Surface modification of implantable biomaterials with biologically active functionalities, including antimicrobials, has wide potential for addressing implant-related design problems. Here, four polymerizable vancomycin derivatives bearing either acrylamide or poly(ethylene glycol) (PEG)-acrylate were synthesized and then polymerized through a surface-mediated reaction. Functionalization of vancomycin at either the V3 or the X1 position decreased monomeric activity by 6−75-fold depending on the modification site and the nature of the adduct (P < 0.08 for all comparisons). A 5000 Da PEG chain showed an order of magnitude decrease in activity relative to a 3400 Da counterpart. Molecular dynamics computational simulations were used to explore the mechanisms of this decreased activity. Assays were also conducted to demonstrate the utility of a living radical photopolymerization to create functional, polymeric surfaces with these monomers and to demonstrate surface-based activity against Staphylococcus epidermidis. In particular, the vancomycin−PEG-acrylate derivatives demonstrated a 7−8 log reduction in bacterial colony forming units (CFU) with respect to nonfunctionalized control surfaces.

BackgroundBiofilm formation on indwelling medical devices is a ubiquitous problem causing considerable patient morbidity and mortality. In orthopaedic surgery, this problem is exacerbated by the large number and variety of material types that are implanted. Metallic hardware in conjunction with polymethylmethacrylate (PMMA) bone cement is commonly used.Questions/purposesWe asked whether polymerizable derivatives of vancomycin might be useful to (1) surface modify Ti-6Al-4V alloy and to surface/bulk modify PMMA bone cement to prevent Staphylococcus epidermidis biofilm formation and (2) whether the process altered the compressive modulus, yield strength, resilience, and/or fracture strength of cement copolymers.MethodsA Ti-6Al-4V alloy was silanized with methacryloxypropyltrimethoxysilane in preparation for subsequent polymer attachment. Surfaces were then coated with polymers formed from PEG(375)-acrylate or a vancomycin-PEG(3400)-PEG(375)-acrylate copolymer. PMMA was loaded with various species, including vancomycin and several polymerizable vancomycin derivatives. To assess antibiofilm properties of these materials, initial bacterial adherence to coated Ti-6Al-4V was determined by scanning electron microscopy (SEM). Biofilm dry mass was determined on PMMA coupons; the compressive mechanical properties were also determined.ResultsSEM showed the vancomycin-PEG(3400)-acrylate-type surface reduced adherent bacteria numbers by approximately fourfold when compared with PEG(375)-acrylate alone. Vancomycin-loading reduced all mechanical properties tested; in contrast, loading a vancomycin-acrylamide derivative restored these deficits but demonstrated no antibiofilm properties. A polymerizable, PEGylated vancomycin derivative reduced biofilm attachment but resulted in inferior cement mechanical properties.Clinical RelevanceThe approaches presented here may offer new strategies for developing biofilm-resistant orthopaedic materials. Specifically, polymerizable derivatives of traditional antibiotics may allow for direct polymerization into existing materials such as PMMA bone cement while minimizing mechanical property compromise. Questions remain regarding ideal monomer structure(s) that confer biologic and mechanical benefits.

Infections in the setting of orthopaedic hardware remain a serious complication. Traditional treatment modalities rely on antibiotic-loaded biomaterials and/or prolonged intravenous therapy, both of which suffer major limitations. We hypothesized a derivatized form of the glycopeptide antibiotic vancomycin could be covalently attached to a Ti-6Al-4V implant alloy to form a bactericidal surface capable of killing bacteria relevant to orthopaedic infections. First, a polymerizable poly(ethylene glycol)-acrylate derivative of vancomycin was synthesized. This monomer was characterized by liquid chromatography, 1H NMR spectroscopy, and MIC and MBC determination. The monomer was subsequently photochemically polymerized to implant grade Ti-6Al-4V alloy. The coating was bactericidal against Staphylococcus epidermidis through initial release of unattached antibiotic species followed by continued surface-contact-mediated bacterial killing by covalently tethered vancomycin. Through this surface-contact mechanism, the number of colony forming units dropped by ca. fivefold from an initial inoculum of 1 x 10(6) cfu/mL over 4 hours and by ca. 100-fold with respect to nonbactericidal control surfaces. An inoculum of 1 x 10(4) cfu/mL was reduced to undetectable levels over 17 hours. This coating method allows a loading dose several thousand times larger than that achieved with monolayer vancomycin coupling approaches and holds promise for the treatment of orthopaedic infections.

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