j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 4 ( 2 0 1 5 ) 1 6 1 e1 6 6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Polyethylene glycol improves elution properties of polymethyl methacrylate bone cements John A. Handal, MD,a,* Nathan C. Tiedeken, MD,a Grigory E. Gershkovich, MD,a Jeffrey A. Kushner, DO,b Benjamin Dratch, DO,c and Solomon P. Samuel, D. Enga a
Department of Orthopedic Surgery, Einstein Medical Center, Philadelphia, Pennsylvania Department of Internal Medicine, Largo Medical Center, Largo, Florida c Family Medicine, Forbes Hospital, Monroeville, Pennsylvania b
article info
abstract
Article history:
Background: Bone cements are used as adjuncts to fracture fixation methods and can also
Received 9 July 2014
function as a local drug delivery system. The ability to elute drugs makes bone cement a
Received in revised form
promising and powerful chemotherapy treatment modality for osseous tumors. However,
9 July 2014
because of poor elution rates, the clinical application of this drug delivery mode remains
Accepted 30 October 2014
challenging. Soluble fillers, such as sugars, salts, or biocompatible polymers, offer a solu-
Available online 6 November 2014
tion to improve elution rates. This study quantified the effect of polyethylene glycol (PEG) on the elution properties of three commercially available bone cements.
Keywords:
Methods: Two grams of Vertebroplastic, Palacos, and Confidence bone cement powder
Soluble fillers
containing three concentrations (0%, 20%, or 50%) of PEG filler were hand mixed with 10 mg
Chemotherapy
of methotrexate. This powder mixture was then polymerized with 1.0 mL of the cement
Bone cement
specific liquid monomer. The cylindrical elution samples were placed in saline solution
Methotrexate
and methotrexate elution was recorded for 720 h.
Porogen
Results: The cumulative and daily elution rate increased as the concentration of PEG increased for each bone cement. However, the percent of increase depended on the bone cement used. Cumulative methotrexate elution increased by 40%e54% in case of the highest PEG filler concentration when compared with controls. Conclusions: PEG soluble filler offers a promising method for improving methotrexate drug elution in bone cement. Future studies need to optimize the PEG and bone cement ratio that produces the greatest drug elution profile without sacrificing the biomechanical properties of bone cement. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Polymethyl methacrylate (PMMA)-based cements are an effective, established method for local antibiotic drug delivery in bone and surrounding tissues [1e5]. The combination of durability, biocompatibility, and cost makes bone cement a
commonly used drug delivery system. Bone cement can potentially serve as an excellent candidate for local chemotherapeutic drug delivery. Similar to antibiotic bone cements, by providing a high dose of drug directly to the affected site, this decreases the systemic absorption and limits deleterious side effects [6]. Previous reports have demonstrated an
* Corresponding author. Department of Orthopedic Surgery, Einstein Medical Center, 5501 Old York Rd, WCB 4, Philadelphia, PA 19141. Tel.: þ1 215 456 8835; fax: þ1 215 324 2426. E-mail address: [email protected] (J.A. Handal). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.10.051
162
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 4 ( 2 0 1 5 ) 1 6 1 e1 6 6
Fig. 1 e The cumulative methotrexate elution profile of Vertebroplastic bone cement containing different soluble fillers obtained during the screening experiment. In this experiment, Vertebroplastic bone cement specimens contained a 100-mg initial methotrexate concentration and 50% desired soluble filler. The soluble fillers tested included glucose, sodium chloride, sucrose, PEG (MW 3500), and PEG (MW 8000).
