skin [18] Other surgical dressings [19, 20]

Biosensor or enzyme electrodes Glucose biosensors [21] Protamine-sensitive polymer membrane electrode [22] Ion-sensors [23]

Drug-delivery system Prostaglandin-releasing polymers [24] Fungicidal and bactericidal additive-releasing PVC [25]

46


References

1. C.R. Blass, Medical Device Technology, 1992, 3, 32.

2. R.S. Brookman, Medical Plastics & Biomaterials, 1998, July, 1.

3. C.R. Blass, The Role of Poly(Vinyl Chloride) in Healthcare, Rapra Technology Limited, Shawbury, UK, 2001.

4. H.J. Gurland, A.M. Davison, V. Bonomini and D. Falkenhagen, Nephrology, Dialysis, Transplantation, 1994, 9, (Supplement 2), 4.

5. E. Piskin, Biologically Modified Polymeric Surfaces, Elsevier Applied Sciences, Amsterdam, The Netherlands, 1992, p.1.

6. D.J. Lyman in Polymer Science and Technology, Ed. R.L. Kronenthal, Plenum Press, New York, NY, USA, 1975, p.8.

7. D. Goodman, Journal of Vinyl Technology, 1994, 16, 3, 156.

8. G. Smistad, T. Waaler and P.O. Roksvaag, Acta Pharmaceutica Nordica, 1989, 1, 5, 287.

9. K. Ono, T. Ikeda, T. Fukumitsu, R. Tatsukawa and T. Wakimoto in Proceedings of the European Dialysis and Transplant Association, Barcelona, 1982, 12, 571.

10. L. Nässberger, A. Arbin and J. Ostelius, Nephron, 1987, 45, 4, 286.

11. R.J. Jaeger and R.J. Rubin, New England Journal of Medicine, 1972, 287, 22, 1114.

12. J.H. Peterson, E.T. Naamansen and P.A. Nielsen, Food Additives and Contaminants, 1995, 12, 2, 245.

13. H.J. Martens, P.V. De Goede and A.C. van Loenen, American Journal of Hospital Pharmacy, 1990, 47, 2, 369.


47

14. E.A. Kowaluk, M.S. Roberts, H.D. Blackburn and A.E. Polack, American Journal of Hospital Pharmacy, 1981, 38, 9, 1306.

15. J.H. Braybrook, Biocompatibility Assessment of Medical Devices and Materials, John Wiley & Sons, New York, NY, USA, 1997, p.129.

16. V.S. Turner, S.G. Mitchell, S.K. Kang and R.J. Hawker, Vox Sanguinis, 1995, 69, 195.

17. R.H. Milner, S.J. Hudson and C.A. Reid, Burns Including Thermal Injury, 1988, 14, 1, 62.

18. P.G. Sekachev, V.S .Vaselov, V.I. Musinskaya, G.F. Shirankov, M.D. Steblyak and S.V. Loginov, Burn Prom-St, 1982, 2, 18.

19. A. Bajda, Z. Pokorski, M. Skipor and J. Wypych, inventors; Centralne Laboratorium Technicznych Wyrobow WloklenniCzych, assignee; Polish 98867, 1978.

20. W. Schroeder and K.W. Hunt, K.P. Heaton, inventors; KCI Licensing., WO/2001/085248, 2001.

21. P. Atanasov and E. Wilkins, Biomedical Instrumentation and Technology, 1995, 29, 2, 125.

22. J.H. Yun, M.E. Meyerkoff and V.C. Yang, Analytical Biochemistry, 1995, 224, 2, 212.

23. G.S. Cha, D. Liu, M.E. Meyerhoff, H.C. Cantor, A.R. Midyley, H.D. Goldberg and R.B. Brown, Analytical Chemistry, 1991, 63, 17, 1666.

24. J.C. McRea and S.W. Kim, in Biocompatible Polymers, Metals and Composites, Ed., M. Szycher, Technomic Publishing Company, Inc., Lancaster, PA, USA, 1983, p.597.

48


25. G. Matthews, PVC, Production, Properties and Uses, The Institute of Materials, London, UK, 1996.

5.1 Introduction

There has been a long-standing interest in the relationship between blood and biomaterials for blood-contacting applications [1]. In the case of plasticised poly(vinyl chloride) (PVC-P), as one of the most conventional blood-contacting biomaterials, it is convenient to review its blood compatibility in terms of blood-biomaterial interactions, factors influencing the blood response and evaluation procedures [2]. Consequently, the objective of an improved understanding of the relationship between the biomaterial and the alteration to blood components can be achieved, which would promote a better utilisation of this existing biomaterial and the development of improved materials [3].

5.2 Blood-biomaterial interactions

A definition of the blood-biomaterial interaction is as follows: any interaction between a biomaterial (device) and blood or any component of blood, resulting in effects on the biomaterial (device), or on the blood, or on any organ or tissue. Such effects may or may not have clinically significant or undesirable consequences [4, 5].

The highly complex ‘blood-biomaterials’ interaction is of a multivariable character [6]. When a blood-biomaterial interface is established, a rapid sequence of processes occurs. It is now generally accepted that the processes can be divided arbitrarily into the following groups of events (which partly occur simultaneously) [6, 7]:

5 Blood compatibility of PVC-P

49

50


blood cells and intrinsic coagulation initiated by the adsorbed proteins from the system.

monocytes) to the protein coating.

of the fibrinolytic system [8].

As expected, blood-biomaterial interactions are very complicated and there are many interrelated reactions and feedback networks [9]. For example, platelet reactions are interrelated with the coagulation system to promote thrombin formation, while platelets can interact with the fibrinolytic system by binding of plasminogen to the glycoprotein GPIIb-IIIa complex [10]. It is found that leucocytes are involved in the intrinsic coagulation, fibrinolysis and complement activation. The leucocyte membrane contains phospholipids, which may play a role in blood clotting via the intrinsic pathway [11]. Marchant and co-workers [12] showed that leucocyte adhesion is complement mediated through the complement proteins C3b and Bb. This interrelationship is very important for extracorporeal blood-contacting applications [6].

In summary, when artificial surfaces are exposed to blood, interrelated blood-response systems occur in order to achieve rapidly a balance between the processes of activation and inhibition of these systems. Although a great deal is known about the blood response to blood-contacting biomaterials or devices, important interrelationships are not fully defined in many instances. A compromise has to be made for blood-contacting biomaterial development [13].

Blood compatibility of PVC-P

51

5.3 Factors influencing blood response to PVC-P

In a similar manner to other blood-contacting biomaterials, such as polyurethane, the blood interactions with plasticised PVC (PVC-P) lead to protein adsorption, coagulation activation, platelet reactions, fibrinolysis, complement activation and other cellular responses. The blood compatibility of PVC-P is dependent on various factors as summarised in Figure 5.1.

Figure 5.1 Influencing factors on the blood compatibility of PVC-P

52


5.3.1 PVC formulation

The final properties of PVC-P are mainly determined by the plasticiser type and the concentration incorporated. The correlation between plasticiser selection and end-product properties, such as mechanical properties, low-temperature properties, surface properties, permanence, electrical properties and cost-effectiveness, has been discussed previously. With respect to the blood compatibility of PVC-P for blood-contacting applications, the PVC formulation in terms of plasticiser selection and plasticiser concentration is considered to be the most important. The surface characteristics of PVC-P, such as plasticiser surface distribution, plasticiser surface level and surface morphology, are also dependent on the formulation.

5.3.2 Selection of plasticiser

When PVC-P is used as a blood and blood-component packaging material, the blood response is strongly affected by the selection of plasticiser.

From the initial introduction of PVC-P into medical applications until the early 1980s, all PVC blood bag plastics contained the plasticiser di-2-ethylhexyl phthalate (DEHP) [14]. DEHP can interact with the red cell membrane [15, 16] and improve the survival time of erythrocytes and their osmotic fragility and flexibility, after prolonged storage, both in vitro [17] and in vivo [18]. DEHP has been found to cause reduced platelet function as defined by hypotonic shock recovery [19] and aggregation [20].

In recognising that DEHP is extracted into the stored blood or blood components, some new-generation plasticisers have been developed during the past decade, mainly for the storage of platelet concentrates. An example is a PVC formulation plasticised with tri-(2-ethylhexyl)trimellitate (TEHTM) [21, 22].

