Antibiotic-releasing Porous Poly(methyl methacrylate) for Space Maintenance and Infection Prevention in Large Bone Defects
Shah, Sarita R.
Mikos, Antonios G.
Doctor of Philosophy
Large tissue defects in the mandible or long bones resulting from trauma or pathology present many challenges to tissue engineers attempting to regenerate lost tissue. These defects present anatomical challenges to regeneration as well as complicating factors, primarily infection. Because infection is a common and debilitating complication, we sought to develop an antibiotic-releasing porous space maintainer as part of a two-stage reconstructive approach that can support the preservation and optimization of large bone defects to facilitate later reconstruction. These porous space maintainers comprise a bulk phase of non-degradable poly(methyl methacrylate) (PMMA) made porous with an aqueous gel porogen. High local concentrations of antibiotic can be achieved by incorporation of drug into the space maintainer and release kinetics can be modified by utilizing different materials for release. In this thesis, we first present the development of poly(lactic-co-glycolic acid) (PLGA) microparticles as a platform for the controlled release of multiple types of antibiotic. We demonstrate in this specific aim that antibiotic physicochemical properties can be used to infer general loading efficiency and release kinetics, providing guidance for efficient decision-making regarding antibiotics suitable for delivery via PLGA microparticles. The second objective of this work was to evaluate antibiotic-loaded porous space maintainers in vivo with regards to the effect of antibiotic dose and release kinetics on bacterial clearance and tissue healing in the craniofacial region using an infected rabbit mandibular defect model. The results from in vitro evaluation demonstrate that the release of antibiotics from porous space maintainers can be controlled by incorporating PLGA microparticles. Furthermore, in vivo evaluation shows that antibiotic dose and release kinetics have significant effects on local tissues and and that these effects may be unique to each antibiotic type, highlighting the importance of evaluating tissue response to antibiotic-releasing constructs in addition to antimicrobial efficacy. In the third specific aim, we evaluated the effects of bacterial contamination and local clindamycin delivery on bacterial clearance and the regenerative potential of an induced in an infected rat femoral defect model. The results from this specific aim demonstrated that local antibiotic delivery influences the gene expression profile of local regenerating tissues and therefore can be leveraged for its effects on host tissues as well as its antimicrobial properties. Finally, we anticipated the future use of space maintainers for one-stage reconstruction. The degradable polymer poly(propylene fumarate) (PPF) was evaluated as a candidate for a degradable antibiotic-releasing porous space maintainer. The results from this study demonstrated that fabrication parameters such as polymer-to-crosslinker ratio and the percent incorporation of PLGA microparticles can be modified to tune the properties of antibiotic-releasing degradable space maintainers suitable for one-stage reconstruction. The overall goal of this work was to develop antibiotic-releasing porous space maintainers as a strategy to support the reconstruction of contaminated bone defects at risk of infection. Through this thesis, we have demonstrated that local antibiotic delivery is a promising strategy for preventing the progression of contamination to infection and that antibiotic dose and release kinetics can be further leveraged to alter local tissue response.