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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

ISBN: 978-1-84735-208-8 Typeset by Kailash Media Pvt. UK ©2009. Shropshire. Shrewsbury.First Published in 2009 by iSmithers Shawbury. Ltd. SY4 4NR. without the prior permission from the copyright holder. Printed and bound by Lightning Source Inc. . 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. 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. Smithers Rapra All rights reserved.

............. 9 2......................... 36 i ......2 Additives ................................................ 1 Plasticiser selection ....1 PVC raw material ...........1 Selection of plasticiser .....................14 2...................1........................................................2 PVC-P compounding ...................................................... 35 3..... 35 3.......2.............4 Surface properties ............16 2.........3 Mass or bulk polymerisation ........ Properties of PVC-P .... 13 2.......3.........14 2........3 PVC-P formulation ....................3............ 13 2.............................2 Low-temperature properties ..................................................................................27 2.............. 36 3...........C ontents Executive summary ........................ Brief history of the medical applications of plasticised PVC....................................... PVC-P formulation......... 16 2....1 Plasticiser .....1 Mechanical properties ............13 2.......................... 3 1........................3 Electrical properties ....................................................................2............2 Other additives ........................................1............................................................................26 2......... 35 3...........................................................2 Emulsion polymerisation .........1 Suspension polymerisation ......31 3........ 27 2.......................1..........................

. 39 4..............59 5.........52 5..........4.............................4.3............................... 42 4................4 Alternatives to PVC-P as a blood-contacting biomaterial...........3...................................1 DEHP migration and extraction .... 44 4.....................3 Factors influencing blood response to PVC-P ....................Medical Plasticised PVC 3..........1 Introduction ..........................................................3................................... 44 5.......... 49 5.... 50 5....6 Summary .............. 36 4......4 Plasticiser migration and regulation...........4....................7 Nature of application as devices ........55 5..1 PVC formulation ...3....8 Blood nature and evaluation procedures ........................6 Surface modification ..52 5....70 5.......59 5............................ 49 5................3...........58 5. 40 4............ Blood compatibility of PVC-P ....65 5......3........................................................... Modification of PVC-P surface for improved blood ii ................. 39 4...2 Blood-biomaterial interactions .......3.2 Selection of plasticiser .............................. 49 5................56 5................55 5............4.......................................5 New development of PVC-P biomaterials ......................................2 Toxicity of DEHP .58 5.....3 Plasticiser concentration ..3 Alternatives to DEHP .1 Introduction ............. 59 5.....5 Permanence properties...................................73 6....2 Advantages of PVC-P .....69 5......4 PVC-P as a blood-contacting biomaterial ...............................4.............4 Plasticiser surface level ..........5 Plasticiser surface distribution .........3..5 Other applications of PVC-P as a biomaterial ............4..................... PVC-P as a biomaterial ..3 Disadvantages .......60 5..............................

......3 Biological treatment ............................ 95 7.......1 Physical treatment .........................................................2......98 7.........2 Market needs........ 83 6...... 95 7.................1 Sterilisation ................... ...................... 109 iii .........................1.........................................1 Environmental and health concerns and regulatory issues............................100 7............99 7....................................................................2 Chemical treatment .................................. 87 7.........................3 Emerging technology .........................................................Contents compatibility .........................................2............................................................................... 99 7................ 85 6... Future perspectives ..................................... 105 Subject Index.... 84 6.........1 Market for PVC ............................................... 102 Abbreviations ...2 Market for PVC medical devices ............................................

Medical Plasticised PVC iv .

There is no covalent bond between PVC and plasticiser but they are very compatible and become an integral part of the matrix. One of the most important additives for PVC is the plasticiser. a portion of it forms an intimate bond with the PVC. 1 . while the remainder is captured in the polymer matrix. PVC-U is used extensively for the construction market because of its low cost and fire resistance. P represents different types of plasticiser. 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. Nowadays. 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. PVC can be divided into plasticised PVC and unplasticised PVC. performance and cost criteria.E xecutive summary Poly(vinyl chloride). When a plasticiser is blended with PVC. PVC-U is a type of rigid material. when the processing technology was available. It can satisfy a wide range of product function. For example. The use of PVC-U did not become significant until the 1960s. the plasticiser content can approach 50% [2]. is the most versatile of all the commodity polymers. This increases the flexibility. safety. abbreviated to PVC. In the case of extra soft PVC-P. 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]. PVC-DEHP is PVC plasticised with 2-di(ethylhexyl) phthalate (DEHP).

2 . Most of them are relevant to blood-contacting applications. Plasticised PVC-based film. sheet and tubing are used in numerous medical products. The relationships between the PVC formulation. The PVC formulation determines the properties of both bulk and surface while the surface modification only influences the surface properties. PVC resin is the most widely used polymeric biomaterial for single use.Medical Plasticised PVC In terms of volume. 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. the PVC surface modification and blood compatibility are highlighted in Figure 2. presterilised medical devices [3]. 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. plasticiser surface level and other surface properties).

3 .Executive summary Figure 2 Blood and PVC-P interface Plasticiser selection PVC is a very hard and rigid substance. It requires the addition of plasticiser to provide flexibility and a stabiliser to prevent degradation at high temperature. storage and delivery is shown in Figure 3 [3]. which is also very sensitive to heat. The composition of the PVC-P formulation used in devices for blood collection.

DEHP is the only plasticiser mentioned in any European Pharmacopoeia Monograph. It remains by far the largest tonnage plasticiser used in medical products [1]. which comprises 30-40% of final polymer weight (mass) [4]. 4 .Medical Plasticised PVC Figure 3 PVC-P formulation for medical devices With respect to the formulation. 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. it might leach from the material into the contacting physiological medium [6]. DEHP is the most commonly utilised plasticiser. As DEHP is not covalently bound within the PVC-DEHP matrix. plasticiser selection is critical in the medical application of PVC-P. 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]. Also.

reducing haemolysis and increasing in vivo survival [7-9]. Both of these have been shown to leach from plastic and into blood components to a lesser extent than DEHP. In Chapters 4 and 5. while PVC-DEHP was shown to confer stability on red cell membranes. and has proved to be an excellent platelet storage plastic for high concentrations of machinederived platelets [11]. the blood compatibility of PVC-P is influenced by the PVC formulation. In summary. in the first three chapters of this book. The research and development of PVC-P as 5 . either at the PVC surface [12] or in the total formulation [13]. Bowry [2] compared extra soft (48% DEHP) and standard PVC (39% DEHP) and found an enhanced platelet adhesion and aggregation with extra soft PVC. mainly in terms of plasticiser selection and level of incorporated plasticiser. PVC-P as a biomaterial and the blood compatibility of PVC-P are examined systematically. PVC-TEHTM was found to be unsuitable for red cell storage because it had no stabilising effect on red cell membranes [7. The selection of plasticisers is a particular focus. 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 content of plasticiser in the PVC-P formulation also influences the blood compatibility. It was also found that plasticiser surface distribution has a pronounced effect on blood compatibility [14]. In brief. PVC-BTHC has been shown to have a stabilising effect on red cell membranes.Executive summary The new-generation PVC-P include PVC plasticised with triethylhexyl trimellitate (TEHTM) and butyryl trihexylcitrate (BTHC). based on the most recent information. 8] and reduced in vivo survival time. The blood compatibility of PVC-P is strongly dependent on the plasticiser selection. Protein adsorption was found to be dependent on the DEHP concentration. similar to that of DEHP [10].

Medical Plasticised PVC
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.

6

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.

7

Medical Plasticised PVC

8

but the production difficulties were enormous. commercial interest shifted to this synthetic polymer. PVC is one of the two largest tonnage plastics materials.1 Brief history of the medical applications of plasticised PVC Poly(vinyl chloride) (PVC) is produced by polymerisation of vinyl chloride monomer. Diemann. Europe represents about a fifth of the world market. the resulting PVC was brittle. it was Baumann [1]. In 1912.222. 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]. Bondt and Laurverenburgh. in Kolbe’s Lehrbuch der Organischen Chemie. second only to polyethylene (PE). In 1996. Trotswyck. when it was discovered how to process PVC using heat stabilisers. ‘the oil of the Dutch chemists’ (dichlorethane). and today. In the same year. In 1795. PVC production by manufacturers in Western Europe reached 5209000 t and the total PVC sales by them was about 5. The European market in 2000 was 5. The first recorded use of the name vinyl chloride appeared in 1854. four Dutchmen.000 t. Klatte reported on a production process for PVC [2]. After 1930.5 million t and growing at around 2% per year. However. which could be heated at 130 °C without decomposition. was obtained. The value of finished PVC products made in Europe is estimated at 9 . and it degraded when exposed to heat and light. who first reported that on exposing vinyl chloride to sunlight. In 1835. prepared a substance that was named after them. a white solid with a specific gravity of 1.406. the basic material for making PVC). Henri Regnault produced a gas that burned with a yellow flame with a green mantle (presumably vinyl chloride.

Medical Plasticised PVC EUR 75. when Parks and Hyatt used camphor to plasticise cellulose nitrate. including plasticisers. in 1882. using tritolyl phosphate. acetyl cellulose and other plastics. such as tricresyl phosphate and dibutyl phthalate. In 1933. Kyrides [7] patented the use of di-beta-ethylhexyl phthalate for plasticisation of nitrocellulose. In 1955. and internal plasticisation. some ‘nontoxic’ plasticisers appeared and achieved US Food and Drug Administration (FDA) regulation in food packaging. The first use of a plasticiser was in the 1860s. These were by external plasticisation. The existing rubber processing machinery was modified to compound and fabricate PVC-P and the routine plasticisers for nitrocellulose.000 million and more than 530. coatings and tubing used in food processing [9]. two approaches had been attempted to reduce the processing temperature in order to mitigate the instability problem. Semon’s patent on plasticisation of PVC with DEHP was issued [8]. The commercial success of PVC is strongly linked to the discovery and development of suitable additives. were selected for PVC plasticisation [6]. From then. based on the in vitro and in vivo testing of stored blood. cellulose nitrate was plasticised to make motion picture film. Later. Since then. As early as 1928. PVC-P as a blood-contacting biomaterial in blood 10 . DEHP began its growth and has become the largest volume plasticiser in the PVC industry. [5]. In this patent. 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. 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.000 people are employed by the sector. The use of plastic blood processing equipment was pioneered by Carl Walter as early as 1949 [10]. Walter and Murphy introduced the use of plastic blood bags to store blood in the presence of acid citrate dextrose (ACD) [11]. Two months later. di-2-ethylhexyl phthalate (DEHP) was also covered. In 1934. In 1952. using vinyl acetate as the comonomer with vinyl chloride. adhesives.

org/upload/documents/document93. British USP 1923938. L. London. PVC-Polyvinyl Chloride Factsheet. It was estimated that about 30. UK. The History of PVC. eurochlor. 1969. inventor. such as medical PVC. the Chemistry and Industrial Production of Polyvinyl Chloride.S.P. Plasticisers. http://www.pdf 6. Medical PVC accounted for 0. Kyrides. The Institute of Materials. Baumann. long-accepted biomaterials. Brydson. UK. Principles and Practices. Monsanto Chemical Company. London. UK.000 t of PVC were used worldwide in 2004. Plastics Materials. J. DEHP-plasticised PVC-based devices for medical application are now under more stringent scrutiny for regulatory approval. 163. J. 11 . 6th Edition. London. with an annual growth rate of 4. 3. Wilson. 7th Edition. MacLaren and Sons Ltd. blood transfusion and other medical uses has been widely applied and intensively investigated. which was approximately 30.3%.A. A. 1999. M. ButterworthHeinemann. 308. 1872. p. 2. Plastics Materials. E.Brief history of the medical applications of plasticised PVC storage.6. Kaufman. Brydson. assignee. Annalen der Chemie und Pharmacie. 1995. However.000. Euro Chlor.5% of the total PVC use. 7. 1933. A. are now being challenged for medical applications by various alternative materials. 5. References 1. 1995. 4.000 t in Europe. Butterworths.

Colwell and K.M. 1982. 11. 94. 1952. Ellenberger. 12 . 46. Walter and W. C. 9. 687. 225. Walter in Proceedings of the Conference on the Preservation of the Formed Elements and of the Proteins of the Blood. W. NY.K. The B. Boston. USA. 183.S.F. Goodrich Company. inventor.Medical Plasticised PVC 8. John Wiley & Sons Inc.L. M. Gynecology and Obstetrics. J. C. Sears and J. L. US 2188396. 10. USA. 12. Journal of Laboratory and Clinical Medicine. Semon. Strumia. 1955. MA. Murphy. Surgery.W. assignee.P. The Technology of Plasticisers. 1949.M.R. New York. 1933. Darby..

such as a peroxydicarbonate.1. and a protective colloid or suspension agent.2 PVC-P formulation 2. The temperature can be controlled 13 . such as hydrolysed poly(vinyl acetate). UÊ Emulsion polymerisation. gelatin or dextran. followed by a pyrolysis processing (Equation 2. capable of withstanding the pressure generated by liquid VCM at the polymerisation temperature [1]. nCH2=CH (VCM) Cl (CH2 . usually a water-soluble polymer.CH)n (PVC) Cl Equation 2. is agitated in a jacketed pressure vessel.1 PVC raw material Poly(vinyl chloride) (PVC) is a thermoplastic formed from the addition polymerisation of vinyl chloride monomer (VCM). a free radical initiator. VCM. 2. and UÊ Mass or bulk polymerisation.1).1 Suspension polymerisation A mixture of water.1 Polymerisation of VCM to PVC There are three major ways to manufacture PVC raw material: UÊ Suspension polymerisation. which is produced from the reaction of ethylene with chlorine.