PVC-TEHTM was found to be unsuitable for red cell storage because this plastic had no stabilising effect on red cell membranes [15, 17]


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and reduced in vivo survival time [16]. Whole blood stored in PVC-TEHTM and other non-PVC materials with no DEHP always had greater haemolysis and increased osmotic fragility [14]. This seems to imply that the blood response to PVC-TEHTM is more reactive than that to PVC plasticised with DEHP.

The most prominent advantages of PVC-TEHTM are its low extraction and improved gas exchange capacity [23-25]. An increased gas exchange rate or O2 permeability is beneficial for platelet survival, and could be achieved by increasing the plasticiser concentration, resulting in a decreased PVC resin. This is the case when using TEHTM [24], while PVC-DEHP with its high level of DEHP is not preferable because of its poor compatibility with platelets [14].

Other than TEHTM, some phthalates have been reported to improve O2 permeability with physicochemical properties that are quite similar to those of DEHP. These are di-n-decylphthalate (DnDP) [26] and diundecyl phthalate (DUP) [27]. DnDP is reported to be the most desirable plasticiser for increasing gas diffusion. This is not achieved by increasing the plasticiser concentration but is related to the nature of DnDP [26]. The selection of DUP for PVC formulation is strongly dependent on the selection of the PVC resin. A highly porous PVC resin must be employed for the formulation with DUP. It was claimed that PVC-DUP could be used not only for platelet storage, but also for the storage of erythrocytes at low temperature, or for storing plasma in a frozen state [27]. Dioctyl terephthalate (DOTP) is regarded as a cost-competitive alternative to DEHP, with a lower cost than TEHTM and citrates, and it has been used for making medical-grade plasticised PVC [28].

One USA patent [29] reported using PVC plasticised with a blend of plasticisers, comprising a plasticiser resistant to extraction by blood, such as TEHTM, and a blood-extractable plasticiser, such as DEHP or di-2-ethylhexyl adipate (DEHA), for storage of red blood cells and platelets. The nature and amount of DEHP present in the PVC were sufficient to allow at least 21 days storage of red blood cells and the total amount of plasticiser blend enhanced the

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gas permeability, enabling at least five days storage of platelets. The important advantage of this invention is that a combination of benefits could be achieved from both DEHP and TEHTM.

Polymeric adipate (PA) plasticiser has been developed for reduced extraction by blood or other body fluids. The influence of PVC formulations with DEHP, PA and TEHTM on the platelet release reaction and complement activation has been studied [30]. Results indicate that plasticiser selection influences the blood response.

Preferably, plasticiser selection should be able to support the storage of red cells, stabilising membranes, while causing few, if any, deleterious effects by any leaching of plasticiser into the blood or blood components. In the meantime, gaseous exchange should be at least as good as that of PVC-TEHTM for platelet storage. PVC plasticised with Butyryl trihexylcitrate (BTHC) may be such a choice [31-34].

Since Hull and Mathur [35] suggested that citrates might be useful as a replacement for DEHP plasticiser in medical-grade PVC formulations, citrates such as BTHC and Acetyl tributyl citrate (ATHC) with a low toxicity have received considerable attention. BTHC has been shown to have a stabilising effect on red blood cell membranes similar to that of DEHP [36], resulting in good autologous in vivo survival [37]. Most importantly, there were no demonstrable toxic effects of BTHC on the livers of rats fed the plasticiser, unlike DEHP [38]. In addition, PVC-BTHC has been found to be suitable for storage of platelets for five days, which is very similar to PVC-TEHTM [34].

Acetyl tributyl citrate (ATBC) was shown to have a membrane-protective effect similar to that of BTHC. There is no significant difference between the values for cells stored in PVC-ATBC and PVC-DEHP containers [14].


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5.3.3 Plasticiser concentration

The blood compatibility of PVC-P is strongly dependent on the plasticiser concentration or level of PVC plastic. Labow and co-workers [39] found that the blood cell deformability changes were reversed by addition of DEHP and that there was a direct correlation between DEHP concentration during storage and red blood cell membrane flexibility. The increased DEHP concentration might be able to enhance gas exchange rate but it is limited by the processability and the blood reactivity to the surface with a high plasticiser level [40-42].

Kicheva and co-workers investigated the effect of DEHP concentration on the biocompatibility of PVC-DEHP [43]. They found that the amount of total protein adsorbed on PVC-DEHP increases with the increased DEHP concentration. A surface-coated layer of paraffin had the effect of decreasing the protein adsorption.

5.3.4 Plasticiser surface level

Efforts to determine the effect of surface plasticiser level on the biocompatibility of PVC-P have been made by Kim and co-workers [44], and Spilezewski and co-workers [45]. It has been shown that the removal of DEHP from the PVC-P surface alters the blood compatibility. An attempt to bring plasticisers to the PVC-P catheter surface by pretreatment at 37 °C for 24 h in PBS solution caused the highest level of inflammation compared to polyurethanes (PU). The high plasticiser surface level in the PVC can alter the inflammatory response to the material and this affects its relative biocompatibility. Zhao and Courtney [46, 47] correlated the plasticiser surface level with fibrinogen adsorption and concluded that a higher plasticiser surface level leads to a higher fibrinogen adsorption at the surface.

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5.3.5 Plasticiser surface distribution

Plasticiser surface distribution has been found to have a strong influence on blood compatibility. Table 5.1 lists three types of haemodialysis blood lines with different surface plasticiser distribution. Blood compatibility in terms of C3a measurement is strongly dependent on the surface composition [48, 49].

Table 5.1 Correlation of surface composition with C3a generation [48]

Blood lines

Surface plasticiser distribution

C3a generation (ng/ml)

5 min 15 min 30 min

PVC-DEHP DEHP mainly 53 ± 48.6 12 ± 13.8 8 ± 14.6

PVC-PU-DEHP * PU mainly 10 ± 21.9 9 ± 16.4 7 ± 10.8

PVC-PU-TEHTM** TEHTM/PU 50 ± 42 23 ± 26.1 35 ± 32.5

*Coextrusion of PVC-DEHP and PU;

**Coextrusion of PVC-TEHTM and PU

It was also found that a higher TEHTM surface distribution leads to a stronger blood response in terms of fibrinogen adsorption and the generation of C3a than that of surface plasticised with DEHP [49] (Table 5.2). However, theoretically, if the DEHP plasticiser level is simply increased by 1.25-fold to the same level as that of TEHTM at the PVC-TEHTM surface, the calculated fibrinogen adsorption and C3a values are found to be approximately the same as those obtained by evaluation of PVC-TEHTM (Table 5.3).


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Table 5.2 Correlation of surface composition with in vitro fibrinogen adsorption and C3a measurement

SamplesPlasticiser distribution (%)

Blood response (in vitro)

Fibrinogen adsorption (ng/cm2)


PVC-DEHP 68 4.1 1309

PVC-TEHTM

85 5.8 1671

Table 5.3 Theoretical evaluation of the effects of plasticiser surface distribution on blood compatibility based on in vitro

evaluation

SamplesPlasticiser distribution (%)

In vitro blood test

Fibrinogen adsorption (ng/cm2)


PVC-DEHP 85 (68 x 1.25) 5.1 (4.1 x 1.25) 1636 (1309 x 1.25)

PVC-TEHTM

85 5.8 1671

Numbers in brackets show how the protein absorption level of PVC-DEHP is increased by the same amount (1.25) compared to PVC-TEHTM

The assessment implies that TEHTM and DEHP, having a similar chemical nature, have a similar effect on the blood compatibility.

Surface contamination, other than with plasticisers has also been reported. Using attenuated total reflectance (ATR)-FT-IR, a layer of

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an amide wax at the inner surface of a PL-146 blood bag was found. The bag was made of PVC-DEHP with the wax as an anti-tack agent. It was believed that the surface contamination would have a marked effect on blood compatibility [50, 51].

In addition, surface roughness has a strong influence on the blood response to PVC-P. It was found that the blood compatibility of PVC-DEHP coextruded with PU was deteriorating after 6 months implantation, which is mainly due to an alteration in surface morphology [48].

