A rapid, flexible method for incorporating controlled antibiotic release into porous polymethylmethacrylate space maintainers for craniofacial reconstruction

Abstract

Severe injuries in the craniofacial complex, resulting from trauma or pathology, present several challenges to functional and aesthetic reconstruction. The anatomy and position of the craniofacial region make it vulnerable to injury and subsequent local infection due to external bacteria as well as those from neighbouring structures like the sinuses, nasal passages, and mouth. Porous polymethylmethacrylate (PMMA) "space maintainers" have proven useful in staged craniofacial reconstruction by promoting healing of overlying soft tissue prior to reconstruction of craniofacial bones. We describe herein a method by which the porosity of a prefabricated porous PMMA space maintainer, generated by porogen leaching, can be loaded with a thermogelling copolymer-based drug delivery system. Porogen leaching, space maintainer prewetting, and thermogel loading all significantly affected the loading of a model antibiotic, colistin. Weeks-long release of antibiotic at clinically relevant levels was achieved with several formulations. In vitro assays confirmed that the released colistin maintained its antibiotic activity against several bacterial targets. Our results suggest that this method is a valuable tool in the development of novel therapeutic approaches for the treatment of severe complex, infected craniofacial injuries.

Figure 1

A schematic depiction of the “pregel” and “dip” methods used to load prefabricated PMMA space maintainers with the various thermogel formulations described in Table 1.

Figure 2

Day 0 space maintainer weight after colistin loading and immediately prior to placement in release medium, expressed as percentage of initial space maintainer weight shown in Table 3. The 12 groups are identified along the bottom of the image using the same notations depicted in the study design (Table 1). Groups marked with the same letter (A-D) did not significantly differ from each other (p > 0.05), but differ from all other groups (p < 0.05). The “L:G 3:1, pregel (+prewet)” group is marked with a “*” to indicate that it significantly differs from all other groups (p < 0.05). Each column represents the mean ± standard deviation for n=4 space maintainers per group. Each space maintainer’s weight was expressed as a percentage of its corresponding initial weight prior to calculation of the mean.

Figure 3

Total colistin loaded into each space maintainer on Day 0. “Actual colistin” values represent the total amount released from each space maintainer, measured until the release reached a consistent zero value. “Theoretical colistin” values were derived from the weight gain of each dried space maintainer upon colistin loading, taking into account the weight percent of colistin in each loading solution as well as the presence of thermogel, if applicable. The 12 groups are identified along the bottom of the image using the same notations depicted in the study design (Table 1). Theoretical values with “+” differed significantly from the corresponding actual value (p < 0.05). Actual values with “#” significantly differed from all other groups (p < 0.05) except those marked with the same notation. Each column represents the mean ± standard deviation for n=4 space maintainers per group.

Figure 4

Colistin release profiles from all 12 groups, measured via HPLC at set timepoints. All groups had a burst release followed by daily non-zero colistin release. Note the per day normalization of the y-axis. Nearly all groups showed significantly different release profiles (p < 0.05), except those marked with letters A-C; groups marked with the same letter did not differ from each other, but differed from all other groups (p < 0.05). Each data point represents the mean ± standard deviation for n=4 space maintainers per group at that timepoint. All points have error bars, though they are not long enough to be visualized in some cases.

Figure 5

Main effects analysis of the effect of leaching of CMC, prewetting, and thermogel loading method on total colistin loaded within the constructs. Each of these variables had a significant effect on loading (p < 0.05), indicated by “*”. Each data point represents the mean ± standard deviation for n=8 space maintainers per variable.