In normal emulsion polymerisation. such as calendered film and thin profile extrusion. 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. Emulsion polymerisation is used to produce general-purpose polymers for special applications. 2. instead of using a centrifuge and hot air drying system. The water is removed by evaporation in a spray dryer.1. Prepolymerisation produces PVC seeds with an 14 .3 Mass or bulk polymerisation In mass polymerisation. it is necessary to reduce the monomer content still further. where particularly easy processing is required. and the agitation rate. most of the residual VCM (10-20% of the original charge) is recovered by gasification and liquefaction. with the steam acting as a carrier for VCM residue. the type and amount of emulsifier present.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. but because of its carcinogenic nature [2]. which is later separated from the water in a suitable condenser [3]. The process is divided into prepolymerisation and postpolymerisation. which can be used in the fabrication of gloves and fabric coatings. In this way. such as ammonium or potassium persulfate. 2. is employed and the desired latex particle size is obtained by controlling the rate of initiation.e. It is also used for the production of PVC paste. i. VCM is polymerised to PVC in the absence of water. a water-soluble initiator.. After 70-90% conversion of VCM to PVC in a given time. PVC suspended in plasticiser.1.Medical Plasticised PVC by hot or cold water in the jacket. the VCM residue level can be reduced to < 1 ppm.

000 (average MW). The more this component is added. has very good processability. such as vinyl acetate and vinylidene chloride. Interaction between PVC and the stabiliser system may be affected by the impurities left during the manufacture. PVC resin is produced by copolymerisation with other vinyl monomers.PVC-P formulation adjustable particle size. in the case of colour. using high-speed agitation. the greater the difficulty in processing and the higher the physical properties. The copolymer component actually acts as an internal plasticiser. made up of a large number of very small particles. the higher the MW. particularly in plasticisation. The advantages of mass polymers are their high purity and enhanced clarity and they are intended particularly for the bottle market [4].000-75. The MW of most commercial PVC resins lies within the range 30. 15 . The features. With respect to the surface morphology. In some cases. In general. are the following: UÊ œiVՏ>ÀÊÜiˆ}…Ì] UÊ *>À̈ViÊÈâiÊ>˜`ʓœÀ«…œœ}Þ] UÊ “«ÕÀˆÌˆiÃ]Ê>˜` UÊ *œÞ“iÀˆVÊVœ“«œÃˆÌˆœ˜Ê­…œ“œ«œÞ“iÀʜÀÊVœ«œÞ“iÀ®° The molecular weight (MW) of the PVC raw material affects both the processability and the physical properties of the compound. which distinguish PVC raw materials one from another and account for the differences in the processability and physical properties of their compounds. the lower the processing temperatures. For example. The final PVC particle type is substantially determined by the nature of the seed. emulsion PVC usually gives compounds which are initially more yellow than those from the granular PVC. while the porous emulsion PVC latex. the granular PVC resin with a lower surface area presents slow processing characteristics.

the plasticiser content can be up to 50% (Figure 2.2. In semi rigid and semi flexible PVC. strength and flexibility. resistance to fire. as shown in Figure 2. the plasticiser content is between 10% and 30%. such as colour.1). heat stabiliser and fillers.Medical Plasticised PVC 2.2. Those majoring in importance and/or proportion incorporated are plasticiser.1 Flexibility of PVC – relation to the plasticisers 16 . The incorporation of plasticisers enables PVC to have versatile applications in the medical field. In rigid PVC. 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. Figure 2. will reduce its brittleness. the plasticiser content is very low and some other polymer modifier. while for the highly flexible PVC. such as polyisoprene.2 Additives A great variety of additives are used in the PVC formulation to give PVC useful properties.

The former is highly compatible with the resin. as by copolymerisation with vinyl acetate.3. about 150 phr should be freely compatible in this division [4].2 Versatile medical applications of PVC with different flexibility PVC can be modified chemically. As a guide. This plasticisation process is through the polymer itself and the copolymer component is termed an internal plasticiser. 17 . plasticisers can be categorised as shown in Figure 2.PVC-P formulation Figure 2. Plasticisers may be divided into two main groups: primary plasticisers and secondary plasticisers. The secondary plasticisers are less compatible and are usually employed together with primary plasticisers to confer some special properties. The primary plasticisers can be readily used alone. Based on the chemical nature or molecular structure. to make the product more flexible or to demonstrate better low-temperature properties.

Medical Plasticised PVC Figure 2. 18 . have dominated the plasticiser market since the 1930s. particularly dialkyl phthalates. Presently.1 Dialkyl phthalates Phthalate esters. Some 92% of the total is used to plasticise PVC and about 95% of these PVC plasticisers are phthalate esters [5]. about one million tonnes of plasticisers are used annually in Western Europe.3 Categories of plasticiser 2.2.1.

DINP – di-isononyl phthalate.PVC-P formulation The phthalate plasticisers are esters of ortho-phthalic acid and they are manufactured from phthalic anhydride via a straightforward esterification process with selected alcohols. compatibility with PVC. low-temperature properties and low volatility.. Its all around performance. Figure 2. are so good that it alone has accounted for a fourth of the total plasticiser production [6]. DEHP has been the accepted industrial standard for a general purpose plasticiser for PVC and is the most commonly utilised plasticiser.4 Chemical structure of di-2-ethylhexyl phthalate (DEHP) (or dioctyl phthalate . namely: DEHP (DIOP) – di-2-ethylhexyl phthalate (or dioctyl phthalate). For many years. e.4). and DIDP – di-isodecyl phthalate.g. DEHP is almost unique among the phthalates for PVC because of its simple chemical structure (Figure 2. The great majority of phthalate consumption is of the ‘big three’ general purpose PVC plasticisers. plasticising efficiency.DIOP) 19 .

. 2. have accounted for another fourth of the market. tri-(2-ethylhexyl)trimellitate (TEHTM) and the mixed esters of almost completely linear heptyl and nonyl alcohols. diundecyl phthalate (DUP) represents the upper useful limit of chain length for linear phthalate plasticisers.Medical Plasticised PVC Various di-isoalkyl phthalates. containing between 50% and 70% of straight chain isomers.5. The TEHTM molecular structure is shown in Figure 2. 2.com/RA). were developed to provide very low volatility and maintain a good all-round balance of performance. They helped satisfy the growing need for lower volatility but with some sacrifice in plasticising efficiency.3 Adipates The same range of monohydric alcohols used as phthalate feed stocks is available for adipates. 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.didp-facts. TEHTM is especially used in situations where migration levels lower than those possible with DEHP are required. DUP has been found capable of increasing the gas permeability of platelet storage bags [7]. The linear dialkyl phthalates account for about another fourth of the total market.com/RA and http://www.2. The flexible linear molecular structure of adipates gives them the common characteristics of low viscosity and good low-temperature plasticising performance.1.2 Trimellitates Trimellitates.g.1. 20 . similar to the phthalates. e. They are manufactured from alcohol with C11 content close to 100%. For example. such as DIDP and DINP.dinp-facts.2.

dating from the early part of the twentieth century. Butyryl trihexylcitrate (BTHC) and acetyl tri-2-ethylhexyl citrate (ATEC). a raw material manufactured from sugars by enzymatic reactions. They are now mainly used as speciality plasticisers to confer fire resistance on PVC. 21 .5 Chemical structure of tri-(2-ethylhexyl)trimellitate (TEHTM) 2. 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.5 Citrates Citrates are esters of citric acid. 2.1.2.PVC-P formulation Figure 2.2.4 Phosphates Phosphate plasticisers are esters of phosphoric acid.1. the most important citrates are acetyl tributyl citrate (ATBC). when tricresyl phosphate was one of the first products to be substituted for camphor in nitrocellulose. They have a long history of use as plasticisers. Commercially.

Medical Plasticised PVC
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.

22

PVC-P formulation

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

23

Medical Plasticised PVC
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

24

a component of castor oil. At higher levels. In the future. the markets for vegetable oilderived plasticisers are mature and are likely to experience growth only with the growth of the PVC market. they may not mix properly into the plastic formulation or may cause PVC formulations to become brittle.PVC-P formulation Figure 2. Most biochemical plasticisers are suitable for use only as secondary plasticisers. and sebacic acid. At current levels of technology.8 Two examples of polymerisable plasticisers acids are the main component of vegetable oils. is the most commonly used fatty acid for plasticisers formulated for PVC. the vegetable oil-derived plasticisers may acquire improved properties and replace DEHP as primary plasticisers. This may provide a solution to those 25 .

surfactants and other surface property modifiers. fillers. metal complexes. only stabilisers and some additives affecting the surface properties of PVC-P are reviewed. zinc. bactericides and pesticides. which is nontoxic. fungicides. flame retardant and smoke suppressers. This stabilising system is widely accepted in PVC-P formulation for medical applications. colourants. Stabilisers are added to protect PVC against thermal decomposition during processing. silicones. 26 . antioxidants. which has a strong influence on the surface properties of PVC-P. barium/cadmium/zinc and calcium/ magnesium/zinc. rather than on a chemical basis [11]. specifically designed for food packaging or medical application. such as the soaps of lead. In the PVC-P formulation. metal soaps.2. 2. natural and modified natural waxes. The common lubricants for PVC-P formulation are stearic acid. commonly applied additives other than plasticisers include: heat stabilisers. A good combination. fatty acid amides. Here. The commonly applied PVC stabilisers include: inorganic metal salts. optical brighteners. lubricants. as well as ‘lubricating type stabilisers’ [12]. Practical stabilisation of PVC has been investigated since the 1930s. such as barium/cadmium. epoxy compounds and organotin compounds.2 Other additives Additives used in plastics formulation are normally classified according to their specific function. barium. particularly in the areas of food packaging and medical applications.Medical Plasticised PVC public concerns about the environment and potential health risks of chemical plasticisers. calcium and magnesium. is the use of calcium stearate. low molecular weight polyethylene. waxes such as paraffin and microcrystalline waxes. such as basic lead carbonate (white lead) and tribasic lead sulfate (TBLS). Lubricants are added to the PVC formulation to avoid excessive sticking on the processing mill. zinc stearate and their mixture with ESBO. cadmium.

the material will show poor low-temperature performance. but better extraction resistance. polarity and linearity of the plasticiser are the three key molecular properties to determine the final properties of plasticised PVC (PVC-P) [8]. For applications involving particular toxic risks in food contact. which indicate that there is a reduction in plasticising efficiencies by TEHTM and PA in comparison with DEHP.2 gives typical physical properties of Shore A74 PVC compounds.1 Selection of plasticiser The ease of PVC processing. Molecular mass.3. 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. 27 .4. If the chemical structure is predominantly cyclic or branched.3 and 2. A higher level of these DEHP alternative plasticisers is needed in order to achieve the same hardness and flexibility characteristics. 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.3 PVC-P formulation 2. Table 2. while PA exhibits excellent extraction resistance to some extractants [13]. difficult processing and low efficiency.PVC-P formulation 2. medical products or children’s toys. listed in Tables 2. the selection is based on a small group of approved plasticisers.

08 Viscosity (Pa-s at 20 °C) 3 390 MW DEHP –10 365 19. 2000 approx.075 5 approx.7 Plasticiser (%) Elongation at break (%) 1.5 Colourless to very pale yellow 1.487 Refractive index –20 400 18.2 1.0 Relative cost 19.8 3.3 547 TEHTM Density (kg/m ) 2 0.3 1.467 1. PA Table 2.23 Density (kg/m3) 355 31.986 0.983 0.28 –20 Cold flex (°C ) 1.9 1.8 3.2 Data on plasticisers and typical physical properties of their plasticised PVC compound (Shore A 74) Medical Plasticised PVC .485 0.0 Colourless Colourless to very pale yellow Liquid appearance Tensile strength (MN/m ) 1.26 33.22 35.

g.1 and 1. USA DEHA 40 Any UK. Baxter licence blood bags PA Some medical applications with plasticiser non-migration requirement ESBO Medical applications as a secondary plasticiser Historically. USA DBS 40 Any UK.2. Europe ATBC 38 Any USA.2 TEHTM Some use in medical applications with better resistance to migration BTHC Medical applications. used in conjunction with a 29 . Europe DACM New developed Any USA Table 2. USA ESBO 11 Any USA. 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.PVC-P formulation Table 2.1. 1.1.4 List of plasticisers acceptable in medical applications Plasticisers Comments DEHP Only plasticiser listed in European Pharmacopoeia IV. USA DEHS 30 Any UK.2. USA BBP 33 Any UK. the main plasticiser for PVC food packaging film has been di-2-ethylhexyl adipate (DEHA).3 List of plasticisers acceptable in food-contact applications Plasticiser Max. e..