5.3.6 Surface modification

The surface of a material (the outermost few atomic layers) is the only part of the material that can interact with blood. Modification of the surface will alter its blood response and it is the most common approach to improving the biomaterial influence on blood [6, 52]. Surface modification can be achieved by an increase in hydrophilicity, chemical modification, attachment of antithrombotic agents, treatment of surfaces with protein and preparation of biomembrane-mimetic surfaces [6]. This is discussed in more detail in Chapter 6.

5.3.7 Nature of application as devices

PVC-P has found wide application as a blood-contacting material for forming a device that will be used for the patient. It can be used for a relatively short time (minutes to hours), as in a catheter, or blood tubing for extracorporeal devices, such as haemodialysers and blood oxygenators, or for a relatively long time (days to months), as in blood or blood-component storage bags, or can be incorporated into cardiovascular systems for extended periods, as in artificial blood vessels and artificial heart components. Therefore, the dynamic flow conditions of blood (shear rates, turbulence, secondary flows, etc.), duration of contact, size of the contact surface area and actual placement site in the cardiovascular system are very important


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parameters, which are related to the nature of the application [5, 8].

5.3.8 Blood nature and evaluation procedures

The clinical application of PVC-P as a blood tubing or blood bag generally requires the administration of an anticoagulant or antithrombotic agent, such as citrate, heparin or prostacyclin (PGI2). The presence of an agent, influences blood compatibility and on the basis of the in vitro assessment of PVC-P tubing, heparin has been reported to cause reduced thrombin-antithrombin (TAT) levels and increased C3a values [49]. In addition, the blood response to a PVC-P biomaterial is influenced by the blood condition of an individual patient [6], which makes the evaluation of blood compatibility in clinical conditions even more complicated and leads to concern over the relevance of evaluation procedures for monitoring the blood response.

5.4 Plasticiser migration and regulation

5.4.1 DEHP migration and extraction

Although the aqueous solubility of DEHP is very low (< 0.04 mg/ml at 20 °C) [53], it is not covalently bound in the PVC matrix and may therefore migrate out of the plastic into the contacting medium. Since 1970, it has been known that DEHP is present in blood stored in PVC bags [54-56] and is released into patients given blood transfusions [57-59]. Reported extraction rates have ranged from 50 to 70 mg/l in blood [55] and 20 mg per pack in platelet concentrates [53, 60]. These observations led to the publication of numerous articles and reviews on this subject [61, 62] and the related toxicological study of DEHP [63-66].

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The migration of DEHP into the human body from haemodialysis blood tubing was found in the early 1970s [67-70].

To determine the total migration potential various reference methods are used, which are all available as CEN standards (ENV 1186-1 to ENV 1186-12). Several new standards in this area are in preparation [71].

It is known that the extraction rate for the plasticiser is dependent on the nature of the extractant, the surface area contacting the device, temperature, flow rate and the contact period [72-77]. In general, lipophilic extractants, such as petroleum or olive oil, have greater power to extract plasticisers than alcohol and water and acetonitrile is more effective in extracting DEHP than alcohol/water [78]. These findings cause great public concern regarding the toxicity of DEHP.

5.4.2 Toxicity of DEHP

DEHP has an extremely low acute toxicity, with an LD50 in excess of 30,000 mg/kg. Putting this into perspective, ethanol has an acute toxicity an order of magnitude higher (LD50 = 3300 mg/kg) [79]. Assessment of the chronic toxicity of DEHP carried out before 1978 showed no evidence of chronic toxic effects. However, some long-term animal feeding studies later suggested adverse effects on several major organ systems, such as the liver and the reproductive system.

The most important finding causing great concern over DEHP toxicity is that resulting from the National Toxicity Program (NTP)/National Cancer Institute (NCI) Bioassay Program of America in 1978. It was concluded that DEHP was carcinogenic in Fischer 344 rats and B6C3F6 mice and caused a significant increase in liver tumours [80]. The dose levels were extremely high, corresponding to a human intake of 0.25 litre per day (on rats) and 0.5 litre per day (on mice).

However, many later experiments indicated that DEHP is a tumour promoter rather than a tumour initiator and that mono-(2-


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ethylhexyl)-phthalate (MEHP), a major hydrolysis product of DEHP, is much more toxic than the parent compound and is effective as a tumour promoter at a lower dose [81]. The International Agency for Research on Cancer classified DEHP to class C (not classifiable as to carcinogenicity to humans) [82].

In Europe, DEHP is not classified as a human carcinogen [83, 84]. In addition, the main work on this subject was coordinated by the European Council for Plasticiser and Intermediates (ECPI). This detailed research has drawn the following conclusions:

it does not react with genetic material,

dosing of rodents is believed to be peroxisome proliferation, which is the same case as some safely used hypolipidaemic drugs,

metabolically closer to humans does not cause peroxisome proliferation or liver tumours,

the alternative general purpose phthalate plasticisers.

The above conclusions do not imply any restriction on the research and development of alternatives to DEHP, which possess a lower migration property, in order to ease the increasing concern over the leaching of DEHP into the human body. In addition, the loss of plasticiser will alter the mechanical properties of PVC-P, making the plastic ineffective and possibly dangerous to the human body. For instance, a linear relationship was demonstrated [42] between hardness and the released amount of DEHP per surface area during extraction. Loss of plasticiser caused the PVC device to become more rigid and, for example, in the case of nasogastric feeding tubes or wound drainage tubes, removal from the body after 21 days could be painful and difficult, possibly involving surgery [30]. Meanwhile,

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the loss of plasticiser must affect the surface properties of the plastic, which will alter the blood compatibility. For the relatively long-term application, the searches for alternatives to DEHP and PVC-P or the modification of PVC are continuing.

In September 2002, the EU Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) adopted an opinion on ‘Medical devices containing DEHP plasticised PVC; neonates and other groups possibly at risk from DEHP toxicity’ according to which ‘there is no evidence that any of these groups do experience DEHP- related adverse effects’. However, ‘a lack of evidence of causation between DEHP-PVC and any disease or adverse effect does not mean that there are no risks’.

In July 2002, the US Food and Drug Administration (FDA) produced a Public Health Notification about PVC Devices Containing the Plasticiser DEHP based on a ‘Safety assessment of di(2-ethylhexyl)phthalate (DEHP) released from PVC medical devices’, in which the following devices of are particularly listed:

(ECMO),


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The following procedures have been identified as posing the highest risk of exposure to DEHP:

bag),

exposure),

(aggregate dose),

The recommendation by the FDA based on the assessment is:

Patients should not avoid the procedures cited above simply because of the possibility of health risks associated with DEHP exposure as the risk of not doing a needed procedure is far greater than the risk associated with exposure to DEHP.

For some of the above procedures, PVC devices that do not contain DEHP can be substituted, or devices made of other materials (such as ethylene vinyl acetate (EVA), silicone, polyethylene or polyurethane) can be used, if available.

If PVC devices containing DEHP must be used, you may be able to minimise exposure to DEHP by, for example, using the freshest

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possible blood products stored at the lowest possible temperature, or by using heparin-coated ECMO circuits.

Considering such alternatives when these high-risk procedures are to be performed on male neonates, pregnant women who are carrying male foetuses and peripubertal males.

For other patient groups, who are presumably at lower risk, the decision to use DEHP alternatives must take into account the medical advantages and drawbacks of the substitute materials and their availability.

In March 2006, the European Commission invited interesting parties to submit information regarding DEHP plasticised PVC or alternative plasticised PVC for an updated evaluation. In February 2008, the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) published a report on ‘Opinion on the safety of medical devices containing DEHP plasticised PVC or other plasticisers on neonates and other groups possibly at risk’ [85].

The abstract of the report is shown below:

‘The Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) has evaluated the exposure to DEHP for the general population and patients during medical procedures. In some cases the exposure is significant and exceeds the toxic doses observed in animal studies. There is limited evidence suggesting a relation between DEHP exposures and some effects in humans. There is a reason for some concern for prematurely born male neonates for which the DEHP exposure may be transiently above the dose inducing reproductive toxicity in animal studies. So far, there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans. But, it is recognised that especially the potentially high exposure during medical treatments may raise a concern, even in the absence of clinical or epidemiological evidence, for harmful effects in humans. Further studies are required to confirm or reject the suggestions of adverse effects of DEHP in


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humans. For certain uses of DEHP alternative plasticizers for PVC are available.

