Surface modification of biomaterials by plasma polymerization

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Surface modification of biomaterials by plasma polymerization E . J . S Z I L I , R . D . S H O R T and D . A . S T E E L E , University of South Australia and J . W . B R A D L E Y , University of Liverpool, UK

Abstract: The use of low pressure, low power plasma established in an atmosphere of precursor monomer(s) affords the deposition of functionalized films. Such films can retain the functional group and molecular structure of the starting compound(s) in an ultrathin `plasma polymer' deposit. A basic introduction to plasma and the modulation of some of the important physical and chemical properties will identify some of the key relationships between the plasma physics and the chemistry of the resultant plasma polymer films. There then follows an examination of where plasma polymerized films have found application in the area of biomaterial preparation and, in summary, identification of the likely direction of future developments. Key words: biomaterials, biomolecules, cell adhesion, plasma polymerization.

1.1

Introduction

The use of low pressure and, most recently atmospheric, low power plasma established in an atmosphere of precursor monomer(s) affords the deposition of functionalized films. Such films can retain the functional group and molecular structure of the starting compound(s) in an ultrathin `plasma polymer' deposit. Most commonly, surfaces are functionalised with oxygen (O), nitrogen (N), and O and N functional groups such as carboxylic acids, alcohols, ethers, amines and amides. This chapter outlines this surface engineering technology and highlights the importance that it has developed. In the first instance a basic introduction to plasma, how it is generated, and the modulation of some of the important physical and chemical properties is provided. In doing so, some of the relationships between the physics of low pressure, low power (radio-frequency) plasma discharges of O and N functionalized monomer(s) and the chemistry of the resultant plasma polymer films will be explored. There then follows, using selected examples, an examination of where plasma polymerized films have found, or have the potential to find biomedical application. We have structured this section according to the physiochemical characteristics of the plasma

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polymer that is being exploited; although rarely is control over one character manipulated to the exclusion of all others. In summary, we identify the likely direction of future developments.

1.2

An overview of plasma and plasma polymerization

Recent years have seen an increased interest in the preparation of functional, organic ultrathin films deposited by plasma. This technology is seen as the method of choice for modifying the surfaces of materials for biomedical and tissue engineering applications where the bulk mechanical properties have dictated the choice of material; however, the surfaces of such materials continue to elicit an undesirable biological-biomaterial response (Griesser et al., 1994; Chan et al., 1996; Daw et al., 1998; Barry et al., 2005; Siow et al., 2006; Zelzer et al., 2008). This is especially true as emerging technologies, which take advantage of events that occur at the nanometre and/or micrometre scale-length have developed (Morgenthaler et al., 2008; Robinson et al., 2008; Walker et al., 2009). For example, in devices utilizing microfluidic channels, the ratio of surface to bulk material is extremely high, hence the property of the surface in relation to the efficacy of the technology is paramount. Thus, in microfluidics, surface functionalization of microchannels can be utilized to both inhibit unwanted surface events and promote others (Hiratsuka et al., 2004; Sibarani et al., 2007). One particular feature of the plasma deposition of organic films, often referred to as `plasma polymerization', that makes these technologies particularly attractive is that such films can be deposited onto a wide range of different substrates without the need for special surface preparation prior to deposition. This provides a substantial advantage over other techniques where specific substrate chemistry is required, e.g. gold for thiols or oxidized surfaces for silanes; however, substantial commercial development of this technique has not yet followed: poor understanding of plasma systems, their operation, the chemical processes responsible for plasma polymer film growth coupled with the blanket description of these surfaces as biocompatible, based mainly upon short term in vitro studies, have restricted the field.

1.3

Plasma generation and system design

Historically the scientific investigation of plasmas began in the late 19th century when Sir William Crookes described a DC discharge in an evacuated column as `the fourth state of matter'; yet, it was Irving Langmuir in 1929, who first defined an ionized gas using the term `plasma'. However, the first industrial application of plasma processing occurred with the development of the modern integrated circuit first developed in the 1950s. Today anisotropic plasma etching allows patterning of integrated circuits (ICs) and the semiconductor industry,

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with its desire for ever smaller features on microchips, has proven to be one of the main driving forces behind the research into plasma processing (Manos and Flamm, 1989; Flamm, 1996; Chang and Coburn, 2003). This research has, in turn, led to the almost ubiquitous implementation of plasma and plasma processing technology throughout the manufacturing sector. In addition to IC manufacture plasma coatings find application for modified adhesion ± both increasing and decreasing this property, scratch, corrosion and wear resistance (Wohlrab and Hofer, 1995; Villermaux et al., 1996; Benitez et al., 2000; Forch et al., 2007). Low temperature plasma surface modification is particularly attractive when applied to polymeric materials where the opportunity to modify surface properties such as wettability, adhesion, permeability and biocompatibility without thermal damage exists (Liston et al., 1993; Chan et al., 1996). Generation of low temperature plasma is achieved by use of DC or AC fields at reduced pressures, typically in the region of 1 to 100s of mTorr (0.133 to 10 s Pascals), such that ionization can occur at reasonable power inputs. Methods of excitation include DC, radio frequency (RF at 13.56 MHz) and microwave (MW at 2.45 GHz) and this power source may be coupled directly, with the electrodes within the plasma chamber, indirectly with the electrodes external to the chamber or by combination (Roth, 1995). For DC plasma the coupling is typically conductive between two electrodes and, depending on the application, a range of conducting materials may be used for electrode fabrication. With RF sources, the power, coupled to the electron current, can be capacitive or inductive. RF power coupling offers some significant advantages over DC and AC sources for industrial applications: · RF plasma can process insulating materials without sputtering of the electrodes and so, can be used for deposition from organic monomers. · Since the RF power is deposited in the plasma by displacement rather than particle currents, it is easier to couple through the chamber wall resulting in less ion and electron bombardment of electrodes. · In general, RF-generated plasma are more stable with electrons with higher temperatures for the same densities than an equivalent DC or AC plasma. This can be beneficial where an increased number of free radicals, plasmachemical reactions or dissociation and ionization reactions are desired. When considering the preparation of plasma polymer films, much of the previous research has been performed with RF power, typically 13.56 MHz, in glass reactor vessels with external coil-configurations, or bands to couple the power, although many studies with capacitively coupled, internal electrodes have also been undertaken (Griesser and Zientek, 1993; O'Toole et al., 1995; Beck et al., 1996; Dai et al., 1997; Alexander and Duc, 1998). Early designs were based on glass tubes which were either purpose made with ports for the vacuum, monomers and any diagnostic equipment, or utilized lengths of glass

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tube supplied `off the shelf' as high pressure column components. These allglass vessels are costly to design and produce and necessitated the use of an external driven coil. With glass tubes, readily available in a range of lengths and diameters, the various ports are incorporated into the flanges specifically constructed to enclose the vessel. Typically, these flanges are fabricated from conducting materials such as stainless steel or aluminium; however, insulating materials such as nylon can be used. Figure 1.1 illustrates the key components of such a plasma system ± the glass vessel is evacuated by a vacuum pump with an inline liquid nitrogen trap. The introduction of the precursor monomer(s) is controlled by manual or automatic valves whilst the vessel pressure is monitored. Power from a generator is coupled to the system via an external driver electrode ± seen here as a coil, although there are many other designs (Clark and Dilks, 1977; O'Toole et al., 1995; Alexander and Duc, 1998; Candan et al., 1998; Voronin et al., 2006). In order to match the impedance of the generator to that of the plasma, a matching network incorporating variable capacitors is required. In the coil configuration, the coil itself can be terminated at ground, or left as an open circuit. An important point to note is that the excitation wire passes over and around the chamber such that for RF at 13.56 MHz oscillating plasma sheaths sustain the plasma. Many researchers utilizing this type of system chose to place the non-conducting polymer substrate on the vessel floor such that any coupling of the RF through the vessel wall and substrate may induce large self-bias potentials on the substrate itself leading to energetic ions bombarding the substrate. Substrates mounted on a platform in the centre of the vessel can also experience this self-bias and energetic ion bombardment; however, these potentials are usually much smaller. The matching network, cables and radiative losses of RF power result in poor power coupling efficiencies such that in a typical coil-wound system (Fig. 1.1) as little as 20±50% of the power on the dial is actually transmitted to the plasma (Barton et al., 1999). As the quantity of this power supplied increases, the coupling efficiency decreases before reaching a maximum, saturation level. The level at which this saturation occurs is dependent on many factors including the geometry and volume of the reaction chamber, the operating pressure and the choice of gas and/or monomer(s). Since no two experimental systems are exactly the same and small differences in design can lead to large changes in power coupling efficiency, it is impossible to directly correlate processes and process parameters between systems. Attempts have been made to eliminate such variations and, for research into plasma treatment and etching, the Gaseous Electronics Conference (GEC) RF reference cell was developed (Hargis et al., 1994). However, comparative studies with these systems have highlighted the difficulty of equivalent system construction and diagnosis (Sobolewski, 1995; Graham et al., 1999). Capacitively coupled systems fitted with internal electrodes are an alternative (Hegemann et al., 2005; Vassallo et al., 2006; Hegemann et al., 2007). In such

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ß Woodhead Publishing Limited, 2011 1.1 Schematic of a typical RF (13.56 MHz) plasma system for the preparation of plasma polymer and co-polymer surfaces. Source: Figure 1, p. 421 in Haddow, D.B., MacNeil, S. and Short, R.D. (2006), `A cell therapy for chronic wounds based upon a plasma polymer delivery surface'. Plasma Processes and Polymers, 3, 419±430. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.

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systems one electrode is driven whilst the second, on which substrates to be coated are generally placed, acts as the return. Such systems are efficient with regards to power coupling, and adjusting the distance between the electrodes offers a further means of modifying the plasma parameters (Kawamura et al., 1999). Drawbacks include the potential to sputter the electrode material during processing ± a source of contamination in the resultant film and the changes to the physical make-up of the plasma when non-conducting polymer film builds up on the electrode surface (Roth, 1995).

1.4

Plasma parameters

Despite there being advantages and disadvantages to either method of RF power coupling, the majority of systems used for research are variations on the first with an external driven coil. The key parameters (cited in the literature) for the configurations of this type are power, as read from a dial on an external meter located on the generator, whether this power is applied continuously or pulsed, the monomer flow rate and the related parameter of the monomer pressure, and the reactor geometry. Each of these parameters affects the intrinsic parameters of the plasma and, as a result, the plasma polymer film formed and the following sections briefly discuss these parameters. For a more detailed description of technological plasmas the reader is directed to a number of excellent texts on the subject in the suggested reading section at the end of this chapter.

1.4.1

Monomer(s) flow rate

One important parameter in plasma processing is the flow rate () of the monomer gas into the system which sets the rate at which fresh monomer replaces fragmented species. This flow rate is related to the number of molecules in the vessel (N) and their residence time () by: N 1:1  Here  is expressed as the number of molecules per second but it is generally quoted and measured in standard cubic centimetres per minute (sccm). Typically monomer flow rates of the order of 1 to 20 sccm are used resulting in discharge pressures in the mTorr to 10s of mTorr range (Candan et al., 1998; Voronin et al., 2007b). For a given pumping speed of the vacuum system used to evacuate the reactor vessel,  will determine the pressure of operation. Hence, in a typical system at 10 mTorr, (N) is 3:3  1020 mÿ3 and so, with a volume of 1  10ÿ3 mÿ3 this equates to 3:3  1017 molecules in the reactor vessel such that a flow rate of 5 sccm, equivalent to 2:64  1018 molecules per second, results in a resident time () of 125 ms. For a greater pressure of 50 mTorr the resident time would equate to 0.6 s at the same flow rate whilst for systems operating with low flow rates (e.g. ˆ

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1 sccm) then () equates to 3 seconds. So we can note that the typical residence times of precursor monomer(s) are in the range of milliseconds to a few seconds.

