Effect of soluble sugars on the elution properties of experimental chemotherapeutic bone cements
1
1
Schulz, J F; +1Handal, J A; 2Kwok, S; 1Samuel S P
Department of Orthopedic Surgery, Albert Einstein Medical Center, Philadelphia, PA, 2ORTD, Albert Einstein Medical Center, Philadelphia, PA
[email protected]
INTRODUCTION:
Bone cement can be used both as a fracture fixation device to provide
stability and as a local drug delivery system to deliver chemotherapeutic
agents, analgesics, antibiotics, etc. Combining these two functions will
have tremendous potential in the field of metastatic bone cancer
treatment. Drug elution from a non-degradable material such as PMMA
depends on a number of factors including, initial volume/weight fraction
of the drug in bone cement, surface area of pores, and how well the
pores are interconnected. Drugs from bone cement are usually released
in a bi-phasic manner; an initial burst followed by a tail of low level
drug release that may continue for years.
Most of the chemotherapy agents are potent and effective at very low
dosage. In fact, administration of a few milligrams of these drugs can
effectively treat certain tumors. Adding these types of chemotherapy
agents to bone cement is a challenge, however. If a few milligrams of
these drugs are mixed with bone cement usually no elution occurs. One
of the ways to improve drug elution is to add soluble space fillers to
bone cements. When selecting soluble fillers for chemotherapeutic bone
cement applications, the fillers should be easily soluble, chemically
inert, biocompatible, easily eliminated from the blood stream, and
should not cause any adverse reaction to the local tissue at high
concentrations. The other major requirement is that these fillers should
not interfere with the polymerization reaction of bone cement. This may
leave us with some of the very simple sugars (e.g. glucose, fructose, and
sucrose), salts (e.g. sodium chloride) and biocompatible water soluble
polymers such as poly anhydrides.
In this study, the effect of addition of soluble sugars (glucose or
sucrose) on the methotrexate elution properties of commercially
available bone cement (Vertebroplastic radiopaque resinous material,
DePuy AcroMed Inc., MA) was evaluated.
METHODS:
The commercially available bone cement (Vertebroplastic radiopaque
resinous material, DePuy AcroMed Inc., Raynham, MA) used in this
study is sold as a two-component self curing system containing a powder
(methylmethacrylate polymer and barium sulfate) and a liquid monomer
(methylmethacrylate monomer). To prepare these experimental bone
cements containing soluble fillers, the powder component of this bone
cement was first thoroughly mixed with methotrexate and soluble filler
(powder glucose or sucrose). The mixing was done using a pestle and
mortar. The exact composition of bone cement mixtures tested is shown
in Table 1. Next, the liquid monomer was added to the powder and the
resulting mixture was immediately molded into cylindrical specimens.
Table 1: This table shows the amount of each component added to
prepare one elution test specimen.
Component
PMMA powder
Monomer
Sucrose/Glucose
Methotrexate
With filler
1.25 g
1 ml
1.25 g
105 mg
Without filler
2.50 g
1 ml
0g
105 mg
Preparation of in vitro test specimens: Glass vials were used as
molds to prepare the cylindrical specimens. The prepared
methotrexate/soluble sugar/bone cement mixtures were molded in glass
vials and were allowed to harden for 1 h at 37o C. The polymerized
cylindrical bone cement specimens were then taken out of the glass
molds by breaking the glass molds carefully. The final dimensions of the
bone cement specimens were 13.5 mm height and 9.5 mm diameter.
Three cylindrical elution test specimens were prepared in each group.
Elution experiment: After 24 h of post curing, the bone cement
specimens were removed from the glass vials and were placed in 10 ml
distilled water (elution media) maintained at 37o C. The amount of drug
eluted at each time interval was measured using a microplate reader
(Spectramax 190, Molecular devices, CA) at a wavelength of 405 nm
(methotrexate). The elution media was completely replaced with 10 ml
distilled water after each measurement. Methotrexate elution was
measured at regular intervals up to 720 h.
RESULTS:
The handling properties of commercially available bone cements did
not change significantly with the addition of chemotherapeutic drugs and
powdered glucose or sucrose. The viscosity or feel of the bone cements
with fillers were similar to the feel of commercially available bone
cements without filler. The cumulative drug elution at 720 h between
bone cements with and without soluble fillers were compared using
Mann-Whitney non parametric test. The results showed that bone
cements containing soluble fillers did elute higher amounts of
chemotherapy drug (Figure 1). The amount of chemotherapeutic drug
eluted also depended on the type of filler used. For the same amount of
soluble filler and methotrexate, bone cement that contained sucrose
eluted more methotrexate than bone cement that contained glucose (pvalue <0.001, Figure 1). Addition of sucrose (35 weight %) facilitated
the almost complete elution of methotrexate within 30 days.
Figure 1: This figure shows the average cumulative elution profile of
methotrexate from bone cements containing; (1) no fillers, (2) glucose
and (3) sucrose. Even though the amount of sucrose or glucose remained
the same we can see stark differences in the amount of drug eluted.
DISCUSSION:
In theory, after implantation the soluble fillers will dissolve over time
and make the bone cement more porous and interconnected. The newly
formed interconnected porous networks within the bone cement will
allow body fluids to have more access to the immobilized chemotherapy
drugs. This will help maintain drug elution at therapeutic levels over a
definite period of time. The porous bone cement that remains after the
elution of soluble fillers/drugs is an insoluble glassy material and will
continue to provide the necessary mechanical support / stability to the
bone for many years.
Soluble fillers added to chemotherapeutic bone cements improved the
overall drug elution rate from the bone cements. The results show that,
with the use of soluble fillers, it is possible to add a few milligrams of
chemotherapy drug and still maintain constant drug elution. In fact, it is
possible to maintain elution in 3 ml volume bone cement containing 1
mg adriyamycin with the help of soluble fillers (results not shown). The
initial amount of soluble fillers added to these bone cements in this
experiment is quite high. However, this amount can be optimized or
reduced by better selection of soluble fillers.
The difference in methotrexate elution rates between bone cememnt
containing the same amount of glucose and sucrose also demonstrate
that drug elution can be customized by varying the type of soluble filler
used. The difference in elution rates between these two soluble fillers
may be due to the differences in molecular weights, solubility, and how
they interacted with the bone cement mixture during polymerization.
However, more studies are needed to evaluate the effect of soluble filler
elution on the mechanical properties of bone cements.
ACKNOELEDGEMENT
The authors would like to thank Depuy Spine Inc., for their support.
Poster No. 1923 • ORS 2011 Annual Meeting