The Committee got access to toxicity data for eight possible alternative plasticizers and compared their toxicity with that of DEHP. In respect to reproductive toxicity in animal studies DEHP induces more severe effects compared with some of the alternatives. A risk assessment of these available alternative plasticizers could not be performed due to a lack of exposure data from medical devices. Each alternative to DEHP, however, must also be evaluated with regard to their functionality in respect to medical devices. The risk and benefits of using alternative plasticizers should be evaluated case by case.’

The UK regulatory body, Medicines and Healthcare Products Regulatory Authority (MHRA) has reviewed the SCENIHR report and has concluded that:

There is no new evidence to suggest that medical devices plasticised with DEHP present an unacceptable health risk to humans. In particular, there is no proven effect of exposure to DEHP on male reproductive health - the adverse effect of concern in the SCENIHR report.

Medical devices containing DEHP-plasticised PVC have important clinical benefits.

In view of the proven clinical benefits of PVC medical devices plasticised with DEHP, it would be premature to recommend a change to other plasticisers.

5.4.3 Alternatives to DEHP

Currently, there are three types of alternatives to DEHP, which have been approved for medical practices. These are trimellitates, such as TEHTM [38, 70], polymeric plasticisers, such as PA [86] and citrates, such as BTHC [33].

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With respect to plasticiser migration or extraction, many studies indicate that less TEHTM is apparently leached from PVC bags or haemodialysis tubing than DEHP. For example, TEHTM migration into stored blood components is 1/100 or less than that of DEHP. Platelet concentrates stored for seven days at room temperature in PVC-TEHTM bags contain only 0.2 mg TEHTM per pack. TEHTM is generally not detectable in refrigerated red cell products, even after a fourty two day storage period [14].

PA is a type of extraction-resistant plasticiser, which has been permitted for use in flexible PVC for food-contact applications and for various medical devices throughout Europe [86].

From the viewpoint of migration, citrates, such as ATHC and BTHC, are not extraction-resistant plasticisers because of their relative lower molecular weight compared with TEHTM and PA. It was found that platelet concentrates stored for seven days in CL-4093 plastic (a PVC-BTHC container) contain about 20 mg of BTHC per unit. This is the same order of magnitude as for DEHP and it seems reasonable to assume that red blood cell (RBC) products would extract BTHC and DEHP at roughly the same rate [14]. However, these esters provide a low order of toxicity when compared with DEHP or other phthalate esters. They are the most promising alternatives to DEHP and have replaced DEHP plasticiser for many blood-contacting applications including:

as red blood cells, platelets and plasma,

products and crystalloid fluids,

devices, corpuscular oxygenators as used in open heart surgery, membrane oxygenators for pulmonary failures, phagocytosis for


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the collection of platelets and leucocytes for transfusions and intensive plasma exchange devices.

Recently, new citrates, such as acetyl-tri-n-(hexyl/octyl/decyl) citrate, have been produced and have been found useful as medical-grade plasticisers in PVC compositions with improved extraction resistance, particularly in soapy water extraction tests in a simulated blood-fluid situation [87]. Blood bags with citrate plasticisers have been abandoned because of problems including reports of swelling around the mouth and face, breathing difficulties and reddening of hands [88].

Findings in the 1970s relating to the leaching and toxicity of DEHP also encouraged the development of internally plasticised PVC to replace DEHP, at least partly, to a level where plasticiser migration problems are eliminated. PVC can be copolymerised with poly(ethylene oxide) (PEO) to form an ABA block copolymer, wherein the A parts are PVC segments. PEO serves as an internal plasticiser. It is also possible to produce a thermoplastic PVC block copolymer of the AB type, where the B block is a flexible linear aliphatic polyester or polyether, which serves as an internal plasticiser [89].

In addition, some new polymeric plasticisers have been developed, such as a carbon monoxide-propylene copolymer and a polyester derived from glutaric acid and a diol [90]. These polymeric plasticisers are claimed to be capable of replacing DEHP, partly or totally, for application in medical devices.

In summary, although numerous alternatives to DEHP have been developed during the past 30 years, a detailed evaluation of their suitability for blood-contacting applications, in particular blood compatibility, is lacking. For their future development, the all round performance has to be compared with that of DEHP, the most extensively studied plasticiser. This coincides with a statement from the Phthalate Esters Panel at the American Chemistry Council, which claims: ‘Alternative materials may not have the long track record and

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unique performance profile that makes PVC with DEHP a proven and lifesaving combination.’

In Europe, Eucomed, which represents the medical device industries of Europe, after reviewing the DEHP risk assessment, concluded on 25 October 2004 that:

use in medical products,

Committee and of recent scientific literature suggest that DEHP-plasticised PVC is still a safe and useful medical material and that there are no scientific grounds, at present, for restrictions on its use, although further scientific research is needed,

exposure to medical products containing DEHP-plasticised PVC in over 40 years without any reports of adverse effects, it can be concluded that the many benefits of the continued use of DEHP-plasticised PVC in medical products offset any perceived or actual risks following risk-benefit analysis,

research from both epidemiological and reproductive cell toxicity perspectives. It is suggested that this research could possibly be carried out, in the public interest, by the European Commission Joint Research Centre (JRC) in Ispra, Italy upon the request of DG Enterprise.

DEHP is now listed as one of the 66 hormone-disrupting substances by the European Commission, based on one animal testing. Although there is no proven evidence showing any harm to human health, the suspicion has resulted in calls for a total ban on DEHP-plasticised PVC by many environmental organisations [91]. The search for


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alternatives to PVC-P in medical applications has focused mainly on medical catheters and packaging materials for blood components.

5.4.4 Alternatives to PVC-P as a blood-contacting biomaterial

PVC-P provides a wide array of functional performance characteristics at a low cost and any potential replacement material will need to provide a similar performance at a comparable total system cost. A list of alternative materials to PVC for blood tubing applications has been given by Blass [92], including polyurethane/PVC co-extrusion material, polyurethanes, silicones and other elastomeric alloys. Obviously, the high cost of these polymers has prevented their application as a replacement for PVC blood tubing. Typically, the tubing costs up to 10 times as much as that made from PVC. Mediplast, Fresenius Medical Care and Gambro have all developed alternatives to PVC-P but it was found that there are no serious alternatives for blood-contacting applications [88].

Recently, some alternatives to PVC-P have been developed. Among these are metallocene polyolefins (polyethylene and polypropylene) [93-95], EVA [96] and polyether-ester plastic [97]. Metallocene polyolefins, such as metallocene polyethylene (mPE), are produced with metallocene as a catalyst. This metallocene technology makes it possible to control precisely the molecular architecture and achieve a narrow molecular weight distribution of polyethylene. mPE has demonstrated enhanced toughness, sealability, clarity and elasticity, with low extractables, and has created opportunities for the medical and healthcare industries. It was concluded that mPE materials might be able to provide a high-performance, practical and cost-effective replacement for PVC-P materials [95]. However, before deciding to use metallocene polyolefins in their medical products, manufacturers must consider simultaneously the material, design, and processing and product performance characteristics of the compounds as they relate to every phase of product development. There is no rapid route to replacement [93].

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EVA film as an alternative to PVC-P film has been promoted as combining toughness and low-temperature sealability with clarity, flexibility and impact and puncture resistance. EVA polymers have been accepted for blood-contacting application in many countries.

An ionomeric modified polyether-ester blended with PVC was reported to be a suitable substitute for PVC as a blood-contacting biomaterial, while offering advantages [97]. This suggests that one of the most promising approaches for obtaining improved extraction resistance while maintaining other high performance characteristics is to modify PVC-P, either through PVC formulation or surface modification.

Several US and European medical device companies now provide PVC-free IV bags, tubing and platelet storage bags, for example B Braun/McGaw and Baxter. However, for red blood cell packaging, efforts are still required for DEHP-PVC alternatives to meet the existing required performance at a competitive cost.

5.4.5 New development of PVC-P biomaterials

As one of the oldest commodity polymers, which has already achieved a prominent role in the medical plastics industry, PVC-P has been developed further by many new technologies, including new PVC resins, enhanced compounding technologies, PVC modification and novel alloys of PVC. These advanced PVC materials in many instances are replacing higher-priced plastics, such as polyurethanes, silicones and other thermoplastic elastomers and are finding a new way into the medical device industry.


