Dynamically evolving piezoelectric nanocomposites for antibacterial and repair-promoting applications in infected wound healing

With an estimated 17 million victims each year, infectiouse diseases caused by bacteria have become one of the major threats to public health [1,2]. Particularly, in bacteria-infected tissue wounds, a severe inflammatory response always results in unsuccessful wound healing [3,4]. Various antibiotics have been developed and introduced into the market since 20th century [5]. However, resistance to antibiotics raises important concerns [6,7]. The overuse of antibiotics in recent year accelerates antibiotic resistance, making the antibiotics less effective and leading to the emergence of “superbugs” [8,9]. Strategies need to be formulated at all levels of society to limit the spread of resistance, and meanwhile optimize antibacterial treatment and wound healing therapy.

For combating bacterial infection and reducing the overuse of antibiotics, many nanomaterials have been developed as potential antimicrobial alternatives, such as nanoparticles (NPs) of silver [10], zinc oxide [11], manganese dioxide and copper oxide [12,13]. Nevertheless, in order to improve the antibacterial efficiency, comparatively high concentrated NPs are needed in conventional treatments, which raises concerns of toxicity to patients [14], [15], [16]. In rencent years, metal-organic frameworks (MOFs), which are organic-inorganic hybrid crystalline nano-porous materials, are emerging as attractive nanoplatforms to kill bacterial [17]. Consisting of metal ions and organic ligands, MOFs are capable of releasing antibacterial metal ions under a degradable environmnent [18]. In addition, owing to their veasatile structure and tunable pore size, MOFs have also been promoted as perfect drug cariers for controllable release of antibiotics [19]. Yao et al. designed a Zn-MOF encapsulated microneedles array, which could release Zn2+ to destroy bacterial envelope and meanwhile exhibit good biocompatibility [20]. Huang et al. reported a Ag-MOF-based pH-stimulus-responsive antibacterial formulation to realize enhanced antibacterial activity with targeted-release of drugs and Ag+ [21]. These stuidies demosntrated that MOFs exhibited antibacterial ability, controllable drug release, and great biocompatibility, offering an optimized treatment strategy for bacterial infection.

Despite these progress, antibacterial therapy alone is not enough for satisfied bacteria-infected wound repair. Typically, wound healing is considered to be a complex biological process, and contain three stages: inflammation, new tissue formation and remodeling [22], [23], [24]. Therefore, it is necessary to develop a multifunctional platform that can not only eliminate wound inflammation, but also accelerate the regeneration of new tissues. While the metal ions released from MOFs, such as Ag+, Cu2+, Zn2+, are essential substances in human body and could potentially help cell growth and tissue formation, their effects are inadequate [25,26]. In recent years, ultrasound-driven sonodynamic therapy (SDT) has attracted extensive attention and been rapidly developed due to the potential to produce toxic reactive oxygen species (ROS) for strong bactericidal effect[27]. In addition, SDT benefits from tissue penetration depth and good controllability of acoustic waves, which allowing the signal to pass through the tissue without loss of energy or tissue damage[28]. Recently, researchers found that piezoelectric materials exhibited an attractive capability to enable cell migration and tissue repair [29]. These electroactive materials could generate a built-in electric field (EF) when subjected to external mechanical stress, such as ultrasonic (US) irradiation, and offer noninvasive treatment for tissue reconstruction [30]. For instance, Suk et al. applied a piezoelectric dermal patch to the wound site, and found that it could induce an EF to accelerate skin regeneration during mechanical deformation caused by animal movement [31]. In addition to promote tissue formation, piezoelectric materials were proved to be an antibacterial candidate. Wu et al. fabricated piezoelectric nanocomposites (NCs) by loading gold NPs on barium titanate (BTO) nanocubes, and discovered that the piezoelectric effect of the NC under US irradiation could trigger the generation of ROS for antibacterial [32]. Nevertheless, the antibacterial efficacy of piezoelectric materials is not good enough to substitute antibiotics. Therefore, to optimize the treatment for antibacterial treatment and wound healing therapy, design of new therapy strategies with enhanced performance is still of high interest.

Herein, we designed a dynamically evolving sonodynamic therapy combined with controlled drug release for antibacterial and repair-promoting by in situ self-assembling of zeolitic imidazolate framework-8 (ZIF-8) on the surface of BTO, and further loaded with a small amount of ciprofloxacin (CIP) in ZIF-8 (the NCs were named as [email protected]/CIP, Scheme 1a). The heterostructures formed by BTO and ZIF-8 enhanced sonodynamic effect at the initial stage of the treatment, causing oxidative stress to inhibit bacterial infection (Scheme 1b). Meanwhile, a small amount of CIP released in an acidic environment induced by the degradation of ZIF-8 was synergistically antibacterial. As ZIF-8 gradually degraded under acidic environment, the sonodynamic effect of the system continuously decreased, inducing a dynamic change of the piezoelectric signal at the wound site. The decreased piezoelectric field combined with gradually released Zn2+ from ZIF-8 benefited cell migration and tissue regeneration (Scheme 1c). Both of the in vitro and in vivo experiments indicated that the unique combination exhibited good biocompatibility and effectively accelerated the wound healing. These findings provide new insights for rational design of electroactive materials for effective wound healing strategies.

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