1.4.2

Plasma power

Power is an important factor which determines such properties as the state of the plasma, its density, ion energies and the degree of monomer fragmentation (Panchalingam et al., 1993; Savage et al., 1993; Waldman et al., 1995; O'Toole et al., 1996; Coulson et al., 2000; Mota et al., 2002, Mitu et al., 2003). The following discussion focuses on RF power coupling (both continuous and pulsed) since, for the purposes of generating plasma polymer coatings for application on biomaterial and medical device surfaces, this is the method of choice. The retention of functionality from monomer(s), through the plasma to polymeric film was perhaps first described by Richard Ward in the early 1980s at the University of Durham (Ward, 1985). Indeed it was Ward who was probably first to observe the inverse relationship between plasma power and functional group retention for a series of carboxylic acids. Many studies followed in the late 1980s and early 1990s focussing on plasma power and the retention of functional groups (Savage et al., 1993; Ward and Short, 1993; Ryan et al., 1996; Alexander and Duc, 1998). For example, Ward and Short, in a study using a series of methacrylate monomer precursors, showed an inverse relationship between power and functional group retention. The explanation given being that reduced power coupled to the plasma results in reduced fragmentation of the monomer. Subsequent studies, both with other compounds and pulsed plasma, confirmed this observation and it is now generally accepted that highly functionalized films, closely resembling their analogue(s) can be obtained from the use of low power (Haddow et al., 2000a; Fraser et al., 2002). However, as shown by Ward, Short and others, perhaps a more meaningful parameter than applied power alone is the power/flow rate ratio (P=) adapted from the ratio (P=M) first described by Yasuda (Yasuda, 1985; Ward and Short, 1995; Candan et al., 1998; Chen and Yang, 1999; Oran et al., 2005). Generally, it will be seen that an increase in power and thus an increase in (P=), can lead to a reduction in the functional group retention from the monomer precursor(s). Figure 1.2 (adapted from Ward and Short, 1995) illustrates this point for plasma polymer films prepared from three methacrylate monomers. As (P=) was increased the functional group retention, here determined by the % retention of carboxylate, decreased. This (P=) ratio also gives a measure of the average energy absorbed per atom or molecule in the reactor system and thus (based upon ) establishes whether the monomer, by the action of dissociating electrons, is consumed or replenishes the fragmented gas: the former regime is known as the monomer deficient regime and the latter the power deficient regime (Yasuda, 1985). It will be seen that control of functional group density in the resultant coating is important in mediating the biological-biomaterial

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1.2 The effect of P= on functional group retention in plasma polymer films prepared from a selection of methacrylate monomer precursors (after Ward and Short, 1995). Reprinted from Polymer, 36, Ward, A.J. and Short, R.D. A t.o.f.s.i.m.s. and x.p.s. investigation of the structure of plasma polymers prepared from the methacrylate series of monomers. 2. The influence of the W/ F parameter on structural and functional-group retention, 3439±3450. Copyright 2009, with permission from Elsevier.

interaction. The average energy available per atom or molecule can be understood in terms of the parameter Emean (Bauer et al., 2005a). Emean is given by: Pabs  1:2 N with Pabs being the true, absorbed power dissipated into the plasma (not that simply read off the power dial), N the number of resident particles (monomer) and  the residence time of a particle in the plasma volume. In using continuous RF power researchers have sought to increase Pabs by increasing the input power as read on the power dial and, with the caveat identified in Section 1.3, thereby control the concentration of specific functional group retained in the coating. This technique has been extensively studied for acrylic acid discharges (O'Toole et al., 1996; Haddow et al., 2000b; Sciarratta et al., 2003; Dhayal, 2006; Voronin et al., 2007b). In general it has been found that for a molecule of acrylic acid a small value of Emean, of the order of < 20 eV/molecule, corresponds to a low degree of fragmentation and so a high degree of functional group retention. A large value of Emean of the order > 100 eV/molecule corresponds to a high degree of fragmentation and so the monomer precursor is completely dissociated and functional group retention diminishes. More recently it has become increasingly popular to pulse the plasma, typically modulating the 13.56 MHz RF in the ms to s range, which is known to Emean ˆ

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adjust the plasma gas and surface chemistry (Rinsch et al., 1996; Ryan et al., 1996; Karkari et al., 2002; Voronin et al., 2006, 2007b). Thus when the plasma is switched off there is a near instantaneous (< 1 s) collapse in the RF and DC electric fields within the plasma and the charged species diffuse to surfaces ± typically within 50±100 s for light species (M < 30 amu) and 150 s for species where M > 30 amu (Voronin et al., 2007b). The analysis of films deposited in pulsed plasma revealed that their structure depends uniquely on the average dissipated energy per source gas molecule Emean in the plasma where Emean in the pulsed regime is now given by: P P ˆ 1:3 N  where is the duty cycle, i.e. the ratio of plasma-on time to total cycle length such that ˆ ton =T, where T is the period. A Pabs of 1 W sccmÿ1 corresponds to 15.5 eV of dissipated energy per source gas molecule (Bauer et al., 2005a, 2005b). Timmons et al. undertook a comprehensive physical and chemical analysis of pulsed plasma polymerization of allyl alcohol (Rinsch et al., 1996). The results (Fig. 1.3) concluded that functional group retention in the plasma polymer film was strongly influenced by the duty cycle employed. In particular, the degree of alcohol functionality retained increased as the RF duty cycle was decreased. It should be emphasized that Equation [1.3] is only applicable if the precursor monomer(s) residence time in the plasma is much longer than the pulse cycle such that Emean can readily be tuned by controlling the duty cycle and/or the plasma power. Pulsing not only changes the applied power but also modifies plasma parameters such as plasma sheath formation and potentials across the sheath which in turn determines ion energies. Indeed for some frequency and duty regimes pulsed plasma can yield greater time-averaged plasma densities and electron temperatures than an equivalent continuous power supply. The application of both continuous and pulsed power in an RF coupled system has been modelled by Liebermann and Ashida using a global power balance (Lieberman and Ashida, 1996). Using an electropositive (argon) discharge and an electronegative (chlorine) discharge they modelled the discharge density and temperature. For an electropositive discharge under the same time-average power they noted increased electron densities (ne) for pulsed discharges as compared to equivalent continuous power ± as much as almost four times greater under certain conditions. Dhayal and Bradley showed in an acrylic acid discharge at 19.5 mTorr pressure, 500 Hz, and a 50% duty cycle that during plasma on times (ton) the electron temperature reached 4±5 eV, with an initial burst of up to 8 eV (Dhayal and Bradley, 2005). During the plasma off time (toff) the electron temperature (Te) decreased to less than 0.5 eV with ion energies of 40 eV. The plasma density (ne) was found to vary over a full duty cycle ranging from 4  1016 mÿ3 during ton and decreasing to 5  1014 mÿ3 during toff. Emean ˆ

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1.3 Functional group retention in a plasma polymer of allyl alcohol as a function of RF duty cycle. Reprinted in part with permission from Rinsch, C.L., Chen, X.L., Panchalingam, V., Eberhart, R.C., Wang, J.H. and Timmons, R.B. (1996) `Pulsed radio frequency plasma polymerization of allyl alcohol: controlled deposition of surface hydroxyl groups'. Langmuir, 12, 2995±3002. Copyright 2009 American Chemical Society.

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1.4.3

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Plasma pressure

Pressure (P) is an important parameter related to the number of molecules in the vessel (N) such that: P ˆ Nkb T

1:4

where T is the gas temperature and kb the Boltzmann constant. Increasing N, generally achieved by increasing , leads to the gas becoming collisional in that the mean free path length for neutral±neutral collisions ˆ 1=N , where  is the collisional cross section, becomes smaller than the reactor vessel dimensions (Chapman, 1980). For argon, assuming a simple geometric cross-section and billiard ball collisions  ˆ 10ÿ20 mÿ2 in a typical system at 10 mTorr, N ˆ 3:3  1020 giving ˆ 30 cm similar to the length of many vessels used. Given the typical pressure range stated in Section 1.4.1 the plasma used for polymer film formation are marginally collisional (Alexander and Duc, 1998; Voronin et al., 2006). These neutral±neutral interactions are essentially elastic scattering; however, within the polymerizing environment other important reactions can and do occur. Studies have demonstrated that ion-neutral collisions between precursor monomer units and charged oligomers, where  may be greater due to charge polarization, occur such that for these interactions is very much smaller that the vessel dimensions (Shepsis et al., 2001; Fraser et al., 2002).

1.5

Intrinsic parameters

We now proceed to identify a number of the important intrinsic parameters of plasma. Namely, potentials in the plasma, at surfaces and at the boundary between the plasma and the space charge sheath that forms in front of these surfaces, the temperature (particle energies) and the particle densities and ion flux arriving at surfaces. In the course of this discussion it will be shown how manipulation of the extrinsic properties of power and pressure can provide a degree of control of these intrinsic parameters and thereby influence the formation of the plasma polymer film. In many of the studies previously undertaken this control has often been rudimentary with results that have been incompletely understood. However, where studies of both the physical and chemical parameters have been made concurrently, a greater, albeit debatable insight into the chemical processes responsible for plasma polymer film formation have arisen (O'Toole et al., 1995, 1996; Beck et al., 1998; Fraser et al., 2002; Barton et al., 2003, 2005; Dhayal, 2006; Voronin et al., 2006, 2007a; Swindells et al., 2007).