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5.4.5.1 Ultrahigh molecular weight PVC resin

Flexible PVC has been recognised for a long time as a material with notoriously poor compression recovery properties, which are less easily resolved. If flexible PVC was available with an elastomer-like recovery property, a number of new applications would become potentially available to this polymer as an alternative to silicones, polyurethanes and other elastomeric biomaterials.

Conventional PVC resin is usually of lower molecular weight (30,000-75,000) with short chains and is highly branched, while the elastomer-like polymers are, for the most part, highly crosslinked or have very high molecular weights (long chains). Therefore, one approach to develop novel PVC with high elasticity is to increase the molecular weight of the PVC resin. Ultrahigh molecular weight (UHMW) PVC is a PVC resin with a molecular weight as high as 150,000 (K value > 100) [98]. Compared with the traditional PVC resin, these materials are more linear and have a higher degree of crystallinity. Flexible compounds based on UHMW-PVC are superior to conventional types, with improved compression recovery properties. They have found application in the automotive industry and have a variety of uses in the medical device industry [99]. Further study of processing techniques due to their high melt viscosity, high cost and limited compatibility, is underway.

5.4.5.2 New crosslinked compounding technology

A characteristic feature of PVC is that it does not contain sites of suitable reactivity to enable it to be crosslinked conveniently by reaction with common reagents. This means that a highly plasticised PVC body often suffers from excessive creep and stress relaxation, when subjected to sustained stress or strain, and there is also the plasticiser migration problem.

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PVC-P produced by a crosslinked compounding technology might be able to solve such problems. The formulation contains PVC plastisol, a polyisocyanate and diol or diamine or their mixtures. After compounding, the PVC-P polymer is produced with a network-like structure, which yields a product with many improved properties [100].

5.4.5.3 PVC modification

For improving the plasticiser migration property, PVC modification, through PVC surface modification and PVC formulation, has been utilised and this will be discussed in Chapter 6.

5.4.5.4 Novel alloys of PVC

PVC, as a slightly polar material, has wide compatibility with many other synthetic or natural polymers. In addition, researchers have developed materials known as compatibilisers that allow some polymers, normally not miscible with PVC, for example, polyethylene, polypropylene and butyl rubber, or natural polymers such as starch and cellulose, to form useful alloys. Cyclodextrin is an example of a compatibiliser, which is applied for improving the mutual compatibility of polymers, including PVC, with starch [101].

Some of the more interesting current alloys include: PVC/Nylon, for enhanced physical and high-temperature properties; PVC/urethanes, for high abrasion resistance, reduced extractables [42]; and PVC/polyolefin, especially suitable for applications requiring soft, oxygen-barrier materials [102]. Polycaprolactams, polyadipates and polyester-plasticised PVC have been applied in medical devices [86]. Polyester urethane and EVA have been used to modify PVC-DEHP to reduce the DEHP migration [103], while poly(methyl methacrylate) (PMMA) has been used to modify PVC to enhance its toughness [104].


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5.4.5.5 Other new technologies in the future

Advances in PVC technology will bring about a new generation of PVC formulated to function in specific medical applications and to replace the conventional ones [98]. By mimicking the success of metallocene catalytic chemistry in polyolefins, a new PVC resin composed of blocks of syndiotactic, atactic or isotactic resin could be designed for different applications.

Another approach to obtaining PVC products with improved resistance to heat degradation and ionising radiation is to use a non-free-radical polymerisation technique, thereby eliminating defects in the structures due to free radical polymerisation.

5.4.6 Summary

The migration problem of DEHP promotes the search for alternatives to both DEHP plasticiser and PVC-P and considerable progress has been made through the past two decades. However, PVC-P, the plastic used in the first blood bags introduced by Carl Walter over 40 years ago, remains the material of choice today. It is likely in the future that PVC technology will direct the development of new synthesis technology, new PVC formulations and PVC surface modification.

References

1. C.D. Forbes and J.M. Courtney in Haemostasis and Thrombosis, 3rd Edition, Eds., A.L. Bloom, D.P. Thomas, C.D. Forbes and E.G.D. Tuddenham, Churchill Livingstone, New York, NY, USA, 1994, p.1301.

2. J.M. Courtney, X.B. Zhao and H. Qian, Perfusion, 1999, 14, 263.

3. J.M. Courtney, N.M.K. Lamba, J.D.S. Gaylor, C.J. Ryan and G.D.O. Lowe, Artificial Organs, 1995, 19, 8, 852.

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5. Y.F. Missirlis, Clinical Materials, 1992, 11, 9.

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22. T.L. Simon, E.R. Sireea, B. Ferdinando and R. Moore, Transfusion, 1991, 31, 335.

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32. S. Seidl, W. Gosda and A.J. Reppucci, Vox Sanguinis, 1991, 61, 8.

33. H. Gulliksson, A. Shanwell, A. Wikman, A.J. Reppucci, S. Sallander and A.M. Udén, Vox Sanguinis, 1990, 61, 3, 165.

34. V.S. Turner, S.G. Mitchell, S.K. Kang and R.J. Hawker, Vox Sanguinis, 1995, 69, 195.

35. E.H. Hull and K.K. Mathur, Modern Plastics, 1984, 61, 66.

36. D. Buchholz, R. Aster, J. Menitove, L. Kagan, T. Simon, A. Heaton, T. Keegan, G.S. Hedber, W. Davisson and A. Lin, Transfusion, 1989, 29, (Supplement), S9.

37. C.F. Hogman, Transfusion, 1991, 31, 26.

38. M.S. Jacobson and S.V. Kevy, 20th Congress of the International Society of Blood Transfusion, London, UK, 1988, p.76.

39. R.S. Labow, R.T. Card and G. Rock, Blood, 1987, 70, 319.

40. S. Fayz, R. Herbert and M. Martin, Journal of Pharmacy and Pharmacology, 1977, 29, 407.

41. L. Fishbein, Progress in Clinical and Biological Research, 1984, 141, 19.

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50. B. Kaswmo and J. Lausmao, Journal of Biomedical and Materials Research, 1988, 22, 145.

51. A.S. Chawla and I. Hinberg, Biomaterials, Artificial Cells and Immobilization Biotechnology, 1991, 19, 4, 761.

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63. J. Autian, Environmental Health Perspectives, 1973, 4, 3.

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6 Modification of PVC-P surface for improved blood compatibility

The surface plays a very important role when the biomaterial contacts body fluid or any other second phase. In particular, when plasticised poly(vinyl chloride) (PVC-P) biomaterials are used as blood-contacting materials, the blood interacts with the materials at the outer layer of the PVC surface [1].

The surface modification of plasticised PVC is summarised in Figure 6.1.

Figure 6.1 PVC-P surface modification for improved biocompatibility

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6.1 Physical treatment

Hatada and Kobayashi [2] patented a PVC sheet for blood or infusion bags, which is modified so that the diffusion of plasticiser to the surface is suppressed, and the compatibility of PVC with respect to the contents of the bag is improved. The key technique is using glow discharge treatment with fluorine gas. The thin fluorinated crosslinked layer formed on the PVC surface acts as a good barrier against the diffusion not only of plasticisers such as di-2-ethylhexyl phthalate (DEHP) to the surface but also to that of stored contents. Price and Clifton [3] reported that the use of ultrasound allows a number of chemical modifications to PVC surfaces to proceed under mild conditions. It was reported that when PVC-DEHP is subjected to ultraviolet (UV) irradiation, the DEHP migration can be significantly reduced [4].

Zhao and Courtney [5] correlated the surface plasticiser level (surface cleanness) with the blood compatibility of PVC-P, based on fibrinogen adsorption. The surface treatment was carried out by a methanol washing procedure, which leads to a reduction in DEHP concentration at the surface. The reduced DEHP level induces less fibrinogen adsorption.

