Remote eradication of biofilm on titanium implant via near-infrared light triggered photothermal/photodynamic therapy strategy
Introduction
Clinically, a foreign implant is vulnerable for bacteria infection. Despite treating with peri-operative antibiotics, very few bacteria may lead to implants-associated infection. The activation of neutrophils on the implant surfaces would result in the release of human neutrophil peptides deactivating granulocytes [1,2]. Staphylococcus aureus (S. aureus) is a typical gram-positive microorganism contributing to life-threatening infections worldwide. The S. aureus tend to organize themselves into sticky and multicellular community known as biofilm, which could withstand host immune system, antibiotics and environmental stress [3,4]. In clinic, bone-implant-associated infections are mostly related to bacteria in biofilm, rather than suspending bacteria. Once biofilm forms, second replacement surgery is inevitable [5,6]. So far, many strategies have been dedicated to prevent or destroy biofilm formation on an implant, including anti-adhesive surface [7], incorporation of antibacterial substances [8,9], noble metal nanoparticles [10,11], antimicrobial peptides [12], ZnO nanorods [13], DNAase I and DNase biomimetics [14,15]. During the survival of implants, once above-mentioned antibacterial surface become invalid, bacterial infection may still emerge in some cases. Thus, it is urgent to develop new remotely controllable noninvasive therapies for combating the biofilms that have been established on an implant.
In recent years, the potential application of PTT based on NIR irradiation has gained increasing attention in nanomedicine field, due to its minimal invasiveness, deep tissue penetration and high selectivity [16]. Moreover, PTT has been recognized as a promising antibacterial strategy through local hyperthermia to destroy bacteria integrity or biofilm structure [[17], [18], [19], [20], [21], [22], [23]]. As for antibacterial application of PTT, graphene [18,19], gold nanoparticles [20,21], CuS nanodots [22] and molybdenum disulfide nanosheets [23,24] were developed. Strikingly, mussel-inspired polydopamine (PDA) is emerging as a competitive photothermal agent, owing to its good biocompatibility, high NIR photothermal conversion efficiency and facile functionalization [[25], [26], [27], [28]]. To the best of our knowledge, few attempts of directly utilizing PDA nanoparticles as antibacterial photothermal agent to destroy biofilm in bone-implant-associated infection were reported so far.
Previous studies confirmed that PTT alone to kill bacteria required relatively high local temperature [29,30]. Consequently, hyperthermia would cause tremendous negative effects on surrounding healthy tissues when killing already-formed biofilms. Although healthy tissues could withstand above 50 °C for a long time, the antibacterial efficiency is limited at such temperature [31]. Thus, the combination PTT (moderate temperature around 50 °C) with other antibacterial strategies is essentially urgent to be developed, leading to remarkable effect for combating bacterial infection or established biofilm [19,28,30]. Thus, the combination PTT (moderate temperature around 50 °C) with other antibacterial strategies is essentially urgent to be developed, leading to remarkable effect for combating bacterial infection or established biofilm. Recent study reported that CuS nanodots irradiated by NIR laser exhibited strong lethal effect for drug-resistant pathogens via a combination treatment of PTT with Cu2+ ions [22]. Additionally, antibacterial PDT is another promising modality. Antibacterial PDT is another promising modality. Nanomaterials or photosensitizers are irradiated with NIR or visible light to motivate reactive oxygen species (ROS), which would destroy the integrity of bacteria membranes and cause bacteria death [32,33]. Destruction of membrane integrity of bacteria is an important step to achieve the final bactericidal effect. A previous study confirmed that bacteria-adhesive antibacterial nanoparticles with the intrinsic function of membrane-disruption combined with antibiotics delivery could effectively combat severe bacterial infection [34]. We envisage that, if the cell membrane permeability of S. aureus bacteria in biofilm increased when exposing to ROS, the biofilm scavenging efficiency would remarkably increase at relatively bio-safe temperature (around 50 °C) from PTT. Moreover, except for antibacterial or anti-biofilm, efficient osseointegration for bone implant is also essentially important. Recently, polydopamine (PDA) served as an important bridge to fabricate biofunctional interface on an implant, exhibiting desirable adhesion and biocompatibility [13,30]. Additionally, surface modification of an implant with osteogenic peptides (e.g. RGD) is an effective approach for facilitating specific cell responses (adhesion, proliferation and differentiation) and final osseointegration in vivo [35,36].
