Fig

Schematic representations of methods to modify surfaces.

TABLE 1 Examples of Surface-Modified Biomaterials

To Modify Blood Compatibility

Octadecyl group attachment to surfaces (albumin affinity) Silicone-containing block copolymer additive Plasma fluoropolymer deposition Plasma siloxane polymer deposition Radiation-grafted hydrogels

Chemically modified polystyrene for heparin-like activity

To Influence Cell Adhesion and Growth

Oxidized polystyrene surface Ammonia plasma-treated surface Plasma-deposited acetone or methanol film Plasma fluoropolymer deposition (reduce endothelial adhesion to lOLs)

To Control Protein Adsorption

Surface with immobilized polyethylene glycol) (reduce adsorption)

Treated EUSA dish surface (enhance adsorption strength) Affinity chromatography particulates (reduce adsorption or enhance specific adsorption) Surface-cross-linked contact lens (reduce adsorption)

To Improve Lubricity

Plasma treatment Radiation-grafted hydrogels Interpenetrating polymeric networks

To Improve Wear Resistance and Corrosion Resistance

Ton implantation Diamond deposition Anodization

To Alter Transport Properties

Plasma depositions (methane, fluoropolymer, siloxane)

To Modify Electrical Characteristics

Plasma depositions (insulation layer) Solvent coatings (insulator or conductor) Parylene 'insulation layer)

general principles

Surface modifications fall into two categories: (1) chemically or physically altering the atoms, compounds, or molecules in the existing surface (treatment, etching, chemical modification), or (2) overcoating the existing surface with a material having a different composition (coating, grafting, thin film deposition) (Fig. 1). A few general principles provide guidance when undertaking surface modification.

chanical and functional properties of the material. Thick coatings are also more subject to delamination. How thin should a surface modification be? Ideally, alteration of only the outermost molecular layer (3—10 A) should be sufficient. In practice, thicker films than this will be necessary since it is difficult to ensure that all of the original surface is uniformly covered when coatings and treatments are so thin. Also, extremely thin layers may be more subject to surface reversal (see later discussion) and mechanical erosion. Some coatings intrinsically have a specific thickness. For example, the thickness of LB films is related to the length of the surfactant molecules that comprise them (25-50 A). Other coatings, such as polyethylene glycol) protein-resistant layers, may require a minimum thickness (i.e., a dimension related to the molecular weight of chains) to function. In general, surface modifications should be the minimum thickness needed for uniformity, durability, and functionality, but no thicker. This must be experimentally defined for each system.

Delamination Resistance

The surface-modified layer should be resistant to delamination. This is achieved by covalently bonding the modified region to the substrate, intermixing the components of the substrate and the surface film at an interfacial zone, incorporating a compatibilizing ("primer") layer at the interface, or incorporating appropriate functional groups for strong intermolecular adhesion between a substrate and an overlayer (Wu, 1982).

Surface Rearrangement

Surface rearrangement occurs readily. Surface chemistries and structures can change as a result of the diffusion or translation of surface atoms or molecules in response to the external environment (see Chapter 1.3 and Fig. 2 in that chapter). A newly formed surface chemistry can migrate from the surface into the bulk, or molecules from the bulk can diffuse to cover the surface. Such reversals occur in metallic and other inorganic systems, as well as in polymeric systems. Terms such as "reconstruction," "relaxation," and "surface segregation" are often used to describe mobility-related alterations in surface structure and chemistry (Ratner and Yoon, 1988; Garbassi et al., 1989; Somorjai, 1990, 1991). The driving force for these surface changes is thermodynamic—to minimize the interfacial energy. However, sufficient atomic or molecular mobility must exist for the surface changes to occur in reasonable periods of time. For a modified surface to remain as it was designed, surface reversal must be prevented or inhibited. This can be done by cross-linking, sterically blocking the ability of surface structures to move, or by incorporating a rigid, impermeable layer between the substrate material and the surface modification.