1.5.1

Potentials in plasma and at surfaces

In a plasma, insulating or electrically isolated surfaces will assume a potential such that the fluxes of positive (ions) and negative (electrons) charge carriers

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arriving will be equal (Lieberman and Lichtenberg, 1994). In the case of classic DC plasma columns the potential of the plasma measured relative to ground, the plasma potential (Vp), is typically a few volts above the most positive surface in the discharge (Chapman, 1980). This potential ensures that positively charged ions are accelerated out of the plasma and, on average, negatively charged ions and electrons are retarded such that the net current flow of each charged species is equal and is given by that delivered by the power supply. However, the picture is different in an RF powered system. Under collisionless conditions, where the number of collisions between ions in the plasma sheath is assumed to be negligible, the potential drop across the sheath separating the surface and the plasma determines the impact energy of ions. For an insulating surface the flow of ions and electrons across the sheath must be equal as no net current can flow to the surface. In the DC case the sheath potential drop, that is the difference between the plasma potential (Vp) and floating potential (Vf), is given by: " r# kTe 1 M ‡ ln V p ÿ Vf ˆ 1:5 e 2 2m where Te is the electron temperature, M the average mass of the ions and m the electron mass (Lieberman and Lichtenberg, 1994). On the right-hand side of the equation in the bracket the 12 is due to the pre-sheath (a region of plasma in front of the sheath) potential drop while the remainder is due to the sheath. Clearly the potential drop (Vp ÿ Vf ) and hence maximum ion energy (Eimax) are a function of Te. In RF powered plasma Vp, measured relative to a grounded surface, has two components arising from the DC and RF currents such that: Vp ˆ VDC ÿ VRF

1:6

The relative magnitudes of these potentials depend strongly on a number of factors including electrode configuration and most especially (such as seen in Fig. 1.1) the effective area of the driver electrode, i.e. the external coil, and the earthed electrode, i.e. the metal flanges (Dendy, 1995). In an RF discharge the insulating substrate potential is usually more negative than the classical floating potential (Vf) arising in a DC discharge. We term this the self-bias potential (Vsb) and this potential is significant because under collisionless conditions ions crossing the plasma-polymer sheath gain a maximum energy: Eimax ˆ Vp ÿ Vsb

1:7

This self-bias potential, in the presence of RF sheath potentials and hence the maximum energy, may be expressed as: " r#   kTe 1 M kTe eVrf ln I0 1:8 ‡ ln Eimax ˆ Vp ÿ Vsb ˆ ‡ e 2 e kTe 2m

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where I0 is the modified Bessel function of zero order and Vp is the mean local plasma potential (Annaratone and Braithwaite, 1991; Annaratone et al., 1992). Consideration of Equation [1.8] shows that as RF potentials increase, the selfbias voltage Vsb becomes more negative and further, for large RF amplitudes where Vrf >> kTe =e the second term on the right-hand side approximates to Vrf and the expression reduces to: Eimax ˆ Vp ÿ Vsb  Vrf

1:9

The potential that the ions fall through to the polymer film in this case is governed by the RF potential in the plasma and not Te. Studies of continuously driven RF plasma of acrylic acid have observed sheath potentials of 60 V where 50% is due to the RF and 50% due to the electrons (Chapman, 1980). In a pulsed RF plasma using the same acrylic acid monomer sheath, potentials of up to 100 eV were observed, 80% of this being due to RF modulation in the sheath (Voronin et al., 2006). Further, in a spectrometric investigation of the plasma polymerization of acrylic acid by Haddow et al. the ion energies were determined as a function of power (Haddow et al., 2000b). Figure 1.4 illustrates this for the m/z 73 ion (i.e. [M + H]+) relative to both a grounded, conducting surface and a self-biased, non-conducting (i.e. electrically insulated) surface. It can clearly be seen from Fig. 1.4 that ions, crossing the plasma sheath, will arrive at substrate surfaces with energies dependent on both the power supplied

1.4 Peak ion energy of the m/z 73 ion arriving at grounded and self-biased surfaces as a function of P in a continuous wave plasma of acrylic acid (after Haddow et al., 2000b). Reprinted in part with permission from Haddow, D.B., France, R.M., Short, R.D., Bradley, J.W. and Barton, D. (2000) `A mass spectrometric and ion energy study of the continuous wave plasma polymerization of acrylic acid'. Langmuir, 16, 5654±5660. Copyright 2009 American Chemical Society.

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to the plasma and the nature of the substrate material. This observation once again serves to caution researchers seeking to make comparisons between different plasma systems.

1.5.2

Temperature (particle energies)

In the various types of plasma used for surface treatments a number of species including electrons, ions, atoms, metastables and, in the case of molecular gases, fragments are present. These species are not in thermodynamic equilibrium; although the electrons have elevated temperatures, the more numerous heavy particles are at ambient temperature ± it is for this reason that these plasma are often referred to as `low temperature'. The mass of ions in a plasma are typically 104±105 times the mass of electrons; however, the electrical charge on these two species is of the same magnitude (with opposite charge). This leads to the electrons experiencing acceleration from the applied electric field 104±105 times greater than ions and so the kinetic electron temperature (Te) has values of a few electron volts (eV) ± sufficient to break chemical bonds. Since the lighter electrons are much more mobile than the ions which, in relative terms, are essentially static in the plasma bulk (but not in the sheaths), they can respond to the RF field and transfer much of their energy in inelastic collisions with the monomer molecules. Even if the energy transferred is insufficient to result in fragmentation, or ionization, the compound may be raised to an excited state. One route by which the excited state may `relax' is by the emission of electromagnetic radiation and plasmas can be rich sources of high-energy (VUV) photons. Indeed, the energy of this VUV emission is sufficient to also effect chemical reactions ± particularly in polymers. Some of this electromagnetic radiation is in the visible region, hence the glow of the discharge.

1.5.3

Plasma density and ion flux

The degree of ionization in `low temperature' plasma is typically small with values of 10ÿ4 to 10ÿ6 being common. In practical terms in systems with internal electrodes this equates to only 1 charged particle per 10 000 to 100 000 neutrals which yields charged particle densities in the order of 1015 to 1016 mÿ3. In systems such as those illustrated in Fig. 1.1, however, the degree of ionization is often increased as much as two-fold with corresponding charged particle densities of 1016 to 1018 mÿ3. In almost all plasma environments the number density of positive and negative species are nearly equal. In the case of noble gas plasmas in the bulk of the plasma the number of electrons will be the equal to the number of ions, i.e. ni ˆ ne since the number of negatively charge ions is considered to be negligible. If negative ions are present such as in the presence of oxygen ions in an acrylic acid plasma or fluoride ions in a fluorocarbon

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ÿ plasma this quasi-neutrality is represented thus: n‡ i ˆ ne ‡ ni (Lieberman and Lichtenberg, 1994; Swindells et al., 2007). The plasma density is determined by the power input into the plasma minus the power lost as particles with energy leaving the boundaries and the energy being radiated away. In most RF plasma polymer discharges this plasma density is peaked at the centre and falls by less than one order of magnitude to the wall sheaths. In the wall sheaths or at a substrate the electron density falls to negligible levels faster than the ion density. At the boundary of the sheath and the plasma the ions require a minimum energy to allow the sheath to be stable. This condition, called the Bohm sheath criterion, sets the ion flux to the sheath edge. For a DC plasma or slowly varying fields in a plasma of electron density (ne) and electron temperature (Te) in the bulk, the flux of ions to a wall or substrate (ÿi ) is given by:   r 1 kTe ne ÿi ˆ exp ÿ 1:10 Mi 2

where Mi is the ionic mass which, in a multi-component plasma, is replaced by an effective mass. At 10 mTorr and 10 W input power, where typically ne  1±5  1015 mÿ3 with kTe/e  1±3 eV, ion fluxes to the substrate are about 6±12  1018 mÿ2 sÿ1 (Voronin et al., 2006). These values compare well with measurements of ion fluxes in other systems where the driver coil is external to the vessel (Beck et al., 1998; Barton et al., 1999).

1.6

Potential biomaterial applications

In addressing the application of plasma polymerization as a method of preparing biomaterial surfaces the following identifies and summarizes the perceived advantages this surface engineering technique offers: 1. Ultra thin films that do not effect bulk material. Plasma polymer coatings have thicknesses that are generally of the order of a few tens of nanometres (although the technology is capable of much greater where desired). As such the coatings have no effect on the underlying bulk material properties such as mechanical strength, flexibility, transparency, etc., that determined the initial material selection (Yasuda, 1985). 2. Conformal, uniform, pin-hole free. Plasma polymer coatings can be applied to complex geometric forms such as tissue culture plates, tubing, synthetic heart valves and porous polymer scaffolds (Tran et al., 1999; Carlisle et al., 2000; Sefton et al., 2001; Wang et al., 2005; Barry et al., 2006). 3. Can be insoluble or, where required, can be made to be soluble. Key to the process of plasma polymer film formation is the control of film chemistry or cross-link density ± properties that can be manipulated through control of plasma processing parameters such as P=. Where desired, this chemistry

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7.

8.

Surface modification of biomaterials can be highly insoluble such as films formed from fluoro-containing monomer precursors. An example where film solubility has proven pivotal is in the development of MySkinTM, a skin cell therapy which is discussed in greater detail in Section 1.6.3 (Haddow et al., 2006). Sterile and sterilizable. A requirement of biomedical and medical devices is that they be free of any potentially harmful pathogens. The twin techniques of plasma polymerization and plasma surface treatment have both shown application as processes of sterilization (Holy et al., 2001; Haddow et al., 2003). Where additional manufacturing steps are required prior to clinical use plasma polymer coatings can withstand further sterilization by internationally accepted methods such as UV irradiation (Haddow et al., 2006). Do not necessarily age. Suppliers of biomaterials and medical devices are required to demonstrate proof of product stability or `shelf-life'. Under suitable storage conditions many plasma polymer coatings have shown resistance to adverse environmental conditions liable to cause degradation or `aging' (Whittle et al., 2000). Process readily integrated into current Good Manufacturing Processes (cGMP). The technology identified in Section 1.3 can be up-scaled to facilitate both batch and continuous manufacturing processes operated under cGMP. Medicinal products based on plasma polymer coatings have received licence to market from international regulatory bodies. As identified previously, there are a range of processing parameters that can be optimized with respect to the coating's physicochemical properties such as functional group retention and film thickness. Identifying the plasma conditions that lead to retention of functional group is perhaps the most significant development in the field since the 1980s; it provides films displaying predominately (if not exclusively) a single functionality and these can be used directly, or as a platform for assembling further chemistry or biomolecules (Kingshott et al., 2002; Siow et al., 2006). Ability to spatially pattern (controlled deposition of sub-millimetre features). Cells of different types co-cultured present both an opportunity and a challenge. On one hand co-culture has been shown to improve culture protocol with enhanced maintenance of cell phenotype; however, one cell may readily overgrow the other. The deposition of patterned plasma polymer coatings such that different chemistries are present on the one surface offers a potential route to overcome this problem (Bullett et al., 2001). A further advantage of plasma in the provision of enhanced culture surfaces is the ability to readily pattern the deposited layers, so different chemistries may be deposited on the one surface whereby each may be tailored to a specific cell type (Phillips et al., 2001).

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Interaction at the biological±biomaterial interface

As noted the biological±biomaterial interaction is mediated at the surface. As a consequence it is the surfaces of these materials that are critically important in determining both the biological responses to the biomaterial and the biomaterial responses to the physiological environment (Hubbell, 1995; Babensee et al., 1998; Ratner and Bryant, 2004). These events are intended to isolate the implant (biomaterial) and subsequently heal the wound site. Indeed the resultant changes to the biomaterial surface brought about by the physiological environment, in turn, modify the biological response resulting in a complex cascade of events (Anderson et al., 2008). The primary goal, then, of biomaterials research is to design surfaces that either do not initiate a response or elicit one that is perceived to be desired. In order to tailor these biological response(s) researchers have sought to modify the physicochemical characteristics of the biomaterial such as surface energy, charge and chemistry. A number of methods have been employed, i.e. plasma treatment with inert gases and reactive gases and ion implantation (Klee and Hocker, 1999; Chu et al., 2002; McKenzie et al., 2004). Whilst these methods have found application, the focus of this chapter is the use of plasma polymer coatings which, by selection of precursor monomer(s) and processing, present a surface with the (perceived) desired physicochemical characteristics as determined by conventional wisdom. Certain features of plasma polymers, as identified in the above summary, are axiomatic to their exploitation as coatings for biomaterials and we do not comment upon these further. Other features such as functional and structural group retention are those that have been exploited and it is these that have been utilized to modify one or more physicochemical properties of a surface.

