Materials Science and Engineering C 33 (2013) 974–978

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Preparation and characterization of acrylic bone cement with high drug release Yu-Hsun Nien ⁎, Shi-wen Lin, You-Ning Hsu Department of Chemical and Materials Engineering, National Yunlin University of Science and Technology, Douliou, Yunlin, 64002, Taiwan

a r t i c l e

i n f o

Article history: Received 17 May 2012 Received in revised form 11 October 2012 Accepted 16 November 2012 Available online 28 November 2012 Keywords: Bone cement PMMA Drug release

a b s t r a c t Drug-loaded bone cement is used as an application method to prevent and treat prosthesis-related infection. Despite the commercial availability of drug-loaded bone cement, low release rate of drugs from drug-loaded bone cement may result in the emergence of drug-resistant coagulase-negative staphylococci in subsequent deep infection. This work presents a method to control and increase both the drug release rate and total release amounts of drugs for drug-loaded bone cement without losing the mechanical properties of cement. A novel drug-loaded bone cement is also developed by introducing cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles into bone cement. Capable of increasing the hydrophilicity of the cement and allowing fluids to pass into the cement, the bone cement developed here supplements both the drug release rate and total release amounts of drugs. © 2012 Elsevier B.V. All rights reserved.

1. Introduction In addition to its use as a grouting agent between a prosthesis and the bone, bone cement anchors a prosthesis in orthopedic implants such as total hip replacement. However, infection often occurs after surgery. Drug-loaded bone cement is used as an application method to prevent and treat prosthesis-related infection [1–11]. Despite its commercial availability, drug-loaded bone cement has several limitations. For instance, release of drugs from drug-loaded bone cement is difficult to control when attempting to maintain a sufficient mechanical strength of the cement. Additionally, release rates of drugs from drug-loaded bone cement are typically low, possibility resulting in the emergence of drug-resistant coagulase-negative staphylococci in subsequent deep infection [12]. Among the various factors influencing the release behavior of drugs from drug-loaded bone cement including porosity of the cement [13,14], as well as surface roughness and hydrophilicity of bone cement [15]. The initial release rates increase with surface roughness since a rougher surface constitutes a larger area for release. To sustain a release, fluids must penetrate the cement. Therefore, the porosity and hydrophilicity of the cement dominate the total release amounts of drugs [15]. The porosity of the cement is caused by air entrapment during the mixture and solidification of cement [16]. However, the increased porosity of the cement may ultimately decrease the mechanical properties of cement [17,18]. Thus, solving the problem of low release of drugs from drug-loaded bone cement involves increasing either the hydrophilicity of cement or the amount of drugs in drug-loaded bone cement. However, bone cement with the

⁎ Corresponding author. Tel.: +886 5 534 2601x4611; fax: +886 5 5312071. E-mail address: [email protected] (Y.-H. Nien). 0928-4931/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.msec.2012.11.032

presence of drugs demonstrates inferior mechanical properties than those of plain cement [19]. This work presents a method to control and increase both the drug release rate and total release amounts of drugs for drug-loaded bone cement without losing the mechanical properties of cement. A novel drug-loaded bone cement is also developed by introducing crosslinked poly(methylmethacrylate-acrylic acid sodium salt) particles into bone cement. Based on introduction of cross-linked poly (methylmethacrylate-acrylic acid sodium salt) particles to the bone cement studied here, the novel drug-loaded bone cement consists of the conventional acrylate based bone cement modified in powder portion, in which a certain amount of cross-linked poly(methylmethacrylate-acrylic acid sodium salt) is introduced, referred to hereinafter as poly(MMA-AAS-AMA) (in powder portion). Allylmethacrylate (AMA) is used as a cross-linking agent. Moreover, ketoprofen (non-steroidal anti-inflammatory drug) is used as a model drug to provide the property of drug release for the modified bone cement [20–22]. 2. Materials and methods 2.1. Preparation of pre-polymerized cross-linked poly(MMA-AAS-AMA) powder All materials were used as received. Polymerization was carried out in bulk using a free radical polymerization with the initiator AIBN (2, 2-azobisisobutyronitrile) (Showa Chemical Co, Ltd). The monomers of methylmethacrylate (MMA)/acrylic acid (AA)/allylmethacrylate (AMA) were mixed at the volume ratios of 80 mL/20 mL/10 mL (mole ratios: 0.80/0.29/0.07) and 70 mL/30 mL/10 mL (mole ratios: 0.70/0.44/0.07) separately with the initiator at the amount of 0.4 g/100 mL of the total mixture. MMA (extra pure reagent), AA (99%) and AMA (98%) were

