2. Literature Review

2.1 Polyvinylpyrrolidone

Polyvinylpyrroldinone (PVP) is a hydrogel created from the momomer N-vinylpyrrolidone. The application of this hydrogel to the surface of a polymer can enhance surface characteristics to a more preferable state with lubricious hydrophilic qualities. This hydrogel is used in many applications like catheters as used in this project. There are many factors to be viewed relating to the application of this solution to the polymer surface which will be investigated. When PVP is dry its state is a dry flaky powder which is very hydrophilic holding vast volumes of fluid.

The above image depicts the molecular make-up of polyvinylpyrrolidone coming from the monomer N-vinylpyrrolidone. The uses of polyvinylpyrrolidone have been vast such as a disintegrate in drugs and hairspray for hair coating.

2.2 Photo Polymerisation

Photopolymerization is the chemical reaction caused where the excitement of a free radical in a liquid compound from UV light that causes the monomers in the formulation to join creating a polymer film. This radical in the compound is the photoinitiator in the process and causes the process to be possible. If the exposure of UV light occurs to a formulation with more than one reactive radical a cross-linked polymer network will emerge. There are two types of photopolymerisation:

- Radical

- Cationic

Polyvinylpyrroldinone is a radical photopolymerised formulation. Free radical polymerization is used to make solid polymers from vinyl monomers by causing the monomers to attach. The process begins with the initiator in the formulation, when the electrons in these molecules are aggravated the electron bonds are broken and will break into fragments, these are called initiator fragments of the original molecule. These molecules then become free radicals. This is a phenomenon as electrons generally do not behave in this manner. These electrons will then tend to reform into a bond so will attack bonds like a carbon-carbon bond in a vinyl monomer. Which has a pair of electrons that are generally easily attacked by free radicals. This new forming of electrons then form a chemical bond between the initiator fragment and one of the carbon double bonds, for example. This electron now associates itself with the carbon atom which is not bonded to the initiator fragment. This entire process is called the initiation step of polymerisation. This initiation step can occur many times but always creates a free rasdical in the electron pairing. The only way to finish this chain effect caused by the initiation step in to link the two unpaired electrons of two chain reactions happening simultaneously in a coupling method to cause a termination reaction. This chain reaction causing the production of free radicals can then be used for photopolymerisation if the correct free radical can be produced to react with the UV light source. The use of light, rather than heat, to create reactions leads to a variety of advantages, such as solvent-free formulations, very high reaction rates at room temperature, three-dimensional control of the polymerization, low energy input, and a flexible chemical advantage since a wide variety of polymers can be polymerized photochemically.

2.3 Photoinitiaors

Photo-initiators are chemical formulations that will photo-react with UV light to aid with the process of polymerization of polymers sometimes known as photopolymers. There are two types of photo-initiators; these are radical which are used in PVP and cationic. The photoinitiator transforms the energy in the UV light into a chemical energy as a catalyst for the polymerisation reaction. The initial reaction of the initiator and the UV light source is called photo-polymerisation or radiation curing. It generally transforms a liquid monomer and aqueous formulation into a hard and insoluble cross-linked polymer network and in the case of PVP the transformed solution is then a lubricious hydrophilic durable coating. “Most radiation curing is performed using near UV light (300-400 nm range)” (BASF 2009). This is true to the radical curing process of photo-polymerisation. There are many photo-initiators available today developed for various purposes. These can move from the stated UV band into the IR range. The photo-initiator used in the process can also depend on other factors of the UV supply such as the IR content. This will be controlled by the use of a hot or cold lamp for the UV supply to the reaction by using or leaving an IR filter from the UV lamp used. In the case of PVP the reaction requires a cold lamp, which means that the use of IR in the radiation curing process is not desired.