1.6.2

Plasma polymers and surface wettability (cell culture)

In 1971 Robert Baier presented a study on the role of surface energy in thrombogenesis addressing issues associated with biomaterials in contact with blood (Baier, 1972). The observations Baier made led him to propose that the most important criterion for good cardiovascular prosthesis was the surface energy of the biomaterial. An important caveat to this was that Baier qualified his observations; stating that whilst a low-critical surface energy was a practical material characteristic, this was not the only criterion to be evaluated when improving biomaterial performance. An early example of how the plasma processing conditions can control surface wettability was demonstrated for Teflon-like plasma polymer films (Favia, 1997). Using feedstock gases of C2F6 with H2 or CH4 in the glow and afterglow regions of an RF driven plasma a series of films with a range of fluorine/carbon ratios, as determined by XPS, were produced. Advancing water

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contact angle measurements on the films ranged from slightly hydrophilic to hydrophobic. This increased hydrophobicity, in good agreement with conventional polymers, correlating with increasing fluorine/carbon ratio. More recently the surface modification of NafionTM, the preferred membrane material for in situ glucose biosensors, using a range of plasma copolymer coatings was examined (Valdes et al., 2008). Plasma copolymers of tetraethylene glycol dimethyl ether (tetraglyme) and 2-hydroxyethyl methacrylate (HEMA) with varying ratios of tetraglyme : HEMA were prepared. Chemical characterisation by XPS and contact angle measurements derived a correlation between the surface wettability and hydroxyl content with this content decreasing as the ratio of HEMA in the feedstock was increased.

1.6.3

Plasma polymers and surface functional groups (cell attachment)

A successful research programme extending over several years was undertaken by groups led by Short and MacNeil at the University of Sheffield, UK, whereby lower plasma power conditions, i.e. a reduction in P=, were used to retain monomer functionality into a coating and, by a plasma copolymerization method, control functional group density (Beck et al., 1996). Note that for the preparation of chemically functionalized surfaces the use of self-assembled monolayers (SAMs) is a well-developed, alternative method (Mrksich et al., 1996; Schreiber, 2004; Ruckenstein and Li, 2005; Morgenthaler et al., 2008; Raynor et al., 2009). However, whilst SAMs have proven to be an excellent aid in studies of the biological±biomaterial interface in vitro, their application in a clinical, in vivo environment presents a number of technological challenges. For Short and MacNeil, the objective of their work was to utilize plasma polymerized coatings and, as the project developed, the subsequent delivery of skin (keratinocytes) from a single surface for wound healing. Initially the collaboration sought to establish if keratinocyte expansion on tissue culture polystyrene (TCPS) could be improved by coating with a plasma polymer in preference to collagen I (the favoured method at that time). The challenge of defining a surface for in vitro keratinocyte expansion was to establish a surface which did not promote cell differentiation but which could, in combination with appropriate culture media, maintain keratinocytes in a proliferative phenotype such that they would be capable of attaching, migrating and forming colonies. Plasma polymer coatings with different densities of acid, amine and alcohol functionality were prepared across two separate studies (France et al., 1998a, 1998b). Using collagen I coated TCPS as a `gold' standard control and uncoated TCPS as a negative control the attachment of keratinocytes on these plasma polymer coated TCPS surfaces was measured at 24 hours (Fig. 1.5) (France et al., 1998a).

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1.5 Attachment of primary keratinocytes to plasma-copolymerized surfaces at 24 hours as a percentage of attachment to collagen I. Data compiled from two studies (France et al., 1998a, 1998b).

The results from the series of acrylic acid plasma polymers were very encouraging with the measured cell number on the 2.3% acid surface at 24 hours being equivalent to that seen on collagen I. Microscopic examination of the cells on this surface and collagen I revealed cell features consistent with good attachment, spreading and colony formation. On the low acid surface, following a more extended culture period, keratinocytes proliferated and spread to form confluent sheets. This behaviour was similar to that observed on collagen I and after 7 days in culture the cells on the 2.3% acid plasma polymer were as confluent as those on the collagen I surface (Haddow et al., 1999). A more complete account of these studies, the development of a bandage (MySkinTM) for delivering skin and its clinically approval for the treatment of burns and chronic wounds, can be found elsewhere (Haddow et al., 2006). In addition, MacNeil and colleagues have continued to extend the use of plasma polymer surfaces in the expansion and delivery of other cell types including corneal and melanocyte (Eves et al., 2005; Bullock et al., 2006; Notara et al., 2007; Deshpande et al., 2009). In another study of cell-biomaterial interaction the group of Timmons examined the effect of amine functionalized plasma polymer films on neuronal cell adhesion (Harsch et al., 2000). Here, pulsed plasma films of allylamine, previously characterized by XPS and trifluoroacetic anhydride (TFAA) derivatization, were prepared using two duty cycles ± 3/45 and 3/5 (ton/toff) with the lower duty cycle films showing greater amine functional group retention (Calderon et al., 1998). At 24 hours cell dispersion was better on the higher amine functionalized (3/45) surface; however, the authors note that after two weeks culture no differences in cell morphology were detectable.

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1.6.4

Surface modification of biomaterials

Plasma polymers and spatial patterning

In developing enhanced culture surfaces a further advantage of surfaces prepared from plasma polymers is the ability to readily pattern the deposited layers (Plate I between pages 208 and 209) such that different chemistries, each tailored to a specific cell type, may be deposited on the one surface (Bullett et al., 2001). Where patterning of surfaces is desired the maintenance of pattern fidelity requires an ability to control the properties and formation of the plasma sheath (Section 1.5.1). Recently it has been shown that plasma sheath formation through masks (and indeed porous structures) influences plasma polymer formation (Zelzer et al., 2009). The relative dimensions of sheath, mask feature size and, in the case of porous three-dimensional substrates, pore diameter are critical in determining the ionic species that participate in film formation. Plasma patterning of this type can overcome an issue often encountered during the co-culture of two cell types where one cell type overgrows the other (Phillips et al., 2001).

1.6.5

Plasma polymers and surface functional group (protein binding)

As previously mentioned the surface of plasma polymer coated biomaterials and implants becomes modified with an adsorbed protein/polysaccharide layer when exposed to the biological fluid in vivo, the cell medium constituents in vitro, or by cell-deposited extracellular matrix proteins. The adsorbed protein/ polysaccharide film is fundamentally important for the success of the biomaterial because the structure and composition of the film determines the type and extent of the biological response towards the entire biomaterial. Furthermore, the nature of this adsorbed film depends on the material surface properties and so researchers have sought to adsorb specific proteins and polysaccharides to plasma polymer surfaces in a controlled manner (Lassen and Malmsten, 1997; Tang et al., 1998; Whittle et al., 2002; Zhang et al., 2003). These studies have sought to better understand: · the orientation and conformation of these adsorbed proteins and polysaccharides, · the spatial density of these and, · to what extent this prepared pseudo-biological surface can mediate the biomaterial±biological interaction. In the simplest instance, a plasma polymer coating can be used to `present' a passively adsorbed biomolecule in an optimal conformation, for subsequent cell attachment. For example, Whittle et al. (2002) have studied the passive adsorption of vitronectin, collagen and immunoglobulin G (IgG) from single protein solutions onto plasma polymer surfaces prepared from alcohol, acid,

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amine and hydrocarbon containing monomers with a range of surface energies. From this study it became apparent that there is no `magical' plasma polymer film that promotes the adsorption of active proteins and that protein adsorption is not entirely dependent on the degree of hydrophilicity of the plasma polymer surface. This work was followed up by Bullett et al. (2003), who demonstrated that the highest amount of immunologically active IgG was achieved on the more hydrophilic plasma polymer deposits. As stated by the authors in the above studies, it is apparent that protein adsorption on plasma polymers is dependent not only on wettability but on a range of other parameters including surface charge and chemistry, solubility, swelling rate and the nature of the protein of interest. A higher concentration of adsorbed protein on the plasma polymer does not necessarily correlate with the surface displaying a higher level of protein activity and these studies provide further evidence that no single physical and/or chemical property dictates biomaterial±biological interaction.

1.6.6

Plasma polymers and functional group retention (immobilization of biologically active molecules)

The `simple' adsorption of proteins and biologically active molecules to a plasma polymer surface is not the only method whereby researchers have sought to develop a pseudo-biological surface. Some of the other strategies employed include the generation of anti-fouling coatings by immobilization of polysaccharides onto amine surfaces via standard carbodiimide cross-linking chemistry or onto aldehyde surfaces through reductive amination (McArthur et al., 2000; McLean et al., 2000; Blattler et al., 2006); the attachment of enzyme to amine surfaces via a glutaraldehyde linker (Abbas et al., 2009); and the immobilization of antibacterial agents to amine surfaces based on azide/nitrene chemistry (Al-Bataineh et al., 2006). Arguably the method of choice for many researchers is the use of surface amine groups using carbodiimide chemistry (Siow et al., 2006). However, carboxylic acid groups can also be used to immobilize biomolecules through the accessible primary amines in the biomolecule. Recently, it has been reported how surface carboxylic acid groups, formed from plasma copolymerization of acrylic acid and 1,7-octadiene, may be used to covalently immobilize an anti-myc-tag (9E10) antibody. This antibody can then be used to capture (any) myc-tagged biomolecules (Walker et al., 2009). In this study the 9E10 antibody was used to immobilize the myc-tagged intercellular signalling molecule delta-like-1 (DII1). The importance of this molecule is that it regulates (inhibits) cell differentiation, and by identifying a critical surface density of DII1, it is possible to fabricate a culture surface for stem cells that permits cell expansion, without differentiation. A gradient of an amine functionalized plasma polymer surface, generated through the plasma copolymerization of allyl amine and 1,7-octadiene, has also

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1.6 Comparison of the amount of heparin bound across the length of the coverslip (represented by S atomic %, ·) and the extent of biological function as measured using the Link_TSG6 binding assay (}). The dotted line indicates the likely background reading that should be deducted from the Link_TSG6 results. Source: Figure 2, p. 1167 in Robinson, D.E., Marson, A., Short, R.D., Buttle, D.J., Day, A.J., Parry, K.L., Wiles, M., Highfield, P., Mistry, A. and Whittle, J.D. (2008) `Surface gradient of functional heparin'. Advanced Materials, 20, 1166±1169. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission.

been described for study of the electrostatic adsorption of functional heparin (Robinson et al., 2008). Heparin is an important biomolecule recognized for its protein-binding capacity which is difficult to use in controlled studies of heparin±protein interactions since it does not readily bind to plastic in a functional state. This study demonstrated that whilst the amount of adsorbed heparin increased according to the surface concentration of amines in a gradient fashion (Fig. 1.6), this increased adsorption was not accompanied with a continued, corresponding rise in heparin function. The functionality of the heparin gradient was shown by using the platform to capture the Link_TSG6 macromolecule, which is known to readily bind to heparin and the activity of the Link_TSG6 determined by ELISA. The advantage of this approach is that a range of biomolecule concentrations can be screened on a single substrate surface thus reducing the amount of (potentially) very expensive biomolecules required for each assay.

