Multifunctional Antimicrobial Microgels
Abstract
Multifunctional Antimicrobial Microgels The high-level treatment of extremity war injury (EWI) usually involves synthetic implants and external/internal fixation devices. However, the recovery of soldiers suffering from EWI is frequently, and sometimes unavoidably, compromised by device-associated infection, which occurs when bacteria colonize implant surfaces and develop into antibiotic-resistant biofilms. Infectious complications can lead to long recovery periods, multiple surgeries, reduced limb function, amputation, or death. Materials that can avoid device-associated infection can thus substantially enhance the recovery of injured soldiers. Incremental progress in this direction is being made using traditional drug-delivery mechanisms to release antimicrobials from device surfaces. However, drug-eluting coatings must contain a reservoir of pre-loaded antibiotic, which is released whether it is needed or not. Needless release not only depletes the reservoir but also introduces selective pressure for the development of resistant bacterial strains throughout the body. With less antimicrobial strength the implant is more susceptible to subsequent bacterial challenges, some of which may be from resistant bacteria. A multifunctional microgel-based approach that exploits emerging concepts of self-assembly and adaptive behavior offers a radically different means with which to inhibit device-associated infection. Sub-monolayer microgel coatings have been shown to dramatically reduce bacterial adhesion rates while still enabling the mammalian-cell interactions required for healing. However, since even only a few viable bacteria can develop into biofilms, microgel coatings with additional bacterial-killing mechanisms are still needed. Traditional drug-delivery mechanisms based on the kinetic control of antibiotic elution will not work with a microgel-based technology because of the small reservoir size and sub-micron diffusion distances associated with microgels. Instead, a thermodynamic approach based on responsive, triggered release is required. This research project addresses the basic hypothesis that controlling both the microgel electrostatic charge and hydrophobicity will provide the thermodynamic basis to not only direct antimicrobial loading into the microgels but also provide for multi-week antimicrobial sequestration and for triggered antimicrobial release during that period if and when bacteria challenge the surface. Specifically PEG-based copolymer microgels will be created from an array of acrylate monomers with varying degrees of hydrophobicity and hydrophilicity, electrostatic charge, and orthogonal chemical moieties. Microgel complexation phenomena will be probed using vancomycin, amikacin, and colistin, which bring a range of charge and hydrophobicity representative of FDA-approved cationic antimicrobials. One key dependent variable will be the microgel ability to sequester these antibiotics when exposed to a salt-containing medium where the electrostatic component of the complexation interaction is partially or fully shielded. A second dependent variable will be the microgel ability to responsively release these antibiotics when an approaching bacterium changes the local thermodynamic environment either by local metabolic changes in pH or by strong electrostatic/hydrophobic interactions activated by bacteria-surface contact. Successful microgel formulations will be further subjected to in vitro challenges by gram-positive and gram-negative bacteria as well as by osteoblasts as a first screening of non-cytotoxic infection resistance.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 11, 2018
- Source ID
- W911NF1710332
Entities
People
- Matthew Libera
Organizations
- Army Contracting Command
- Stevens Institute of Technology
- United States Army