interest in treating osseous tumors locally through the use of chemotherapy drug containing bone cements or polymers [7e14]. Before bone cement is universally accepted as a chemotherapeutic drug delivery system, many challenges remain. Current literature demonstrates a paucity of knowledge regarding the elution properties of bone cement containing low doses of chemotherapeutic agents. The rate of drug elution from a nondegradable material, such as PMMA, is dependent on several factors. The initial concentration of drug in the cement, surface area, and pore interconnectivity all affect the rate of drug elution [1,15]. Drugs from bone cement are released in a biphasic manner. An initial burst of drug elution is followed by a decreased, steady state of drug release. Previous studies have shown that up to 80%e90% of an initial drug added to the PMMA remains immobilized within the bone cement [10,16]. Adding soluble fillers, or porogens, to PMMA is a technique to improve drug elution rates and increase the cumulative amount of drug eluted [17e27]. The filler dissolves and increases the pore channel formation within the cement construct. This increased interconnectivity of pores results in an increased drug elution. However, the addition of secondary substances may jeopardize the mechanical properties of bone cement, creating a possible disadvantage when using soluble fillers [23,28]. As previously stated, if 80%e90% of drugs added to bone cement remain immobilized, this approach may be clinically ineffective when attempting to locally treat osseous tumors [10,16]. Although the use of soluble fillers may increase drug elution, several criteria exist when selecting these porogens for clinical use. Fillers should be easily soluble, nontoxic, chemically inert, and easily eliminated. Some examples of biocompatible fillers that may fit these criteria include simple
sugars, salts, and hydrophilic polymers. This study evaluated the elution properties of three commercially available bone cements that were modified with polyethylene glycol (PEG) soluble filler and a commonly used chemotherapy drug, methotrexate.
2.
Materials and methods
Vertebroplastic (DePuy AcroMed Inc, Raynham, MA), Confidence (DePuy AcroMed Inc), and Palacos (Heraeus Medical GmbH, Wehrheim, Germany) were the three bone cements used in this study. PEG (molecular weight 8000) was selected as the experimental porogen or soluble filler as it had the greatest elution profile in a separate screening experiment using Vertebroplastic bone cement. Figure 1 demonstrates the elution profile results of this screening experiment. In this
Fig. 2 e A sample of each bone cement with 20% PEG concentration. (A) Palacos (B) Vertebroplastic, and (C) Confidence. (Color version of the figure is available online.)
163
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 4 ( 2 0 1 5 ) 1 6 1 e1 6 6
Table 1 e The exact bone cement compositions used to prepare the elution test specimens. Category Bone cement No filler Bone cement 20% filler Bone cement 50% filler
PMMA powder
Liquid monomer
Soluble filler (PEG)
Methotrexate
2g
1 mL
0g
10 mg
1.6 g 1g
1 mL 1 mL
0.4 g 1g
10 mg 10 mg
screening experiment, each Vertebroplastic bone cement elution samples were prepared using 100 mg of methotrexate and 50% desired test filler (glucose, sodium chloride, sucrose, PEG [MW 3500] [Sigma-Aldrich, St. Louis, MO], and PEG [MW 8000]). The amount of methotrexate used in the screening experiment is equivalent to adding 1 g of drug to a 20-g packet of bone cement. Because of cost and toxicity reasons, such high initial drug concentration may not be feasible for many chemotherapy agents. Preparation of each elution test sample entailed hand mixing the cement powder component with 10 mg of methotrexate powder (Bedford Laboratories, Bedford, OH). The three concentrations of PEG used in this study were 0%, 20%, and 50% of the total weight of each sample. Each elution specimen was prepared with 2.0 g of the respective prepared powder mixture with 1.0 mL of the corresponding methyl methacrylate liquid monomer. The resultant viscous sample was poured into a 13.5 mm 9.5 mm cylindrical mold (Fig. 2). Table 1 demonstrates the composition of each bone cement sample. Each cement group had three specimens for each PEG concentration. The prepared cement mixtures polymerized within 20 min at room temperature. Each bone cement specimen was placed in a sealed vial containing 10-mL lactated ringers and maintained at a constant temperature of 37 C. The amount of methotrexate eluted at each tested time interval was measured using a microplate reader (SpectraMax 190; Molecular devices,
Sunnyvale, CA). As methotrexate is a yellow powder, the concentration of this drug in the elution media can be measured at a visible wavelength of 405 nm. The elution media was replaced with 10-mL lactated ringers after each measurement. The drug elution from each specimen in the bone cement groups were averaged and recorded over a 720-h time span. The differences in cumulative elution for each bone cement group were evaluated using a one way analysis of variance with a P value of
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Polyethylene glycol improves elution properties of polymethyl methacrylate bone cements John A. Handal, MD,a,* Nathan C. Tiedeken, MD,a Grigory E. Gershkovich, MD,a Jeffrey A. Kushner, DO,b Benjamin Dratch, DO,c and Solomon P. Samuel, D. Enga a
Department of Orthopedic Surgery, Einstein Medical Center, Philadelphia, Pennsylvania Department of Internal Medicine, Largo Medical Center, Largo, Florida c Family Medicine, Forbes Hospital, Monroeville, Pennsylvania b
article info
abstract
Article history:
Background: Bone cements are used as adjuncts to fracture fixation methods and can also
Received 9 July 2014
function as a local drug delivery system. The ability to elute drugs makes bone cement a
Received in revised form
promising and powerful chemotherapy treatment modality for osseous tumors. However,
9 July 2014
because of poor elution rates, the clinical application of this drug delivery mode remains
Accepted 30 October 2014
challenging. Soluble fillers, such as sugars, salts, or biocompatible polymers, offer a solu-
Available online 6 November 2014
tion to improve elution rates. This study quantified the effect of polyethylene glycol (PEG) on the elution properties of three commercially available bone cements.