2.4 UV Curing

Radiation curing through UV exposure has many distinct advantages for the curing of water based coatings and now has many applications throughout industry. This method of curing is used on such applications as adhesives, printing inks and the subject of this project, lubricious hydrophilic coatings for use with medical devices. “A liquid resin can be transformed almost instantly into a solid polymer material by simple exposure to UV light at ambient temperature, without emission of volatile organic compounds.” (Masson, 2000). The curing rate will vary depending on the formulation of the liquid resin such as the incorporation of photo initiators. The use UV-curable formulations is now reducing the reducing the use of acrylate monomers for such liquid resins and using more water based UV-curable systems where water can now be used as the only dilute. The viscosity of the liquid will determine the procedure to apply this to the object, where such methods as spraying, rolling or in the case of this project dipping can be used. This in turn will affect the curing rate as the application method will determine the density of the liquid coating. There is one distinct disadvantage wherein the system must firstly incur a drying stage before beginning the UV curing stage. The step that must be incurred before UV curing is dependent on many factors such as, temperature, coating thickness and formulation viscosity. As the water is being removed from the aqueous based coating “the PUA particles tend to aggregate to each other and form finally a cohesive film by coalescence” (Masson, 2000) which can then be turned into the clear coating required. From experimentation done by F. Masson in 2000 the results showed that water can be removed quicker from a thin film in contact with air as expected. The film on catheters in use with this project will also be of thin film application so the drying step can be expected to be short in comparison to other applications but will also result in small quantities of water trapped in the aqueous based mixture as results have also shown by Masson. UV curing is a form of radiation curing which would be the most used in the area. UV curing refers to “the use of luminous radiation as a energy source to induce the rapid conversion of especially formulated 100% reactive liquids to solids.” (Austins Paper). UV curing takes place in two steps:

1. Formation of free radicals by the excitement and breakdown of a photoinitiator when presented under a UV source.

2. Then the free radicals must react with double bonds in the system.

These reactions then cause further reactions which form polymer chains. A linked network can be formed by free radicals reacting with more than one double bond systems. For radical UV curing “Most radiation curing is performed using near UV light (300-400 nm range)” (BASF 2009). But the curing range for PVP is in a wider band of 200-400nm from the studies of the material from Devine.

Dipping And Coating Process. (Coffey et al, 2003)

The diagram above shows the basic method of equipment used with UV curing of hydrogels where the polymer catheter is clamped and dipped into the solution and then moved into the UV chamber where the process described takes place.

2.5 Curing PVP

Charlesby and Alexander (1955), were the first to reportedly discover cross-linking of poly(N-vinyl-2-pyrrolidone) (PVP) through use of irradiation sources. Photopolymerizable hydrogels have been greatly developed in recent times. These have been researched and suggested for compatibility with many biomedical applications such as cell encapsulation, drug delivery systems and the subject of this project, catheter coatings. These suggestions have been made as the views on hydrogels are that they are cost effective, and have low toxic potential. To assess these suggestions there has been considerable testing to determine if they are feasible such as the works of Lopérgolo et al in 2003. Their work was “addressed to the analysis of poly(N-vinyl-2-pyrrolidone) (PVP) submitted to direct photocrosslinking in aqueous solution, using low pressure Hg lamp (lem ¼ 254 nm).” (Lopérgolo et al, 2003) which is directly related to this project, where slight variations can be undergone such as the use of UV-LEDs as opposed to low pressure Hg lamps. Their work such as this project was designed to assess the use of such hydrogels with biomedical applications. The testing procedures used by Lopérgolo et al were to determine such factors as swelling ratio, cytotoxicity and testing of irradiation curing compatabilities. This concluded from this experimentation “Photocrosslinking of PVP was confirmed as an inexpensive alternative for PVP hydrogel production. This can be achieved by direct irradiation using a low-pressure Hg lamp eliciting 254 nm light. The material formed showed to be well suited to all PVP hydrogel applications like wound dressings and drug delivery devices. The easy of its production also opens the possibility of its use in situations where high-energy radiation is not available.” (Lopérgolo et al, 2003), has given this project a good grounding by giving initial testing where variations of experimentation in the area can be tried such as light source changes as discussed by McDermott in 2009, which now can be analysed by this project.

2.6 Surface Photografting Polymerization

The surface of the polymer that the gel formulation is being applied can be very important to consider when applying coatings. Most polymer surfaces have low surface energies, and are generally hydrophobic compared to the hydrophilic effect desired with this project. This can cause a serious problem when applying the coating to the polymer as hydrophobic and polar surfaces are difficult to mate with each other. Also with the use of hydrophobic surfaces which takes in proteins causing the growth of microorganisms on surfaces, this is called “Bio-fouling” (Deng et al, 2009) which would be very dangerous with the use of catheters as with this project as insertion into the body could cause infection. For this reason the “grafting to” techniques of polymerisation have been developed in recent years to apply coatings for medical devices. This grafting technique applies polymer chains to the surface of the polymer by coupling reactions to get the preferred polymer surface characteristics. The simple dipping of the polymer into the solution would generally result in a non-covalently bound coating. The most common reasons for surface grafting are to improve capabilities in wettability, antifouling and adhesive qualities. There are many disadvantages with the use of surface photografting such as difficulty incorporated with uniform distribution of film over the polymer to give uniform effects prior to process. This is why surface photografting by UV irradiation is used as the advantages are much greater. The photografting with use of UV irradiation is generally the fastest method of reaction with simple setup and ease of introduction to an industrialised process. Also probably the greatest advantage of the process is the cost saving as the area effected is for a “shallow region near the surface” (Deng et al, 2009) which will cost less than redesign of the entire polymer chemical makeup and also allow the use of more readily available cheaper polymers with a preferred surface effect. “Surface photografting polymerization thus offers the unique ability to tune and manipulate surface properties without damaging the bulk material.” (Deng et al, 2009).