1.6.7

Plasma polymers and bioactive incorporation

An alternative to covalent immobilization or adsorption of biomolecules is to encapsulate the biomolecule or drugs into a plasma polymer coating. This approach allows the drug to be delivered to the targeted site and released over an

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extended period through simple diffusion or by biodegradation of the plasma polymer. Susut and Timmons encapsulated crystals of aspirin (acetylsalicylic acid), an inflammatory analgesic, into an allyl alcohol plasma polymer by coating the crystals in a rotatable cylindrical glass plasma reactor using pulsed RF power to lower the duty cycle and so minimize drug decomposition. Power input, coating time and duty cycle were all found to affect the drug release rates with lower rates of release being observed when any one of the above parameters was increased. Another case in point is the preparation of antimicrobial coatings (Del Nobile et al., 2004; Hume et al., 2004; Jiang et al., 2004). In one study, the group of Favia utilized a silver electrode and simultaneously sputtered/deposited a plasma polymer film in an atmosphere of diethyleneglycol dimethylether (DEGDME). The poly(ethyleneoxide) (PEO)-like coating, loaded with silver ions, demonstrated enhanced inhibition to Alicyclobacillus acidoterrestris growth when compared to both an unloaded (DEGDME) plasma polymer film or an uncoated substrate of polyethylene.

1.6.8

Plasma polymers and structural retention

Plasma polymer coatings produced using N-ispopropyl acrylamide (NiPAAm) have also attracted interest due to poly(NiPAAm)'s unique reverse transition behaviour (Bullett et al., 2006). This characteristic has significant advantages in tissue engineering because the surface of poly(NiPAAm) can be used at the physiological temperature of 37 ëC as a cell adhesive layer; however, when the temperature is reduced below a critical lower value, the material uptakes water and swells. In doing so cells are repelled from the surface allowing for an entire cell sheet to be transferred to a tissue or wound site (Matsuda, 2004). Characterization of the surface chemical and mechanical properties of a plasma polymerzied NiPAAm film has recently been presented by Cheng et al. In this study, NiPAAm, polymerized in an RF discharge in a step-wise (gradual power reduction) procedure, was compared to polyNiPAAm conventionally formed through free radical polymerziation (Cheng et al., 2005). The wettability and phase transition temperature (of 31±32 ëC) was close to that of traditional polyNiPAAm and, although the plasma polymerized NiPAAm had a higher elastic moduli and decreased swelling rate, attributed to a greater degree of cross-linking in the plasma polymer film, the values were still in the range characteristic of such hydrogels.

1.6.9

Plasma polymers and function and structure retention (low biofouling plasma polymers)

Low fouling plasma polymer coatings are seen to be advantageous when minimal biological interaction with the biomaterial is desired. For instance, to improve the longevity of contact lens wear, transparent plasma polymers have

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been used as coatings to resist protein adsorption (and so, cell attachment) for several decades (Yasuda et al., 1975; Nicolson and Vogt, 2001; Weikart et al., 2001). It is well known that polymers containing ethylene oxide units (CH2± CH2±O) inhibit protein adsorption (Beyer et al., 1997; Shen et al., 2002; Zhang et al., 2003). Low or anti-biofouling polymer coatings have been achieved through methods such as grafting, covalent immobilization and chemical crosslinking (Ulbricht and Belfort, 1996; Griesser et al., 2002; Kingshott et al., 2002; Kang et al., 2008). Low biofouling plasma polymer coatings have traditionally been achieved using glymes as the precursor monomer specifically tri(ethylene glycol) and tetra(ethylene glycol) (Mar et al., 1999; Shen et al., 2002). As an alternative to long chain PEO coatings produced from traditional precursors, Wu et al. (2000) assessed the protein-resistant capability of a plasma polymer coating produced from a low molecular weight diethylene glycol vinyl ether ± EO2V. Here the lower duty cycles used in a pulsed plasma polymerization of the EO2V monomer produced films with lower water contact angles and higher C±O/C±C ratios reflecting a higher level of ethylene oxide retention with the observation made that it was these films that were most effective in resisting protein adorption. However, it was observed that the decrease in protein adsorption was not necessarily related to an increase in surface wettability ± alternatively it was proposed that strong bonding of H2O molecules to the ethylene oxide units assisted in screening the surface to proteins. This hypothesis was considered by Zhang et al. (2003) in using surface plasmon resonance (SPR) to study the adsorption of several proteins onto EO2V coatings produced by continuous wave and pulsed plasma polymerization. The films produced by pulsed plasma polymerization under the lower duty cycles displayed a lower level of crosslinking, allowing for more water to penetrate the polymer. This resulted in increased swelling after immersion in aqueous solutions and a higher level of protein resistance compared to the other coatings.

1.7

Future trends in plasma polymers

In concluding this chapter, some emerging applications of plasma polymers in biomedical engineering will be briefly discussed. The two examples given serve to illustrate the development that both fields continue to experience. The use of stem cells in the field of advanced medical treatment has garnered significant interest in recent years and plasma polymer surfaces have a role in the development of stem cell based therapies (Wells et al., 2009). Here, surface chemical gradients from a hydrophobic plasma polymerized 1,7-octadiene to a more hydrophilic plasma polymerized acrylic acid were formed on glass coverslips. Culture of E14 and R1 mouse embryonic stem cells (mES) in differing culture media was assessed on these surfaces with cell pluripotency determined by alkaline phosphatase staining. The results demonstrated that for

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these cell lines the capacity for self-renewal was maintained if cell spreading was restricted to <120 m2. The preparation of atmospheric plasma polymers is rapidly developing into a new generation of plasma polymer technology for several reasons. Atmospheric plasma have the same capabilities of low pressure plasma with additional advantages; a very large operational pressure range from mTorr to over 10s of atmospheres and the potential for the generally low temperature plasma to be miniaturized into dimensions of the order of a few microns. The scaling down of atmospheric plasma into a microplasma with a very small `footprint' enables this technology to be directly used for chemically patterning surfaces at a biologically relevant scale without the need for any masking techniques. Thus, Fig. 1.7 illustrates features (200 m in diameter) of a plasma polymer deposit of acrylic acid on a silicon wafer produced at atmospheric pressure with a microcavity discharge source. A recent report by Aizawa et al. (2007) further serves to demonstrate the flexibility of this patterning technique. Here the authors used an atmospheric plasma jet to locally deposit films of polystyrene (Fig. 1.8) that accurately reflected a pattern generated using computer aided drawing (CAD) data inputted to a motorized stage.

1.7 An XPS image of microplasma generated acrylic acid plasma polymer spots (dark) coated onto a silicon wafer (light). The image represents a surface plot of the Si 2p peak. Silicon is absent inside the areas covered by the acrylic acid plasma polymer coating, which has a spot diameter of approximately 200 m.

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1.8 Patterns of microplasma polymerized styrene deposited using a scanning microplasma jet coating system with automatic motion controller (SMPJCSAMC). Source: Figure 2, p. 218 in Aizawa, H., Makisako, T., Reddy, S. M., Terashima, K., Kurosawa, S. and Yoshimoto, M. (2007) `On-demand fabrication of microplasma-polymerized styrene films using automatic motion controller'. Journal of Photopolymer Science and Technology, 20, 215±220. Reproduced by permission of The Conference of Photopolymer Science and Technology (CPST).

In a separate approach, plasma printing technology has emerged as a tool for generating plasma polymer patterns of a very high resolution (below 100 m). This is accomplished by stamping the sample directly against the patterned microplasma source, which inhibits the diffusion of the monomer gas. Plasma polymerized amine patterns have been generated with this technology and potential commercial applications for production of flexible printed circuits are being pursued (Kreitz et al., 2005; Hinze et al., 2008; Mobius et al., 2009). Heyse et al. have recently taken plasma polymerization further by directly incorporating biomolecules in an active state into the plasma polymer deposit (Heyse et al., 2007, 2008; Ortore et al., 2008). The few examples mentioned above are only a few possibilities that atmospheric plasmas can offer. Furthering our understanding of this technology will see atmospheric plasmas become equally as important, if not more so, than existing surface engineering techniques in the very near future. In summary the use of plasma polymers in preparing modified surfaces for biomaterials has developed since the early 1970s to become a foundation technique. Rather than attempting to capture a complete history the examples above serve to highlight the role that these surfaces have played in the (continuing) evolution of our understanding of the biomaterial-biological interface. As the knowledge of plasma polymer processes has developed, so too has that of the interface and vice versa such that an almost symbiotic relationship has now emerged.

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Sources of further information and advice

Chapman, B. (1980) Glow Discharge Processes, New York, John Wiley and Sons Ltd. Dee, K. C., Puleo, D. A. & Bizios, R. (2002) An Introduction to Tissue-Biomaterial Interactions, New York, Wiley-Liss. Dendy, R. O. (1995) Plasma Physics: An Introductory Course, Cambridge, Cambridge University Press. Grill, A. (1993) Cold Plasmas in Materials Fabrication: From Fundamentals to Applications, New York, Wiley-IEEE Press. Liberman, M. A. & Lichtenberg, A. J. (1994) Principles of Plasma Discharges and Materials Processing, Chichester, John Wiley and Sons Ltd. Manos, D. M. & Flamm, D. L. (1989) Plasma Etching; An Introduction, Boston, MA, Academic Press. Ratner, B. D., Hoffman, A. S., Schoen, F. J. & Lemons, J. E. (2004) Biomaterials Science: An Introduction to Materials in Medicine, Amsterdam, Elsevier. Reece Roth, J. (1995) Industrial Plasma Engineering, Vol. 1: Principles, Bristol and Philadelphia, IOP Publishing. Williams, D. F. (1999) The Williams' Dictionary of Biomaterials, Liverpool University Press.

1.9

References

Abbas, A., Vercaigne-Mark, D., Supiot, P., Bocquet, B., Vivien, C. & Guillochon, D. (2009) Covalent attachment of trypsin on plasma polymerized allylamine. Colloids and Surfaces B: Biointerfaces, 73, 315±324. Aizawa, H., Makisako, T., Reddy, S. M., Terashima, K., Kurosawa, S. & Yoshimoto, M. (2007) On-demand fabrication of microplasma-polymerized styrene films using automatic motion controller. Journal of Photopolymer Science and Technology, 20, 215±220. Al-Bataineh, S. A., Britcher, L. G. & Griesser, H. J. (2006) XPS characterization of the surface immobilization of antibacterial furanones. Surface Science, 600, 952±962. Alexander, M. R. & Duc, T. M. (1998) The chemistry of deposits formed from acylic acid plasmas. Journal of Materials Chemistry, 8, 937±943. Anderson, J. M., Rodriguez, A. & Chang, D. T. (2008) Foreign body reaction to biomaterials. Seminars in Immunology, 20, 86±100. Annaratone, B. M. & Braithwaite, N. S. J. (1991) A comparison of a passive (filtered) and an active (driven) probe for RF plasma diagnostics. Measurement Science & Technology, 2, 795±800. Annaratone, B. M., Counsell, G. F., Kawano, H. & Allen, J. E. (1992) On the use of double probes in RF discharges. Plasma Sources Sci. Technol., 1, 232±241. Babensee, J. E., Anderson, J. M., McIntire, L. V. & Mikos, A. G. (1998) Host response to tissue engineered devices. Advanced Drug Delivery Reviews, 33, 111±139. Baier, R. E. (1972) The role of surface energy in thrombogenesis. Bulletin of the New York Academy of Medicine, 48, 257±272. Barry, J. J. A., Silva, M., Shakesheff, K. M., Howdle, S. M. & Alexander, M. R. (2005) Using plasma deposits to promote cell population of the porous interior of threedimensional poly(D,L-lactic acid) tissue-engineering scaffolds. Advanced Functional Materials, 15, 1134±1140. Barry, J. J. A., Howard, D., Shakesheff, K. M., Howdle, S. M. & Alexander, M. R. (2006)