Keywords:
Methods: Two grams of Vertebroplastic, Palacos, and Confidence bone cement powder
Soluble fillers
containing three concentrations (0%, 20%, or 50%) of PEG filler were hand mixed with 10 mg
Chemotherapy
of methotrexate. This powder mixture was then polymerized with 1.0 mL of the cement
Bone cement
specific liquid monomer. The cylindrical elution samples were placed in saline solution
Methotrexate
and methotrexate elution was recorded for 720 h.
Porogen
Results: The cumulative and daily elution rate increased as the concentration of PEG increased for each bone cement. However, the percent of increase depended on the bone cement used. Cumulative methotrexate elution increased by 40%e54% in case of the highest PEG filler concentration when compared with controls. Conclusions: PEG soluble filler offers a promising method for improving methotrexate drug elution in bone cement. Future studies need to optimize the PEG and bone cement ratio that produces the greatest drug elution profile without sacrificing the biomechanical properties of bone cement. ª 2015 Elsevier Inc. All rights reserved.
1.
Introduction
Polymethyl methacrylate (PMMA)-based cements are an effective, established method for local antibiotic drug delivery in bone and surrounding tissues [1e5]. The combination of durability, biocompatibility, and cost makes bone cement a
commonly used drug delivery system. Bone cement can potentially serve as an excellent candidate for local chemotherapeutic drug delivery. Similar to antibiotic bone cements, by providing a high dose of drug directly to the affected site, this decreases the systemic absorption and limits deleterious side effects [6]. Previous reports have demonstrated an
* Corresponding author. Department of Orthopedic Surgery, Einstein Medical Center, 5501 Old York Rd, WCB 4, Philadelphia, PA 19141. Tel.: þ1 215 456 8835; fax: þ1 215 324 2426. E-mail address: [email protected] (J.A. Handal). 0022-4804/$ e see front matter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jss.2014.10.051
162
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 4 ( 2 0 1 5 ) 1 6 1 e1 6 6
Fig. 1 e The cumulative methotrexate elution profile of Vertebroplastic bone cement containing different soluble fillers obtained during the screening experiment. In this experiment, Vertebroplastic bone cement specimens contained a 100-mg initial methotrexate concentration and 50% desired soluble filler. The soluble fillers tested included glucose, sodium chloride, sucrose, PEG (MW 3500), and PEG (MW 8000).
