No abstract

Staphylococcus aureus is the most common pathogen associated with bacterial infections in orthopedic procedures. Infections often lead to implant failure and subsequent removal, motivating the development of bifunctional materials that both promote repair and prevent failure due to infection. Lysostaphin is an anti-staphylococcal enzyme resulting in bacterial lysis and biofilm reduction. Lysostaphin use is limited by the lack of effective delivery methods to provide sustained, high doses of enzyme to infection sites. We engineered a BMP-2–loaded lysostaphin-delivering hydrogel that simultaneously prevents S. aureus infection and repairs nonhealing segmental bone defects in the murine radius. Lysostaphin-delivering hydrogels eradicated S. aureus infection and resulted in mechanically competent bone. Cytokine and immune cell profiling demonstrated that lysostaphin-delivering hydrogels restored the local inflammatory environment to that of a sterile injury. These results show that BMP-2–loaded lysostaphin-delivering hydrogel therapy effectively eliminates S. aureus infection while simultaneously regenerating functional bone resulting in defect healing.

The ring-opening copolymerization of 3,6-bis­(chloro­methyl)-1,4-dioxane-2,5-dione and l-lactide affords a chloro-substituted polylactide copolymer (chloro-PL). Base-promoted dehydrochlorination of chloro-PL provides a copolymer (ene-PL) that contains electrophilic α,β-unsaturated ester units. The copolymer undergoes conjugate addition with a variety of thiols in solution under mildly basic conditions and also in the presence of AIBN. Reaction on the surface of films of the unsaturated copolyester is demonstrated by the addition of a thiol-substituted fluorescent dye.

Polylactide (PL) co-polymers substituted with pendant azide groups (azido-PL) were synthesized by the nucleophilic conjugate addition of 3-azido-1-propanethiol to a co-polymer of PL containing α,β-unsaturated ester units, poly(lactide-co-methylene glycolide) (ene-PL) that is obtained from the base-promoted dehydrochlorination of poly(lactide-cochlorolactide) (chloro-PL). Alternatively, azido-PL was prepared by the treatment of chloro-PL with 3-azido-1-propanethiol without isolation of the ene-PL intermediate. The azido-PL was functionalized by copper-catalyzed [3 + 2] cycloaddition reactions with four alkynes: propargyl 4-methoxybenzoate, N,N,N-trimethyl-N-propargylammonium bromide, N,N-dimethyl-Noctyl-N-propargylammonium bromide, and N,N,N-trioctyl-N-propargylammonium bromide. Polymer adducts with N,N,Ntrioctyl-N-propargylammonium bromide displayed potent antimicrobial activity both in suspension and as a polymer film.

Tricomponent amphiphilic brush-grafted copolymers of poly-(lactic acid)-graf t-poly(oligo(ethylene glycol) methacrylate) (PLA-g-POEG-MA) were prepared by atom-transfer radical polymerization (ATRP) of oligo(ethylene glycol) methacrylate (OEGMA) macromer using brominated poly(lactic acid) (Br-PLA) as a multisite macroinitiator. Br-PLA was prepared by free radical bromination of poly(lactic acid) (PLA) with N-bromosuccinimide (NBS). The amphiphilic copolymer, PLA-g-POEGMA, selfassembled to form sub-100 nm nanoparticles in aqueous solution. We report the uptake and release of hydrophobic dyes by the nanoparticles in buffer and in the presence of serum proteins and the low toxicity toward mammalian cells.