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Using a core-sheath distribution of surface chemistry through 3D tissue engineering scaffolds to control cell ingress. Advanced Materials, 18, 1406±1410. Barton, D., Bradley, J. W., Steele, D. A. & Short, R. D. (1999) Investigating radio frequency plasmas used for the modification of polymer surfaces. Journal of Physical Chemistry B, 103, 4423±4430. Barton, D., Short, R. D., Fraser, S. & Bradley, J. W. (2003) The effect of ion energy upon plasma polymerization deposition rate for acrylic acid. Chemical Communications, 348±349. Barton, D., Shard, A. G., Short, R. D. & Bradley, J. W. (2005) The effect of positive ion energy on plasma polymerization: a comparison between acrylic and propionic acids. Journal of Physical Chemistry B, 109, 3207±3211. Bauer, M., Schwarz-Selinger, T., Kang, H. & Von Keudell, A. (2005a) Control of the plasma chemistry of a pulsed inductively coupled methane plasma. Plasma Sources Science and Technology, 14, 543±548. Bauer, M., Schwarz-Selinger, T., Jacob, W. & Von Keudell, A. (2005b) Growth precursors for a-C : H film deposition in pulsed inductively coupled methane plasmas. Journal of Applied Physics, 98. Beck, A. J., Jones, F. R. & Short, R. D. (1996) Plasma copolymerization as a route to the fabrication of new surfaces with controlled amounts of specific chemical functionality. Polymer, 37, 5537±5539. Beck, A. J., France, R. M., Leeson, A. M., Short, R. D., Goodyear, A. & Braithwaite, N. S. (1998) Ion flux and deposition rate measurements in the RF continuous wave plasma polymerisation of acrylic acid. Chemical Communications, 1221±1222. Benitez, F., Martinez, E., Galan, M., Serrat, J. & Esteve, J. (2000) Mechanical properties of plasma deposited polymer coatings. Surface & Coatings Technology, 125, 383± 387. Beyer, D., Knoll, W., Ringsdorf, H., Wang, J. H., Timmons, R. B. & Sluka, P. (1997) Reduced protein adsorption on plastics via direct plasma deposition of triethylene glycol monoallyl ether. Journal of Biomedical Materials Research, 36, 181±189. Blattler, T. M., Pasche, S., Textor, M. & Griesser, H. J. (2006) High salt stability and protein resistance of poly(L-lysine)-g-poly(ethylene glycol) copolymers covalently immobilized via aldehyde plasma polymer interlayers on inorganic and polymeric substrates. Langmuir, 22, 5760±5769. Bullett, N. A., Short, R. D., O'Leary, T., Beck, A. J., Douglas, C. W. I., Cambray-Deakin, M., Fletcher, I. W., Roberts, A. & Blomfield, C. (2001) Direct imaging of plasmapolymerized chemical micropatterns. Surface and Interface Analysis, 31, 1074± 1076. Bullett, N. A., Whittle, J. D., Short, R. D. & Douglas, C. W. I. (2003) Adsorption of immunoglobulin G to plasma-co-polymer surfaces of acrylic acid and 1,7octadiene. Journal of Materials Chemistry, 13, 1546±1553. Bullett, N. A., Talib, R. A., Short, R. D., McArthur, S. L. & Shard, A. G. (2006) Chemical and thermo-responsive characterisation of surfaces formed by plasma polymerisation of N-isopropyl acrylamide. Surface and Interface Analysis, 38, 1109±1116. Bullock, A. J., Higham, M. C. & MacNeil, S. (2006) Use of human fibroblasts in the development of a xenobiotic-free culture and delivery system for human keratinocytes. Tissue Engineering, 12, 245±255. Calderon, J. G., Harsch, A., Gross, G. W. & Timmons, R. B. (1998) Stability of plasmapolymerized allylamine films with sterilization by autoclaving. Journal of Biomedical Materials Research, 42, 597±603.

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Candan, S., Beck, A. J., O'Toole, L. & Short, R. D. (1998) Effects of `processing parameters' in plasma deposition: acrylic acid revisited. Journal of Vacuum Science & Technology A, 16, 1702±1709. Carlisle, E. S., Mariappan, M. R., Nelson, K. D., Thomes, B. E., Timmons, R. B., Constantinescu, A., Eberhart, R. C. & Bankey, P. E. (2000) Enhancing hepatocyte adhesion by pulsed plasma deposition and polyethylene glycol coupling. Tissue Engineering, 6, 45±52. Chan, C. M., Ko, T. M. & Hiraoka, H. (1996) Polymer surface modification by plasmas and photons. Surface Science Reports, 24, 3±54. Chang, J. P. & Coburn, J. W. (2003) Plasma-surface interactions. Journal of Vacuum Science & Technology A, 21, S145±S151. Chapman, B. (1980) Glow Discharge Processes, New York, John Wiley and Sons Ltd. Chen, M. & Yang, T. C. (1999) Diagnostic analysis of styrene plasma polymerization. Journal of Polymer Science Part A ± Polymer Chemistry, 37, 325±330. Cheng, X. H., Canavan, H. E., Stein, M. J., Hull, J. R., Kweskin, S. J., Wagner, M. S., Somorjai, G. A., Castner, D. G. & Ratner, B. D. (2005) Surface chemical and mechanical properties of plasma-polymerized N-isopropylacrylamide. Langmuir, 21, 7833±7841. Chu, P. K., Chen, J. Y., Wang, L. P. & Huang, N. (2002) Plasma-surface modification of biomaterials. Materials Science & Engineering R ± Reports, 36, 143±206. Clark, D. T. & Dilks, A. (1977) ESCA Applied to polymers. XV. RF Glow-discharge modification of polymers, studied by means of ESCA in terms of a direct and radiative energy-transfer model. Journal of Polymer Science, Polymer Chemistry Edition, 15, 2321±2345. Coulson, S. R., Woodward, I. S., Badyal, J. P. S., Brewer, S. A. & Willis, C. (2000) Ultralow surface energy plasma polymer films. Chemistry of Materials, 12, 2031±2038. Dai, L. M., Griesser, H. J. & Mau, A. W. H. (1997) Surface modification by plasma etching and plasma patterning. Journal of Physical Chemistry B, 101, 9548±9554. Daw, R., Brook, I. M., Devlin, A. J., Short, R. D., Cooper, E. & Leggett, G. J. (1998) A comparative study of cell attachment to self assembled monolayers and plasma polymers. Journal of Materials Chemistry, 8, 2583±2584. Del Nobile, M. A., Cannarsi, M., Altieri, C., Sinigaglia, M., Favia, P., Iacoviello, G. & D'Agostino, R. (2004) Effect of Ag-containing nano-composite active packaging system on survival of Alicyclobacillus acidoterrestris. Journal of Food Science, 69, E379±E383. Dendy, R. O. (1995) Plasma Physics: An Introductory Course, Cambridge University Press. Deshpande, P., Notara, M., Bullett, N., Daniels, J. T., Haddow, D. & MacNeil, S. (2009) Development of a surface-modified contact lens for the transfer of cultured limbal epithelial cells to the cornea for ocular surface diseases. Tissue Engineering: Part A, 15, 1±14. Dhayal, M. (2006) Control of the plasma polymerized acrylic acid film surface chemistry at low electron temperature in low pressure discharge. Journal of Vacuum Science & Technology A, 24, 1751±1755. Dhayal, M. & Bradley, J. W. (2005) Time-resolved electric probe measurements in the pulsed-plasma polymerisation of acrylic acid. Surface & Coatings Technology, 194, 167±174. Eves, P. C., Beck, A. J., Shard, A. G. & MacNeil, S. (2005) A chemically defined surface for the co-culture of melanocytes and keratinocytes. Biomaterials, 26, 7068±7081. Favia, P. (1997) Plasma Processing of Polymers, Dordrecht, Kluwer Academic Publishers.

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Surface modification of biomaterials

Flamm, D. L. (1996) Plasma chemistry, basic processes, and PECVD. In Williams, P. F. (ed.), Plasma Processing of Semiconductors: Proceedings of the NATO Advanced Study Institute. Chateau De Bonas, France, 17±28 June 1996, Kluwer Academic. Forch, R., Chifen, A. N., Bousquet, A., Khor, H. L., Jungblut, M., Chu, L. Q., Zhang, Z., Osey-Mensah, I., Sinner, E. K. & Knoll, W. (2007) Recent and expected roles of plasma-polymerized films for biomedical applications. Chemical Vapor Deposition, 13, 280±294. France, R. M., Short, R. D., Dawson, R. A. & MacNeil, S. (1998a) Attachment of human keratinocytes to plasma co-polymers of acrylic acid octa-1,7-diene and allyl amine octa-1,7-diene. Journal of Materials Chemistry, 8, 37±42. France, R. M., Short, R. D., Duval, E., Jones, F. R., Dawson, R. A. & MacNeil, S. (1998b) Plasma copolymerization of allyl alcohol 1,7-octadiene: Surface characterization and attachment of human keratinocytes. Chemistry of Materials, 10, 1176±1183. Fraser, S., Short, R. D., Barton, D. & Bradley, J. W. (2002) A multi-technique investigation of the pulsed plasma and plasma polymers of acrylic acid: Millisecond pulse regime. Journal of Physical Chemistry B, 106, 5596±5603. Graham, W. G., Mahony, C. M. O. & Steen, P. G. (1999) Electrical and optical characterisation of capacitively and inductively coupled GEC reference cells. Symposium D ± Measurement Techniques for Technological Plasmas at the 1999 EMRS Spring Meeting. Strasbourg, France, Pergamon-Elsevier Science Ltd. Griesser, H. J. & Zientek, P. (1993) Characterization of hydrophilic plasma polymercoatings on contact-lenses. Abstracts of Papers of the American Chemical Society, 206, 237±PMSE. Griesser, H. J., Chatelier, R. C., Gengenbach, T. R., Johnson, G. & Steele, J. G. (1994) Growth of human-cells on plasma polymers ± putative role of amine and amide groups. Journal of Biomaterials Science ± Polymer Edition, 5, 531±554. Griesser, H. J., Hartley, P. G., McArthur, S. L., McLean, K. M., Meagher, L. & Thissen, H. (2002) Interfacial properties and protein resistance of nano-scale polysaccharide coatings. Smart Materials & Structures, 11, 652±661. Haddow, D. B., France, R. M., Short, R. D., MacNeil, S., Dawson, R. A., Leggett, G. J. & Cooper, E. (1999) Comparison of proliferation and growth of human keratinocytes on plasma copolymers of acrylic acid/1,7-octadiene and self-assembled monolayers. Journal of Biomedical Materials Research, 47, 379±387. Haddow, D. B., Beck, A. J., France, R. M., Fraser, S., Whittle, J. D. & Short, R. D. (2000a) Mass spectral investigation of the plasma phase of a pulsed plasma of acrylic acid. Journal of Vacuum Science & Technology A ± Vacuum Surfaces and Films, 18, 3008±3011. Haddow, D. B., France, R. M., Short, R. D., Bradley, J. W. & Barton, D. (2000b) A mass spectrometric and ion energy study of the continuous wave plasma polymerization of acrylic acid. Langmuir, 16, 5654±5660. Haddow, D. B., Steele, D. A., Short, R. D., Dawson, R. A. & MacNeil, S. (2003) Plasmapolymerized surfaces for culture of human keratinocytes and transfer of cells to an in vitro wound-bed model. Journal of Biomedical Materials Research Part A, 64A, 80±87. Haddow, D. B., MacNeil, S. & Short, R. D. (2006) A cell therapy for chronic wounds based upon a plasma polymer delivery surface. Plasma Processes and Polymers, 3, 419±430. Hargis, P. J. J., Greenberg, K. E., Miller, P. A., Gerardo, J. B., Torczynski, J. R., Riley, M. E., Hebner, G. A., Roberts, J. R., J.K, O., Vanbrunt, R. J., Sobolewski, M. A., Anderson, H. M., Splichal, M. P., Mock, J. L., Bletzinger, P., A, G., Gottscho, R.

