Despite clinical, material, and pharmaceutical advances, infection remains a major obstacle in total joint revision surgery. Successful solutions must extend beyond bulk biomaterial and device modifications, integrating locally delivered pharmaceuticals and physiological cues at the implant site, or within large bone defects with prominent avascular spaces. One approach involves coating clinically familiar allograft bone with an antibiotic-releasing rate-controlling polymer membrane for use as a matrix for local drug release in bone. The kinetics of drug release from this system can be tailored via alterations in the substrate or the polymeric coating. Drug-loaded polycaprolactone coating releases bioactive tobramycin from both cadaveric-sourced cancellous allograft fragments and synthetic hybrid coralline ceramic bone graft fragments with similar kinetics over a clinically relevant 6-week timeframe. However, micron-sized allograft particulate provides extended bioactive tobramycin release. Addition of porogen polyethylene glycol to the polymer coating formulation changes tobramycin release kinetics without significant impact on released antibiotic bioactivity. Incorporation of oil-microencapsulated tobramycin into the polymer coating did not significantly modify tobramycin release kinetics. In addition to releasing inhibitory concentrations of tobramycin, antibiotic-loaded allograft bone provides recognized beneficial osteoconductive potential, attractive for decreasing orthopedic surgical infections with improved filling of dead space and new bone formation.

Perivascular delivery of anti-proliferative agents is an attractive approach to inhibit hyperplasia that causes stenosis of synthetic hemodialysis grafts and other vascular grafts. Perivascular drug delivery systems typically release drugs to both the vascular wall and non-target extravascular tissue. The objective of this study was to develop a biodegradable, perivascular delivery system for localized, sustained and unidirectional drug release in the context of synthetic arteriovenous (AV) grafts used for chronic hemodialysis. To this end, a dense non-porous polymer barrier layer was laminated to either i) a drug-loaded non-porous polymer layer, or ii) a porous polymer layer. To provide tuneability, the porous layer could be loaded with drug during casting or later infused with a drug-loaded hydrogel. The polymer bilayer wraps were prepared by a solvent casting, thermal-phase inversion technique using either polylactide-co-glycolide (PLGA) or polycaprolactone (PCL). Sunitinib, a multi-target receptor tyrosine kinase inhibitor, was used as a model drug. In a modified transwell chamber system, the barrier function of the non-porous PLGA backing was superior to the non-porous PCL backing although both markedly inhibited drug diffusion. As assessed by in vitro release assays, drug release duration from the drug-loaded non-porous PCL construct was almost 4-fold greater than release from the porous PCL construct infused with drug-laden hydrogel (22 days vs. 5 days); release duration from the drug-loaded non-porous PLGA construct was prolonged approximately 3-fold over release from the porous PLGA construct infused with drug-laden hydrogel (9 days vs. 3 days). Complete in vitro degradation of the PLGA porous and non-porous constructs occurred by approximately 35 days whereas the PCL constructs remained intact even after most drug was released (49 days). The PLGA non-porous bilayer wrap containing 143±5.5 mg sunitinib in the inner layer was chosen for further pharmacokinetic assessment in vivo where the construct was placed around the external jugular vein in a porcine model. At one week, no drug was detected by HPLC/MS/MS in any examined extravascular tissue whereas high levels of drug were detected in the wrapped vein segment (1048 ng/g tissue). At four weeks, drug was detected in adjacent muscle (52 ng/g tissue) but 13-fold greater amounts were detected in the wrapped vein segment (1742 ng/g tissue). These results indicate that the barrier layer effectively impedes extravascular drug loss. Tensile testing showed that the initially flexible PLGA construct stiffened with hydration, a phenomenon also observed after in vivo placement. This characteristic may be useful to resist undue circumferential venous tensile stress produced in AV grafting. The PLGA wrap bilayer formulation is a promising perivascular drug delivery design for local treatment of hemodialysis AV graft hyperplasia and possibly other hyperplastic vascular disorders.