We have described a simple, cheap, and effective formulation and preparation process for gentamicin-releasing PMMA beads, with release kinetics that are somewhat better than those observed for commercially available Septopal beads. The improved release kinetics are mainly the result of increased porosity of the beads, due to the use of only 50% of the prescribed amount of monomer, which causes sintering rather than polymerization fusion of polymer particles, leaving a porous matrix. Secondly, the addition of a gel-forming, water-soluble polymeric filler, PVP 17, ensures penetration of fluids into all parts of the matrix (full percolation), thereby increasing the total amount of drug that is released.
The efficiency of the polymerization reaction became less when the proportion of liquid monomer added to the polymeric bone cement powder was reduced. If the amount of monomer is insufficient for the reaction to occur at all possible contact sites of the polymer particles, a more porous matrix will be formed, allowing penetration of water to most sites in the beads. This will lead to a higher amount of gentamicin being released (Frutos Cabanillas et al. 2000
). On the other hand, with the reduction in the amount of monomer, the hardening time of the acrylic becomes considerably reduced (Pascual et al. 1999
) and it requires some dexterity to prepare beads within the time available. Yet, it is possible to produce beads, although the last beads prepared out of a batch tend to appear brittle. In general, however, manual examination of the beads prepared with 50% monomer showed that they had sufficient strength for this non-load-bearing application of bone cement. Reduction of the monomer content to below 50% was impossible, as no coherence could be obtained at these lower concentrations (Willert et al. 1979
The use of gel-forming, water-soluble polymeric fillers turned out to be indispensable to increase the gentamicin release to levels comparable to or higher than the release of gentamicin by the commercially available Septopal beads. Although we chose to use PVP 17 for this purpose, other biodegradable fillers might also have served the purpose. PVP 17-filled beads showed excellent gentamicin release profiles, and the Kollidon PVP 17 PF grade is considered safe for parenteral use in humans (Böhler 1999). Moreover, the PVP 17 could easily be combined with the acrylic polymer in the production process.
Several studies have been done to investigate the effect of biodegradable fillers on the drug release of antibiotic-loaded bone cement. Frutos et al. (2002)
studied the influence of PVP 12 on the antibiotic release from commercially available gentamicin-loaded bone cement. Incorporation of PVP into the cement matrix led to a remarkable increase in the maximum amount of gentamicin released, and this effect was proportional to the PVP concentration incorporated. Virto et al. (2003)
studied the antibiotic release of gentamicin-loaded bone cement after addition of HPMC. HPMC did not produce an increase in the gentamicin release and these authors hypothesized that dissolution of HPMC creates a surrounding similar to a gel that makes gentamicin release from the cement matrix difficult. However, we found a distinct increase in the gentamicin release after addition of HPMC to bone cement, with the clear distinction that our bone cement was made with 50% of the prescribed monomer. Also, McLaren et al. (2007a)
investigated the use of biodegradable fillers but, like Frutos et al. (2002)
and Virto et al. (2003)
, they did not use less monomer, and thus no additional intrinsic porosity was created (i.e. porosity achieved without dissolution of any filler material). In line with our findings, McLaren et al. (2007a
) showed that it is not the filler material that is crucial but rather its particle size, and fillers with a larger particle size led to larger pores, less pore interconnectivity, and faster fluid penetration. Smaller-size particles led to smaller pores, greater pore interconnectivity, and smaller areas between the pores with no fluid penetration.
The gentamicin-loaded beads based on the use of half the prescribed amount of monomer and the addition of gel-forming polymeric filler reduced biofilm formation as effectively as commercially available Septopal beads. The (statistically insignificant) reduction in efficacy of our hand-rolled beads is presumably due to a less favorable area-to-volume ratio, as the hand-rolled beads were larger than the commercially available beads. Moreover, hand-rolled beads are usually not uniform in size, giving much larger standard deviations than obtained with commercially available beads and attesting to the greater reproducibility of Septopal beads. To solve this problem, a beads template system could be used, in which antibiotic-loaded beads of uniform size and small diameter could be produced. A template system should also be considered because of the short time available to prepare beads with half of the prescribed amount of monomer.
To verify the significance of our in vitro observations, in vivo studies will be required that take into account both complete eradication of the infection and the time required to achieve this outcome, but we believe the results reported here support our hypothesis that acrylic beads containing half the prescribed amount of monomer and PVP may offer a therapeutic efficacy similar to that of commercially available Septopal beads. Application of this novel formulation of acrylic beads in combination with a bead-template system would be useful for three different groups of orthopedic surgeons, to make chains of antibiotic-loaded bone cement beads: (1) surgeons in countries where they are not allowed to import the Septopal beads, such as the USA; (2) surgeons in developing countries, since these beads are approximately 3 times cheaper than the commercial ones (apart from the costs of the template system); and (3) surgeons who are familiar with the use of the Septopal beads but who need to treat their patients with another antibiotic because of the increasing number of patients infected with gentamicin-resistent bacteria. The method we describe here also makes it possible to create bone cement beads loaded with vancomycin, clindamycin, or other antibiotics that are not yet available commercially.
HR: concept, study design, data collection, analysis, and manuscript preparation. HvdM, HF, SS, JvH, and HB: study design, analysis, and revision of manuscript. DN: concept, study design, analysis, and revision of manuscript.
No competing interests declared.