Messoria and co-workers [6] developed a coating process, in which a sol-gel of material based on poly(ethylene oxide) (PEO) was prepared and used to produce organic/inorganic hybrids. These hybrids were used as coatings for flexible PVC tubing, in order to reduce leaching of the plasticiser from PVC medical devices. Extraction tests carried out with hexane indicated that all coating compositions investigated were able to reduce strongly (about one order of magnitude) the leaching of DEHP. The best results were obtained by an accurate balance of organic and inorganic phase content. X-ray photoelectron spectroscopy (XPS) analysis showed a preferential segregation of silica onto the outer surface, suggesting that a high inorganic content at the coating-extraction medium interface was present.

Modification of PVC-P surface for improved blood compatibility

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Li and Chen [7] reported the effects of long-distance and direct argon radio frequency plasma surface treatment on PVC films, in terms of changes in surface wettability and surface chemistry. The surface properties were characterised by the water contact angle measurement, XPS and scanning electron microscopy (SEM). The results showed that plasma treatments modify the PVC surface in morphology and composition and both modifications cause surface oxidation of PVC films, in the forming of functional groups enhancing polymer wettability.

Bento and co-workers [8] studied commercial PVC sheets treated by plasma immersion ion implantation. The samples were immersed in argon glow discharges and biased with 25 kV negative pulses. Exposure time to the bombardment plasma changed from 900 to 10,800 s. Through contact angle measurements, the effect of the exposure time on the PVC wettability was investigated. Independent of time, all samples presented contact angles, equal to zero after the treatment. However, in some cases, surface hydrophilisation was not stable. Samples bombarded for shorter periods recovered their hydrophobic character partially or totally, while those exposed for the longest time stayed highly hydrophilic. These modifications are ascribed to the loss of chlorine and the incorporation of oxygen, as shown by XPS measurements. Furthermore, the mobility of surface polar groups and the variation in the degree of crosslinking can also affect the PVC wettability.

Tu and co-workers [9] described the modification of PVC using liquid crystal to modify the surface.

6.2 Chemical treatment

Levin [10] introduced to the PVC surface some functional groups, which can be crosslinked under the influence of heat. Such crosslinking provides a thin coating, which prevents leakage of plasticiser and additives from the PVC-P substrate when it is in contact with extractants. Jayakrishnan and co-workers [11] coated PVC-P with

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crosslinkable PVC resin to reduce the migration of the plasticiser to potential organic extractants such as hexane. Based on the hypothesis that hydrophilic and negatively charged surfaces are blood compatible, many hydrophilic polymers, such as poly(2-hydroxyethyl-methacrylate) (PHEMA) [12, 13], poly(N-vinyl-N-methylacetamide) [14], negatively charged poly(methacrylic acid) [15, 16], a combination of two different hydrophilic polymers [17], and PEO [18-20] have been grafted onto a PVC-P surface by chemical modification of the PVC surface.

The PVC-P surface grafted with hydrophilic polymers exhibited improved blood compatibility, as well as the ability to prevent plasticiser migration. In addition, it is also possible to produce a low-friction PVC-P catheter by such hydrophilic polymer grafting technology [21].

By entrapping PEO surface active additives, such as (C12 - EO10), (EO13-PO30-EO13), (EO20-PO30-EO20), and (EO80-PO30-EO80) onto the PVC-P surface by a solvent casting method, the modified surface has improved blood compatibility in terms of suppression of platelet adhesion [22].

Surface modification of PVC-P is also achieved by PVC surface coating and blending with surface-active additives, such as PEO-poly(propylene oxide) (PPO) surfactant and HEMA-styrene copolymer, having a microdomain structure. The materials show high anticoagulant activity and inhibition action of platelet loss [23]. Blending of PVC-P with hydrophilic polymers, such as PEO and polyvinylpyrrolidone (PVP), has also been employed to prepare a protein-resistant surface, as previously stated [24].

Reducing plasticiser migration by modification of the PVC formulation using some specific additives is also possible. An example is the use of cyclodextrins. It was reported that a film cast from the mixed solution of PVC, DEHP and -cyclodextrin ( -CD) has a reduced DEHP migration property [25].


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Biodegradable polycaprolactone (PCL) has been used to replace partially or totally the DEHP and PVC compositions intended for medical devices, with poly( -caprolactone) (PCL-biodegradable, biocompatible and macromolecular plasticiser). After comparing the experimental results with the data from the literature, corresponding to traditional PVC-P, it can be concluded that the PCL and even the PCL-DEHP mixture behave as better plasticisers for PVC, providing a lower extraction risk and similar or even improved thermal and mechanical properties.

Tween 80 or Triton X-100 and anionic bis(2-ethylhexyl) hydrogen phosphate have been used for modification of PVC-P and this modified PVC demonstrated the best biocompatibility; the cationic surfactant tricaprylylmethylammonium chloride-modified PVC membrane exhibited the poorest biocompatibility [26] .

6.3 Biological treatment

Immobilisation of bioactive substances onto biomaterial surfaces has been widely accepted in the medical device industry. Heparinisation of PVC-P is one of the approaches used to obtain improved blood compatibility. It can be achieved by simple coating and ionic complexation. Tridodecylmethylammonium chloride (TDMAC)/heparin complex is soluble in some organic solvents. Miyama and co-workers introduced a photoactive group onto PVC and then a dimethylamino-containing monomer was photografted onto the PVC-P surface, making it capable of ionically bonding heparin [27]. Similarly, poly(amido-amines) have been found to be capable of forming stable complexes with heparin. By grafting such moieties, a heparinisable PVC-P surface was achieved with powerful heparin retention ability [28, 29].

Covalent end-point immobilisation of heparin onto a PVC-P surface has been investigated extensively [30, 31] and the heparinised PVC-P produced has been reported to show an improved blood compatibility [32]. The influence of heparin coating by end-point attachment

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technology on in vitro bacterial adherence on PVC-P was also investigated [33]. Heparinised PVC circuits have been found to reduce the incidence of cerebral injury in cardiac surgical patients due to the attenuation of systemic inflammation [34] and the use of coated circuitry should be encouraged in cardiac surgery, although very few centres use this technique routinely [35].

It was discovered by surface characterisation using XPS that the DEHP level was reduced when heparin was covalently attached to the PVC-P, which has an influence on blood compatibility [36]. Indeed, surface modification by heparinisation coating can enhance the blood compatibility but the finding that heparinisation reduces DEHP migration into the blood have not been widely reported. For pregnant women, neonates and children, the use of the available surface-coated plasticised PVC tubing sets, but free of DEHP, was strongly recommend [37].

Hsu and Balding [38] employed various hydrophobic cationic substances, such as polyethyleneimine, dimethylstearylamine, benzalkonium, stearalkonium and tridodecylmethylammonium, to form complexes with heparin. The formed complexes are soluble in lower organic alcohol, such as isopropyl alcohol. By coating the complex on PVC-P, followed by -radiation sterilisation, the heparin moiety can be bound to the PVC-P surface.

By incorporation of prostacyclin into a PVC-P blending system [39], the controlled delivery of prostacyclin can lead to improved surface blood compatibility. In contrast to this activity of prostacyclin, albumination of the PVC surface has been shown to suppress effectively the adhesion and activation of platelets when the surface contacts whole blood [40].

Biomimetic modification of PVC-P has been approached by coating 2-methacryloyloxyethyl phosphorylcholine (MPC)/lauryl methacrylate copolymer to incorporate phosphorylcholine polar groups onto the surface and achieve biomembrane-like surface properties [41, 42]. It has been hypothesised that the coated surface


89

properties are mainly influenced by the underlying material surfaces [42]. In addition to those modifications based on a MPC copolymer, some different phospholipids have been bound onto PVC tubing [43] to achieve improved blood compatibility. The PVC-P surface is also improved for cell adhesion [44].

A novel approach for surface modification of PVC-P for improved blood compatibility involves the utilisation of oligosaccharides, such as cyclodextrins and cyclodextrin/PEO or cyclodextrin/PEO-PPO combinations. A commercially available cyclodextrin, -cyclodextrin, has been utilised to modify the surface of biomedical adsorbents for biospecific adsorption in blood purification [45, 46]. The amphiphilic nature of cyclodextrins and their ability to form inclusion complexes with many bioactive substances are of interest for the exploitation of their potential applications for modification of polymers. Zhao and Courtney [47, 48] have developed an anchor modification procedure for PVC-P. PEO-PPO-PEO and cyclodextrin inclusion complexes were blended with PVC-DEHP for surface modification. The significant reduction in fibrinogen adsorption at the surface indicates the effect of anchoring of the complex on the alteration of the surface properties, which leads to an improved blood compatibility.