2.7 Hydrogen Abstraction

Hydrogen abstraction is a very important part of photo polymerisation as it is generally used to begin the process as UV irradiation causes hydrogen abstraction from a H-donor molecule to produce a ketyl radical and other donor radicals from “Ketones”. “The initiation of photopolymerization usually occurs through the H-donor radical while the ketyl radical undergoes radical coupling with the growing macromolecular chains.” (Nguyen et al, 2002).

1 above displays “Radical photo polymerization by hydrogen abstraction. Upon UV irradiation, these photoinitiators undergo hydrogen abstraction from the H-donor (DH) to generate radicals.” (Nguyen et al, 2002). The efficiency of the photo polymerisation process is greatly increased with the presence of hydrogen donors which contain detachable hydrogen atoms located adjacent to heteroatoms (which are any atoms that are not carbon or hydrogen) such as oxygen, nitrogen and sulphur. After the hydrogen abstraction, these donors create free radicals that are capable of initiating polymerisation. Polyvinylpyrroldinone is initiated in this way which will be seen in this project.

2.8 Contact Angle for Wettability

Contact angle measurement is used to determine surface characteristics of many materials. “On the other hand, surface free energy of polymers control their adhesion, adsorption, lubrication, steric stabilization, wettability and their similar surface related properties.” (Abbasian, 2004). The surface energy of a polymer is the molecular disruption that happens when a surface is added to the existing polymer. Wetting refers to how a liquid reacts with a surface once applied to it. There are two types of wetting, total and partial. Total wetting is when the liquid applied to the surface makes a good bond with the surface and partial wetting is when the fluid and surfaces bond is weak. This means that the total wetting would be applied to hydrophilic surfaces where the liquid would be spread easily and even absorbed by the surface but partial would be the hydrophobic surfaces. This reaction can be measured by a spreading parameter equation as shown below.

(http://web.mit.edu/nnf/education/wettability/wetting.html, 19/11/09)

When S in this calculates to greater than zero in this equation total wetting is applied, and when the equation calculates to less than zero partial wetting is applied. When partial wetting is applied in this case the balance between liquid and surface is in equilibrium and this has a contact angle which is displayed as θ. “A liquid is said to be "mostly wetting" when θ < 90°, and "mostly non-wetting" when θ > 90°.” (Agrawal, 2009). This contact angle (θ) can then be calculated by Young's equation for contact angle as follows:


γsl - γs + γlv.cos θ = 0 or cos θ = (γs - γsl )/ γlv

(http://web.mit.edu/nnf/education/wettability/wetting.html, 19/11/09)

This equation can vary depending on parameters like plane angle which will affect wettability in general. This contact angle will be important to this project as the spreading parameter will directly affect the coating dispersion over the catheter.

2.9 Hydrogels for Biomedical Applications

In recent years the use of hydrogels in the biomedical industry has steadily increased. This is due to the fact that hydrogels are generally cost efficient in comparison to some other choices such as complete polymer redesign for preferential surface characteristics. “Hydrogels have been widely used in such applications because of their biocompatibility with the human body” (Devine et al, 2006). There are several other factors in their use with the human body such as their resemblance to human tissue which is due to water content of general hydrogels and their soft exterior which makes the hydrogels resemble human tissue more than other biomaterials. Some of the major advantages of using hydrogels for biomedical applications are the control incorporated with dissolution rates especially in relation to drug release to the body as compared with the use of fillers in the polymer matrix which is also much more cost efficient. From the studies of Devine et al. the results were shown that the use of such hydrogels as PVP in biomedical applications are greater than some traditional methods. “We have shown that the extractable content of these hydrogels is relatively low, allowing these hydrogels to be used in applications where this is advantageous.” (Devine et al. 2006).