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purchased from Kanto Chemical Co. Inc. (Japan), Alfa Aesar (U.S.A.) and Acros Organics (U.S.A), respectively. Polymerization was conducted in glass test tubes, which were tightly sealed and placed upright in a temperature controlled water bath. The temperature was gradually raised (3 °C/h) over several days to 65 °C and kept at that temperature for two days. The glass tubes were then removed from the bath, and allowed to cool, followed by retrieval of the polymer samples after breaking the tubes. Following completion of this primary polymerization stage, the samples were post-cured to complete the cross-linking reaction and ensure that there were no left free monomers. This was accomplished by placing the samples in a temperature-controlled oven where the temperature was raised slowly (1 °C/min) up to 150 °C. The samples were left at 150 °C for at least five hours, followed by overnight cooling. Next, the cross-linked poly(MMA-AA-AMA) in bulk form was dipped into an excess amount of 1 M of sodium hydroxide solution for several days until full neutralization, followed by washing with distilled water to fabricate cross-linked poly(MMA-AAS-AMA). Additionally, the cross-linked poly(MMA-AAS-AMA) was dried and washed alternatively for several times. Finally, the dried cross-linked poly(MMA-AAS-AMA) was ground into fine powder and sieved on a 140 mesh screen. 2.2. Preparation of drug-loaded bone cement Commercial bone cement (Osteobond bone cement purchased from Zimmer, Inc.) was used in this work. Several systems of drug-loaded bone cement, including an additive of cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles in bone cement, were prepared. Specimens of the bone cement were prepared by well mixing (1) 10 mL of the liquid portion, (2) 20 g of the powder portion and (3) 0.844 g of ketoprofen in powder portion (the weight percentage of ketoprofen loaded in this work was 4.22% of the powder portion of the bone cement). Next, the mixture was left to solidify in a designed shape. The composition of the liquid portion for all of the bone cement systems was the same, and 10 mL of the liquid portion from the commercial product were used in each bone cement system. Table 1 lists the various compositions of the powder portion of the bone cement for each system. Denotation of the conventional cement loaded with ketoprofen was Osteobond bone cement mixed with ketoprofen, which contained 20 g of commercial powder and 0.844 g of ketoprofen in powder form. System 80-19-S-k was the drug-loaded bone cement, as formed by introducing cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles to bone cement, which was contained in the following powder form: 19 g of commercial powder, 1 g of cross-linked poly(MMA-AAS-AMA) at a volume ratio of 80/20/10 (MMA/AAS/ AMA) and 0.844 g of ketoprofen. System 70-19-S-k was the drug-loaded bone cement, as formed by introducing cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles to bone cement, which was contained in following powder form: 19 g of commercial powder, 1 g of cross-linked poly(MMA-AAS-AMA) at a volume ratio of 70/30/10 (MMA/AAS/AMA) and 0.844 g of ketoprofen.