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44. D. Klee, R.V. Villari, H. Hocker B. Dekker and C. Mittermayer, Journal of Materials Science: Materials in Medicine, 1994, 5, 9-10, 592.

45. X. Zhao and B.L. He, Reactive Polymers, 1994, 24, 9.

46. X. Zhao and B.L. He, Reactive Polymers, 1994, 24, 1.

47. X. Zhao and J.M. Courtney, Journal of Biomedical Materials Research, 2007, 80A, 3, 539.

48. X. Zhao and J.M. Courtney, Journal of Biomedical Materials Research, 2008, online publication.

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7.1 Environmental and health concerns, and regulatory issues

Plasticised poly(vinyl chloride) PVC-P, due to its wide application in the past 50 years and concerns over the leaching of plasticiser, has been the centre of controversy for quite a long time. Now, product life cycle analysis has been adopted to cover the environmental analysis of any products through the whole supply chain to the end-of-life for legal compliance. PVC is under even more scrutiny as it contains chlorinated compounds and additives and the focus now is moving from the manufacture of PVC to the end-use, and to after the end-use or end-of-life (Figure 7.1). The European PVC and additive industries have already adopted the responsible care programme and a voluntary commitment to improve the PVC product system throughout its entire life cycle [1].

As stated below, there are challenges facing the PVC and associated industries, relating to plasticisers [2, 3]:

commit to phasing out all substances that accumulate in nature or instigate reasonable doubt as to toxic effects.

manufacturers.

waste, e.g., upon landfill disposal.

7 Future perspectives

95

96


doubt.

alternatives.

Figure 7.1 Environmental and health concerns over PVC-based products

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In the UK, the position of the Medicines and Healthcare Products Regulatory Agency (MHRA) is that no additional regulatory measures are necessary to facilitate the phasing out of di-2-ethylhexyl phthalate (DEHP)-plasticised PVC in medical devices. The provisions of the Medical Devices Directive are adequate to ensure that any material known to present a toxic hazard is replaced as soon as alternatives with a more positive risk-to-benefit balance are available. Meanwhile, recognising that the undesirable characteristics of DEHP-plasticised PVC represent only one facet of a complex risk-to-benefit equation, it appears at present that this material is essential in some medical devices used in critical circumstances (Figure 7.2). In some situations, coatings that lead to a significant reduction in DEHP exposure can improve the total risk-to-benefit ratio. Where DEHP is not essential, the manufacturer’s risk assessment (required by the Medical Devices Directive) should lead to the conclusion that alternative materials that do not result in exposure to DEHP should be used.

Figure 7.2 Regulatory considerations of plasticised PVC as extracorporeal blood-contacting devices - risks and benefits

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7.1.1 Sterilisation

For medical devices, there is a regulatory requirement to ensure that products are sterile. There are a range of ISO standards for sterilisation such as:

products - General requirements for characterisation of a sterilising agent and the development, validation and routine control of a sterilisation process for medical devices, 2003.

oxide - Part 1: Requirements for development, validation anf routine control of a sterilation process for medical devices, 2007.

oxide - Part 2: Guidance on the Application of ISO 11135-1, 2008.

- Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices, 2006.

Part 2: Establishing the sterilisation dose, 2006.

Part 3: Guidance on dosimetric aspects, 2006.

methods:

microorganisms on products, 2007.

sterilisation process, 1998.

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Figure 7.3 Sterilisation methods for medical PVC.

For medical PVC, the most commonly used sterilisation methods are summarised in Figure 7.3.

7.2 Market needs

7.2.1 Market for PVC

PVC is the third most consumed polymer worldwide, and is the most widely used biomaterial for medical devices. As the PVC industry continues to grow, so does the plasticiser industry.

There are about 25 key players in PVC manufacturing in North America. The annual output is about 8 million t. There are ten key PVC manufacturers in Europe, accounting for 98% of PVC production and two manufacturers are based in the UK. They are INEOS Vinyls and Hydro Polymers. The annual capacity of INEOS Vinyls alone is 1.4 million t (INEOS have taken over Hydro).

A report compiled by Chemical Market Associates, Inc. (CMAI): 2005 World Vinyls Analysis includes the market analysis of the global PVC, vinyl chloride monomer (VCM) and ethylene dichloride (EDC) markets for the period 1999-2009 [4]. Topics covered in this analysis include capacity, supply, demand, trade, prices and

100


profitability, technology and production costs. Some significant conclusions include:

The PVC industry is emerging from several weak years in terms of profitability. Economic growth of 2.8% per year from 1999 to 2004 is forecast, to accelerate to 3.6% from 2004 through 2009. Global PVC demand recovered in 2004 and is forecast to continue to grow at a rate of 4.1% per year through 2009.

China will be the key country for world demand and supply issues. China is planning on adding most of the world’s new PVC capacity over the next few years.

7.2.2 Market for PVC medical devices

7.2.2.1 General market analysis

It is estimated that soft PVC accounted for 48% of all disposable medical devices in 2005. The present world demand for PVC medical compounds is between 210,000 and 250,000 t per year. The major manufacturing centres are Western Europe, the USA and Japan [5]. The European market for plastics in medical disposables was estimated at 120.5 million Euros in 1998 and was expected to reach 191.5 million Euros in 2005. PVC makes up 26.0% of the market for the total use of polymers in medical devices.

7.2.2.2 General Chinese market analysis

The popular medical plastics in the Chinese market are high-density polyethylene, low-density polyethylene, polypropylene (PP), PVC, polystyrene, thermoplastic polyester, polyurethane, acrylics, polycarbonate, acrylonitrile-butadiene-styrene, thermoplastic elastomers and polyamide. China’s high economic growth for nearly two decades has excited the rapidly rising consumption of medical

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plastics. Since 1990, the country’s medical plastics consumption has grown 13.5% annually. It is forecast that the Chinese medical equipment, medical supplies and pharmaceutical packaging industries will continue to fuel demand for medical plastics and lead the industry in growth. The total market demand for medical plastics was forecast to increase 12.4% annually to 294,000 t by the year 2005 (http://www.researchandmarkets.com). In order to become less dependent on medical plastics imports, China will continue to expand its production capacity. Output of medical plastics reached 114,000 t in 2000 and was expected to advance to 205,700 t by 2005, increasing by 12.5% per year (http://www.researchandmarkets.com). In spite of new facility construction and capacity expansions, China’s medical plastics demand will continue to outstrip supply. In 2000, China imported 57,000 t, accounting for 34.7% of the total medical plastics consumption. The country will remain a large importer of medical plastics over the next 10 years.

7.2.2.3 Factors influencing the PVC medical device market

Demand for PVC in the medical device sector is still growing, but at a lower rate than for polyolefins [6]. This is due to the health concern about the migration of DEHP from the flexible PVC material into the surrounding environment. However, there is no scientific evidence to prove the risk of using DEHP in soft PVC.

A statement on ‘Baxter’s position’ on the company website (www.baxter.com/pvc) states that; ‘in many applications, PVC remains the material of choice because of its long history of safe use and because of its outstanding performance characteristics.’ At the same time, Baxter plans to remain a pioneer in materials research. A Baxter spokesman explained that ‘any shift to non-PVC alternatives will be very gradual and could take more than a decade.’

SPI’s Vinyl Institute in Washington, DC, USA, states that IV bags and medical tubing account for about 4-6% of all PVC extrusion - around 0.27-0.4 t in 1998. Meanwhile, B. Braun McGaw in Bethlehem,

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PA, USA has been manufacturing a non-PVC bag for standard IV solution for 10 years. This multilayer structure of polypropylene, a copolyester and a synthetic elastomer contains no plasticiser. A company spokesman says this IV bag accounts for about 20% of the 500-600 million bags made yearly in the USA. All these alternatives will compete to share the market with PVC-P in medical devices.

7.3 Emerging technology

Christopher [7] has developed a manufacturing process to produce PVC in a more environmental friendly condition.