Greensboro. USA. while DEHP is the widely accepted and the most commonly used in medical-grade PVC formulations. PVC-P compounding can be achieved using dry blending via compounding machines. characteristic Freezing point –55 °C Specific gravity 0. TEHTM and PA have been used as alternatives to DEHP in haemodialysis tubing and blood storage containers [13]. internal mixers. USA 2.5 Data on BTHC Product name Citroflex B-6 Chemical name n-Butyryl trihexylcitrate (BTHC) Molecular weight 514 Molecular formula C28H50O8 Appearance Clear. Table 2. which is based on the BTHC manufacturer’s data sheet from Morflex. 30 .. oily liquid Odour Mild. which involves a mixing procedure with a melting process.5. NC 27403.2 PVC-P compounding The process of preparation of a PVC-P compound is defined as compounding. a form of citrate plasticiser.3. N-Butyryl trihexylcitrate (BTHC). Greensboro. was first introduced by Hull and Mathur to medical-grade PVC formulations [14]. The data on BTHC are shown in Table 2. NC 27403. such as two-roll mills. Inc.Medical Plasticised PVC proportion of epoxy soyabean oil [8]. Because of the concern over migration problems of DEHP. Inc..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.

they are now rarely employed for production purposes [1]. 31 . The structures and physical properties of films are strongly dependent on the nature of the solvent employed. unless an additional homogenisation process is introduced. based on the modification of extruders with screws designed to ensure that adequate homogenisation is achieved. and for the preparation of specimens. can be carried out continuously. 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. Owing to the rather low output rates and high labour usage of compounding. The solution can also be cast as a film. In an extruder with two or more screws. According to the PVC processing. the PVC compound can be further processed into a final product. such as a flexible sheet. with a suitable adaptation and modification. Usually.PVC-P formulation single-screw and twin-screw compounding machines. PVC composition can be dissolved in a suitable organic solvent to achieve a homogeneous solution as a coating material. Batch hot melting and mixing of PVC composition can be achieved in an internal mixer. the single-screw extruder is inadequate to homogenise any PVC dry blend in a single pass. Continuous compounding of PVC composition has been developed. there exists the possibility of increasing homogenisation of PVC composition. film or tubing by injection moulding. which contains a well-designed mixing chamber with a heating system. but also a more uniform repetition from batch to batch. The whole operation of mixing and compounding. Two-roll mills are extensively used in laboratories to examine the compounding behaviour of different components of PVC formulations. and also of extrusion to the finished product. extrusion or calendering [1]. evaporation rate of solvent and residue of solvent. plasticiser and other ingredients. but are mainly dependent on the compatibility between PVC.

http://www. US 5464903. 9.111. G. 1995.L.V. Manufacture and Processing of PVC. UK. 4. 3rd Edition. Burgess.W. Principles and Practices. Morishima. 5. Developments in PVC Production and Processing. 3. 10. DuPont de Nemours and Company. ECPI. Technical Data Sheet GF-01806176. The Role of Additives in Plastics. Plasticisers. p. Properties and Uses. 1982. Hoffman and D. Whelan and J. 1977. inventors. 1995. London. R. J. Seats and N. UK. 8. T. 1971. 2. Wilson.H. Midland. Edward Arnold.H.S. John Wiley & Sons. Shimizu. A. Applied Science Publishers. 4. G. PVC. Transfusion. Penn. Craft. 1989. The Institute of Materials. London. 1975. 11. 292. Dow Chemical Co.plasticisers. 1982.org. USA. Applied Science Publishers.Medical Plasticised PVC References 1. New York. Mascia. UK.S. Effects of CPE on Properties of Plasticised PVC. UK. Production. assignee. UK. London. http://www.K. London. 7. UK. E. Wilmington. Applied Science Publishers.J. 3rd Edition. Information on phthalate esters used in plasticised PVC. The Institute of Materials. L. 32 . 1974. Titow and B. Lanham. PVC Technology. Koukelsu and Y. USA. MI. London.org 6. 29.E. A. Matthews. 1996. Touchette in Kirk-Othmer Encyclopedia of Chemical Technology.ecpi. W. NY. I. W. K. London.

Darby. 315.K. C.L. NY. 33 . 14. USA. NY. The Technology of Plasticisers.. Mathur. Gebelein and R. Modern Plastics. C. New York. 61. E. 66. USA. Dunn.G. J.H. Blass in Progress in Biomedical Polymer.R.K. Plenum Press. Sears and J. New York. 13.. 1990. Eds. Hull and K.R.PVC-P formulation 12. John Wiley & Sons Inc. 1984. 1982.

Medical Plasticised PVC 34 .

Table 3.0 Compressive strength (MPa) D695 6-12 55-90 Flexural yield strength (MPa) D790 — 69-110 13 Tensile modulus 10 The tensile strength and modulus decrease and elongation at break increases with increase in plasticiser content.1 Mechanical properties Generally. in terms of cold flex temperature. with a much lower tensile strength and much higher elongation at break (%).3 Properties of PVC-P 3.0 (MPa) D638 — 2. have 35 .1 shows the range of mechanical properties of PVC-P compared with those of PVC-U [1]. are also affected by the selection of plasticiser and the concentration incorporated.4-4. linear plasticisers. Normally.2 Low-temperature properties Low-temperature properties. plasticised poly(vinyl chloride) (PVC-P) differs from unplasticised PVC (PVC-U) most markedly in flexibility or rigidity. which also depends on the particular plasticiser [2]. 3. such as adipates.0-40. D651 10-24 34-62 Elongation at break (%) D638 200-450 2.1 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. Table 3.

which enables it to soften. such as detergent or dimethylformamide (DMF). related to wear and abrasion resistance. 3. For this reason. With Gc for pure PVC at about 0. flexibilise and toughen PVC.Medical Plasticised PVC good low-temperature properties. 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].5 Permanence properties Volatility is the first permanence property that needs to be considered for the application of PVC-P. the Gc of various plasticised PVC increased about 0. tack and blocking actions increase with increasing plasticiser content. Surface friction is another important property.01 N/m or more. As the concentration of plasticiser increases. The mobility of a plasticiser.4 Surface properties Plasticisation normally lowers the critical surface tension (Gc) of PVC. in terms of volume resistivity (VR). lubricant or stabiliser was removed and rigid PVC remained [3].039 N/m. type and temperature. suggesting that the plasticiser. the amount of deformation for a given load increases and the coefficient of friction also increases [5]. are strongly influenced by plasticiser content. which in turn are influenced by plasticisers and other additives [4].3 Electrical properties Insulating properties.038-0. However. while the high molecular weight polyesters show poor flexibility at low temperatures. 3. the Gc for PVCDBP (10-20 phr) falls to 0. when the surface was etched by solvents. also permits it to 36 . It is influenced by the deformation properties of PVC-P.024 N/m. 3.

but the true extraction process is much more complex because of the nature of the extractant [6]. the resistance to migration increases according to the order: polyethylene > rubber polyisoprene > cellulose nitrate. 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. 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]. such as solvents. lipid. coefficients of diffusion are independent of concentration of the liquid in the polymer. blood and detergent. but the polyester (polymeric plasticiser) can be ‘solubilised’ faster than it can diffuse to the surface from inside the PVC sheet. When a diffusing liquid has no solvent action on a polymer supermolecular structure. if the liquid does show some solvent or swelling action on the polymer.Properties of PVC-P leave the PVC and go into other media. In general. which depends on the compatibility between the plasticisers and these materials. the extraction of DEHP is surface controlled. Alcohol and alcohol-water blends can extract plasticiser from PVC. linear molecules migrate faster than bulky. The problems concerning migration and extraction of plasticiser into 37 . while extraction of the polyester is diffusion controlled [6]. small molecules migrate faster than large ones. Plasticisers may be extracted from PVC-P by liquid media. The extraction may theoretically be controlled by the rate of loss from the surface or by the rate of diffusion inside the PVC. Therefore. the diffusion coefficient may vary widely with solvent concentration [7]. It is found that DEHP can diffuse to the surface faster than it can be ‘solubilised’ into blood. which are in contact. However. For the contacted materials. branched ones and highly solvating ones that produce an open gel structure migrate faster than those that are ‘frozen in’ to isolated pockets [6].

Sears and J. 7. Kazumi and T. Applied Science Publishers. The Technology of Plasticisers. A. Penn. 6. 3rd Edition. 1969. 1995. 16. 2727. PVC Technology. M. Y.4. Darby. Wilson. John Wiley & Sons Inc.S. W. References 1. Lanham. Decoste. 1972. UK.C. 5. 3. USA. 1982. 8. Principles and Practices. 1327.S. Kosaku. Journal of Polymer Science: Polymer Chemistry Edition. London. D. 5. NY. Nakamura. Journal of Applied Polymer Science.R. 1465. Journal of Applied Polymer Science. 1. 10. New York. Slattery. Owens. UK. London. 4.K. 67.K.J. J. 1971.L. Plasticisers. The Institute of Materials. 38 . S. 1967. 1964. W. Laurence and J.Medical Plasticised PVC blood or the human body during medical applications and approaches for overcoming these problems are discussed in Chapter 5. Kunio. 2. SPE Journal. R. Titow and B.V. J.B. 25.

connectors.4 PVC-P as a biomaterial 4. 39 . a biomaterial is defined as ‘a material used for or suitable for use in prostheses that come in direct contact with living tissues’. a biomaterial can be defined as a nonviable material used in a medical device intended to interact with a biological system [4]. its estimated market share was around 25% of all the polymeric materials used in medical devices [1]. In more detail. disposable. By 1995. with worldwide percentages believed to be even higher [2]. PVC-P became by far the most commonly used polymer in the medical plastics industry. In 2004. soft plasticised PVC (PVC-P) is the most widely applied biomaterial for medical applications. trays. As the increasing need for flexible. about 40.3% [3]. According to Webster’s New Collegiate Dictionary. Briefly. such as containers. blister packaging and drip chambers. sterilised sugars and electrolytes for intravenous infusion and peritoneal dialysis during World War II.1 Introduction Semi-rigid poly(vinyl chloride) (PVC) or PVC-rubber blended materials have been used to make medical disposables. 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]. 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. it was estimated that PVC represented 37% of all medical plastics used in the USA.000 t of plasticised PVC was used in the medical field in Europe and there is an annual growth rate of 4. a biomaterial is a substance. Flexible. biocompatible plastics for medical devices evolved over 50 years. In 1990.

ranging from rigid components to flexible sheeting.Medical Plasticised PVC Synthetic polymers form the most diverse class of biomaterials. UÊ /…iÊ«œÞ“iÀÊŜՏ`Ê«œÃÃiÃÃÊ̅iÊÀiµÕˆÀi`ÊV…i“ˆV>]Ê«…ÞÈV>Ê>˜`Ê mechanical properties for performing its function. 4. and thereby establishes its versatility. The typical requirements for tubing as the intravenous (IV) set. scratch resistance. toughness. UÊ /…iÊ«œÞ“iÀÊŜՏ`ÊLiÊLˆœVœ“«>̈Li° The following sections discuss how PVC-P meets these basic requirements as a biomaterial and where its drawbacks are. which in turn defines its flexibility and lowtemperature properties. sheet and tubing are used in numerous medical products. The type and amount of plasticiser used determine the compound’s glass transition temperature (Tg). a synthetic polymer needs to meet the following criteria [6]: UÊ /…iÊ«œÞ“iÀÊŜՏ`ÊLiʜ˜iÊ̅>ÌÊV>˜ÊLiÊÀi«Àœ`ÕVˆLÞʜLÌ>ˆ˜i`Ê>ÃÊ a pure material. As a biomaterial for medical products. ethylene oxide (EO) or electron-beam sterilisation. PVC-P 40 . PVC can be used to produce a variety of medical products. flexibility. As a biomaterial. for example. include clarity. 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.2 Advantages of PVC-P PVC-P-based film. ease of bonding with common solvents or adhesives and suitability for gamma. kink resistance. UÊ /…iÊ«œÞ“iÀÊŜՏ`ÊLiʜ˜iÊ̅>ÌÊV>˜ÊLiÊv>LÀˆV>Ìi`ʈ˜ÌœÊ̅iÊ`iÈÀi`Ê form without being degraded or adversely changed. PVC-P has achieved its prominent role in the medical plastics industry by virtue of a unique combination of desirable properties. As an ideal biomaterial.

In summary.3 Disadvantages According to the criteria that an ideal biomaterial should meet. The most commonly cited shortcomings involve toxic effluents such as vinyl chloride monomer (VCM) produced during manufacture 41 . Medical products made from PVC have passed many critical toxicological. PVC-P can have a Tg as low as –40 °C and still be suitable for steam sterilisation at 121 °C. Additional characteristics that make PVC attractive include its low cost. very low toxicity and chemical stability. as previously considered. stabilisers. or safely disposed of in landfill.1). wide range of gas permeability. while at the same time they are continuously receiving criticism [7]. For PVC-P. a polymer should be sufficiently pure without any influence of biocompatibility due to any unintentional additives. however. PVC-P is one of the best medical materials in terms of cost and function. ethylene oxide or gamma radiation.ecvm. low molecular weight polymers and other reaction residues. lubricants and fillers. UÊ i`ˆV>‡}À>`iÊ*6 Ê«Àœ`ÕVÌÃÊ>ÀiÊ`ÕÀ>Li] UÊ i`ˆV>‡}À>`iÊ*6 ÊV>˜ÊLiÊÃ>viÞʈ˜Vˆ˜iÀ>Ìi`]Ê>œÜˆ˜}Êi˜iÀ}ÞÊ recovery. such as monomer residues. 4.PVC-P as a biomaterial can be sterilised by most commonly employed sterilisation methods. No other single material has such broad advantages (Figure 4. PVC-P has excellent biocompatibility. it is the additives that make PVC versatile and useful. In terms of life management of medical PVC. such as plasticisers. such as steam. fire resistance and good insulation properties. high transparency. the environmental advantages of PVC use in medical devices are (www. thermoplastic elastomer-like material properties. and intentional additives. biological and physiological tests according to national or international standards.org): UÊ œ“«>À>̈ÛiÞʏœÜÊi˜iÀ}ÞÊ>˜`ÊÀiÜÕÀViÊÕÃiʈ˜Ê«Àœ`ÕV̈œ˜Ê>˜`Ê conversion.

isosorbide dinitrate.1 Advantages of PVC-P in medical applications and the generation of hydrogen chloride (HCl) during incineration. With regard to the leaching of the plasticiser di-2-ethylhexyl 42 . during a 24 h study period [13]. 10].Medical Plasticised PVC Figure 4. the human body during long-term dialysis [9. stored human blood [11] and foodstuffs [12]. respectively. PVC-P pharmaceutical packaging bags have been found to cause drug loss during storage periods. drugs such as diazepam. Other concerns related to PVC-P depend largely on the type and amount of plasticisers used. nitroglycerin and warfarin sodium can be adsorbed by PVC-P with 55%. 51% and 24% loss. For example. Kowaluk and co-workers [14] have studied the interaction between 46 injectable drugs and PVC-P infusion bags. Plasticisers have been found to leach into medical solutions [8]. They found that the drug loss is due to a diffusion-controlled sorption process. 23%.

CellTran developed a ‘living bandage’ using plasticised PVC as a base to carry cells for treatment of chronic wounds. The blood products collected and packaged using PVC-P include whole blood. PVC. Generally.PVC-P as a biomaterial phthalate (DEHP).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.butyryl trin-hexyl citrate (BTHC) has been shown to be capable of maintaining them under optimum conditions [16]. the most commonly applied plasticiser for medical applications. there are many divided opinions.2. however. while its beneficial effect on red blood cell survival is a valued property. 4. as shown in Figure 4. 43 . but both are relatively expensive. the major applications are in the first area as external communicating devices. while for red blood cells and platelets. such as haemodialysis equipment and lung-heart bypass sets. blood-contacting devices are categorised in the ISO10993-4 standard into ‘external communicating devices’ and ‘implant devices’ [15]. It appears that no proof has been found that DEHP is toxic or is a carcinogenic initiator. PVC-DEHP is currently the most widely used packaging material for the storage of whole blood. presterilised and disposable blood-contacting devices. Medical tubing made of polyurethane and silicone have been utilised. For PVC-P. Blood tubing made of PVC-P is widely used in blood extracorporeal circulating devices. red blood cells and platelet concentrates.