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A., Selwyn, G., Dalvie, M., Heidenreich, J. E., Butterbaugh, J. W., Brake, M. L., Passow, M. L., Pender, J., Lujan, A., Elta, M. E., Graves, D. B., Sawin, H. H., Kushner, M. J., Verdeyen, J. T., Horwath, R. & Turner, T. R. (1994) The gaseous electronics conference radio-frequency reference cell: A defined parallel-plate radio-frequency system for experimental and theoretical-studies of plasmaprocessing discharges. Review of Scientific Instruments, 65, 140±154. Harsch, A., Calderon, J., Timmons, R. B. & Gross, G. W. (2000) Pulsed plasma deposition of allylamine on polysiloxane: a stable surface for neuronal cell adhesion. Journal of Neuroscience Methods, 98, 135±144. Hegemann, D., Oehr, C. & Fischer, A. (2005) Design of functional coatings. Journal of Vacuum Science & Technology A, 23, 5±11. Hegemann, D., Hossain, M. M., Korner, E. & Balazs, D. J. (2007) Macroscopic description of plasma polymerization. Plasma Processes and Polymers, 4, 229±238. Heyse, P., Dams, R., Paulussen, S., Houthofd, K., Janssen, K., Jacobs, P. A. & Sels, B. F. (2007) Dielectric barrier discharge at atmospheric pressure as a tool to deposit versatile organic coatings at moderate power input. Plasma Processes and Polymers, 4, 145±157. Heyse, P., Roeffaers, M. B. J., Paulussen, S., Hofkens, J., Jacobs, P. A. & Sels, B. F. (2008) Protein immobilization using atmospheric-pressure dielectric-barrier discharges: A route to a straightforward manufacture of bioactive films. Plasma Processes and Polymers, 5, 186±191. Hinze, A., Klages, C. P., Zanker, A., Thomas, M., Wirth, T. & Unger, W. E. S. (2008) ToF-SIMS imaging of DBD-plasma-printed microspots on BOPP substrates. Plasma Processes and Polymers, 5, 460±470. Hiratsuka, A., Muguruma, H., Lee, K. H. & Karube, I. (2004) Organic plasma process for simple and substrate-independent surface modification of polymeric BioMEMS devices. Biosensors & Bioelectronics, 19, 1667±1672. Holy, C. E., Cheng, C., Davies, J. E. & Shoichet, M. S. (2001) Optimizing the sterilization of PLGA scaffolds for use in tissue engineering. Biomaterials, 22, 25± 31. Hubbell, J. A. (1995) Biomaterials in tissue engineering. Bio-Technology, 13, 565±576. Hume, E. B. H., Baveja, J., Muir, B., Schubert, T. L., Kumar, N., Kjelleberg, S., Griesser, H. J., Thissen, H., Read, R., Poole-Warren, L. A., Schindhelm, K. & Willcox, M. D. P. (2004) The control of Staphylococcus epidermidis biofilm formation and in vivo infection rates by covalently bound furanones. Biomaterials, 25, 5023±5030. Jiang, H. Q., Manolache, S., Wong, A. C. L. & Denes, F. S. (2004) Plasma-enhanced deposition of silver nanoparticles onto polymer and metal surfaces for the generation of antimicrobial characteristics. Journal of Applied Polymer Science, 93, 1411±1422. Kang, G. D., Cao, Y. M., Zhao, H. Y. & Yuan, Q. (2008) Preparation and characterization of crosslinked poly(ethylene glycol) diacrylate membranes with excellent antifouling and solvent-resistant properties. Journal of Membrane Science, 318, 227±232. Karkari, S. K., Backer, H., Forder, D. & Bradley, J. W. (2002) A technique for obtaining time- and energy-resolved mass spectroscopic measurements on pulsed plasmas. Measurement Science & Technology, 13, 1431±1436. Kawamura, E., Vahedi, V., Lieberman, M. A. & Birdsall, C. K. (1999) Ion energy distributions in rf sheaths; review, analysis and simulation. Plasma Sources Science & Technology, 8, R45±R64. Kingshott, P., Thissen, H. & Griesser, H. J. (2002) Effects of cloud-point grafting, chain

ß Woodhead Publishing Limited, 2011

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Surface modification of biomaterials

length, and density of PEG layers on competitive adsorption of ocular proteins. Biomaterials, 23, 2043±2056. Klee, D. & Hocker, H. (1999) Polymers for biomedical applications: Improvement of the interface compatibility. Biomedical Applications: Polymer Blends, 149, 1±57. Kreitz, S., Penache, C., Thomas, M. & Klages, C. P. (2005) Patterned DBD treatment for area-selective metallization of polymers-plasma printing. Surface & Coatings Technology, 200, 676±679. Lassen, B. & Malmsten, M. (1997) Competitive protein adsorption at plasma polymer surfaces. Journal of Colloid and Interface Science, 186, 9±16. Lieberman, M. A. & Ashida, S. (1996) Global models of pulse-power-modulated high-density, low-pressure discharges. Plasma Sources Science and Technology, 5, 145±158. Lieberman, M. A. & Lichtenberg, A. J. (1994) Principles of Plasma Discharges & Materials Processing, Chichester, John Wiley and Sons Ltd. Liston, E. M., Martinu, L. & Wertheimer, M. R. (1993) Plasma surface modification of polymers for improved adhesion ± a critical review. Journal of Adhesion Science and Technology, 7, 1091±1127. Manos, D. M. & Flamm, D. L. (1989) Plasma Etching: An Introduction, Boston, MA, Academic Press. Mar, M. N., Ratner, B. D. & Yee, S. S. (1999) An intrinsically protein-resistant surface plasmon resonance biosensor based upon a RF-plasma-deposited thin film. Sensors and Actuators B ± Chemical, 54, 125±131. Matsuda, T. (2004) Poly(N-isopropylacrylamide)-grafted gelatin as a thermoresponsive cell-adhesive, mold-releasable material for shape-engineered tissues. Journal of Biomaterials Science ± Polymer Edition, 15, 947±955. McArthur, S. L., McLean, K. M., Kingshott, P., St John, H. A. W., Chatelier, R. C. & Griesser, H. J. (2000) Effect of polysaccharide structure on protein adsorption. Colloids and Surfaces B ± Biointerfaces, 17, 37±48. McKenzie, D. R., Newton-McGee, K., Ruch, P., Bilek, M. M. & Gan, B. K. (2004) Modification of polymers by plasma-based ion implantation for biomedical applications. Surface & Coatings Technology, 186, 239±244. McLean, K. M., Johnson, G., Chatelier, R. C., Beumer, G. J., Steele, J. G. & Griesser, H. J. (2000) Method of immobilization of carboxymethyl-dextran affects resistance to tissue and cell colonization. Colloids and Surfaces B ± Biointerfaces, 18, 221±234. Mitu, B., Bauer-Gogonea, S., Leonhartsberger, H., Lindner, M., Bauer, S. & Dinescu, G. (2003) Plasma-deposited parylene-like thin films: process and material properties. Surface & Coatings Technology, 174, 124±130. Mobius, A., Elbick, D., Weidlich, E. R., Feldmann, K., Schuessler, F., Borris, J., Thomas, M., Zanker, A. & Klages, C. P. (2009) Plasma-printing and galvanic metallization hand in hand ± a new technology for the cost-efficient manufacture of flexible printed circuits. Electrochimica Acta, 54, 2473±2477. Morgenthaler, S., Zink, C. & Spencer, N. D. (2008) Surface-chemical and -morphological gradients. Soft Matter, 4, 419±434. Mota, R. P., Bigansolli, A. R., Antunes, E. F., Rangel, E. C., Da Cruz, N. C., Honda, R. Y., Algatti, M. A., Aramaki, E. A. & Kayama, M. E. (2002) Optical and structural properties of PEO-like plasma polymers. Molecular Crystals and Liquid Crystals, 374, 415±420. Mrksich, M., Chen, C. S., Xia, Y. N., Dike, L. E., Ingber, D. E. & Whitesides, G. M. (1996) Controlling cell attachment on contoured surfaces with self-assembled monolayers of alkanethiolates on gold. Proceedings of the National Academy of Sciences of the United States of America, 93, 10775±10778.