Herein, for the first time, we develop a multifunctional hybrid coating on Ti surface that was capable of combating established biofilm by remotely controllable way and improving osteointegration of the Ti implants. MPDA nanoparticles were immobilized onto amino-modified Ti surface to simultaneously act as photothermal material and photosensitizer carrier. Abundant aromatic rings and mesoporous structure in PDA would facilitate substantial loading of Indocyanine Green (ICG) via π-π stacking interaction. Importantly, sufficient dihydroxyindole/indolequinone groups on MPDA surface further facilitate the conjugation of biocompatible RGD peptide via Michael addition reaction or Schiff base reaction. The final sample was named as Ti-M/I/RGD. Scheme 1 presents the elimination process of Ti-M/I/RGD implant for already-established S. aureus biofilm in vivo through PDT/PTT synergistic effect. The hyperthermia firstly improves the ICG diffusion into biofilm. The PDT generated ROS would destroy the bacteria membranes to make them sensitive for moderate hyperthermia. The NIR triggered hyperthermia further accelerates the bacteria death. Thus, we hypothesized that our strategy would effectively eradicate already-formed biofilms and simultaneously improve osseointegration in vivo.
Section snippets
Materials
Commercial pure Ti foils (0.25 mm thick, 99.5% purity) were purchased from Alfa Awsar Co. (Tianjin, China) and Ti rods (1.2 mm of diameter, 10 mm of length) were purchased from Northwest Institute for Non-ferrous Metal Research (Shaanxi, China). 1,3,5-trimethylbenzene (TMB, 97%), tris(hydroxymethyl)aminomethane (TRIS, 99.9%), indocyanine green (ICG), (3-Aminopropyl) trimethoxysilane (APTES) and dopamine hydrochloride were bought from Aladdin Industrial Co. (Shanghai, China). The RGDC peptide
Characterization of MPDA nanoparticles
Firstly, MPDA nanoparticles were prepared by a facile one-pot synthesis method, with stable and high drug loading capacity under physiological environment [25,26,35]. As shown in Fig. 1A, Pluronic F127 and TMB were employed as organic templates in water/ethanol solution. The primary PDA would self-assemble at water/TMB interface via π-π stacking [27,39]. After removal of templates, MPDA nanoparticles were obtained with good dispersity in water. Dopamine monomer in water solution is colorless
Conclusions
In summary, we developed an original strategy for surface modification of Ti implants based on MPDA nanoparticles with RGD peptide immobilization and photosensitizer (ICG) loading. The anti-biofilm ability based on synergistic PDT/PTT effect of Ti-M/I/RGD samples was systematically evaluated with NIR laser irradiation both in vitro and in vivo. Specifically, due to ROS generation from ICG induced the bacterial membrane destruction, S. aureus in biofilm became was sensitive to moderate
Conflicts of interest
The authors declare no competing interests.
Acknowledgements
This work was financially supported by State Key Project of Research and Development (2016YFC1100300 & 2017YFB0702603), National Natural Science Foundation of China (51825302, 21734002 & 51673032), Fundamental Research Funds for the Central Universities (2018CDYJSY0055, 2019CDXYSG0004 & 2018CDXYSW0023), Chongqing Research Program of Technological Innovation and Application Demonstration (cstc2018jscx-msybX0299), Innovation Team in University of Chongqing Municipal Government (CXTDX201601002).