Thin Surface Modifications

Thin surface modifications are desirable. The modified zone at the surface of the material should be as thin as possible. Modified surface layers that are too thick can change the me

Surface Analysis

Surface analysis is needed. The surface-modified region is usually thin and consists of only minute amounts of material. Undesirable contamination can be readily introduced during

TABLE 2 Physical and Chemical Surface Modification Methods

Polymer Metal Ceramic Glass

Noncovalent coatings Solvent coating

Langmuir-Blodgett film deposition V V V V

Surface-active additives

Vapor deposition of carbons and metals" V V V V

Vapor deposition of Parvlene (p-xylylene) v* v* v* v*

Covalently attached coatings

Radiation grafting (electron accelerator and gamma) V — — —

Plasma (gas discharge) (RF, microwave, acoustic) V V V V

Gas phase deposition Ion beam sputtering

Flame spray deposition — v*

C hemical grafting (e.g., ozonation + grafting)

Silanization V V V V

Biological modification (biomolecule immobilization) v* v* v*

Modifications of the original surface

Plasma etching (e.g., nitrogen, argon, oxygen, water v* v* v*

vapor)

Corona discharge (in air) v* v*

Ion exchange V V V

UV irradiation V V V V

Chemical reaction

Nonspecific oxidation (e.g., ozone) v*

Functional group modifications (oxidation, reduction) V — — —

Addition reactions (e.g., acetylation, chlorination) — — —

Conversion coatings (phosphating, anodization) — V — —

"Some covalent reaction may occur. "For polymers with ionic groups.

modification reactions. The potential for surface reversal to occur during surface modification is also high. The reaction should be monitored to ensure that the intended surface is indeed being formed. Since conventional analytical methods are often not sensitive enough to detect surface modifications, special surface analytical tools are called for (Chapter 1.3).

CommerdallzablUty

The end products of biomaterials research are devices and materials that are mass produced for use in humans. A surface modification that is too complex will be difficult and expensive to commercialize. It is best to minimize the number of steps in a surface modification process and to design each step to be relatively insensitive to small changes in reaction conditions.

methods for modifying the surfaces of materials

General methods to modify the surfaces of materials are illustrated in Fig. 1, with many examples listed in Table 2. A

few of the more widely used of these methods are briefly described here. Some of the conceptually simpler methods, such as solution coating a polymer on a substrate or metallization by sputtering or thermal evaporation, are not elaborated upon here.

Chemical Reaction

There are hundreds of chemical reactions that can be used to modify the chemistry of a surface. In the context of this chapter, chemical reactions are those reactions performed with reagents that react with atoms or molecules at the surface, but do not overcoat those atoms or molecules with a new layer. Chemical reactions can be classified as nonspecific and specific.

Nonspecific reactions leave a distribution of different functional groups at the surface. An example of a nonspecific surface chemical modification is the chromic acid oxidation of polyethylene surfaces. Other examples include the corona discharge modification of materials in air; radiofrequency glow discharge (RFGD) treatment of materials in oxygen, argon,

Utottrnttoa Grafting and Photografting

Radiation grafting and related methods have been widely used for the surface modification of biomatersals, and comprehensive review articles are available {Ratner, 1980; Hoffman et ai, 1983; Stannett, 1990). Within this category, three types of reactions can be distinguished; grafting using ionizing radiation sources {most commonly, a cobalt-60 gamma radiation source), grafting using LTV radiation (photografting) (Matsuda and Inoue, 1990; Dunkirk et ai., 1991), and grafting using high-energy electron beams. In all cases, similar processes occur. The radiation breaks chemical bonds in the material to be grafted, forming free radicals, peroxides, or other reactive species. These reactive surface groups are then exposed to a monomer. The monomer reacts with the free radicals at the surface and propagates as a free radical chain reaction, incorporating other monomers into a surface-grafted polymer.

Three distinct reaction modes can be described; (1) In the mutual irradiation method, the substrate material is immersed in a solution (monomer solvent) that is then exposed to the radiation source. (2) The substrate materials can also be exposed to the radiation under an inert atmosphere or at low temperatures. In this case, the materials are later contacted with a monomer solution to initiate the graft process. (3) Finally, the exposure to the radiation can take place in atr ot oxygen, leading to the formation of peroxide groups on the surface. Heating the material to be grafted in the presence of a monomer or the addition of a redox reactant (e.g., Fe2-r) will decompose the peroxide groups to form free radicals that can initiate the graft polymerization.

Graft layers formed by energetic irradiation of the substrate are often thick (>1 (¿m). However, they are well bonded to the substrate material, Since many polymerizable monomers are available, a wide range of surface chemistries can be created Mixtures of monomers can form unique graft copolymers (Ratner and Hoffman, 1980). For example, the hydrophilic/

hydrophobic ratio of surfaces can be controlled by varying the ratio of a hydrophilic and a hydrophobic monomer in the grafting mixture (Ratner and Hoffman, 1980; Ratner et al., 1979).