ß Woodhead Publishing Limited, 2011

Surface modification of biomaterials by plasma polymerization

35

Nicolson, P. C. & Vogt, J. (2001) Soft contact lens polymers: an evolution. Biomaterials, 22, 3273±3283. Notara, M., Bullett, N. A., Deshpande, P., Haddow, D. B., MacNeil, S. & Daniels, J. T. (2007) Plasma polymer coated surfaces for serum-free culture of limbal epithelium for ocular surface disease. Journal of Materials Science-Materials in Medicine, 18, 329±338. O'Toole, L., Beck, A. J., Ameen, A. P., Jones, F. R. & Short, R. D. (1995) Radiofrequency-induced plasma polymerisation of propenoic acid and propanoic acid. Journal of the Chemical Society-Faraday Transactions, 91, 3907±3912. O'Toole, L., Beck, A. J. & Short, R. D. (1996) Characterization of plasma polymers of acrylic acid and propanoic acid. Macromolecules, 29, 5172±5177. Oran, U., Swaraj, S., Friedrich, J. F. & Unger, W. E. S. (2005) Surface analysis of plasma deposited polymer films, 5 ± ToF-SSIMS characterization of plasma deposited allyl alcohol films. Plasma Processes and Polymers, 2, 563±571. Ortore, M. G., Sinibaldi, R., Heyse, P., Paulussen, S., Bernstorff, S., Sels, B., Mariani, P., Rustichelli, F. & Spinozzi, F. (2008) Grazing-incidence small-angle X-ray scattering from alkaline phosphatase immobilized in atmospheric plasmapolymer coatings. Applied Surface Science, 254, 5557±5563. Panchalingam, V., Poon, B., Huo, H. H., Savage, C. R., Timmons, R. B. & Eberhart, R. C. (1993) Molecular-surface tailoring of biomaterials via pulsed RF plasma discharges. Journal of Biomaterials Science ± Polymer Edition, 5, 131±145. Phillips, J., Gawkrodger, D. J., Caddy, C. M., Hedley, S., Dawson, R. A., Smith-Thomas, L., Freedlander, E. & MacNeil, S. (2001) Keratinocytes suppress TRP-1 expression and reduce cell number of co-cultured melanocytes ± implications for crafting of patients with vitiligo. Pigment Cell Research, 14, 116±125. Ratner, B. D. & Bryant, S. J. (2004) Biomaterials: Where we have been and where we are going. Annual Review of Biomedical Engineering, 6, 41±75. Raynor, J. E., Capadona, J. R., Collard, D. M., Petrie, T. A. & Garcia, A. J. (2009) Polymer brushes and self-assembled monolayers: versatile platforms to control cell adhesion to biomaterials (Review). Biointerphases, 4, FA3±FA16. Rinsch, C. L., Chen, X. L., Panchalingam, V., Eberhart, R. C., Wang, J. H. & Timmons, R. B. (1996) Pulsed radio frequency plasma polymerization of allyl alcohol: controlled deposition of surface hydroxyl groups. Langmuir, 12, 2995±3002. Robinson, D. E., Marson, A., Short, R. D., Buttle, D. J., Day, A. J., Parry, K. L., Wiles, M., Highfield, P., Mistry, A. & Whittle, J. D. (2008) Surface gradient of functional heparin. Advanced Materials, 20, 1166±1169. Roth, J. R. (1995) Industrial Plasma Engineering, Vol. 1: Principles, Bristol and Philadelphia, IOP Publishing. Ruckenstein, E. & Li, Z. F. (2005) Surface modification and functionalization through the self-assembled monolayer and graft polymerization. Advances in Colloid and Interface Science, 113, 43±63. Ryan, M. E., Hynes, A. M. & Badyal, J. P. S. (1996) Pulsed plasma polymerization of maleic anhydride. Chemistry of Materials, 8, 37±42. Savage, C. R., Timmons, R. B. & Lin, J. W. (1993) Spectroscopic characterization of films obtained in pulsed radiofrequency plasma discharges of fluorocarbon monomers. Advances in Chemistry Series, 745±768. Schreiber, F. (2004) Self-assembled monolayers: from `simple' model systems to biofunctionalized interfaces. Journal of Physics-Condensed Matter, 16, R881± R900. Sciarratta, V., Vohrer, U., Hegemann, D., Muller, M. & Oehr, C. (2003) Plasma

ß Woodhead Publishing Limited, 2011

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Surface modification of biomaterials

functionalization of polypropylene with acrylic acid. Surface & Coatings Technology, 174, 805±810. Sefton, M. V., Sawyer, A., Gorbet, M., Black, J. P., Cheng, E., Gemmell, C. & PottingerCooper, E. (2001) Does surface chemistry affect thrombogenicity of surface modified polymers? Journal of Biomedical Materials Research, 55, 447±459. Shen, M. C., Martinson, L., Wagner, M. S., Castner, D. G., Ratner, B. D. & Horbett, T. A. (2002) PEO-like plasma polymerized tetraglyme surface interactions with leukocytes and proteins: in vitro and in vivo studies. Journal of Biomaterials Science ± Polymer Edition, 13, 367±390. Shepsis, L. V., Pedrow, P. D., Mahalingam, R. & Osman, M. A. (2001) Modeling and experimental comparison of pulsed plasma deposition of aniline. Thin Solid Films, 385, 11±21. Sibarani, J., Takai, M. & Ishihara, K. (2007) Surface modification on microfluidic devices with 2-methacryloyloxyethyl phosphorylcholine polymers for reducing unfavorable protein adsorption. Colloids and Surfaces B ± Biointerfaces, 54, 88± 93. Siow, K. S., Britcher, L., Kumar, S. & Griesser, H. J. (2006) Plasma methods for the generation of chemically reactive surfaces for biomolecule immobilization and cell colonization ± a review. Plasma Processes and Polymers, 3, 392±418. Sobolewski, M. A. (1995) Current and voltage measurements in the gaseous electronics conference RF reference cell. Journal of Research of the National Institute of Standards and Technology, 100, 341±351. Swindells, I., Voronin, S. A., Fotea, C., Alexander, M. R. & Bradley, J. W. (2007) Detection of negative molecular ions in acrylic acid plasma: Some implications for polymerization mechanisms. Journal of Physical Chemistry B, 111, 8720±8722. Tang, L. P., Wu, Y. L. & Timmons, R. B. (1998) Fibrinogen adsorption and host tissue responses to plasma functionalized surfaces. Journal of Biomedical Materials Research, 42, 156±163. Tran, H. S., Puc, M. M., Hewitt, C. W., Soll, D. B., Marra, S. W., Simonetti, V. A., Cilley, J. H. & Delrossi, A. J. (1999) Diamond-like carbon coating and plasma or glow discharge treatment of mechanical heart valves. Journal of Investigative Surgery, 12, 133±140. Ulbricht, M. & Belfort, G. (1996) Surface modification of ultrafiltration membranes by low temperature plasma. 2. Graft polymerization onto polyacrylonitrile and polysulfone. Journal of Membrane Science, 111, 193±215. Valdes, T. I., Ciridon, W., Ratner, B. D. & Bryers, J. D. (2008) Surface modification of a perfluorinated ionomer using a glow discharge deposition method to control protein adsorption. Biomaterials, 29, 1356±1366. Vassallo, E., Cremona, A., Laguardia, L. & Mesto, E. (2006) Preparation of plasmapolymerized SiOx-like thin films from a mixture of hexamethyldisiloxane and oxygen to improve the corrosion behaviour. Surface & Coatings Technology, 200, 3035±3040. Villermaux, F., Tabrizian, M., Yahia, L., Czeremuszkin, G. & Piron, D. L. (1996) Corrosion resistance improvement of NiTi osteosynthesis staples by plasma polymerized tetrafluoroethylene coating. Bio-Medical Materials and Engineering, 6, 241±254. Voronin, S. A., Alexander, M. R. & Bradley, J. W. (2006) Time-resolved mass and energy spectral investigation of a pulsed polymerising plasma struck in acrylic acid. Surface & Coatings Technology, 201, 768±775. Voronin, S. A., Bradley, J. W., Fotea, C., Zelzer, M. & Alexander, M. R. (2007a)

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Surface modification of biomaterials by plasma polymerization

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Characterization of thin-film deposition in a pulsed acrylic acid polymerizing discharge. Journal of Vacuum Science & Technology A, 25, 1093±1097. Voronin, S. A., Zelzer, M., Fotea, C., Alexander, M. R. & Bradley, J. W. (2007b) Pulsed and continuous wave acrylic acid radio frequency plasma deposits: Plasma and surface chemistry. Journal of Physical Chemistry B, 111, 3419±3429. Waldman, D. A., Ziu, Y. L. & Netravali, A. N. (1995) Ethylene ammonia plasma polymer deposition for controlled adhesion of graphite fibers to PEEK. 1. Characterization of plasma formed polymers. Journal of Adhesion Science and Technology, 9, 1475± 1503. Walker, R. A., Cunliffe, V. T., Whittle, J. D., Steele, D. A. & Short, R. D. (2009) Submillimeter-scale surface gradients of immobilized protein ligands. Langmuir, 25, 4243±4246. Wang, J., Pan, C. J., Huang, N., Sun, H., Yang, P., Leng, Y. X., Chen, J. Y., Wan, G. J. & Chu, P. K. (2005) Surface characterization and blood compatibility of poly(ethylene terephthalate) modified by plasma surface grafting. Surface & Coatings Technology, 196, 307±311. Ward, A. J. & Short, R. D. (1993) A time-of-flight secondary-ion mass-spectrometry and X-ray photoelectron-spectroscopy investigation of the structure of plasma polymers prepared from the methacrylate series of monomers. Polymer, 34, 4179±4185. Ward, A. J. & Short, R. D. (1995) A t.o.f.s.i.m.s. and x.p.s. investigation of the structure of plasma polymers prepared from the methacrylate series of monomers. 2. The influence of the W/F parameter on structural and functional-group retention. Polymer, 36, 3439±3450. Ward, R. J. (1985) An investigation of the plasma polymerisation of organic compounds and its relationship with surface photopolymerisation. Department of Chemistry. Durham, University of Durham. Weikart, C. M., Matsuzawa, Y., Winterton, L. & Yasuda, H. K. (2001) Evaluation of plasma polymer-coated contact lenses by electrochemical impedance spectroscopy. Journal of Biomedical Materials Research, 54, 597±607. Wells, N., Baxter, M. A., Turnbull, J. E., Murray, P., Edgar, D., Parry, K. L., Steele, D. A. & Short, R. D. (2009) The geometric control of E14 and R1 mouse embryonic stem cell pluripotency by plasma polymer surface chemical gradients. Biomaterials, 30, 1066±1070. Whittle, J. D., Short, R. D., Douglas, C. W. I. & Davies, J. (2000) Differences in the aging of allyl alcohol, acrylic acid, allylamine, and octa-1,7-diene plasma polymers as studied by X-ray photoelectron spectroscopy. Chemistry of Materials, 12, 2664± 2671. Whittle, J. D., Bullett, N. A., Short, R. D., Douglas, C. W. I., Hollander, A. P. & Davies, J. (2002) Adsorption of vitronectin, collagen and immunoglobulin-G to plasma polymer surfaces by enzyme linked immunosorbent assay (ELISA). Journal of Materials Chemistry, 12, 2726±2732. Wohlrab, C. & Hofer, M. (1995) Application of plasma polymerization on ophthalmic lenses ± equipment and processes. Optical Engineering, 34, 2712±2718. Wu, Y. L. J., Timmons, R. B., Jen, J. S. & Molock, F. E. (2000) Non-fouling surfaces produced by gas phase pulsed plasma polymerization of an ultra low molecular weight ethylene oxide containing monomer. Colloids and Surfaces B ± Biointerfaces, 18, 235±248. Yasuda, H. (1985) Plasma Polymerization, London, Academic Press. Yasuda, H., Bumgarner, M. O., Marsh, H. C., Yamanashi, B. S., Devito, D. P., Wolbarsht, M. L., Reed, J. W., Bessler, M., Landers III, M. B., Hercules, D. M. & Carver, J.

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(1975) Ultrathin coating by plasma polymerization applied to corneal contact lens. Journal of Biomedical Materials Research, 9, 629±643. Zelzer, M., Majani, R., Bradley, J. W., Rose, F., Davies, M. C. & Alexander, M. R. (2008) Investigation of cell-surface interactions using chemical gradients formed from plasma polymers. Biomaterials, 29, 172±184. Zelzer, M., Scurr, D., Abdullah, B., Urquhart, A. J., Gadegaard, N., Bradley, J. W. & Alexander, M. R. (2009) Influence of the plasma sheath on plasma polymer deposition in advance of a mask and down pores. Journal of Physical Chemistry B, 113, 8487±8494. Zhang, Z., Menges, B., Timmons, R. B., Knoll, W. & Forch, R. (2003) Surface plasmon resonance studies of protein binding on plasma polymerized di(ethylene glycol) monovinyl ether films. Langmuir, 19, 4765±4770.

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Plate I Attachment of rat bone cancer cells (ROS cells) to regions of a polystyrene surface that have been plasma-coated using acrylic acid. The grid (top) was used to create the pattern. Scale bar is 50 micrometres.

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