2 Applications of PVC-P as a blood-contacting biomaterial 44 .Medical Plasticised PVC Figure 4.

1 Applications of PVC-P as a non-blood-contacting biomaterial Pharmaceutical solution packaging or delivery sets Intravenous solution pack. floor-coverings Electrical systems Appliances and furnishings Oxygen tents Tissue-contacting biomaterials Burn dressings [17] Artificial skin [18] Other surgical dressings [19. Table 4.PVC-P as a biomaterial 4. 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. 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] 45 .5 Other applications of PVC-P as a biomaterial The applications of PVC-P as a biomaterial other than for bloodcontacting use are summarised in Table 4.1.

Food Additives and Contaminants. C. Elsevier Applied Sciences. T. Tatsukawa and T. 7. 13. Dialysis.H. New York. 2001.Medical Plasticised PVC References 1.J. 9. Jaeger and R. 16.A. Waaler and P. 286. R. p. K. Fukumitsu.R. 4.J. Biologically Modified Polymeric Surfaces.8. D. 46 . 287. Smistad. July. 1990. 1114. 1972. 1982. Ed. Ikeda.J.R. 1. D. Davison. A. Nephron. 45. Gurland. 1989. Journal of Vinyl Technology. 6. 4. E. 8. 369. L. G. Goodman. Kronenthal. 1994. Nässberger. Piskin. Shawbury. (Supplement 2). 12. 1. Wakimoto in Proceedings of the European Dialysis and Transplant Association. 2. 2. Rapra Technology Limited. Medical Plastics & Biomaterials. Barcelona. 1975. 5. Ostelius. A.S. Rubin. V. 12. Arbin and J. H. 2. C. Roksvaag. R. 10. UK. Bonomini and D. 5. 12.V. 156. 1998. The Role of Poly(Vinyl Chloride) in Healthcare. 1987. 22. E. R. p. 245. Peterson. New England Journal of Medicine. 4. Nielsen. Acta Pharmaceutica Nordica. 1994. 1992. Falkenhagen. Plenum Press.M. T. The Netherlands.J. USA. Blass. Naamansen and P. van Loenen. Ono. 9.L. 3. Lyman in Polymer Science and Technology. 11. 3. Transplantation. 32. Medical Device Technology. R.J. Nephrology.C. T. J. Brookman.1. 47. 3. American Journal of Hospital Pharmacy. H. NY.O. Martens. 571. P.T. 1995. 1992. 287. Amsterdam. Blass. De Goede and A.

R. Wypych. 195.S . Vox Sanguinis. Liu. Steblyak and S. H. inventors. 2. Burn Prom-St. Meyerhoff. Hunt. Roberts.W.C.S. 1306.S.S. A. D. Burns Including Thermal Injury. WO/2001/085248.G. 1995.D.A. Braybrook. 18. 23. S. 1978. 24.R. 1997.H. Brown. 2. Technomic Publishing Company. 21. Goldberg and R. Analytical Chemistry. assignee. P. Centralne Laboratorium Technicznych Wyrobow WloklenniCzych. John Wiley & Sons.J.V. Blackburn and A. 1983. M. p.E. Biomedical Instrumentation and Technology. 9. V. p. PA. Shirankov. Loginov. USA.W. Hawker. S.P. V. American Journal of Hospital Pharmacy. 212. Kang and R.B. A. 69. Meyerkoff and V..129. 224.597. Polish 98867. Kim. S. 19. 16. 18. E. Pokorski. 22. M..H. Bajda. W. Reid. 2001. Mitchell. Yang. Atanasov and E. Kowaluk. Schroeder and K.H. 47 . in Biocompatible Polymers. KCI Licensing. Cha.PVC-P as a biomaterial 14. J. M. H. 29. 125. G. 17. H. Inc. Turner. Z. 1991. J.E. M. Heaton. Midyley. Biocompatibility Assessment of Medical Devices and Materials.K. Sekachev. 17. 1982.. Skipor and J.J. New York. Lancaster.C. inventors. Cantor. Metals and Composites. 1995. Yun. Musinskaya. 1981.Vaselov. 14. G. 38. Wilkins.F. 15. Hudson and C.D.A.C. Analytical Biochemistry. USA. 1995.D. 63. P. 1666. NY.I. V. 1988. Ed.G. 20. M. J. McRea and S. Szycher. Milner.E. 2. K. M. Polack. 62. 1.

G. Properties and Uses. London.Medical Plasticised PVC 25. The Institute of Materials. 1996. PVC. UK. Production. Matthews. 48 .

When a blood-biomaterial interface is established. or on any organ or tissue. Consequently. 5. the objective of an improved understanding of the relationship between the biomaterial and the alteration to blood components can be achieved. a rapid sequence of processes occurs. resulting in effects on the biomaterial (device). It is now generally accepted that the processes can be divided arbitrarily into the following groups of events (which partly occur simultaneously) [6. as one of the most conventional blood-contacting biomaterials. The highly complex ‘blood-biomaterials’ interaction is of a multivariable character [6]. or on the blood. factors influencing the blood response and evaluation procedures [2]. 5]. In the case of plasticised poly(vinyl chloride) (PVC-P). 7]: 49 . Such effects may or may not have clinically significant or undesirable consequences [4. which would promote a better utilisation of this existing biomaterial and the development of improved materials [3].5 Blood compatibility of PVC-P 5.1 Introduction There has been a long-standing interest in the relationship between blood and biomaterials for blood-contacting applications [1].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. it is convenient to review its blood compatibility in terms of blood-biomaterial interactions.

platelet reactions are interrelated with the coagulation system to promote thrombin formation. UÊ œÀ“>̈œ˜ÊœvÊwLÀˆ˜Êœ˜ÌœÊ̅iÊÃÕÀv>ViÊ>˜`Ê>ÃœÊ«œÃÈLiÊ>V̈Û>̈œ˜Ê of the fibrinolytic system [8]. A compromise has to be made for blood-contacting biomaterial development [13]. which may play a role in blood clotting via the intrinsic pathway [11]. As expected. For example. blood-biomaterial interactions are very complicated and there are many interrelated reactions and feedback networks [9]. 50 . UÊ `…iȜ˜ÊœvÊViÊVœ“«œ˜i˜ÌÃʭ̅Àœ“LœVÞÌiÃ]Ê}À>˜ÕœVÞÌiÃÊ>˜`Ê monocytes) to the protein coating. fibrinolysis and complement activation. 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.Medical Plasticised PVC UÊ `ÜÀ«Ìˆœ˜ÊœvÊ«>Ó>Ê«ÀœÌiˆ˜Ãʜ˜ÌœÊ̅iÊ«œÞ“iÀÊÃÕÀv>Vi° UÊ V̈Û>̈œ˜Ê œvÊ Ì…iÊ Vœ“«i“i˜ÌÊ ÃÞÃÌi“]Ê Žˆ˜ˆ˜ÉŽ>ˆŽÀiˆ˜Ê ÃÞÃÌi“]Ê blood cells and intrinsic coagulation initiated by the adsorbed proteins from the system. when artificial surfaces are exposed to blood. In summary. important interrelationships are not fully defined in many instances. interrelated blood-response systems occur in order to achieve rapidly a balance between the processes of activation and inhibition of these systems. Marchant and co-workers [12] showed that leucocyte adhesion is complement mediated through the complement proteins C3b and Bb. The leucocyte membrane contains phospholipids. This interrelationship is very important for extracorporeal bloodcontacting applications [6]. Although a great deal is known about the blood response to bloodcontacting biomaterials or devices.

Blood compatibility of PVC-P 5. fibrinolysis. complement activation and other cellular responses. Figure 5. the blood interactions with plasticised PVC (PVC-P) lead to protein adsorption. such as polyurethane.3 Factors influencing blood response to PVC-P In a similar manner to other blood-contacting biomaterials.1 Influencing factors on the blood compatibility of PVC-P 51 .1. The blood compatibility of PVC-P is dependent on various factors as summarised in Figure 5. platelet reactions. coagulation activation.

DEHP can interact with the red cell membrane [15. such as plasticiser surface distribution. electrical properties and cost-effectiveness. permanence. An example is a PVC formulation plasticised with tri-(2-ethylhexyl) trimellitate (TEHTM) [21. plasticiser surface level and surface morphology. mainly for the storage of platelet concentrates.1 PVC formulation The final properties of PVC-P are mainly determined by the plasticiser type and the concentration incorporated. PVC-TEHTM was found to be unsuitable for red cell storage because this plastic had no stabilising effect on red cell membranes [15. after prolonged storage. such as mechanical properties. 22]. the PVC formulation in terms of plasticiser selection and plasticiser concentration is considered to be the most important.3. From the initial introduction of PVC-P into medical applications until the early 1980s. 16] and improve the survival time of erythrocytes and their osmotic fragility and flexibility.3. With respect to the blood compatibility of PVC-P for blood-contacting applications. surface properties. the blood response is strongly affected by the selection of plasticiser. are also dependent on the formulation. In recognising that DEHP is extracted into the stored blood or blood components.Medical Plasticised PVC 5. The correlation between plasticiser selection and end-product properties. both in vitro [17] and in vivo [18]. 5. 17] 52 . The surface characteristics of PVC-P. all PVC blood bag plastics contained the plasticiser di-2-ethylhexyl phthalate (DEHP) [14]. has been discussed previously. low-temperature properties. some new-generation plasticisers have been developed during the past decade. DEHP has been found to cause reduced platelet function as defined by hypotonic shock recovery [19] and aggregation [20].2 Selection of plasticiser When PVC-P is used as a blood and blood-component packaging material.

This is not achieved by increasing the plasticiser concentration but is related to the nature of DnDP [26]. resulting in a decreased PVC resin.Blood compatibility of PVC-P and reduced in vivo survival time [16]. These are di-n-decylphthalate (DnDP) [26] and diundecyl phthalate (DUP) [27]. It was claimed that PVC-DUP could be used not only for platelet storage. and it has been used for making medical-grade plasticised PVC [28]. The selection of DUP for PVC formulation is strongly dependent on the selection of the PVC resin. such as TEHTM. but also for the storage of erythrocytes at low temperature. or for storing plasma in a frozen state [27]. with a lower cost than TEHTM and citrates. while PVC-DEHP with its high level of DEHP is not preferable because of its poor compatibility with platelets [14]. Other than TEHTM. comprising a plasticiser resistant to extraction by blood. Dioctyl terephthalate (DOTP) is regarded as a cost-competitive alternative to DEHP. This seems to imply that the blood response to PVC-TEHTM is more reactive than that to PVC plasticised with DEHP. some phthalates have been reported to improve O2 permeability with physicochemical properties that are quite similar to those of DEHP. DnDP is reported to be the most desirable plasticiser for increasing gas diffusion. An increased gas exchange rate or O2 permeability is beneficial for platelet survival. 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 53 . A highly porous PVC resin must be employed for the formulation with DUP. One USA patent [29] reported using PVC plasticised with a blend of plasticisers. and a blood-extractable plasticiser. Whole blood stored in PVCTEHTM and other non-PVC materials with no DEHP always had greater haemolysis and increased osmotic fragility [14]. This is the case when using TEHTM [24]. The most prominent advantages of PVC-TEHTM are its low extraction and improved gas exchange capacity [23-25]. such as DEHP or di-2-ethylhexyl adipate (DEHA). for storage of red blood cells and platelets. and could be achieved by increasing the plasticiser concentration.

Most importantly. Acetyl tributyl citrate (ATBC) was shown to have a membraneprotective effect similar to that of BTHC. there were no demonstrable toxic effects of BTHC on the livers of rats fed the plasticiser. if any. PVC plasticised with Butyryl trihexylcitrate (BTHC) may be such a choice [31-34]. PVC-BTHC has been found to be suitable for storage of platelets for five days. The influence of PVC formulations with DEHP. In the meantime. deleterious effects by any leaching of plasticiser into the blood or blood components. resulting in good autologous in vivo survival [37]. The important advantage of this invention is that a combination of benefits could be achieved from both DEHP and TEHTM. while causing few. unlike DEHP [38]. 54 . There is no significant difference between the values for cells stored in PVC-ATBC and PVC-DEHP containers [14]. plasticiser selection should be able to support the storage of red cells. Since Hull and Mathur [35] suggested that citrates might be useful as a replacement for DEHP plasticiser in medical-grade PVC formulations. Polymeric adipate (PA) plasticiser has been developed for reduced extraction by blood or other body fluids. stabilising membranes. In addition. which is very similar to PVC-TEHTM [34].Medical Plasticised PVC gas permeability. gaseous exchange should be at least as good as that of PVC-TEHTM for platelet storage. Preferably. PA and TEHTM on the platelet release reaction and complement activation has been studied [30]. BTHC has been shown to have a stabilising effect on red blood cell membranes similar to that of DEHP [36]. citrates such as BTHC and Acetyl tributyl citrate (ATHC) with a low toxicity have received considerable attention. enabling at least five days storage of platelets. Results indicate that plasticiser selection influences the blood response.

and Spilezewski and co-workers [45]. 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 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].Blood compatibility of PVC-P 5. 5. Kicheva and co-workers investigated the effect of DEHP concentration on the biocompatibility of PVC-DEHP [43]. A surface-coated layer of paraffin had the effect of decreasing the protein adsorption. They found that the amount of total protein adsorbed on PVC-DEHP increases with the increased DEHP concentration. Zhao and Courtney [46.3 Plasticiser concentration The blood compatibility of PVC-P is strongly dependent on the plasticiser concentration or level of PVC plastic.3. It has been shown that the removal of DEHP from the PVC-P surface alters the blood compatibility.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].3. 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. Labow and coworkers [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. 55 . The high plasticiser surface level in the PVC can alter the inflammatory response to the material and this affects its relative biocompatibility.

