Antibacterial Designs for Implantable Medical Devices: Evolutions and Challenges

Abstract

The uses of implantable medical devices are safer and more common since sterilization methods and techniques were established a century ago; however, device-associated infections (DAIs) are still frequent and becoming a leading complication as the number of medical device implantations keeps increasing. This urges the world to develop instructive prevention and treatment strategies for DAIs, boosting the studies on the design of antibacterial surfaces. Every year, studies associated with DAIs yield thousands of publications, which here are categorized into four groups, i.e., antibacterial surfaces with long-term efficacy, cell-selective capability, tailored responsiveness, and immune-instructive actions. These innovations are promising in advancing the solution to DAIs; whereas most of these are normally quite preliminary "proof of concept" studies lacking exact clinical scopes. To help identify the flaws of our current antibacterial designs, clinical features of DAIs are highlighted. These include unpredictable onset, site-specific incidence, and possibly involving multiple and resistant pathogenic strains. The key point we delivered is antibacterial designs should meet the specific requirements of the primary functions defined by the "intended use" of an implantable medical device. This review intends to help comprehend the complex relationship between the device, pathogens, and the host, and figure out future directions for improving the quality of antibacterial designs and promoting clinical translations.

Keywords: antibiotic resistance; antimicrobials; bacterial charging; biocompatibility; cell-selective surfaces; implantable antibacterial surfaces; polymicrobial infections; protein adsorption; surface modification; tissue integration.

Figure 1

Rethinking the interplay among device surface, host, and pathogen.

Figure 2

Contact killing of silver nanoparticles synthesized and immobilized on titanium by ion implantation: (a) schematic representation of the silver plasma immersion ion implantation and deposition (Ag PIII&D) process; (b) SEM image of the silver nanoparticles synthesized and immobilized on titanium by Ag PIII&D under a 30 kV bias for 30 min; (c) cross-sectional TEM of the silver nanoparticles synthesized and immobilized on titanium by Ag PIII&D, with corresponding fast Fourier transform patterns (FFT, 1 and 2) inserted; (d) SEM image of the Staphylococcus aureus cells cultured on an Ag PIII&D treated (treated for 30 min under a 30 kV bias) titanium for 24 h at 37 °C with a bacteria concentration of 10⁸ CFU/mL; (e) possible antibacterial mechanism of the Ag PIII&D treated titanium; (b, d, and e) reused with permission from Elsevier [143]; (c) reused with permission from American Chemical Society [144].

Figure 3

Typical methods toward pH-responsive surfaces: (a) protonation of polystyrene-b-poly(4-(1-(2-(4-methylthiazol-5-yl)ethyl)-1H-1,2,3-triazol-4-yl)butyl methacrylate) (PS₅₄-b-PTTBM₂₃) at acidic pH levels and increase of the positive charge density on the surfaces [151]; (b) breaking the Schiff base bonds between antibacterial gentamicin and alginate dialdehyde by acidic environments [157]; (c) hydrolyzation of the hemiaminal ether linkage of antimicrobial 6-Chloropurine in 4-(1-(6-chloro-7H-purin-7-yl) ethoxy) butyl methacrylate (CPBMA) by mild acidic conditions [158]; (d) destruction of dopamine-conjugated oxidized dextran polymer to release the contained silver nanoparticles by disintegration the Schiff base structures in the polymer [160]. (a,c) reused with permission from John Wiley and Sons and American Chemical Society, respectively; (b,d) reused with permission from Elsevier.

Figure 4

Silver nanoparticle decorated titanium oxide coating acting against bacterial colonization by taking advantage of extracellular electron transfer in bacteria: collection and storage of bacteria-extruded electrons on the immobilized silver nanoparticles (“bacterial charging”), accumulation of valence-band hole (h⁺) at the titanium oxide side of the silver–titanium oxide boundaries, and disruption of bacterial cell walls (cytosolic content leakage) by those accumulated valence-band holes (oxidation) [169]. Reused with permission from Elsevier.

Figure 5

A photothermal antibacterial surface: (a) schematic illustration of the coordinated assembly of tannic acid (TA) and Fe³⁺ ions (iron chloride hexahydrate) on gold (can be other materials), yielding the Au-TA/Fe; (b) near-infrared (NIR) irradiation (808 nm, 2.2 W·cm⁻²) induced temperature changes on the material surface immersed in phosphate-buffered saline (PBS), with corresponding thermal images inserted; (c) SEM images of adherent bacteria (E. coli or MRSA) on materials surface with/without NIR irradiation (5 min), together with the typical photographs of bacterial colonies re-cultured from materials surface of different processing histories. Adapted from reference [178] with permission from the American Chemical Society.

Figure 6

A photodynamic antibacterial material surface: (a) schematic illustration of the killing actions of the composite coating composed of black phosphorus nanosheets (BPS) and poly (4-pyridonemethylstyrene) (PPMS). Under light irradiation (660 nm, 0.5 W·cm⁻²), BPSs generate reactive oxygen species (ROS), which can directly act on bacterial cells or are stored by the coating itself through the transfer of PPMS into poly (4-pyridonemethylstyrene) endoperoxide (PPMS-EPO), yielding antibacterial activity in the dark (killing without light). (b) UV-vis spectra show the capability of ROS production in PPMS/BPS with the increasing irradiation duration in the air (20 °C, 660 nm, 0.5 W·cm⁻²). The insert shows the capability of ROS production by a PMMS-EPO/BPS (fabricated by illuminating the PPMS/BPS group for 40 min in presence of oxygen gas (O₂) after being contained in the dark at 37 °C for 24 h. (c) ¹H NMR spectra show the reversible structure change of PPMS and PPMS-EPO. Peaks corresponding to the endoperoxide ring and proton of endoperoxide were detected. Adapted from reference [181] with permission from John Wiley and Sons.

Figure 7

A cell-selective titanium surface: (a) SEM surface morphology of the microbes (E. coli) cultured for 24 h on titanium doped with both calcium and silver (Ti-Ag/Ca), with a high magnification image, inserted; (b) typical morphology of rat bone marrow stem cells (BMSCs) cultured for 1 h on Ti-Ag/Ca, with a high magnification image inserted; (c,d) potential mechanism underlying the actions of Ti-Ag/Ca on microbes and mammalian cells, respectively [215]. Reused with permission from the Royal Society of Chemistry.

Figure 8

An antibacterial surface targeting the adsorption of fibrinogen: the calcium released by titanium turns the intramolecular interactions between αC regions and the amino-terminal of Bβ chains, and subsequently contributes to the exposure of the antibacterial peptide in fibrinogen. The Gly-His-Arg-Pro (Gly: glycine; His: histidine; Pro: proline; Arg: arginine) are the start sequences of the antibacterial peptide Bβ15–42 which locates at the N-terminal end of the β chain [16]. Reused with permission from the Royal Society of Chemistry.