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2.3. Swelling measurements Swelling measurements (referred to herein as percentage weight and volume changes) were conducted on the drug-loaded commercial bone cement and the modified bone cement containing MMA/AAS/ AMA at various ratios. Four specimens of each systems were fully immersed in 10 mL phosphate buffer saline, PBS, (NaCl 8.76 g/L, K2HPO4 0.87 g/L, KH2PO4 0.68 g/L, pH 7.4) at 37 °C. At designated sampling intervals, the specimen was removed for swelling measurements, and then placed in 10 mL of fresh PBS; a 10 mL sample of the stored PBS solution was taken for further analysis of the drug release. The specimens had the dimensions of a diameter of 6.0 mm and a length of 12.5 mm. Next, after the surface dried, the swelling percentage was measured by evaluating the weight and volume of a specimen at various time intervals. The weight percentage swell at any given time (% weight gain, %W) was calculated as follows: %W ¼ ½ðWt −W0 Þ=W0   100 where Wt is the weight of the specimen at time t, and W0 is the weight of the specimen in the dry state at time zero. The volume percentage swell at any given time (% volume gain, %V) was calculated as follows: %V ¼ ½ðVt −V0 Þ=V0   100 where Vt is the volume of the specimen at time t, and V0 is the volume of the specimen in the dry state at time zero. 2.4. Drug release study As mentioned above, the drug-loaded bone cements (diameter of 6.0 mm and length of 12.5 mm) were immersed fully in 10 mL of PBS for a period and then removed from the stored 10 mL of PBS. The stored PBS was consumed to determine the absorbance by UV spectrophotometer (Jasco, B550). The ketoprofen release was monitored by monitoring the absorbance at λmax = 260 nm as a function of time. Release experiments were performed in quadruplicate. 2.5. Compressive test Before testing, all specimens were immersed fully in PBS and kept at 37 °C for 107 days. The compressive strength of bone cement was then measured using INSTRON 5582. The compressive analyses of the bone cements were according to ASTM F451. The diameter and length of a specimen for compressive analysis of bone cement were 6.0 mm and 12.5 mm, respectively. The cross head speed for compressive test was 25 mm/min. 2.6. Contact angle measurements and morphology observation Contact angles of all bone cements were measured with water using a contact angle meter (Kyowa Interface Science Co., Ltd, Model CA-D).

Table 1 The different compositions for the powder portion of the bone cement in each system. Bone cement

Powder (g) Commercial Product

Conventional cement loaded with ketoprofen System 80-19-S-k System 70-19-S-k ⁎ Weight percent ketoprofen in bone cement: 2.74%.

20 19 19

Liquid (mL) Cross-linked poly(MMA-AAS-AMA) (volume ratio of MMA/AAS/ AMA) 80/20/10

70/30/10

0 1 0

0 0 1

⁎Ketoprofen

Commercial Product

0.844 0.844 0.844

10 10 10

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Three samples prepared separately were analyzed per cement, putting three droplets on each sample. The morphologies of the samples were observed using scanning electron microscope (JEOL, JSM-7000F). 2.7. Setting time and maximum curing temperature Measurements of setting time and maximum curing temperature of bone cement systems correspond to those of ASTM F451. 3. Results and discussion Fig. 1 shows the volume gain percentages and the weight gain percentages of various bone cement systems after immersion in PBS for 60 days. System 80-19-S-k, System 70-19-S-k and the conventional cement loaded with ketoprofen had a volume gain percentage of 1.33 ± 0.19%, 1.28 ± 0.3% and 0.67 ± 0.3%, respectively. The weight gain percentages of System 80-19-S-k, System 70-19-S-k and the conventional cement loaded with ketoprofen were 2.94 ± 0.32%, 2.76 ± 0.18% and 1.39 ± 0.27%, respectively. Obviously, adding cross-linked poly(MMA-AAS-AMA) powder to the modified bone cement resulted in a higher volume gain. The absorption of water was mainly contributed by the portion of acrylic acid sodium salt. System 80-19-S-k and System 70-19-S-k do not significantly differ in terms of volume gain percentage or weight gain percentage, owing to that these two modified bone cements only slightly differ in the amount of cross-linked poly(MMA-AAS-AMA) powder added. As a source of prosthetic loosening, shrinkage of bone cement during polymerization may cause a loss of load transfer through the interface between the bone and bone cement. The typical shrinkage of conventional acrylate based bone cements without reduced mixing pressure is about 1–2% [23–26]. According our measurements, the volume percentage swell of System 80-19-S-k is 1.33 ± 0.19% after 60 days immersion. Therefore, System 80-19-S-k might compensate for the shrinkage of bone cement during polymerization. Fig. 2 shows the accumulated drug release of various bone cement systems. After a high initial release of ketoprofen, a reduced yet constant, sustained release of ketoprofen was observed. Additionally, the amount of ketoprofen released from System 80-19-S-k or System 70-19-S-k was higher than that from the conventional cement loaded with ketoprofen. In the first 8 days, the ketoprofen was released promptly from the region near the surface of bone cement. After 16 days of the ketoprofen release, the release rate of ketoprofen became constant. A slope of a curve from 18 days to 60 days indicated the release rate of ketoprofen (mg/hour) by diffusion through the