Recently, a newly developed polyolefin-based elastomer plastic has been compared with PVC-P and thermoplastic urethane (TPU) urinary catheters, in terms of ecological environmental performance. It was clearly demonstrated that this new polyolefin-based catheter has a better environmental performance than TPU, while it has an almost equivalent environmental performance to PVC [8]. For blood-contacting applications, however, the new polyolefin-based catheters require further study to confirm good blood compatibility.

Longer-term potential developments in PVC include the use of nanocomposite formulations, designed to improve certain properties such as stiffness, fire resistance and heat stability. Research is under way to investigate the use of novel polymerisation techniques to remove structural defects from the PVC chain, resulting in a far more thermally stable polymer. Such techniques also offer the potential to produce an internally plasticised PVC polymer by incorporating a medium-chain olefin, or by polymerising other polar monomers.

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References

1. European Council of Environmental Manufacturers, www.ecvm.org

2. I. Mersiowsky, M. Weller and J. Ejlertsson, Water Research, 2001, 35, 3063.

3. I. Mersiowsky, Journal of Progress in Polymer Sciences, 2002, 27, 10, 2227.

4. Chemical Market Associates Inc., 2005 World Vinyls Analysis, http://www.cmaiglobal.com

5. C.R. Blass, The Role of Poly(Vinyl Chloride) in Healthcare, Rapra Technology Ltd, Shawbury, Shrewsbury, UK, 2001.

6. European Plastic News, 2007, 34, 10.

7. H. Christopher, Green Chemistry, 2007, 9, 243.

8. H. Stripple, R. Westman and D. Holm, Journal of Cleaner Production, 2008, 16, 16, 1764.

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ACO Acid citrate dextrose

ASTM American Society for Testing and Materials

ATBC Acetyl tributyl citrate

ATEC Acetyl tri-2-ethylhexyl citrate

ATHC Acetyl trihexyl citrate

ATR Attenuated total reflectance

BBP Butyl benzyl phthalate

BTHC Butyryl trihexylcitrate

CMAI Chemical Market Associates, Inc.

CPB Cardiopulmonary bypass

CPE Chlorinated polyethylene

DACM Distilled acetylated monoglyceride

DBP Dibutyl phthalate

DBS Dibutyl sebate

DEHA Di-2-ethylhexyl) adipate

DEHP 2-Di(ethylhexyl) phthalate

DEHS 2-Di-(ethylhexyl) sebate

DIDP Di-isodecyl phthalate

DINP Di-isononyl phthalate

DIOP Dioctyl phthalate

DMF Dimethylformamide

DnDP Di-n-decylphthalate

DOTP Dioctyl terephthalate

DUP Diundecyl phthalate

Abbreviations

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106


ECMO Extracorporeal membrane oxygenation

ECPI European Council for Plasticiser and Intermediates

EDC Ethylene dichloride

EO Ethylene oxide

ESBO Epoxidised soya bean oil

EU European union

EVA Ethylene vinyl acetate

FDA US Food and Drug Administration

FT-IR Fourier transform infra red spectroscopy

HCl Hydrogen chloride

HEMA Hydroxyethyl-methacrylate

ISO International Standards Organisation

IUPAC International Union of Pure and Applied Chemistry

IV Intravenous

JRC European Commission Joint Research Centre

LD50 Dose of a chemical which kills 50% of the population

MEHP Mono-(2-ethylhexyl)-phthalate

MHRA Medicines and Healthcare Products Regulatory Authority

MPC Methacryloyloxyethyl phosphorylcholine

MPE Metallocene polyethylene

MW Molecular weight

NCI National Cancer Institute

NTP National Toxicity Program

PA Polymeric adipate

PCL Polycaprolactone

PE Polyethylene

PEO Poly(ethylene oxide)

PGI2 Prostacyclin

PHEMA Poly(2-hydroxyethyl-methacrylate)

PMMA Poly(methyl methacrylate)

Abbreviations

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PO Polyethylene oxide

ppm Parts per million

PPO Poly(propylene oxide)

PU Polyurethane(s)

PVC Poly(vinyl chloride)

PVC-P Plasticised PVC

PVC-U Unplasticised PVC

SCENIHR Scientific Committee on Emerging and Newly Identified Health Risks

SCMPMD EU Scientific Committee on Medicinal Products and Medical Devices

SEM Scanning electron microscopy

TAT Thrombin-antithrombin

TDMAC Tridodecylmethylammonium chloride

TEHTM Triethylhexyl trimellitate

Tg Glass transition temperature

TPN Total parenteral nutrition

TPU Thermoplastic urethane

UHMW Ultra-high molecular weight

VCM Vinyl chloride monomer

VR Volume resistivity

XPS X-ray photoelectron spectroscopy

-CD -Cyclodextrin

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Subject Index

109

A

Adipates, 20

B

Biochemical plasticisers, 24 25Blood-contacting applications, 50 52Blood-contacting biomaterials, 50 51 69Blood-contacting devices, 97Blood-contacting materials, 83

C

Copolymerisation, 15 17

D

DEHP, 4 5 19 22 25 27 28 36 37 52 54-57 59-68 72 73 86-88 97 101DEHP-PVC, 70DEHP risk assessment, 68DEHP toxicity, 60Di-2-ethylhexyl phthalate (DEHP), 10 84Dialkyl phthalates, 18

H

Heparinisation, 87

110


N

N-butyryl trihexylcitrate (BTHC), 30 43 54 65 66

P

Phosphate plasticisers, 21Plasticisation, 1 15 17Plasticised PVC (PVC-P), 1 9 10 26 28 36 37 39 40-43 45 52 55 58

59 61 62 68 70 72 73 83-85 88 95 97 102Plasticised PVC biomaterials, 39 45 70Plasticised PVC blending system, 88Plasticised PVC blood compatibility, 49 51Plasticised PVC compounding, 30Plasticised PVC formulation, 3 4 5 13 26 27Plasticised PVC properties, 35Plasticised PVC surface, 83 86 87 89Plasticised PVC surface modification, 2 73 83 86 89Plasticiser categories, 18Plasticiser migration, 59Plasticiser regulation, 59Plasticiser surface distribution, 56Plasticisers, Primary 17 25Plasticisers, secondary 17 25Plastics industry, 40Polymer matrix, 1Polymeric plasticisers, 22 23 65Polymerisable plasticisers, 24 25Polymerisation, 9 13 24 73Polymerisation, bulk, 13 14Polymerisation, emulsion, 13 14Polymerisation,suspension, 13 14Post-polymerisation, 14Pre-polymerisation, 14PVC alloys, 72PVC formulation, 2 25 26 27 70 73 86PVC industry, 10 100PVC latex, 15PVC market, 99PVC medical device market, 101

Subject IndexMedical Plasticised PVC

111

PVC medical devices, 100PVC modification, 70 72PVC plasticisation, 10 26PVC processing, 27 31PVC product system, 95PVC raw material, 13 15PVC resins, 2 15 24 27 53 70 71 73 86Pyrolysis, 13

S

Scanning electron microscopy, 85Sterilisation, 98 99

T

TEHTM, 30 36 52 53 54 56 57 65 66Trimellitates, 20

U

Unplasticised PVC (PVC-U) 1 35

W

Water contact angle measurement, 85

X

X-ray photoelectron spectroscopy, 84 85 88

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Shawbury, Shrewsbury, Shropshire, SY4 4NR, UK Telephone: +44 (0)1939 250383 Fax: +44 (0)1939 251118 Web: www.rapra.net

Published by iSmithers, 2009

Poly(vinyl chloride) (PVC) is the most versatile of all the commodity

polymers. It can satisfy a wide range of product function, safety, performance,

and cost criteria.

This book considers the history of plasticised PVC in medical applications

and the manufacturing and processing of plasticised PVC together with its

properties are reviewed. The selection of plasticisers is a particular focus.

In Chapters 4 and 5, and the blood compatibility of plasticised PVC is

examined, based on the most recent information.

The regulatory requirements and environment concerns over the leaching of

plasticisers and the generating of dioxins during the incineration of PVC-P

medical products after use are discussed in detail.

This book will be of interest both to those who manufacture products using

plasticised PVC, and to those who use the products and need to know about

the using PVC in medical applications.

medical plasticised pvcdocshare01.docshare.tips/files/29637/296371339.pdf · update on medical...

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