2.10 PVP For Intravenous Use

In general catheters are synthetic polymeric biomaterials which are used intravenously generally through the upper or lower urinary tract. As the intended application of this project is to apply a lubricious hydrophilic hydrogel coating to a catheter and UV cure the gel and then is to be intravenously used the use of polyvinylpyrroldinone with the body must be looked at. From some studies by M.M. Tunney and S.P. Gorman it was shown that due to the contact made by the catheter materials and human urine that bacterial films can grow on, and encrust urethral catheters which can cause infection to the patient and cause serious discomfort. “The ability of uropathogens to adhere to the surface of biomaterials is recognised as a mechanism in the initiation and pathogenesis of infection.” (Tunney et al, 2002). For this reason the use of PVP hydrogel coatings on catheters was studied. Their paper “Evaluation of a poly(vinyl pyrrolidone)-coated biomaterial for urological use” evaluated many impacting factors of this problem such as bacterial growth on PVP, bacterial isolates adhesion to the hydrogel and also encrustation development on the surface. Through this study it was shown that the lubricious hydrophilic hydrogel coating PVP to be used with this project was useful in preventing bacterial growth on the catheter itself which directly reduced possibilities of impacting the patient to be treated by infection. This was studied as a comparison to typical hydrophobic biomaterial already in use such as Polyurethane. “Differences in biomaterial surface characteristics such as roughness, hydrophobicity and charge have all been proposed as possible reasons why one biomaterial is less prone to bacterial adherence and encrustation than another. ”. (Tunney et al, 2002).

2.11 Light Sources

Light sources have been developing at a fast rate throughout the last few decades. The area has been developed from fuel burning light sources to gas emission light sources such as fluorescent lamps and then to solid state sources like LED's (Light Emitting Diodes) being the most recent and ultraviolet (UV) mercury lamps. These are used in a wide variety of applications due to their low energy needs to produce light. Both fluorescent and UV mercury lamps have been used most popularly for photopolymerisation most recently but now available to replace these are UV-LED's which produce the same light and UV effect as the standard fluorescent and mercury lamps for a fraction of the energy input. For the decision of UV light source required for phopolymerisation many factors are required to be reviewed such as UV output intensity and wavelength range. Also for a large scale photopolymerisation process start up speeds should be considered and also lamp life span for efficiency. “For photopolymerisation processes it is important that the light source emits the majority of the output intensity at the key photopolymerisation wavelength with high efficiency, rapid start-up and stabilisation and constant output.” (McDermott et al, 2007).

Table 1 (McDermott et al, 2008)

From the information gathered by McDermott on his study of “A comparison of the emission characteristics of UV-LEDs and fluorescent lamps for polymerisation applications”, table 1 was compiled showing that the UV-LED range would be most desirable for this project as the UV-LED's are cost efficient, fit easier into the modern electrical circuit and have a more controlled wavelength range which is important as polyvinylpyrroldinone is to be cured between 200-400nm range. The study also showed that the LED's have a shorter warm up time than the standard fluorescent lamp which suits the intended purposes in this project as the photopolymerisation process to be undergone will be happening after large intervals and will be turned off during these. Also the formulation in this project requires a cold lamp to react with the photoinitiator where UV-LED's can be supplied with an inbuilt IR filter. On examination of both UV light sources the use of UV-LED's will have the best effect on this project. “It was found that the currently available UV-LED used in this study is comparable to the lamp in terms of intensity, maximum peak wavelength, spectral output and the extent of photopolymerisation.” (McDermott et al, 2008).

2.12 Classification of UV lamps

UV lamps may be classified in two groups, “hot” or “cold” lamps. This is because the lamps can cause a thermal boost to the process. This thermal boost can be introduced by the infrared emissions from the lamp. The classification is then decided by the use or lack of use of an IR filter. This can have a substantial effect on the formulation used in the UV curable liquid. For a liquid suitable with use under a hot lamp which will give desirable results when cured may need a change in insertion speed and / or photoinitiator type when in use with a cold lamp curing system. “Since PVP has an absorption spectrum in the region of 200–280 nm, the use of arc mercury lamps seems plausible.” (Lopérgolo 2003) There are several types of UV emitting lamps that can be used for UV curing such as Cold-cathode lamps, Low-power low-pressure mercury lamps, Standard low-pressure mercury lamps, and High-power/ultra high-power low-pressure mercury lamps. All can be used effectively with certain photo initiators but some could have an undesired effect also. The lamp that should prove most effective with polyvinylpyrroldinone is a standard cold lamp, but as the lamp is to be introduced in an enclosed area with high heat generating potential the use of a fan should be incorporated to the design of the UV enclosure to ensure the desired cool UV effect is applied to the photo polymerisation process.