interest in treating osseous tumors locally through the use of chemotherapy drug containing bone cements or polymers [7e14]. Before bone cement is universally accepted as a chemotherapeutic drug delivery system, many challenges remain. Current literature demonstrates a paucity of knowledge regarding the elution properties of bone cement containing low doses of chemotherapeutic agents. The rate of drug elution from a nondegradable material, such as PMMA, is dependent on several factors. The initial concentration of drug in the cement, surface area, and pore interconnectivity all affect the rate of drug elution [1,15]. Drugs from bone cement are released in a biphasic manner. An initial burst of drug elution is followed by a decreased, steady state of drug release. Previous studies have shown that up to 80%e90% of an initial drug added to the PMMA remains immobilized within the bone cement [10,16]. Adding soluble fillers, or porogens, to PMMA is a technique to improve drug elution rates and increase the cumulative amount of drug eluted [17e27]. The filler dissolves and increases the pore channel formation within the cement construct. This increased interconnectivity of pores results in an increased drug elution. However, the addition of secondary substances may jeopardize the mechanical properties of bone cement, creating a possible disadvantage when using soluble fillers [23,28]. As previously stated, if 80%e90% of drugs added to bone cement remain immobilized, this approach may be clinically ineffective when attempting to locally treat osseous tumors [10,16]. Although the use of soluble fillers may increase drug elution, several criteria exist when selecting these porogens for clinical use. Fillers should be easily soluble, nontoxic, chemically inert, and easily eliminated. Some examples of biocompatible fillers that may fit these criteria include simple
sugars, salts, and hydrophilic polymers. This study evaluated the elution properties of three commercially available bone cements that were modified with polyethylene glycol (PEG) soluble filler and a commonly used chemotherapy drug, methotrexate.
2.
Materials and methods
Vertebroplastic (DePuy AcroMed Inc, Raynham, MA), Confidence (DePuy AcroMed Inc), and Palacos (Heraeus Medical GmbH, Wehrheim, Germany) were the three bone cements used in this study. PEG (molecular weight 8000) was selected as the experimental porogen or soluble filler as it had the greatest elution profile in a separate screening experiment using Vertebroplastic bone cement. Figure 1 demonstrates the elution profile results of this screening experiment. In this
Fig. 2 e A sample of each bone cement with 20% PEG concentration. (A) Palacos (B) Vertebroplastic, and (C) Confidence. (Color version of the figure is available online.)
163
j o u r n a l o f s u r g i c a l r e s e a r c h 1 9 4 ( 2 0 1 5 ) 1 6 1 e1 6 6
Table 1 e The exact bone cement compositions used to prepare the elution test specimens. Category Bone cement No filler Bone cement 20% filler Bone cement 50% filler
PMMA powder
Liquid monomer
Soluble filler (PEG)
Methotrexate
2g
1 mL
0g
10 mg
1.6 g 1g
1 mL 1 mL
0.4 g 1g
10 mg 10 mg
screening experiment, each Vertebroplastic bone cement elution samples were prepared using 100 mg of methotrexate and 50% desired test filler (glucose, sodium chloride, sucrose, PEG [MW 3500] [Sigma-Aldrich, St. Louis, MO], and PEG [MW 8000]). The amount of methotrexate used in the screening experiment is equivalent to adding 1 g of drug to a 20-g packet of bone cement. Because of cost and toxicity reasons, such high initial drug concentration may not be feasible for many chemotherapy agents. Preparation of each elution test sample entailed hand mixing the cement powder component with 10 mg of methotrexate powder (Bedford Laboratories, Bedford, OH). The three concentrations of PEG used in this study were 0%, 20%, and 50% of the total weight of each sample. Each elution specimen was prepared with 2.0 g of the respective prepared powder mixture with 1.0 mL of the corresponding methyl methacrylate liquid monomer. The resultant viscous sample was poured into a 13.5 mm 9.5 mm cylindrical mold (Fig. 2). Table 1 demonstrates the composition of each bone cement sample. Each cement group had three specimens for each PEG concentration. The prepared cement mixtures polymerized within 20 min at room temperature. Each bone cement specimen was placed in a sealed vial containing 10-mL lactated ringers and maintained at a constant temperature of 37 C. The amount of methotrexate eluted at each tested time interval was measured using a microplate reader (SpectraMax 190; Molecular devices,
Sunnyvale, CA). As methotrexate is a yellow powder, the concentration of this drug in the elution media can be measured at a visible wavelength of 405 nm. The elution media was replaced with 10-mL lactated ringers after each measurement. The drug elution from each specimen in the bone cement groups were averaged and recorded over a 720-h time span. The differences in cumulative elution for each bone cement group were evaluated using a one way analysis of variance with a P value of
