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Medical Engineering & Physics 30 (2008) 12701274

Accelerated aging for testing polymeric biomaterials and medical devices

D.W.L. Hukins a, , A. Mahomed a,b , S.N. Kukureka b
a b

School of Mechanical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK School of Metallurgy and Materials, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK Received 28 February 2008; received in revised form 28 May 2008; accepted 1 June 2008

Abstract Elevated temperature is frequently used to accelerate the aging process in polymers that are associated with medical devices and other applications. A common approach is to assume that the rate of aging is increased by a factor of 2T/10 , where T is the temperature increase. This result is a mathematical expression of the empirical observation that increasing the temperature by about 10 C roughly doubles the rate of many polymer reactions. It is equivalent to assuming that the aging process is a rst order chemical reaction with an activation energy of 10R/loge 2, where R is the universal gas constant. A better approach would be to determine the activation energy for the process being considered but this is not always practicable. The simple approach does not depend on the temperature increase, provided that it is not so great that it initiates any physical or chemical process that is unlikely to be involved in normal aging. If a temperature increment were to increase a given polymer reaction rate n times, then an elevated temperature would increase the rate of aging by a factor of n T/ . 2008 IPEM. Published by Elsevier Ltd. All rights reserved.
Keywords: Accelerated aging; Elastomer; Implant; Medical device; Polymer

1. Introduction Materials that are to be implanted into the human body should not deteriorate unacceptably during their intended period of use; in addition, neither they nor any packaging materials should deteriorate before implantation, during their intended shelf-life. If materials have performed satisfactorily in similar, previous applications it is reasonable to suppose that they will be suitable for future applications. Often materials are implanted into animals [1,2] but the time-scales involved (typically no more than 2 years) are less than the intended period of use of most implants. Further information on the performance of materials during aging in the body can be obtained from retrieval studies [35]. In these studies, implants are retrieved, after many years inside the human body, and the properties of their constituent materials investigated. However, it is often necessary to predict how aging will affect the properties of a material that may be implanted into the body.

The purpose of this paper is to consider the application of elevated temperature as a means of simulating the aging process, so-called accelerated aging, applied to polymers that are associated with medical devices [6]. A common approach is to assume that the rate of aging is increased by a factor: f =2
T/10

(1)

Corresponding author. E-mail address: D.W.Hukins@bham.ac.uk (D.W.L. Hukins).

In Eq. (1), T = T Tref , where Tref is a reference temperature, at which the effects of aging are to be determined, and T is an elevated temperature used to accelerate these effects [6,7]. For a material that is to be implanted into the human body, Tref will be the body temperature of 37 C. Maintaining the material for 1 month at 87 C is then considered to be equivalent to aging it for 2(8737)/10 = 25 = 32 months. For testing shelf-life, Tref will be the storage temperature; accelerated aging tests are then normally followed by aging at room temperature. This paper will review the application of accelerated aging to the investigation of elastomers, since they have been the subjects of much of the research on aging of polymeric

1350-4533/$ see front matter 2008 IPEM. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.medengphy.2008.06.001

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biomaterials. It will start by considering a variety of studies of elastomer aging and then concentrate on the application to biomaterials. The origin, relationship to the principles of chemical kinetics, validity and generalisation of Eq. (1) will be covered in Section 3.

2. Applications of accelerated aging 2.1. General There have been several studies of accelerated aging of silicones. When silicones were maintained at a temperature of 100 C for 2 years, X-ray photoelectron spectroscopy (XPS) and Fourier transform infra-red (FTIR) spectroscopy showed that the bulk material was unaffected; however, there was some modication of a surface layer although only to a thickness of about 100 m [8]. Silicones appear to retain their mechanical properties after being heated to 150 C for 30 days [9]; according to Eq. (1), this is equivalent to approximately 7 years of aging at body temperature. Maintaining silicones in a moist inert gas atmosphere at temperatures of up to 190 C can lead to loss of volatile products and some softening [10]; softening is also observed in naturally aged silicones but there are no clear trends [11]. Elastomers that are not related to those used for implants have also been investigated [1214]. These studies are mentioned because they demonstrate that the use of accelerated aging is not conned to the healthcare sector. A study of rubber tyres provides information on the validity of accelerated aging. Accelerated aging of rubber tyres, at temperatures up to 70 C [15], reproduced the changes seen after tyres had been used by customers [16]; it was possible to age tyres an equivalent of 6 years in 8 weeks or less. It is important to note that different factors may affect the aging of elastomers with different chemical compositions. 2.2. Biomedical applications There have been several studies of the combined effect of light and increased temperature on maxillofacial implant materials and soft denture liners; typically these have involved light from a xenon source (to mimic natural sunlight) and exposure to air at a high relative humidity at 63 C for 600900 h [1720]. According to Eq. (1), the harshest of these conditions corresponds to less than 1 year of aging at body temperature. Under these conditions the tensile strength of some silicones was unaffected but the tensile strength of other silicones decreased. There was little change in the tensile strength of poly(vinylchloride) (PVC) or a poly(phosphazine) but a polyurethane (PU) showed considerable degradation. The tear resistance of silicones did not decrease as much for silicones as for PVC or PU; indeed the tear resistance of one silicone was found to increase. The tear resistance of plasticised polymers was also found