Photoinitiated grafting (usually with visible or UV light) represents a unique subcategory of surface modifications for which there is growing interest. There are many approaches to effect this photoinitiated covalent coupling. For example, a phenyl azide group can be converted to a highly reactive nitrene upon UV exposure. This nitrene will quickly react with many organic groups. If a synthetic polymer is prepared with phenyl azide side groups and this polymer is exposed simultaneously to UV light and a substrate polymer or polymeric medical device, the polymer containing the phenyl azide side groups will be immobilized to the substrate (Matsuda and Inoue, 1990). Another method involves the coupling of a benzophenone molecule to a hydrophilic polymer (Dunkirk et al., 1991). In the presence of UV irradiation, the benzophenone is excited to a reactive triplet state that can covalently couple to many polymers.

Radiation, electron, and photografting have frequently been used to bond hydrogels to the surfaces of hydrophobic polymers (Matsuda and Inoue, 1990; Dunkirk et al., 1991) (see also Chapter 2.4), The protein interactions (Horbett and Hoffman, 1975), cell interactions (Ratner et ah, 1975; Matsuda and Inoue, 1990), blood compatibility (Chapiro, 1983; Hoffman et al., 1983), and tissue reactions (Greer et al., 1979) of hydro-gel graft surfaces have been investigated.

RFGD Plasma Deposition and Other Plasma Cas Processes

RFGD plasmas, as used for surface modification, are low-pressure ionized gas environments typically at ambient (or slightly above ambient) temperature. They are also referred to as glow discharge or gas discharge depositions or treatments. Plasmas can be used to modify existing surfaces by ablation or etching reactions or, in a deposition mode, to overcoat surfaces (Fig. 1). Good review articles on plasma deposition and its application to biomaterials are available (Yasuda and Gazicki, 1982; Hoffman, 1988; Ratner et al., 1990). Some biomedical applications of plasma-modified biomaterials are listed in Table 3. Since we believe that RFGD plasma surface modifications have special promise for the development of improved biomaterials, they will be emphasized in this chapter.

The specific advantages of plasma-deposited films (and to some extent, plasma-treated surfaces) for biomedical applications are:

1. They are conformai. Because of the penetrating nature of a low-pressure gaseous environment in which transport of mass is governed by both molecular (line-of-sight) diffusion and convective diffusion, complex geometric shapes can be treated.

2. They are free of voids and pinholes. This continuous barrier structure is suggested by transport and electrical property studies (Charlson et al., 1984).

3. Plasma-deposited polymeric films can be placed upon almost any solid substrate, including metals, ceramics, table 3 Biomedical Applications of Glow Discharge Plasma-Induced Surface Modification Processes

A. Plasma treatment (etching)

1. Clean

2. Sterilize

3. Cross-link surface molecules

B. Plasma treatment (etching) and plasma deposition

1. Form barrier films

Protective coating Electrically insulating coating

Reduce absorption of material from the environment Inhibit release of leachables Control drug delivery rate

2. Modify cell and protein reactions

Improve biocompatibility Promote selective protein adsorption Enhance cell adhesion Improve cell growth Form nonfouling surfaces Increase lubricity

3. Provide reactive sites

For grafting or polymerizing polymers For immobilizing biomolecules and semiconductors. Other surface grafting or surface modification technologies are highly dependent upon the chemical nature of the substrate.

4. They exhibit good adhesion to the substrate. The energetic nature of the gas phase species in the plasma reaction environment can induce mixing, implantation, penetration, and reaction between the overlayer film and the substrate.

5. Unique film chemistries can be produced. The chemical structure of the polymeric overlayer films produced by the plasma deposition usually cannot be synthesized by conventional organic chemical methods.

6. They can serve as excellent barrier films because of their pinhole-free and dense, cross-linked nature.

7. Plasma-deposited layers generally show low levels of leachables. Owing to their highly cross-linked nature, plasma-deposited films contain negligible amounts of low-molecular-weight components that might lead to an adverse biological reaction and can also prevent leaching of low-molecular-weight material from the substrate.

8. These films are easily prepared. Once the apparatus is set up and optimized for a specific deposition, treatment of additional substrates is rapid and simple.

9. There is a mature technology for the production of these coatings. The microelectronics industry has made extensive use of inorganic plasma-deposited films (Sawin and Reif, 1983).

10. Although they are chemically complex, plasma surface modifications can be characterized by infrared (IR) (In-agaki et al., 1983; Haque and Ratner, 1988), nuclear magnetic resonance (NMR) (Kaplan and Dilks, 1981), electron spectroscopy for chemical analysis (ESCA) (Chilkoti et al., 1991a), chemical derivatization studies (Gombotz and Hoffman, 1988; Griesser and Chatelier, 1990; Chilkoti et al., 1991a), and static secondary ion mass spectrometry (SIMS) (Chilkoti et al., 1991b, 1992).