2.13 Testing procedures

For experimentation on lubricious hydrophilic hydrogel coatings there are many experiments and testing procedures that can be used to test the integrity of the formulation and the final cured solution. Some of these tests are;

- DSC analysis for phase transition phenomenon.

- Modulated differential scanning calorimetry

- Cloud point measurements

- Swelling studies

- Fourier transform infrared spectroscopy

These testing methods are applicable to testing for controlled drug delivery systems mainly but can be applied to the thin films use for catheters. Studies from Geever et al show the most effective use of these testing systems in relation to PVP which will be applicable to the studies to be undertaken in this project.

2.14 Differential Scanning Calorimetry (DSC) Analysis

Modern thermal analysis techniques have been used extensively in the area of thermoplastics characterisation. Historically, differential scanning calorimetry (DSC) has been used to measure melting points, heats of fusion and crystallization, oxidative induction time and glass transition temperature. Recent developments involve the use of a sinusoidal heating rate to extract additional information from the classical thermal analysis experiments. In 1992, Modulated DSC (MDSC) was introduced. This technique employs the use of a sinusoidal heating rate and then de-convolutes the resulting heat flow signal to generate heat capacity, as well as additional heat flow signals. MDSC has been used extensively in the area of materials characterization, particularly in the fields of polymer science, food science, and inorganic materials. This testing method can be used with this project as used previously by Devine in 2005 using a Perkin Elmer Pyris 6 DSC.

2.15 Fourier Transform Infrared Spectroscopy

Fourier transform infrared spectroscopy has been used for over seventy years in laboratory experimentation and analysis. FTIR is a non-destructive analysis of a material using IR radiation which is run through a sample piece. Some of the radiation is absorbed by the sample piece where the remaining is completely passed through. By gathering the radiation passed through an analysis can be undergone to calculate molecular absorption and transmission, and by this analysis the results show a molecular fingerprint of the test specimen. This method is very precise and mechanically simple with other advantages such as no calibration required from external sources. An infrared spectrum represents a fingerprint of a test specimen by showing absorption peaks which directly relate to the vibration frequencies between the bonds of the atoms in the material. “Like a fingerprint no two unique molecular structures produce the same infrared spectrum. This makes infrared spectroscopy useful for several types of analysis.” (Thermo Nicolet Corporation, 2001). FTIR can be used for many analysis reasons such as identification method of unknown materials and component amounts in a mixture. The reason for analysis in this project will be the consistency of sample solution over the catheter which can ensure best and most consistent results for other testing.

2.16 Modulated Differential Scanning Calorimetry MDSC Analysis

In 1992, Reading introduced the temperature sine wave forcing function to thermal analysis in the form known as Modulated DSC. In MDSC, a linear temperature ramp is modulated with a sinusoidal temperature oscillation producing a corresponding oscillatory heat flow (i.e., rate of heat transfer) proportional to physical properties of the test specimen. “Deconvolution” (Geever et al, 2006) of the oscillatory temperature and heat flow lead to the separation of the overall heat flow into heat capacity and kinetic components, called reversing and non-reversing heat flow. Modulated DSC allows for the separation of total heat flow into two constituents, which provides for increased understanding of the phenomena occurring simultaneously in the sample. Modulated DSC adds to the sensitivity of the DSC technique in its ability to separate reversing melting from non-reversing melting. The former is associated with amorphous materials which crystallize upon heating, only to re-melt as the temperature is increased further. Non-reversing melting is associated with the highly crystalline domains of the sample, present before any thermal history is applied to the material.

2.17 Swelling studies

A swelling study is carried out by cutting cured hydrogels into disks then precisely weighing the dried disks to determine Wo, then the disks are placed in solutions different disks can be in varying solutions with ph variance, and other characteristics depending on the information required. The “swollen” disks which due to their hydrophilic nature have taken in as much of the solution as possible are then weighed to determine Ws, where then the following equation is applied to determine the swelling ratio in specific ph ranges.

The swelling ratio is also a very important parameter as it describes the amount of water that is contained within the hydrogel at equilibrium and is a function of the network structure, crosslinking ratio, hydrophilicity, and ionisation of the functional groups.” (Devine et al, 2006).

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