Table 5.4 50 ± 42 7 ± 10.6 PVC-PU-DEHP * PU mainly PVC-PU-TEHTM** TEHTM/PU 10 ± 21.8 23 ± 26. **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 5.3). However.5 Plasticiser surface distribution Plasticiser surface distribution has been found to have a strong influence on blood compatibility.1 Correlation of surface composition with C3a generation [48] Blood lines C3a generation (ng/ml) Surface plasticiser distribution 5 min 15 min 30 min PVC-DEHP DEHP mainly 53 ± 48. Blood compatibility in terms of C3a measurement is strongly dependent on the surface composition [48.9 9 ± 16.2).6 12 ± 13.25-fold to the same level as that of TEHTM at the PVC-TEHTM surface. Table 5. 56 .5 *Coextrusion of PVC-DEHP and PU. if the DEHP plasticiser level is simply increased by 1.Medical Plasticised PVC 5.1 lists three types of haemodialysis blood lines with different surface plasticiser distribution. 49].3.8 8 ± 14. theoretically. the calculated fibrinogen adsorption and C3a values are found to be approximately the same as those obtained by evaluation of PVC-TEHTM (Table 5.1 35 ± 32.

Using attenuated total reflectance (ATR)-FT-IR. a layer of 57 .25) PVCTEHTM 85 5.3 Theoretical evaluation of the effects of plasticiser surface distribution on blood compatibility based on in vitro evaluation In vitro blood test Samples Plasticiser distribution (%) PVC-DEHP 85 (68 x 1. having a similar chemical nature. other than with plasticisers has also been reported.1 1309 85 5.1 x 1.Blood compatibility of PVC-P Table 5.2 Correlation of surface composition with in vitro fibrinogen adsorption and C3a measurement Samples Plasticiser distribution (%) PVC-DEHP PVCTEHTM Blood response (in vitro) Fibrinogen adsorption (ng/cm2) C3a generation (ng/ml) 68 4.25) 5.25) 1636 (1309 x 1. Surface contamination.1 (4.25) compared to PVCTEHTM The assessment implies that TEHTM and DEHP.8 Fibrinogen adsorption (ng/cm2) C3a generation (ng/ml) 1671 Numbers in brackets show how the protein absorption level of PVCDEHP is increased by the same amount (1.8 1671 Table 5. have a similar effect on the blood compatibility.

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. turbulence. The bag was made of PVC-DEHP with the wax as an anti-tack agent. It was found that the blood compatibility of PVC-DEHP coextruded with PU was deteriorating after 6 months implantation.3. or blood tubing for extracorporeal devices. 5. etc. 5. 52]. such as haemodialysers and blood oxygenators. secondary flows. Therefore. or can be incorporated into cardiovascular systems for extended periods. the dynamic flow conditions of blood (shear rates. as in a catheter. 51]. This is discussed in more detail in Chapter 6. Surface modification can be achieved by an increase in hydrophilicity. as in artificial blood vessels and artificial heart components. size of the contact surface area and actual placement site in the cardiovascular system are very important 58 . or for a relatively long time (days to months). duration of contact.3. Modification of the surface will alter its blood response and it is the most common approach to improving the biomaterial influence on blood [6. attachment of antithrombotic agents.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. as in blood or blood-component storage bags.). surface roughness has a strong influence on the blood response to PVC-P. It can be used for a relatively short time (minutes to hours). which is mainly due to an alteration in surface morphology [48]. treatment of surfaces with protein and preparation of biomembranemimetic surfaces [6].Medical Plasticised PVC an amide wax at the inner surface of a PL-146 blood bag was found. It was believed that the surface contamination would have a marked effect on blood compatibility [50. In addition. chemical modification.

59 .3.4 Plasticiser migration and regulation 5. In addition. heparin has been reported to cause reduced thrombin-antithrombin (TAT) levels and increased C3a values [49]. heparin or prostacyclin (PGI2). The presence of an agent. 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]. These observations led to the publication of numerous articles and reviews on this subject [61. which are related to the nature of the application [5. 60]. it is not covalently bound in the PVC matrix and may therefore migrate out of the plastic into the contacting medium.04 mg/ml at 20 °C) [53]. 62] and the related toxicological study of DEHP [63-66]. Reported extraction rates have ranged from 50 to 70 mg/l in blood [55] and 20 mg per pack in platelet concentrates [53.1 DEHP migration and extraction Although the aqueous solubility of DEHP is very low (< 0. influences blood compatibility and on the basis of the in vitro assessment of PVC-P tubing. Since 1970. 8].Blood compatibility of PVC-P parameters. such as citrate. 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. 5.8 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.4. 5. the blood response to a PVC-P biomaterial is influenced by the blood condition of an individual patient [6].

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 1978.25 litre per day (on rats) and 0. flow rate and the contact period [72-77]. lipophilic extractants. which are all available as CEN standards (ENV 1186-1 to ENV 1186-12). In general. such as petroleum or olive oil. temperature. These findings cause great public concern regarding the toxicity of DEHP. To determine the total migration potential various reference methods are used. 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. Several new standards in this area are in preparation [71]. such as the liver and the reproductive system. However. some long-term animal feeding studies later suggested adverse effects on several major organ systems. It was concluded that DEHP was carcinogenic in Fischer 344 rats and B6C3F6 mice and caused a significant increase in liver tumours [80]. 5.000 mg/kg.2 Toxicity of DEHP DEHP has an extremely low acute toxicity. The dose levels were extremely high. the surface area contacting the device.Medical Plasticised PVC The migration of DEHP into the human body from haemodialysis blood tubing was found in the early 1970s [67-70].5 litre per day (on mice). corresponding to a human intake of 0. many later experiments indicated that DEHP is a tumour promoter rather than a tumour initiator and that mono-(2- 60 .4. However. Putting this into perspective. with an LD50 in excess of 30. have greater power to extract plasticisers than alcohol and water and acetonitrile is more effective in extracting DEHP than alcohol/water [78]. It is known that the extraction rate for the plasticiser is dependent on the nature of the extractant.

84]. In addition. a major hydrolysis product of DEHP. The International Agency for Research on Cancer classified DEHP to class C (not classifiable as to carcinogenicity to humans) [82]. This detailed research has drawn the following conclusions: UÊ . is much more toxic than the parent compound and is effective as a tumour promoter at a lower dose [81]. the main work on this subject was coordinated by the European Council for Plasticiser and Intermediates (ECPI). DEHP is not classified as a human carcinogen [83.Blood compatibility of PVC-P ethylhexyl)-phthalate (MEHP). In Europe.

UÊ /…iʓiV…>˜ˆÃ“ÊLÞÊ܅ˆV…ʈÌÊV>ÕÃiÃÊÌՓœÕÀÃÊ>vÌiÀÊÀi«i>Ìi`ʅˆ}…Ê dosing of rodents is believed to be peroxisome proliferation. UÊ /…iÊÀiÃՏÌÃÊ>ÀiÊëiVˆwVÊ̜ÊÀœ`i˜ÌðÊii`ˆ˜}ʜvÊ. *ʈÃʘœÌÊ}i˜œÌœÝˆV]Ê̅>ÌʈÃÊ̜ÊÃ>ÞÊ՘ˆŽiÊ`ˆÀiVÌÊV>ÀVˆ˜œ}i˜Ã]Ê it does not react with genetic material. which is the same case as some safely used hypolipidaemic drugs.

*Ê̜ÊëiVˆiÃÊ metabolically closer to humans does not cause peroxisome proliferation or liver tumours. UÊ /…iÀiʈÃʘœÊÈ}˜ˆwV>˜ÌÊ`ˆvviÀi˜Viʈ˜ÊivviVÌÊLiÌÜii˜Ê.

removal from the body after 21 days could be painful and difficult. Loss of plasticiser caused the PVC device to become more rigid and. the loss of plasticiser will alter the mechanical properties of PVC-P. *Ê>˜`Ê the alternative general purpose phthalate plasticisers. making the plastic ineffective and possibly dangerous to the human body. The above conclusions do not imply any restriction on the research and development of alternatives to DEHP. in order to ease the increasing concern over the leaching of DEHP into the human body. possibly involving surgery [30]. a linear relationship was demonstrated [42] between hardness and the released amount of DEHP per surface area during extraction. which possess a lower migration property. for example. For instance. Meanwhile. 61 . In addition. in the case of nasogastric feeding tubes or wound drainage tubes.

‘a lack of evidence of causation between DEHP-PVC and any disease or adverse effect does not mean that there are no risks’. the EU Scientific Committee on Medicinal Products and Medical Devices (SCMPMD) adopted an opinion on ‘Medical devices containing DEHP plasticised PVC. in which the following devices of are particularly listed: UÊ ˜ÌÀ>Ûi˜œÕÃÊ­6®ÊL>}ÃÊ>˜`ÊÌÕLˆ˜}] UÊ 1“LˆˆV>Ê>ÀÌiÀÞÊV>̅iÌiÀÃ] UÊ œœ`ÊL>}ÃÊ>˜`ʈ˜vÕȜ˜ÊÌÕLˆ˜}] UÊ ˜ÌiÀ>Ê˜ÕÌÀˆÌˆœ˜Êvii`ˆ˜}ÊL>}Ã] UÊ >Ü}>ÃÌÀˆVÊÌÕLiÃ] UÊ *iÀˆÌœ˜i>Ê`ˆ>ÞÈÃÊL>}ÃÊ>˜`ÊÌÕLˆ˜}] UÊ /ÕLˆ˜}ÊÕÃi`ʈ˜ÊV>À`ˆœ«Õ“œ˜>ÀÞÊLÞ«>ÃÃÊ­ * ®Ê«ÀœVi`ÕÀiÃ] UÊ /ÕLˆ˜}ÊÕÃi`ʈ˜ÊiÝÌÀ>VœÀ«œÀi>Ê“i“LÀ>˜iʜÝÞ}i˜>̈œ˜Ê (ECMO). neonates and other groups possibly at risk from DEHP toxicity’ according to which ‘there is no evidence that any of these groups do experience DEHPrelated adverse effects’.Medical Plasticised PVC the loss of plasticiser must affect the surface properties of the plastic. In September 2002. However. UÊ /ÕLˆ˜}ÊÕÃi`Ê`ÕÀˆ˜}ʅ>i“œ`ˆ>ÞÈð 62 . For the relatively long-term application. which will alter the blood compatibility. In July 2002. the searches for alternatives to DEHP and PVC-P or the modification of PVC are continuing. 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’.

silicone. UÊ >i“œ`ˆ>ÞÈÃʈ˜Ê«iÀˆ«ÕLiÀÌ>Ê“>iÃ] UÊ >i“œ`ˆ>ÞÈÃʈ˜Ê«Ài}˜>˜ÌʜÀʏ>VÌ>̈˜}Êܜ“i˜] UÊ ˜ÌiÀ>Ê˜ÕÌÀˆÌˆœ˜Êˆ˜Ê˜iœ˜>ÌiÃÊ>˜`Ê>`ՏÌÃ] UÊ i>ÀÌÊ ÌÀ>˜Ã«>˜Ì>̈œ˜Ê œÀÊ VœÀœ˜>ÀÞÊ >ÀÌiÀÞÊ LÞ«>ÃÃÊ }À>vÌÊ ÃÕÀ}iÀÞÊ (aggregate dose). for example. using the freshest 63 . UÊ >ÃÈÛiʈ˜vÕȜ˜ÊœvÊLœœ`ʈ˜ÌœÊÌÀ>Փ>Ê«>̈i˜Ì] UÊ /À>˜ÃvÕȜ˜Êˆ˜Ê>`ՏÌÃÊ՘`iÀ}œˆ˜}Ê "° 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. you may be able to minimise exposure to DEHP by. or devices made of other materials (such as ethylene vinyl acetate (EVA). If PVC devices containing DEHP must be used.Blood compatibility of PVC-P The following procedures have been identified as posing the highest risk of exposure to DEHP: UÊ ÝV…>˜}iÊÌÀ>˜ÃvÕȜ˜Êˆ˜Ê˜iœ˜>ÌiÃ] UÊ "ʈ˜Ê˜iœ˜>ÌiÃ] UÊ /œÌ>Ê«>Ài˜ÌiÀ>Ê˜ÕÌÀˆÌˆœ˜Ê­/* ®Êˆ˜Ê˜iœ˜>ÌiÃʭ܈̅ʏˆ«ˆ`Ãʈ˜Ê*6 Ê bag). For some of the above procedures. PVC devices that do not contain DEHP can be substituted. polyethylene or polyurethane) can be used. if available. UÊ Տ̈«iÊ «ÀœVi`ÕÀiÃÊ ˆ˜Ê ÈVŽÊ ˜iœ˜>ÌiÃÊ ­…ˆ}…Ê VՓՏ>̈ÛiÊ exposure).

Medical Plasticised PVC possible blood products stored at the lowest possible temperature. the decision to use DEHP alternatives must take into account the medical advantages and drawbacks of the substitute materials and their availability. 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]. pregnant women who are carrying male foetuses and peripubertal males. there is no conclusive scientific evidence that DEHP exposure via medical treatments has harmful effects in humans. There is limited evidence suggesting a relation between DEHP exposures and some effects in humans. it is recognised that especially the potentially high exposure during medical treatments may raise a concern. But. who are presumably at lower risk. So far. In March 2006. For other patient groups. 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. Considering such alternatives when these high-risk procedures are to be performed on male neonates. In February 2008. or by using heparin-coated ECMO circuits. 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 64 . 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. the European Commission invited interesting parties to submit information regarding DEHP plasticised PVC or alternative plasticised PVC for an updated evaluation. In some cases the exposure is significant and exceeds the toxic doses observed in animal studies.

which have been approved for medical practices. such as PA [86] and citrates. 65 . there is no proven effect of exposure to DEHP on male reproductive health .4. such as BTHC [33]. A risk assessment of these available alternative plasticizers could not be performed due to a lack of exposure data from medical devices. polymeric plasticisers. however. The Committee got access to toxicity data for eight possible alternative plasticizers and compared their toxicity with that of DEHP. These are trimellitates. In view of the proven clinical benefits of PVC medical devices plasticised with DEHP. there are three types of alternatives to DEHP. For certain uses of DEHP alternative plasticizers for PVC are available. such as TEHTM [38.’ The UK regulatory body. it would be premature to recommend a change to other plasticisers. 70].the adverse effect of concern in the SCENIHR report. The risk and benefits of using alternative plasticizers should be evaluated case by case.Blood compatibility of PVC-P humans. must also be evaluated with regard to their functionality in respect to medical devices. Medical devices containing DEHP-plasticised PVC have important clinical benefits. Each alternative to DEHP. In particular. 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 respect to reproductive toxicity in animal studies DEHP induces more severe effects compared with some of the alternatives. 5.3 Alternatives to DEHP Currently.