entire cement. The release rates of ketoprofen from System 80-19-S-k, System 70-19-S-k and the conventional cement loaded with ketoprofen were 2 × 10−5 mg/h, 1 × 10 −5 mg/h and 8 × 10−6 mg/h, respectively. Experimental results indicated that System 80-19-S-k and System 70-19-S-k had a higher release rate of ketoprofen by diffusion through the entire cement than the conventional cement loaded with ketoprofen. This observation was owing to the cross-linked poly(MMA-AAS-AMA) copolymer inside the bone cement swelled after immersion of the modified bone cement in PBS. Ketoprofen could be diffused easily through the swollen cross-linked poly(MMA-AAS-AMA) particles distributed in bone cement, as shown in Fig. 3. However, System 70-19-S-k had a lower release rate of ketoprofen than that of System 80-19-S-k during the sustained release stage. Although the swell of drug-loaded bone cement by introduction of cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles was mainly contributed by the portion of acrylic acid sodium salt, the increase of acrylic acid sodium salt portion in cross-linked poly(MMA-AAS-AMA) might reduce the release rate of ketoprofen. This observation may be attributed to that a larger amount of the \COO− functional group of cross-linked poly(MMA-AAS-AMA) after swelling may attract more ketoprofen, which possesses \OH functional group, ultimately retarding the diffusion of ketoprofen. Table 2 shows the initial ketoprofen release rate (μg/cm 2/h) as calculated over the first 6 h of release and total ketoprofen release after 1 week as a percentage of the total amount. The initial ketoprofen

Fig. 1. Volume gain percentages and weight gain percentages of various bone cement systems after immersion for 60 days.

Fig. 3. Schematics of drug release in bone cement, where the drug is represented as a red dot, cross-linked poly(MMA-AAS-AMA) particles are represented as a larger yellow circle, bone cement is represented as white, and the solution is represented as blue.

Fig. 2. Accumulated drug release percentages of various bone cement systems (a: System 80-19-S-k, b: System 70-19-S-k, c: Conventional cement loaded with ketoprofen).

Y.-H. Nien et al. / Materials Science and Engineering C 33 (2013) 974–978 Table 2 The initial ketoprofen release rate as calculated over the first 6 h of release and total ketoprofen release after 1 week as a percentage of the total amount. Bone cement

Initial release rate (μg/cm2/h) ± SD

Conventional cement loaded with ketoprofen System 80-19-S-k System 70-19-S-k

18.1 ± 0.4

6.4 ± 0.3

23.8 ± 0.5 34.1 ± 0.8

11.9 ± 0.5 10.6 ± 0.2

Total release after 1 week (%) ± SD

Table 3 The results of the compressive strength and contact angles of the bone cement tested in this study. Bone cement

Compressive strength (MPa)⁎

Contact angle (°)

Conventional cement loaded with ketoprofen System 80-19-S-k System 70-19-S-k

75.8 ± 9.2

80 ± 4

80.8 ± 1.1 73.1 ± 5.3

70 ± 3 65 ± 4

⁎ Before tests, all of the specimens were fully immersed in PBS and kept at 37 °C for 107 days.