to increase and this was attributed to increased polymerisation and/or loss of plasticisers [18]. In one study the hardness of two silicones was found to increase while the hardness of another was unaffected [19]. The viscoelastic properties, as measured by the storage and loss modulus, of silicones and a poly(phosphazine) were affected by exposure to increased temperature. The effect of elevated temperature on the properties of medical grade silicones was investigated after maintaining them in saline solution at 100 C for 45 h [21]. According to Eq. (1), these conditions are equivalent to maintaining the materials in the body for about 10 years. However, their tensile strength remained unaffected. There was a change in the contact angle of a liquid drop on the surface of the silicones before and after heat treatment, indicating that there was a change in surface properties. These results are consistent with the observation, discussed in Section 2.1, that increased temperature affects the surface but not the bulk properties of silicones [8]. However, recent studies indicate that maintaining at least some silicones in saline solution at an elevated temperature may reduce their mechanical strength [22]. The shelf-life of Elast-EonTM (AorTech, Melbourne, Australia), following sterilisation by -irradiation or with ethylene oxide, was investigated by accelerated aging at 70 C for 2 weeks [2]. This material is a made by modifying PU. It was found that accelerated aging led to micro-crack formation in an unmodied PU, which could impair its mechanical properties. However, accelerated aging, under the same conditions, had no effect on Elast-EonTM . This result is of interest because it has been suggested that Elast-EonTM is a suitable material for making a exible nger joint that resists fracture [23].

3. Principles 3.1. Eq. (1) The 10-degree rule is simply an empirical observation that increasing the temperature by about 10 roughly doubles the rate of many polymer reactions [6]. Inspection of Eq. (1) shows that it is no more than a mathematical expression of this empirical rule, since f = 2 when T = 10 C. Therefore, Eq. (1) cannot be justied using the theory of chemical kinetics in the absence of further information. It has been argued that accelerated aging should be based on a proper consideration of the principles of chemical kinetics rather than on empirical rules [24]. Therefore, this approach is explored in Section 3.2. 3.2. Principles of chemical kinetics If changes occur to a polymer such that it spontaneously changes from form A to form B, in the absence of other effects, it is reasonable to suppose that this is a rst order

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reaction [25], i.e. that: dCA = kCA dt Eact RT (2)

where CA is the molar concentration of A and k is given by k = K exp (3)

where Eact is the activation energy for the aging reaction, R is the universal gas constant (8.314 J mol1 ). The coefcient K may be regarded as an empirical factor although, in some reactions, it may represent the probability of the material interacting with other molecules involved in the aging process. If kref is the value of k when T = Tref , Eq. (3) can be manipulated to dene: f = k = exp kref k kref R T Eact (4)

Fig. 1. Predictions of Eq. (1) (data points) compared with the results of chemical kinetics (continuous line computed from Eq. (7)). A temperature rise of T increases the rate of aging by a factor f.

It is often convenient to express Eq. (4) in the form: log = R T . Eact (5)

Here, Eact represents the value of Eact when the aging reaction follows the 10-degree rule. Substituting the value for R into Eq. (6) gives a value for Eact of 120 J mol1 . Thus the 10-degree rule is equivalent to assuming this value for the activation energy. Substituting the expression for Eact from Eq. (6) into Eq. (4) yields a value for f of f = exp T loge 2 10 (7)