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]. platelets and plasma. which has been permitted for use in flexible PVC for food-contact applications and for various medical devices throughout Europe [86]. corpuscular oxygenators as used in open heart surgery. these esters provide a low order of toxicity when compared with DEHP or other phthalate esters. PA is a type of extraction-resistant plasticiser. membrane oxygenators for pulmonary failures. For example.Medical Plasticised PVC With respect to plasticiser migration or extraction. However.2 mg TEHTM per pack. TEHTM migration into stored blood components is 1/100 or less than that of DEHP. TEHTM is generally not detectable in refrigerated red cell products. Platelet concentrates stored for seven days at room temperature in PVC-TEHTM bags contain only 0. phagocytosis for 66 . are not extraction-resistant plasticisers because of their relative lower molecular weight compared with TEHTM and PA. many studies indicate that less TEHTM is apparently leached from PVC bags or haemodialysis tubing than DEHP. even after a fourty two day storage period [14]. UÊ ˜`Üiˆ˜}ʈ˜ÌÀ>Ûi˜œÕÃÊ>˜`ʈ˜ÌÀ>‡>ÀÌiÀˆ>ÊV>̅iÌiÀÃ] UÊ œœ`Ê ÌÕLˆ˜}Ê ˆ˜Ê Vœ˜Ì>VÌÊ ÜˆÌ…Ê Lœœ`Ê >ÃÊ ÕÃi`Ê ˆ˜\Ê …>i“œ`ˆ>ÞÈÃÊ devices. citrates. From the viewpoint of migration. such as ATHC and BTHC. UÊ ˜ÌÀ>Ûi˜œÕÃÊ ÌÕLˆ˜}Ê vœÀÊ Ì…iÊ ÌÀ>˜Ã«œÀÌ>̈œ˜Ê œvÊ Lœœ`]Ê Lœœ`Ê products and crystalloid fluids. They are the most promising alternatives to DEHP and have replaced DEHP plasticiser for many blood-contacting applications including: UÊ >}ÃÊvœÀÊ̅iÊÃ̜À>}iʜvÊ܅œiÊLœœ`Ê>˜`ÊLœœ`ÊVœ“«œ˜i˜ÌÃ]ÊÃÕV…Ê as red blood cells. It was found that platelet concentrates stored for seven days in CL-4093 plastic (a PVCBTHC container) contain about 20 mg of BTHC per unit.

PVC can be copolymerised with poly(ethylene oxide) (PEO) to form an ABA block copolymer. in particular blood compatibility. which serves as an internal plasticiser [89]. although numerous alternatives to DEHP have been developed during the past 30 years. to a level where plasticiser migration problems are eliminated. at least partly. In addition. PEO serves as an internal plasticiser. Findings in the 1970s relating to the leaching and toxicity of DEHP also encouraged the development of internally plasticised PVC to replace DEHP. new citrates. This coincides with a statement from the Phthalate Esters Panel at the American Chemistry Council. the most extensively studied plasticiser. wherein the A parts are PVC segments. which claims: ‘Alternative materials may not have the long track record and 67 . In summary. the all round performance has to be compared with that of DEHP. such as acetyl-tri-n-(hexyl/octyl/decyl) citrate. For their future development. These polymeric plasticisers are claimed to be capable of replacing DEHP. Recently. such as a carbon monoxide-propylene copolymer and a polyester derived from glutaric acid and a diol [90]. It is also possible to produce a thermoplastic PVC block copolymer of the AB type. for application in medical devices.Blood compatibility of PVC-P the collection of platelets and leucocytes for transfusions and intensive plasma exchange devices. 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]. particularly in soapy water extraction tests in a simulated bloodfluid situation [87]. is lacking. some new polymeric plasticisers have been developed. have been produced and have been found useful as medical-grade plasticisers in PVC compositions with improved extraction resistance. partly or totally. a detailed evaluation of their suitability for blood-contacting applications. where the B block is a flexible linear aliphatic polyester or polyether.

after reviewing the DEHP risk assessment.Medical Plasticised PVC unique performance profile that makes PVC with DEHP a proven and lifesaving combination.’ In Europe. concluded on 25 October 2004 that: UÊ . which represents the medical device industries of Europe. Eucomed.

based on one animal testing. by the European Commission Joint Research Centre (JRC) in Ispra. UÊ /…iÊ œ““ˆÃȜ˜Ê ŜՏ`Ê LiÊ >Îi`Ê ÌœÊ ÀiµÕiÃÌÊ vÕÀ̅iÀÊ ÃVˆi˜ÌˆwVÊ research from both epidemiological and reproductive cell toxicity perspectives. UÊ /…iÊ œ«ˆ˜ˆœ˜ÃÊ œvÊ Ì…iÊ ÀiiÛ>˜ÌÊ ÕÀœ«i>˜Ê œ““ˆÃȜ˜Ê -Vˆi˜ÌˆwVÊ Committee and of recent scientific literature suggest that DEHPplasticised PVC is still a safe and useful medical material and that there are no scientific grounds. The search for 68 . in the public interest. although further scientific research is needed. 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. UÊ ÌiÀ˜>̈Ûiʓ>ÌiÀˆ>Ãʓ>ÞÊLiÊ>Û>ˆ>LiÊvœÀÊܓiÊ>««ˆV>̈œ˜Ã]Ê UÊ ÃÊ Ì…iÀiÊ …>ÛiÊ Lii˜Ê “>˜ÞÊ Ìi˜ÃÊ œvÊ “ˆˆœ˜ÃÊ œvÊ «>̈i˜ÌÊ `>ÞÃÊ œvÊ exposure to medical products containing DEHP-plasticised PVC in over 40 years without any reports of adverse effects. at present. Although there is no proven evidence showing any harm to human health. Italy upon the request of DG Enterprise. *‡«>Ã̈VˆÃi`Ê*6 ʅ>ÃÊ>ʏœ˜}ʅˆÃ̜ÀÞʜvÊÃ>viÊ>˜`ÊivviV̈ÛiÊ use in medical products. the suspicion has resulted in calls for a total ban on DEHP-plasticised PVC by many environmental organisations [91]. It is suggested that this research could possibly be carried out. for restrictions on its use. DEHP is now listed as one of the 66 hormone-disrupting substances by the European Commission.

and processing and product performance characteristics of the compounds as they relate to every phase of product development. such as metallocene polyethylene (mPE). 5. mPE has demonstrated enhanced toughness. A list of alternative materials to PVC for blood tubing applications has been given by Blass [92]. 69 . the high cost of these polymers has prevented their application as a replacement for PVC blood tubing. are produced with metallocene as a catalyst.Blood compatibility of PVC-P alternatives to PVC-P in medical applications has focused mainly on medical catheters and packaging materials for blood components. Obviously. However. Among these are metallocene polyolefins (polyethylene and polypropylene) [93-95]. clarity and elasticity. Mediplast. Recently. with low extractables. Metallocene polyolefins.4. Typically. silicones and other elastomeric alloys.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. EVA [96] and polyether-ester plastic [97]. polyurethanes. This metallocene technology makes it possible to control precisely the molecular architecture and achieve a narrow molecular weight distribution of polyethylene. the tubing costs up to 10 times as much as that made from PVC. practical and cost-effective replacement for PVC-P materials [95]. There is no rapid route to replacement [93]. including polyurethane/PVC coextrusion material. sealability. 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]. some alternatives to PVC-P have been developed. before deciding to use metallocene polyolefins in their medical products. manufacturers must consider simultaneously the material. and has created opportunities for the medical and healthcare industries. design. It was concluded that mPE materials might be able to provide a high-performance.

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. An ionomeric modified polyether-ester blended with PVC was reported to be a suitable substitute for PVC as a blood-contacting biomaterial. for example B Braun/McGaw and Baxter. silicones and other thermoplastic elastomers and are finding a new way into the medical device industry. including new PVC resins.Medical Plasticised PVC EVA film as an alternative to PVC-P film has been promoted as combining toughness and low-temperature sealability with clarity. These advanced PVC materials in many instances are replacing higher-priced plastics. either through PVC formulation or surface modification. which has already achieved a prominent role in the medical plastics industry. tubing and platelet storage bags. PVC modification and novel alloys of PVC. 5. flexibility and impact and puncture resistance. for red blood cell packaging. while offering advantages [97]. 70 . However.4.5 New development of PVC-P biomaterials As one of the oldest commodity polymers. Several US and European medical device companies now provide PVC-free IV bags. such as polyurethanes. PVC-P has been developed further by many new technologies. enhanced compounding technologies. efforts are still required for DEHP-PVC alternatives to meet the existing required performance at a competitive cost. EVA polymers have been accepted for blood-contacting application in many countries.

which are less easily resolved.1 Ultrahigh molecular weight PVC resin Flexible PVC has been recognised for a long time as a material with notoriously poor compression recovery properties. when subjected to sustained stress or strain. with improved compression recovery properties.00075. Flexible compounds based on UHMW-PVC are superior to conventional types. polyurethanes and other elastomeric biomaterials. high cost and limited compatibility.000) with short chains and is highly branched. Ultrahigh molecular weight (UHMW) PVC is a PVC resin with a molecular weight as high as 150. Further study of processing techniques due to their high melt viscosity.5. They have found application in the automotive industry and have a variety of uses in the medical device industry [99]. highly crosslinked or have very high molecular weights (long chains). 71 .Blood compatibility of PVC-P 5. for the most part. This means that a highly plasticised PVC body often suffers from excessive creep and stress relaxation. Conventional PVC resin is usually of lower molecular weight (30. while the elastomerlike polymers are. one approach to develop novel PVC with high elasticity is to increase the molecular weight of the PVC resin. is underway. 5.4. and there is also the plasticiser migration problem. Compared with the traditional PVC resin.4. a number of new applications would become potentially available to this polymer as an alternative to silicones.000 (K value > 100) [98].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.5. Therefore. these materials are more linear and have a higher degree of crystallinity. If flexible PVC was available with an elastomer-like recovery property.

polyethylene. especially suitable for applications requiring soft. 5.4. PVC modification. to form useful alloys. In addition. with starch [101]. has been utilised and this will be discussed in Chapter 6. which yields a product with many improved properties [100]. while poly(methyl methacrylate) (PMMA) has been used to modify PVC to enhance its toughness [104]. oxygen-barrier materials [102]. Some of the more interesting current alloys include: PVC/Nylon. PVC/ urethanes. which is applied for improving the mutual compatibility of polymers. for high abrasion resistance.3 PVC modification For improving the plasticiser migration property. polyadipates and polyester-plasticised PVC have been applied in medical devices [86]. 5. polypropylene and butyl rubber. a polyisocyanate and diol or diamine or their mixtures. through PVC surface modification and PVC formulation. Polyester urethane and EVA have been used to modify PVCDEHP to reduce the DEHP migration [103]. and PVC/polyolefin. reduced extractables [42]. normally not miscible with PVC.4 Novel alloys of PVC PVC. The formulation contains PVC plastisol. 72 . as a slightly polar material. has wide compatibility with many other synthetic or natural polymers. including PVC. the PVC-P polymer is produced with a network-like structure. Cyclodextrin is an example of a compatibiliser. or natural polymers such as starch and cellulose. Polycaprolactams. After compounding.4.5. researchers have developed materials known as compatibilisers that allow some polymers. for example. for enhanced physical and high-temperature properties.5.Medical Plasticised PVC PVC-P produced by a crosslinked compounding technology might be able to solve such problems.

S. Ryan and G. Churchill Livingstone.L. It is likely in the future that PVC technology will direct the development of new synthesis technology.5.M.. USA. thereby eliminating defects in the structures due to free radical polymerisation. A. 1994. J. References 1.M.D.M. 2.D. New York. 73 . 852. 3rd Edition.D. Forbes and J. Qian.1301.Blood compatibility of PVC-P 5. 14.M. Zhao and H.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. Tuddenham. 19. However.D. By mimicking the success of metallocene catalytic chemistry in polyolefins. C. Another approach to obtaining PVC products with improved resistance to heat degradation and ionising radiation is to use a nonfree-radical polymerisation technique. Lowe.4. Artificial Organs.D.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].4. Courtney. N. D. Courtney in Haemostasis and Thrombosis. Thomas. Eds. Lamba. Courtney. 5. 1999. Forbes and E. J.G.K. J. X. Perfusion. 263. 1995. NY. C. remains the material of choice today. atactic or isotactic resin could be designed for different applications. 8.P.B. 3. PVC-P. C. Gaylor.J. the plastic used in the first blood bags introduced by Carl Walter over 40 years ago. Bloom.O. a new PVC resin composed of blocks of syndiotactic. p. new PVC formulations and PVC surface modification.

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Medical Plasticised PVC 82 .

In particular. The surface modification of plasticised PVC is summarised in Figure 6. when plasticised poly(vinyl chloride) (PVC-P) biomaterials are used as blood-contacting materials.1 PVC-P surface modification for improved biocompatibility 83 .1.6 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. Figure 6. the blood interacts with the materials at the outer layer of the PVC surface [1].

and the compatibility of PVC with respect to the contents of the bag is improved. in which a sol-gel of material based on poly(ethylene oxide) (PEO) was prepared and used to produce organic/inorganic hybrids. Price and Clifton [3] reported that the use of ultrasound allows a number of chemical modifications to PVC surfaces to proceed under mild conditions. 84 . 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. The surface treatment was carried out by a methanol washing procedure. based on fibrinogen adsorption. The reduced DEHP level induces less fibrinogen adsorption. 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 key technique is using glow discharge treatment with fluorine gas.1 Physical treatment Hatada and Kobayashi [2] patented a PVC sheet for blood or infusion bags. The best results were obtained by an accurate balance of organic and inorganic phase content.Medical Plasticised PVC 6. which is modified so that the diffusion of plasticiser to the surface is suppressed. the DEHP migration can be significantly reduced [4]. It was reported that when PVC-DEHP is subjected to ultraviolet (UV) irradiation. Zhao and Courtney [5] correlated the surface plasticiser level (surface cleanness) with the blood compatibility of PVC-P. suggesting that a high inorganic content at the coating-extraction medium interface was present. Messoria and co-workers [6] developed a coating process. in order to reduce leaching of the plasticiser from PVC medical devices. which leads to a reduction in DEHP concentration at the surface. X-ray photoelectron spectroscopy (XPS) analysis showed a preferential segregation of silica onto the outer surface. These hybrids were used as coatings for flexible PVC tubing.