release rate and total ketoprofen release after 1 week (i.e. a percentage of the total amount) of the conventional bone cement loaded with ketoprofen are 18.1±0.4 μg/cm2/h and 6.4±0.3%, respectively. Belt et al. indicated that the antibiotic release of commercial gentamicinimpregnated bone cements: CMW1, CMW3, CMW Endurance, and CMW2000 all have 4.22 w/w% gentamicin sulphate (DePuy International Ltd., UK) of the powder component. The initial gentamicin release rates and total gentamicin release after 1 week (i.e. a percentage of the total amount) of CMW1, CMW3, CMW Endurance, and CMW2000 range from 9.2 ± 0.3 μg/cm2/h to 13.1 ± 0.6 μg/cm2/h and from 4.0 ± 0.2% to 5.3 ± 0.2%, respectively [15]. The initial drug release rates and total drug release after 1 week of CMW1, CMW3, CMW Endurance, and CMW2000 are similar to those of the conventional bone cement loaded with ketoprofen (18.1 ± 0.4 μg/cm2/h and 6.4± 0.3%, respectively), because the release mechanism of the conventional bone cement loaded with ketoprofen is similar to that of CMW1, CMW3, CMW Endurance, and CMW2000. The initial ketoprofen release rates of System 80-19-S-k and System 70-19-S-k are 23.8 ± 0.5 μg/cm2/h and 34.1 ± 0.8 μg/cm2/h, respectively. The initial ketoprofen release rates of System 80-19-S-k and System 70-19-S-k increase 31.5% and 88.4%,

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respectively, compared with that of the conventional bone cement loaded with ketoprofen. The total ketoprofen release after 1 week (i.e. a percentage of the total amount) of System 80-19-S-k and System 70-19-S-k are 11.9 ±0.5% and 10.6 ± 0.2%. The total ketoprofen release after 1 week (i.e. a percentage of the total amount) of System 80-19-S-k and System 70-19-S-k also increase 85.9% and 65.6%, respectively. The increase of both the initial ketoprofen release rate and total ketoprofen release after 1 week (i.e. a percentage of the total amount) of System 80-19-S-k and System 70-19-S-k is due to an increase of hydrophilicity and swell of both cements that contain hydrophilic cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles. Notably, the initial release of ketoprofen of System 80-19-S-k is less than that of System 70-19-S-k; in addition, the total ketoprofen release after 1 week (i.e. a percentage of the total amount) of System 80-19-S-k is higher than that of System 70-19-S-k. The above results demonstrate that the initial release of ketoprofen from the cement is partially a surface phenomenon (implying a larger area for release), whereas the total amount released depends on the penetration depth (i.e. a diffusion mechanism) [15]. During the initial release phase, with the help of cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles (swollen in fluids), System 80-19-S-k and System 70-19-S-k acquire a larger area for release than the conventional bone cement loaded with ketoprofen. In particular, System 70-19-S-k has the highest hydrophilicity, leading to the largest area for release and the highest initial ketoprofen release rate. During the total ketoprofen release phase (i.e. a combination of initial release and sustained release), because System 80-19-S-k and System 70-19-S-k consist of cross-linked poly(methylmethacrylate-acrylic acid sodium salt particles (swollen in fluids) provide better hydrophilicity and diffusion than that of the conventional bone cement loaded with ketoprofen, System 80-19-S-k and System 70-19-S-k illustrate a better total ketoprofen release after 1 week than the conventional bone cement loaded with ketoprofen. Table 3 summarizes the results of the compressive strength of the bone cement tested in this work. The compressive strength of the conventional bone cement loaded with ketoprofen, System 80-19-S-k and System 70-19-S-k are 75.8 ± 9.2 MPa, 80.8± 1.1 MPa and 73.1± 5.3, respectively. The compressive strength of bone cement usually varies from 44 to 103 MPa [18]. The compressive strength of the Osteobond bone cement (105.3±21.9 MPa, tested after immersion in saline solution at 37 °C for 50 days) [27] is higher than that of the conventional bone cement loaded with ketoprofen (75.8±9.2 MPa, tested after immersion in PBS at 37 °C for 107 days), because drug-loaded cement is mechanically

Fig. 4. SEM images of System 80-19-S-k before swelling (a) and after swelling (b), System 70-19-S-k before swelling (c) and after swelling (d), the conventional cement loaded with ketoprofen before swelling (e) and after swelling (f).

