The eradication of deep-seated infections induced by antibiotic-resistant bacteria using purposely designed stimulus-responsive biomaterials

Abstract

The rapid emergence and dissemination of drug-resistant bacteria undoubtedly poses a serious challenge to global public health. Developing new antibiotics has proved to be a feasible approach to coping with such drug-resistant bacteria; however, the development of new antibiotics consistently lags behind the emergence of new drug-resistant bacteria. Moreover, antibiotics treatments for deep-seated infections often fail because antibiotics are unable to reach the infection sites precisely. Hence, in this study, advanced exogenous technology (i.e., light, ultrasound, and microwave) stimuli-responsive biomaterials were fabricated to overcome drug-resistant bacteria in deep tissues. Under exogenous stimulation, the stimuli-responsive biomaterials rapidly produced bactericidal reactive oxygen species (ROS) and/or heat through electron transfer and a series of REDOX reactions. An oxide perovskite-type calcium titanate (CaTiO3, CTO)/fibrous red phosphorus (RP) heterojunction nanofilm was first designed on the surface of titanium (Ti) to treat implant-associated Methicillin-resistant Staphylococcus aureus (MRSA) biofilm infections (Chapter 4). It was noted that a P-N heterojunction and internal electric fields were formed at the heterointerfaces, which significantly promoted the electron transfer and generation of bactericidal ROS under irradiation with 808 nm near infrared light (NIRL). Additionally, the efficient charge transfer endowed the nanofilm with an excellent NIRL-responsive thermal property. The in vivo result demonstrated that the nanofilm eradicated 99.42% ± 0.22% of the mature MRSA biofilms under NIRL irradiation for 20 min. Meanwhile, the nanofilm showed superior osteo-conductive ability and promoted implant-to-bone osseointegration. Notwithstanding, traditional phototherapy has a limitation with respect to tissue penetration. By capitalising on the powerful tissue penetration depth (~10 cm) of ultrasound (US), I therefore designed US-mediated sonodynamic therapy (SDT) based on slip dislocation defects with abundant Ti3+ species‐engineered Ti3C2 [Ti3C2-SD(Ti3+)] nanosheets to treat bony infections (Chapter 5). The abundant ultrasonic two-dimensional (2D) catalytic planar defects in the Ti3C2-SD(Ti3+) induced phonon–electron coupling and realised a superior ROS yield under US irradiation. After being decorated with a neutrophil membrane (NM), the NM-Ti3C2-SD(Ti3+) exhibited robust antibacterial efficiency in the treatment of MRSA-induced bony tissue infection owing to the effective ROS release triggered by the US and precise bacterial capture. Additionally, the NM-Ti3C2-SD(Ti3+) potentiated the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and accelerated the bone remodelling. Multidrug-resistant (MDR) Gram-negative bacteria are more difficult to overcome than Gram-positive bacteria because they have been immunised against available antibiotics through a series of biogenetic effects, including the β-barrel assembly machine (BAM complex) in the outer membrane (OM), MDR efflux pumps, and enzymatic degradation/modification. Microwave (MW)-responsive poly(lactic-co-glycolic acid) microparticles (PLGA MPs) were further fabricated and effectively convert MW radiation to thermal energy (Chapter 6). The corresponding MW hyperthermia (MWH) therapy not only interrupted the essential surface-exposed BamA protein of the BAM complex, but also enhanced the permeability of the OM. The MWH additionally impaired the hydrogen bond interaction between the catalytic residues of the bacterial enzymes and functional groups of the antibiotic molecules. Lastly, the MWH revitalised the bactericidal effects of conventional antibiotics against MDR Escherichia coli (E. coli) associated with urinary tract infection and peritonitis.