These modifications are ascribed to the loss of chlorine and the incorporation of oxygen. Tu and co-workers [9] described the modification of PVC using liquid crystal to modify the surface. while those exposed for the longest time stayed highly hydrophilic. Bento and co-workers [8] studied commercial PVC sheets treated by plasma immersion ion implantation. equal to zero after the treatment. as shown by XPS measurements. Through contact angle measurements. The samples were immersed in argon glow discharges and biased with 25 kV negative pulses. which can be crosslinked under the influence of heat. However. XPS and scanning electron microscopy (SEM). Samples bombarded for shorter periods recovered their hydrophobic character partially or totally. The surface properties were characterised by the water contact angle measurement.Modification of PVC-P surface for improved blood compatibility Li and Chen [7] reported the effects of long-distance and direct argon radio frequency plasma surface treatment on PVC films. the mobility of surface polar groups and the variation in the degree of crosslinking can also affect the PVC wettability. surface hydrophilisation was not stable. in the forming of functional groups enhancing polymer wettability. the effect of the exposure time on the PVC wettability was investigated. 6. in some cases. Jayakrishnan and co-workers [11] coated PVC-P with 85 . all samples presented contact angles.800 s. Exposure time to the bombardment plasma changed from 900 to 10. Independent of time.2 Chemical treatment Levin [10] introduced to the PVC surface some functional groups. Furthermore. in terms of changes in surface wettability and surface chemistry. Such crosslinking provides a thin coating. The results showed that plasma treatments modify the PVC surface in morphology and composition and both modifications cause surface oxidation of PVC films. which prevents leakage of plasticiser and additives from the PVC-P substrate when it is in contact with extractants.

has also been employed to prepare a protein-resistant surface. 16]. poly(N-vinyl-Nmethylacetamide) [14]. Surface modification of PVC-P is also achieved by PVC surface coating and blending with surface-active additives. a combination of two different hydrophilic polymers [17]. Blending of PVC-P with hydrophilic polymers. and (EO80-PO30-EO80) onto the PVC-P surface by a solvent casting method. such as PEOpoly(propylene oxide) (PPO) surfactant and HEMA-styrene copolymer. it is also possible to produce a low-friction PVC-P catheter by such hydrophilic polymer grafting technology [21]. (EO13-PO30-EO13). Reducing plasticiser migration by modification of the PVC formulation using some specific additives is also possible. 13]. It was reported that a film cast from the mixed solution of PVC. 86 . An example is the use of cyclodextrins. and PEO [18-20] have been grafted onto a PVC-P surface by chemical modification of the PVC surface. the modified surface has improved blood compatibility in terms of suppression of platelet adhesion [22]. such as (C12 . negatively charged poly(methacrylic acid) [15. many hydrophilic polymers. as previously stated [24]. By entrapping PEO surface active additives.EO10). DEHP and B-cyclodextrin (B-CD) has a reduced DEHP migration property [25]. The PVC-P surface grafted with hydrophilic polymers exhibited improved blood compatibility. such as poly(2hydroxyethyl-methacrylate) (PHEMA) [12. The materials show high anticoagulant activity and inhibition action of platelet loss [23]. having a microdomain structure. (EO20-PO30-EO20). as well as the ability to prevent plasticiser migration.Medical Plasticised PVC crosslinkable PVC resin to reduce the migration of the plasticiser to potential organic extractants such as hexane. such as PEO and polyvinylpyrrolidone (PVP). In addition. Based on the hypothesis that hydrophilic and negatively charged surfaces are blood compatible.

By grafting such moieties. 29]. the cationic surfactant tricaprylylmethylammonium chloride-modified PVC membrane exhibited the poorest biocompatibility [26] . Tridodecylmethylammonium chloride (TDMAC)/ heparin complex is soluble in some organic solvents. making it capable of ionically bonding heparin [27]. Similarly.Modification of PVC-P surface for improved blood compatibility Biodegradable polycaprolactone (PCL) has been used to replace partially or totally the DEHP and PVC compositions intended for medical devices. providing a lower extraction risk and similar or even improved thermal and mechanical properties. 6. Covalent end-point immobilisation of heparin onto a PVC-P surface has been investigated extensively [30. poly(amido-amines) have been found to be capable of forming stable complexes with heparin. corresponding to traditional PVC-P. The influence of heparin coating by end-point attachment 87 . it can be concluded that the PCL and even the PCL-DEHP mixture behave as better plasticisers for PVC. 31] and the heparinised PVC-P produced has been reported to show an improved blood compatibility [32]. a heparinisable PVC-P surface was achieved with powerful heparin retention ability [28. biocompatible and macromolecular plasticiser). Miyama and co-workers introduced a photoactive group onto PVC and then a dimethylamino-containing monomer was photografted onto the PVC-P surface.3 Biological treatment Immobilisation of bioactive substances onto biomaterial surfaces has been widely accepted in the medical device industry. After comparing the experimental results with the data from the literature. with poly(E-caprolactone) (PCL-biodegradable. It can be achieved by simple coating and ionic complexation. Heparinisation of PVC-P is one of the approaches used to obtain improved blood compatibility. 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.

to form complexes with heparin. benzalkonium. such as isopropyl alcohol. Hsu and Balding [38] employed various hydrophobic cationic substances. 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.Medical Plasticised PVC technology on in vitro bacterial adherence on PVC-P was also investigated [33]. stearalkonium and tridodecylmethylammonium. was strongly recommend [37]. 42]. Indeed. although very few centres use this technique routinely [35]. By incorporation of prostacyclin into a PVC-P blending system [39]. such as polyethyleneimine. neonates and children. albumination of the PVC surface has been shown to suppress effectively the adhesion and activation of platelets when the surface contacts whole blood [40]. but free of DEHP. For pregnant women. the controlled delivery of prostacyclin can lead to improved surface blood compatibility. By coating the complex on PVC-P. the use of the available surface-coated plasticised PVC tubing sets. followed by G-radiation sterilisation. the heparin moiety can be bound to the PVC-P surface. The formed complexes are soluble in lower organic alcohol. It was discovered by surface characterisation using XPS that the DEHP level was reduced when heparin was covalently attached to the PVC-P. It has been hypothesised that the coated surface 88 . which has an influence on blood compatibility [36]. 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. dimethylstearylamine. In contrast to this activity of prostacyclin. 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.

2.A. has been utilised to modify the surface of biomedical adsorbents for biospecific adsorption in blood purification [45. 303. Seshimo and Y. B. 1982. Zhao and Courtney [47. Nova Science Publisher. Inc.. Toray Industries. assignee. The significant reduction in fibrinogen adsorption at the surface indicates the effect of anchoring of the complex on the alteration of the surface properties. K.. USA. which leads to an improved blood compatibility. Ed. Price and A. 1141. Caruta. A commercially available cyclodextrin. Ito. Kobayashi. R. 11. 48] have developed an anchor modification procedure for PVC-P. 48.1.M. 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. US 4337768. Inventors. B-cyclodextrin. 104. NY. The PVC-P surface is also improved for cell adhesion [44]. References 1.M. Zhao and J. 4.J. such as cyclodextrins and cyclodextrin/PEO or cyclodextrin/PEO-PPO combinations. X. G. PEO-PPO-PEO and cyclodextrin inclusion complexes were blended with PVC-DEHP for surface modification. some different phospholipids have been bound onto PVC tubing [43] to achieve improved blood compatibility.Modification of PVC-P surface for improved blood compatibility properties are mainly influenced by the underlying material surfaces [42]. Hatada and H. Clifton. Haishima. p. International Journal of Pharmaceutics. 2006. 89 . Courtney in Focus on Polymeric Materials Research. 2005. In addition to those modifications based on a MPC copolymer. 2006. Polymer International. 3. F. A novel approach for surface modification of PVC-P for improved blood compatibility involves the utilisation of oligosaccharides. Hauppauge.

Biomaterials. 45. 2006. 1. M. US 4806393. 11. A.H. 2175. 1. J. Tosellib. Paul. 22. J. Levin and I. 8.K. Feng and C. J. 185.Y. 131. Rajan.N. P. Messoria. 473. Nannarone. 90 . Singh. Ray. 6. Lai. Journal of Applied Polymer Science. 51. 17. Yeda Research and Development Company Limited. W. Chen. British Polymer Journal. 1999. Courtney. A.C. Karlheinz. 104. 9.E. Jayakrishan. Singh. Schreiner.A. 13. inventors. N. Singhal and H. 105. Singh. Ray and H.R. 11. Sreenivasan. 805. 1989. M. J.C. Tu. K. F. 51. M. P. 10. V. 5. Honda.H. Zhou. 13. Angewandte Makromolekulare Chemie. 74. A. M. Pilatia.R. 6. 56. 1990. Plasmas and Polymers.C. 1187. X.R. 23. 615. Jayakrishnan. 1990. Kayama. G. 16. 15. Polymer. M.H. Journal of Applied Polymer Science. Zhao. Journal of Applied Polymer Science. 1995. Cruz and E. R. Singh. Nanobiotechnology (IET). Z. 1982. 1994.M. 7. M. W. Fabbria and S. B. Journal of Materials Science: Materials in Medicine. 8. Krishahnan and A. 89. 2003. Rehovot. 113. 1. Fabbria. E. 1990. 7. R.P.F. Li and J. J. 2004. 1999. Sunny. 1. W. 2007.C. Chinese Science Bulletin.G. 1. Peter and B. Rangel. Lee and C. 14. Artificial Organs. 12. 87.Medical Plasticised PVC 5. Cha. assignee. Bento. Zhao and J.

S. Ferruti. 2005. Journal of Colloid & Interface Science. 1984. 18. 1-2. Trends in Biomaterial & Artificial Organs. Mastacchi and M.E. F.. Tadokoro and Y. Barbucci. Golander and E. 234. 1996. Tanzawa. 5. Otsuka Pharmaceutical Factory. Y. G. Ju. Artificial Organs. R. Torrisi. 121. Journal of Biomedical Materials Research. 24. 1998.H. 1998. Reddy and P. 91 . Balakrishnan and A. Danzo. R. 12. 11. inventors. Analytica Chimica Acta. 26. K. assignee. 23. 33.G. 28. 77. Uyama. Jayakrishnan. Y. Ltd. Medical Plastics & Biomaterials. 4 1. Lee. 251.Modification of PVC-P surface for improved blood compatibility 18.O. Jayakrishnan. 59. 1977. Miyama. Biomaterials. 1999. 3. Barbucci. Pignataro and P. Sreenivasan. Higashino. S. Ikada. 1988. 21. 19. 1996.M. Sarret. C. 222. S. 1. K.S. B. 29. N. S. Kim and Y. 230. Vagama. Journal of Biomedical Materials Research. 350. Qin and B. C. Kiss. 23. US 5756553. Biomaterials. Lakshmi and A. Harumiya. 48.. and Otsuka Pahrmaceutical Co. 2. Casini. 1991. Ding. P. Spartano. Y. Iguchi and R. 27. A. Rabinow. 2089. H. R. O. J. 20. P. H. 3. 1982. Mori and H. 240. 328. Inc. 1997. N. Biomaterials. Journal of Applied Polymer Science. 4. 71. 25. Ferruti. Puglisi.. 3.M. 22. Part B Applied Biomaterials. Tempesti.M.

D. J. Journal of Materials Science: Materials in Medicine.O. Journal of Material Science: Materials in Medicine. Baxter International Inc. Journal of Biomaterials Science Polymer Edition. Spanier and C. H. Anesthesia & Analgesia. J. R. Wendel. Farhat. 6. inventors. 1365. H. Heyer. 667. 103. 1999. Hallberg and C.D. 20. 1995. 10. McRea and S.B. S. 34. 9. 2. Larm. Yin. Artificial Organs. West and G. 2006. Medical Device Technology. Hsu.R.D.. Sanchez and T. J. L. Inc. 8. 40. Lancaster.Q. 92 . H. L. X. R. p. Kim in Biocompatible Polymers. Olsson. J. 1995. 39.R. Mollnes.P. 41. Wodarz. 11. X. Larsson and P.M. Mongero.E.E. J. 9. Smith. 33. West and G. Medical Device Technology.Medical Plasticised PVC 30. 1997. A. J.A. Jessen.597.H. B.. Ziemer and H. 8. 37. Zhao. 2001. O. Manspeizer. R. Lee.C. Technomic Publishing Co. 825.Q. Balding and L. H. G. R. 11. 1997. Metals and Composites. Courtney.W. 2. 31.R. 107.M. 713.. Riesenfeld. assignee. 1983. Szycher. 527. Courtney.P. 1983.L. Lowe.A. 24. 32. Koul. 19.E.C. Beck. 2. Journal of Biomaterials Science Polymer Edition. Perfusion. 7. Zdanowski. 161. 6. de Queiroz. C. 16. Lowe. USA. Zhao. Ed. US 5417969. Yianni. PA. 35. M. 2008. J. Olsson. P. 351. 38.P. Yin. 20. Hildenbrand. K. Perfusion. Schalen.H. 6. 36. Lehmann. 1995. Z. M. D. E. E. T. 2005.J. Blass.