References (52)
- et al.
Bioinspired anchoring AgNPs onto micro-nanoporous TiO2 orthopedic coatings: trap-killing of bacteria, surface-regulated osteoblast functions and host responses
Biomaterials
(2016) - et al.
CaP coated mesoporous polydopamine nanoparticles with responsive membrane permeation ability for combined photothermal and siRNA therapy
Acta Biomater.
(2019) - et al.
Near-infrared light-controllable on-demand antibiotics release using thermo-sensitive hydrogel-based drug reservoir for combating bacterial infection
Biomaterials
(2019) - et al.
Characterization and in vitro biological evaluation of mineral/osteogenic growth peptide nanocomposites synthesized biomimetically on titanium
Appl. Surf. Sci.
(2015) - et al.
Calcium-carbonate packaging magnetic polydopamine nanoparticles loaded with indocyanine green for near-infrared induced photothermal/photodynamic therapy
Acta Biomater.
(2018) - et al.
Biocompatible MoS2/PDA-RGD Coating on Titanium Implant with Antibacterial Property via Intrinsic ROS-independent Oxidative Stress and NIR Irradiation
(2019) - et al.
Defensins impair phagocytic killing by neutrophils in biomaterial-related infection
Infect. Immun.
(1984) - et al.
Prosthetic-joint infections
N. Engl. J. Med.
(2004) - et al.
Biofilm formation and dispersal in gram-positive bacteria
Curr. Opin. Biotechnol.
(2011) - et al.
The biofilm matrix
Nat. Rev. Microbiol.
(2010)
Economic burden of periprosthetic joint infection in the United States
J. Arthroplast.
Nanotechnology-based antimicrobials and delivery systems for biofilm-infection control
Chem. Soc. Rev.
Pathological‐condition‐driven construction of supramolecular nanoassemblies for bacterial infection detection
Adv. Mater.
Designer dual therapy nanolayered implant coatings eradicate biofilms and accelerate bone tissue repair
ACS Nano
Self-Adaptive antibacterial porous implants with sustainable responses for infected bone defect therapy
Adv. Funct. Mater.
Antibacterial surface design of titanium-based biomaterials for enhanced bacteria-killing and cell-assisting functions against periprosthetic joint infection
ACS Appl. Mater. Interfaces
Self‐defensive biomaterial coating against bacteria and yeasts: polysaccharide multilayer film with embedded antimicrobial peptide
Adv. Funct. Mater.
Balancing bacteria–osteoblast competition through selective physical puncture and biofunctionalization of ZnO/polydopamine/Arginine-Glycine-Aspartic Acid-Cysteine nanorods
ACS Nano
A functional DNase I coating to prevent adhesion of bacteria and the formation of biofilm
Adv. Funct. Mater.
A multinuclear metal complex based DNase‐mimetic artificial enzyme: matrix cleavage for combating bacterial biofilms
Angew. Chem. Int. Ed.
Functional nanomaterials for phototherapies of Cancer
Chem. Rev.
Nanomaterials for photohyperthermia: a review
Curr. Pharm. Design
Graphene-based photothermal agent for rapid and effective killing of bacteria
ACS Nano
Rapid sterilization and accelerated wound healing using Zn2+ and graphene oxide modified g-C3N4 under dual light irradiation
Adv. Funct. Mater.
Pretreated macrophage-membrane-coated gold nanocages for precise drug delivery for treatment of bacterial infections
Adv. Mater.
Surface-adaptive gold nanoparticles with effective adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm
ACS Nano
Cited by (186)
Functional nanomaterials as photosensitizers or delivery systems for antibacterial photodynamic therapy
2024, Biomaterials AdvancesElectrophoretic deposition of photothermal responsive antibacterial coatings on titanium with controlled release of silver ions
2024, Progress in Organic CoatingsPolydopamine-Modified functional materials promote bone regeneration
2024, Materials and Design