11. Plasma-treated surfaces are sterile when removed from the reactor, offering an additional advantage for cost-efficient production of medical devices.

It would be inappropriate to cite all these advantages without also discussing some of the disadvantages of plasma deposition and treatment for surface modification. First, the chemistry produced on a surface can be ill defined. For example, if tetra-fluoroethylene gas is introduced into the reactor, polytetraflu-oroethylene will not be deposited on the surface. Rather, a complex, branched fluorocarbon polymer will be produced. This scrambling of monomer structure has been addressed in studies dealing with retention of monomer structure in the final film (Lopez and Ratner, 1991, 1992). Second, the apparatus used to produce plasma depositions can be expensive. A good laboratory-scale reactor will cost $10,000-$30,000, and a production reactor can cost 5100,000 or more. Third, a uniform reaction within long, narrow pores can be difficult to achieve. Finally, contamination can be a problem and care must be exercised to prevent extraneous gases and pump oils from entering the reaction zone. However, the advantages of plasma reactions outweigh these potential disadvantages for many types of modifications that cannot be accomplished by any other method.

the nature of the plasma environment

Plasmas are atomically and molecularly dissociated gaseous environments. A plasma environment contains positive ions, negative ions, free radicals, electrons, atoms, molecules, and photons. Typical conditions within the plasma include an electron energy of 1—10 eV, a gas temperature of 25-60°C, an electron density of 10"9 to 10"12/cm2, and an operating pressure of 0.025-1.0 torr.

A number of processes can occur on the substrate surface that lead to surface modification or deposition. First, a competition takes place between deposition and etching by the high-energy gaseous species (ablation) (Yasuda, 1979). When ablation is more rapid than deposition, no deposition will be observed. Because of its energetic nature, the ablation or etching process can result in substantial chemical and morphological changes to the substrate.

A number of mechanisms have been postulated for the deposition process. A reactive gaseous environment may create free radical and other reactive species on the substrate surface that react with and polymerize molecules from the gas phase. Alternatively, reactive small molecules in the gas phase could combine to form higher molecular weight units or particulates that may settle or precipitate onto the surface. Most likely the depositions observed are formed by some combination of these two processes.

production of plasma environments for deposition

Many experimental variables relating both to reaction conditions and to the substrate onto which the deposition is placed affect the final outcome of the plasma deposition process (Fig. 3). A diagram of a typical inductively coupled radio frequency plasma reactor is presented in Fig. 3. The major subsystems that comprise this apparatus are a gas introduction system (control of gas mixing, flow rate, and mass of gas entering the reactor), a vacuum system (measurement and control of reactor pressure and inhibition of backstreaming of components from the pumps), an energizing system to efficiently couple energy into the gas phase within the reactor, and a reactor zone in which the samples are treated. Radio frequency, acoustic, or microwave energy can be coupled to the gas phase. Devices for monitoring the molecular weight of the gas phase species (mass spectrometers), the optical emission from the glowing plasma (spectrometers), and the deposited film thickness (ellip-someters, vibrating quartz crystal microbalances) are also commonly found on plasma reactors.

rfgd plasmas for the immobilization of molecules

Plasmas have often been used to introduce organic functional groups (e.g., amine, hydroxyl) on a surface that can be activated to attach biomolecules (see Chapter 2.11). Certain reactive gas environments can also be used to directly immobilize organic molecules such as surfactants. For example, a polyethylene glycol-propylene glycol) block copolymer surfactant will adsorb to polyethylene via the propylene glycol block. If the polyethylene surface with the adsorbed surfactant is briefly exposed to an argon plasma, the poly(propylene glycol) block will be cross-linked, thereby leading to the covalent attachment of pendant poly(ethylene glycol) chains (Sheu et al., 1992).

high-temperature and high-energy plasma treatments

The plasma environments described here are of relatively low energy and low temperature. Consequently, they can be used to deposit organic layers on polymeric or inorganic substrates. Under higher energy conditions, plasmas can effect unique and important inorganic surface modifications on inorganic substrates. For example, flame-spray deposition involves injecting a high-purity, relatively finely divided (—100 mesh) metal powder into a high-velocity plasma or flame. The melted or partially melted particles hit the surface and solidify rapidly (see Chapter 2.2 for additional information).

SHanizatlon

The proposed chemistry of a typical silane surface modifica tion reaction is illustrated in Fig. 4. Silane reactions can be samples to be capacikir plate coated

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