Reactive Polymers. 45. M. 1994. Lian. Zhao and J. 17. 9-10.Modification of PVC-P surface for improved blood compatibility 42. Wright. Klee. 24. 24. Zhang. He. 7-9. R.M. X. 44. Journal of Biomedical Materials Research. P. D. Courtney. 539. Reactive Polymers. 592.L. 3. Hocker B. Courtney. 691. 1. Zhao and B. 46.L. International of Journal of Artificial Organs. Tanaka and K. L. S. Zhao and J. 2007. Rolfe. Dekker and C. 48.V.J. 1994. X. Milling. Turina. 9.F. B. 5. 43. 1998. Biomaterials. 47. Villari. 5. 80A. 1994. X. 294. A. X. He. H. 2008. von Segesser.M. Ishihara. online publication. W. Mittermayer. 1994. Leskosek and M. Tonz. 93 . S.K. Zhao and B. Journal of Materials Science: Materials in Medicine. 19. Journal of Biomedical Materials Research. G.

Medical Plasticised PVC 94 .

1 Environmental and health concerns. Now.g.7 Future perspectives 7. 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.1). e. upon landfill disposal. and to after the end-use or end-of-life (Figure 7. relating to plasticisers [2. there are challenges facing the PVC and associated industries. 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]. UÊ “«ÀœÛiʎ˜œÜi`}iÊ>LœÕÌÊvœÀ“Տ>̈œ˜ÃÊ>˜`ÊÕÃiʜvÊ>``ˆÌˆÛiÃÊLÞÊ manufacturers. UÊ . 3]: UÊ .iۈiÜÊVÀˆÌˆV>Ê>««ˆV>̈œ˜ÃÊ>˜`ÊÀiÃi>ÀV…Ê>ÌiÀ˜>̈Ûið 95 . UÊ “«ÀœÛiÊ Ž˜œÜi`}iÊ >LœÕÌÊ v>ÌiÊ œvÊ >``ˆÌˆÛiÃÊ ˆ˜Ê «œÃ̇Vœ˜ÃՓiÀÊ waste. has been the centre of controversy for quite a long time. due to its wide application in the past 50 years and concerns over the leaching of plasticiser..iۈiÜÊ̅iÊÕÃiʜvÊ>Ê>``ˆÌˆÛiÃÊ܈̅ÊÀiëiVÌÊ̜ÊÃÕÃÌ>ˆ˜>LˆˆÌÞ]Ê>˜`Ê commit to phasing out all substances that accumulate in nature or instigate reasonable doubt as to toxic effects. As stated below. product life cycle analysis has been adopted to cover the environmental analysis of any products through the whole supply chain to the endof-life for legal compliance. and regulatory issues Plasticised poly(vinyl chloride) PVC-P.

Medical Plasticised PVC UÊ “«œÞÊ Ì…iÊ «ÀiV>Ṏœ˜>ÀÞÊ «Àˆ˜Vˆ«i]Ê ˆvÊ Ì…iÀiÊ ˆÃÊ Ài>ܘ>LiÊ doubt.1 Environmental and health concerns over PVC-based products 96 . Figure 7. UÊ ÝiVÕÌiÊ>ÊÃÕLÃ̈ÌṎœ˜Ê«œˆVÞʜ˜ÞÊ>vÌiÀÊV>ÀivՏÊ>ÃÃiÃÓi˜ÌʜvÊ̅iÊ alternatives.

Future perspectives In the UK.2). 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. 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 Regulatory considerations of plasticised PVC as extracorporeal blood-contacting devices . coatings that lead to a significant reduction in DEHP exposure can improve the total risk-to-benefit ratio. In some situations. Figure 7. 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. Meanwhile.risks and benefits 97 .

1.>`ˆ>̈œ˜Ê‡Ê Part 3: Guidance on dosimetric aspects. UÊ -"Ê££ÇÎÇʇÊ-ÌiÀˆˆÃ>̈œ˜Êœvʓi`ˆV>Ê`iۈViÃʇʈVÀœLˆœœ}ˆV>Ê methods: UÊ ". UÊ -"Ê/-Ê£££Îx‡ÓʇÊ-ÌiÀˆˆÃ>̈œ˜Êœvʅi>Ì…ÊV>ÀiÊ«Àœ`ÕVÌÃʇÊi̅ޏi˜iÊ oxide .Ê ÓääÎÊ ‡Ê -ÌiÀˆˆÃ>̈œ˜Ê œvÊ …i>Ì…Ê V>ÀiÊ products .>`ˆ>̈œ˜Ê . 2008.Ê ÓääÇÊ *>ÀÌÊ £\Ê . UÊ -"Ê£££ÎÎLJ£Ê-ÌiÀˆˆÃ>̈œ˜Êœvʅi>Ì…ÊV>ÀiÊ«Àœ`ÕVÌÃʇÊ. 2007. validation and routine control of a sterilization process for medical devices. there is a regulatory requirement to ensure that products are sterile. validation anf routine control of a sterilation process for medical devices.1 Sterilisation For medical devices.Part 1: Requirements for development.General requirements for characterisation of a sterilising agent and the development. There are a range of ISO standards for sterilisation such as: UÊ -"Ê £{™ÎÇ\ÓäääÊ ".Medical Plasticised PVC 7.>`ˆ>̈œ˜Ê‡Ê Part 2: Establishing the sterilisation dose. 2006. 2003. UÊ -"Ê£££Îxʇ£Ê‡Ê-ÌiÀˆˆÃ>̈œ˜Êœvʅi>Ì…ÊV>ÀiÊ«Àœ`ÕVÌÃʇÊi̅ޏi˜iÊ oxide . UÊ -"Ê£££ÎLJÎÊ-ÌiÀˆˆÃ>̈œ˜Êœvʅi>Ì…ÊV>ÀiÊ«Àœ`ÕVÌÃʇÊ. UÊ -"Ê£££ÎLJÓÊ-ÌiÀˆˆÃ>̈œ˜Êœvʅi>Ì…ÊV>ÀiÊ«Àœ`ÕVÌÃʇÊ.Part 2: Guidance on the Application of ISO 11135-1.Part 1: Requirements for development. 2006. 2006. validation and routine control of a sterilisation process for medical devices.

UÊ *>ÀÌÊ Ó\Ê /iÃÌÃÊ vœÀÊ ÃÌiÀˆˆÌÞÊ «iÀvœÀ“i`Ê ˆ˜Ê ̅iÊ Û>ˆ`>̈œ˜Ê œvÊ >Ê sterilisation process. 1998. 2007. 98 .iÌiÀ“ˆ˜>̈œ˜Ê œvÊ >Ê «œ«Õ>̈œ˜Ê œvÊ microorganisms on products.

4 million t (INEOS have taken over Hydro). so does the plasticiser industry. The annual output is about 8 million t.1 Market for PVC PVC is the third most consumed polymer worldwide. As the PVC industry continues to grow. vinyl chloride monomer (VCM) and ethylene dichloride (EDC) markets for the period 1999-2009 [4]. There are ten key PVC manufacturers in Europe. the most commonly used sterilisation methods are summarised in Figure 7. (CMAI): 2005 World Vinyls Analysis includes the market analysis of the global PVC.2.3. prices and 99 .3 Sterilisation methods for medical PVC. There are about 25 key players in PVC manufacturing in North America. accounting for 98% of PVC production and two manufacturers are based in the UK. The annual capacity of INEOS Vinyls alone is 1.2 Market needs 7. A report compiled by Chemical Market Associates.Future perspectives For medical PVC. They are INEOS Vinyls and Hydro Polymers. trade. Topics covered in this analysis include capacity. and is the most widely used biomaterial for medical devices. 7. Figure 7. Inc. demand. supply.

Medical Plasticised PVC profitability. 7.5 million Euros in 2005. Global PVC demand recovered in 2004 and is forecast to continue to grow at a rate of 4. Economic growth of 2. 7.2. polyurethane.2.2 Market for PVC medical devices 7. acrylics. acrylonitrile-butadiene-styrene.2.2 General Chinese market analysis The popular medical plastics in the Chinese market are highdensity polyethylene. technology and production costs.5 million Euros in 1998 and was expected to reach 191. polystyrene. China will be the key country for world demand and supply issues. polypropylene (PP). Some significant conclusions include: The PVC industry is emerging from several weak years in terms of profitability.000 t per year. China is planning on adding most of the world’s new PVC capacity over the next few years. China’s high economic growth for nearly two decades has excited the rapidly rising consumption of medical 100 . The present world demand for PVC medical compounds is between 210.2. low-density polyethylene. The European market for plastics in medical disposables was estimated at 120. polycarbonate.1% per year through 2009. thermoplastic elastomers and polyamide.0% of the market for the total use of polymers in medical devices.8% per year from 1999 to 2004 is forecast.2.1 General market analysis It is estimated that soft PVC accounted for 48% of all disposable medical devices in 2005. the USA and Japan [5].000 and 250. thermoplastic polyester. PVC.6% from 2004 through 2009. PVC makes up 26. to accelerate to 3. The major manufacturing centres are Western Europe.

4 t in 1998.7% of the total medical plastics consumption.27-0.com). In spite of new facility construction and capacity expansions. 101 . In order to become less dependent on medical plastics imports.’ SPI’s Vinyl Institute in Washington.researchandmarkets. Output of medical plastics reached 114. The total market demand for medical plastics was forecast to increase 12. increasing by 12. China imported 57. In 2000.5% annually.researchandmarkets.com). PVC remains the material of choice because of its long history of safe use and because of its outstanding performance characteristics.700 t by 2005.Future perspectives plastics. ‘in many applications. 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.000 t by the year 2005 (http://www. China will continue to expand its production capacity.000 t. This is due to the health concern about the migration of DEHP from the flexible PVC material into the surrounding environment. medical supplies and pharmaceutical packaging industries will continue to fuel demand for medical plastics and lead the industry in growth. B. A Baxter spokesman explained that ‘any shift to non-PVC alternatives will be very gradual and could take more than a decade. The country will remain a large importer of medical plastics over the next 10 years.4% annually to 294. states that IV bags and medical tubing account for about 4-6% of all PVC extrusion . It is forecast that the Chinese medical equipment. the country’s medical plastics consumption has grown 13. Since 1990.3 Factors influencing the PVC medical device market Demand for PVC in the medical device sector is still growing. DC.2. but at a lower rate than for polyolefins [6].com/pvc) states that. accounting for 34.5% per year (http://www.000 t in 2000 and was expected to advance to 205. Baxter plans to remain a pioneer in materials research. Meanwhile. 7. baxter.’ At the same time. However. China’s medical plastics demand will continue to outstrip supply. USA. Braun McGaw in Bethlehem.around 0.2.

Medical Plasticised PVC
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 bloodcontacting 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.

102

Future perspectives

References
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European Council of Environmental Manufacturers, www.
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I. Mersiowsky, M. Weller and J. Ejlertsson, Water Research,
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I. Mersiowsky, Journal of Progress in Polymer Sciences,
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4.

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

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

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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.

103

Medical Plasticised PVC

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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 105 .A bbreviations 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.

Medical Plasticised PVC 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) 106 .

Abbreviations 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 B-CD B-Cyclodextrin 107 .

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60 Di-2-ethylhexyl phthalate (DEHP). 97 Blood-contacting materials. 70 DEHP risk assessment. 50 51 69 Blood-contacting devices. 20 B Biochemical plasticisers. 10 84 Dialkyl phthalates. 83 C Copolymerisation.S ubject Index A Adipates. 18 H Heparinisation. 68 DEHP toxicity. 24 25 Blood-contacting applications. 87 109 . 4 5 19 22 25 27 28 36 37 52 54-57 59-68 72 73 86-88 97 101 DEHP-PVC. 50 52 Blood-contacting biomaterials. 15 17 D DEHP.

10 100 PVC latex. 88 Plasticised PVC blood compatibility. 13 14 Post-polymerisation. 83 86 87 89 Plasticised PVC surface modification. 59 Plasticiser regulation. 21 Plasticisation. 99 PVC medical device market. 59 Plasticiser surface distribution. bulk. 3 4 5 13 26 27 Plasticised PVC properties. secondary 17 25 Plastics industry. 30 Plasticised PVC formulation.Medical Plasticised PVC N N-butyryl trihexylcitrate (BTHC). 14 PVC alloys. 2 73 83 86 89 Plasticiser categories. 24 25 Polymerisation. 40 Polymer matrix. 72 PVC formulation. 49 51 Plasticised PVC compounding. 13 14 Polymerisation. 13 14 Polymerisation. 2 25 26 27 70 73 86 PVC industry. 9 13 24 73 Polymerisation. 56 Plasticisers. 14 Pre-polymerisation. 18 Plasticiser migration. 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 97 102 Plasticised PVC biomaterials. 30 43 54 65 66 P Phosphate plasticisers. 22 23 65 Polymerisable plasticisers. emulsion.suspension. 35 Plasticised PVC surface. 101 110 . Primary 17 25 Plasticisers. 1 15 17 Plasticised PVC (PVC-P). 15 PVC market. 1 Polymeric plasticisers. 39 45 70 Plasticised PVC blending system.

27 31 PVC product system. 84 85 88 111 . 98 99 T TEHTM. 30 36 52 53 54 56 57 65 66 Trimellitates. 2 15 24 27 53 70 71 73 86 Pyrolysis. 100 PVC modification. 13 15 PVC resins. 85 X X-ray photoelectron spectroscopy. 20 U Unplasticised PVC (PVC-U) 1 35 W Water contact angle measurement. 10 26 PVC processing.Medical Plasticised PVC Subject Index PVC medical devices. 95 PVC raw material. 70 72 PVC plasticisation. 13 S Scanning electron microscopy. 85 Sterilisation.

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Shropshire. 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. Shawbury. safety. performance. 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. 2009 Poly(vinyl chloride) (PVC) is the most versatile of all the commodity polymers. and cost criteria. In Chapters 4 and 5.rapra. and to those who use the products and need to know about the using PVC in medical applications. Shrewsbury. based on the most recent information. and the blood compatibility of plasticised PVC is examined. UK Telephone: +44 (0)1939 250383 Fax: +44 (0)1939 251118 Web: www. SY4 4NR. It can satisfy a wide range of product function.Published by iSmithers. This book will be of interest both to those who manufacture products using plasticised PVC.net . The selection of plasticisers is a particular focus.