Eq. (5) can be used to determine Eact by determining k over a range of T values; a graph of log(k/kref ) against T has a slope of R/Eact [25]. This value of Eact can be substituted into Eq. (4) to determine the factor by which elevating the temperature from Tref to T increases the rate of application. The approach described in the previous paragraph is better than the application of Eq. (1) because it is based on experimental measurements specic to the process being investigated rather than an empirical observation [24]. The only major assumption is then that the aging process follows rst order chemical kinetics. However, it is not always feasible to adopt this approach in routine testing of implant materials so it is important to understand the conditions under which Eq. (1) is valid. 3.3. Validity of Eq. (1) The view that Eq. (1) is an approximation to a more rigorous kinetic treatment leads to speculation about the range of T values over which it is valid. For example, it has been stated that Eq. (1) is only valid for T 60 C [6]; it has also been recommended that the maximum value of T should be 70 C [7]. An analysis of the consequences of Eq. (1) for the kinetics of accelerated aging enables these claims to be examined. According to the 10-degree rule, f = 2 when T = 10 C. Substituting these values into Eq. (5) gives: loge 2 = Eact 10R Eact 10R = loge 2

The results of this analysis are illustrated in Fig. 1 which shows that the results are identical to the predictions of the 10degree rule over a T range of 100 C. Thus the predictions of the 10-degree rule are identical to the predictions of the theory of chemical kinetics, if the value of Eact is given by Eq. (6). Eq. (1) will break down if the ambient temperature is increased to a value that initiates other processes in the material. Examples include physical changes such as a glass transition or melting [6]. More generally, the ambient temperature should not be so high that it initiates any physical or chemical process that is unlikely to be involved in normal aging. However, any such change would also invalidate the assumption that accelerated aging follows rst order chemical kinetics, so that the approach of Section 3.2 would be equally invalid. The main weakness of Eq. (1) is that it assumes that increasing the temperature by 10 C doubles the rate of aging. The only way to overcome this weakness is to determine Eact for the aging process, as described in Section 3.2. However, this approach is still subject to the condition that the ambient temperature should not be so high that it initiates any physical or chemical process that is unlikely to be involved in normal aging. 3.4. Generalisation of Eq. (1) Eq. (1) assumes that a temperature increment of 10 C increases polymer reaction rates by a factor of two; for some purposes it may be useful to generalise this observation so that a temperature increment increases the reaction rate n times.

(6)

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Then raising the ambient temperature by the rate of aging by a factor of f =n

T/

T will increase

Acknowledgements This work has beneted from collaboration with Mike Jenkins, Dang Lei, Laura Leslie and Duncan Shepherd. Aziza Mahomed holds an EPSRC research studentship.

(8)

Using the same arguments as in the previous section, this observation is equivalent to assuming that the aging reaction has an activation energy of Eact = R . loge n (9)

Conict of interest There are no conicts of interest.

4. Discussion It is commonly assumed that elevated temperature can be used as a method of accelerated aging. Elevated temperatures have been used to investigate the effects of aging on several polymers that are implanted into the body, especially silicones. The results of different studies on silicones do not all agree but this may well be because different silicones were used in the various investigations. Eq. (1) is sometimes used to determine the effect of elevated temperature on aging. This result is a mathematical expression of the empirical observation that increasing the temperature by about 10 C roughly doubles the rate of many polymer reactions. It is equivalent to assuming that the aging process is a rst order chemical reaction with an activation energy of 10R/loge 2. A better approach would be to determine the activation energy for the process being considered and calculate its effect on the chemical reactions involved using Eq. (3). However, this approach is not always practicable, so it is important to understand the physical signicance and validity of Eq. (1). The validity of Eq. (1) does not depend on the value of T, provided that it is not so great that it initiates any physical or chemical process that is unlikely to be involved in normal aging. If the elevated temperature initiates other processes, the approach based on rst order chemical kinetics (Section 3.2) is not valid either. Eq. (1) is based on the empirical observation that increasing the temperature by about 10 C roughly doubles the rate of many polymer reactions. If increasing the temperature by were to increase a given polymer reaction rate by a factor of n, then Eq. (1) could be generalised to give Eq. (8) that corresponds to the activation energy given by Eq. (9). Finally, in vivo aging may involve effects that are not simulated by an in vitro test. Even if samples are maintained in buffered physiological saline solution, they are not subjected to all the chemical interactions (e.g. with fats, proteins, calcium ions, etc.), or with cells that may modify their environment. This chemical environment will also be different in different parts of the body. It is not possible to simulate all the conditions that will be encountered in vivo so that, the ultimate test of the success of any replacement material must be its long-term performance in the human body [26].

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