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Table 4 The measurements of setting time and maximum curing temperature of bone cement systems.

Conventional cement loaded with ketoprofen System 80-19-S-k System 70-19-S-k

Setting time

Maximum curing temperature (°C)

4 min 46 s

69

5 min 28 s 5 min 08 s

67.5 67.5

less strong than plain cement and higher absorption of fluids weakens the mechanical properties. However, System 80-19-S-k displays a slightly better compressive strength than that of the conventional bone cement loaded with ketoprofen. This finding suggests that System 80-19-S-k tends to provide a high drug release without sacrificing the mechanical properties of bone cement. Contact angles of the conventional bone cement loaded with ketoprofen, System 80-19-S-k and System 70-19-S-k are 80± 4, 70± 3 and 65± 4°, respectively (Table 3). System 70-19-S-k shows the highest hydrophilicity, and the conventional bone cement loaded with ketoprofen shows the highest hydrophobility. Notably, a higher content of acrylic acid sodium salt implies an improved hydrophilicity of the cement. Fig. 4 shows the SEM images of System 80-19-S-k before swelling (a) and after swelling (b), System 70-19-S-k before swelling (c) and after swelling (d) as well as the conventional cement loaded with ketoprofen before swelling (e) and after swelling (f). Additionally, the surfaces of both System 80-19-S-k and System 70-19-S-k after swelling become rougher than those of both System 80-19-S-k and System 70-19-S-k before swelling. Moreover, the surfaces of the conventional cement loaded with ketoprofen before and after swelling do not significantly differ from each other because the conventional cement loaded with ketoprofen lacks hydrophilic cross-linked poly(MMA-AAS-AMA) powder. Table 4 summarizes the measurements of setting time and maximum curing temperature of bone cement systems. The three bone cement systems have a similar setting time and maximum curing temperature. This similarity is owing to that additives such as cross-linked poly(MMA-AAS-AMA) powder fail to react further during the curing of bone cement. 4. Conclusions This work presents a novel approach for increasing drug release from acrylic bone cement. Experimental results indicate that the drug-loaded bone cement formed by introducing cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles into bone cement can increase the hydrophilicity of the cement, allow fluids to pass into the cement more efficiently, and supplement both the drug release rate and total release amounts of drugs. Additionally, System 80-19-S-k, System 70-19-S-k and the conventional cement loaded with ketoprofen have volume gain percentages of 1.33± 0.19%, 1.28 ±0.3% and 0.67 ± 0.3%, respectively, after immersion in PBS for 60 days. Also, adding cross-linked poly(MMA-AAS-AMA) powder to the modified bone

cement increase the volume gain. With the help of cross-linked poly(methylmethacrylate-acrylic acid sodium salt particles (swollen in fluids), System 80-19-S-k and System 70-19-S-k have a higher initial release rate and total release than those of the conventional bone cement loaded with ketoprofen. The drug-loaded bone cement by introduction of cross-linked poly(methylmethacrylate-acrylic acid sodium salt) particles to bone cement such as System 80-19-S-k can provide an improved drug release. Furthermore, mechanical properties of the bone cement are not sacrificed.

Acknowledgments The authors would like to thank the National Science Council of the Republic of China, Taiwan for financially supporting this research under Contract No. NSC 97-2221-E-224-068-. Ted Knoy is appreciated for his editorial assistance.

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Preparation and characterization of acrylic bone cement with high drug release.

Drug-loaded bone cement is used as an application method to prevent and treat prosthesis-related infection. Despite the commercial availability of dru...
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