Fabrication of polymeric microspheres for biomedical applications.

Polymeric microspheres (PMs) have attracted great attention in the field of biomedicine in the last several decades due to their small particle size, special functionalities shown on the surface and high surface-to-volume ratio. However, how to fabricate PMs which can meet the clinical needs and transform laboratory achievements to industrial scale-up still remains a challenge. Therefore, advanced fabrication technologies are pursued. In this review, we summarize the technologies used to fabricate PMs, including emulsion-based methods, microfluidics, spray drying, coacervation, supercritical fluid and superhydrophobic surface-mediated method and their advantages and disadvantages. We also review the different structures, properties and functions of the PMs and their applications in the fields of drug delivery, cell encapsulation and expansion, scaffolds in tissue engineering, transcatheter arterial embolization and artificial cells. Moreover, we discuss existing challenges and future perspectives for advancing fabrication technologies and biomedical applications of PMs.

Three lines of defense: A multifunctional coating with anti-adhesion, bacteria-killing and anti-quorum sensing properties for preventing biofilm formation of Pseudomonas aeruginosa.

Surfaces of synthetic materials are highly susceptible to pathogenic bacteria colonization and further biofilm formation, leading to device failure in both biomedical and industrial applications. Complete elimination of the mature biofilms formed on the surfaces, however, remains a great challenge due to the complexity of chemical composition and physical structure. Therefore, prevention of biofilm formation becomes a preferred strategy for solving the biofilm-associated problems. Herein, a multifunctional coating showing three lines of defense to prevent biofilm formation of Pseudomonas aeruginosa is fabricated by a simple and versatile method. This coating is composed of multilayers of quaternized chitosan with bactericidal property and acylase with anti-quorum sensing property and a topmost layer of hyaluronic acid with anti-adhesion property. The substrate deposited with this coating could suppress initial adhesion of a majority of bacteria, and then kill the attached bacteria and interfere with their quorum sensing systems related to biofilm formation. The results of short-term antibacterial experiments show that our coating reduced 98 ± 2% of attached live bacteria. In long-term antibiofilm experiments, this "three lines of defense" design endows the coating with enhanced antibiofilm property against the biofilm formation for at least 3 days by reducing 98 ± 1% of bacterial proliferation and 71 ± 2% of biomass production. Benefiting from the natural building blocks with good biocompatibility and the versatile and environmentally friendly preparation method, this coating shows negligible cytotoxicity and broad applicability, providing great potential for a variety of biomedical applications. STATEMENT OF SIGNIFICANCE: Pathogenic biofilms formed on the surfaces of medical devices and materials pose an urgent problem, and it remains challenging to treat and eradicate the established biofilms. Herein, we developed an antibiofilm coating showing three lines of defense to prevent biofilm formation, which could be deposited on diverse substrates via a simple and versatile method. This coating was based on three natural materials with anti-adhesive, bactericidal, and anti-quorum sensing properties and showed different function in a self-adaptive way to target the sequential stages of biofilm formation by preventing initial bacterial adhesion, killing attached bacteria and interfering with their quorum sensing system to inhibit bacterial proliferation and biofilm maturation. This coating with improved antibiofilm performance might provide a simple and reliable solution to the problems associated with biofilm on surfaces.

The construct of triple responsive nanocomposite and its antibacterial effect.

The current serious mismatch between the increasing severity of bacterial infections and antibiotic production capacity urgently requires the emergence of novel antimicrobial materials. In this paper, dopamine methacrylamide (DMA) and N-isopropylacrylamide (NIPAM) were polymerized as the monomers into a block copolymer poly(dopamine methacrylamide-block-N-isopropylacrylamide) (P(DA-NIP)) and then encapsulated with polydopamine-coated magnetic nanoparticle clusters (MNC) to produce an antibacterial nanocomposite (MNC@P(DA-NIP)). This nanocomposite has triple responses respectively to light, heat and magnetism, which endow MNC@P(DA-NIP) with the abilities to kill bacteria effectively and capture/release bacteria conveniently. Under near-infrared (NIR) light irradiation, MNC@P(DA-NIP) could significantly elevate the temperature through photothermal conversion. The increased temperature favored both the capture of bacteria on MNC@P(DA-NIP), and the damage of bacterial cells, causing bacterial death almost completely. While low temperatures could promote the release of dead bacteria from the nanocomposites, might through the recovery of the hydrophilic state of the outlayer PNIPAM. Moreover, thanks to the magnetic responsibility, MNC@P(DA-NIP) could be easily separated from the bacterial cells and perform better biofilm penetration. The results showed that the antibacterial effect of MNC@P(DA-NIP) was 3.5 times higher than that of MNC, and the recycling capacity of MNC@P(DA-NIP) was better than MNC@PDA. What's more, MNC@P(DA-NIP) possessed the excellent anti-biofilm properties under magnetic field (MF) and NIR. The most important features of the triple-responsive nanocomposites are excellent antibacterial effect, good recyclability and easy preparation, which provide the nanocomposites with great potential in eliminating harmful bacterial cells.

A Photothermal Nanoplatform with Sugar-Triggered Cleaning Ability for High-Efficiency Intracellular Delivery.

Intracellular delivery of functional molecules is of great importance in various biomedical and biotechnology applications. Recently, nanoparticle-based photothermal poration has attracted increasing attention because it provided a facile and efficient method to permeabilize cells transiently, facilitating the entry of exogenous molecules into cells. However, this method still has some safety concerns associated with the nanoparticles that bind to the cell membranes or enter the cells. Herein, a nanoplatform with both photothermal property and sugar-triggered cleaning ability for intracellular delivery is developed based on phenylboronic acid (PBA) functionalized porous magnetic nanoparticles (named as M-PBA). The M-PBA particles could bind to the target cells effectively through the specific interactions between PBA groups and the cis-diol containing components on the cell membrane. During a short-term near-infrared irradiation, the bound particles convert absorbed light energy to heat, enabling high-efficiency delivery of various exogenous molecules into the target cells via a photothermal poration mechanism. After delivery, the bound particles could be easily "cleaned" from the cell surface via mild sugar-treatment and collected by a magnet, avoiding the possible side effects caused by the entrance of particles or their fragments. The delivery and cleaning process is short and effective without compromising the viability and proliferation ability of the cells with delivered molecules, suggesting that the M-PBA particles could be used as promising intracellular delivery agents with a unique combination of efficiency, safety, and flexibility.

Universal Antifouling and Photothermal Antibacterial Surfaces Based on Multifunctional Metal-Phenolic Networks for Prevention of Biofilm Formation.

Biofilms formed from the pathogenic bacteria that attach to the surfaces of biomedical devices and implantable materials result in various persistent and chronic bacterial infections, posing serious threats to human health. Compared to the elimination of matured biofilms, prevention of the formation of biofilms is expected to be a more effective way for the treatment of biofilm-associated infections. Herein, we develop a facile method for endowing diverse substrates with long-term antibiofilm property by deposition of a hybrid film composed of tannic acid/Cu ion (TA/Cu) complex and poly(ethylene glycol) (PEG). In this system, the TA/Cu complex acts as a multifunctional building block with three different roles: (i) as a versatile "glue" with universal adherent property for substrate modification, (ii) as a photothermal biocidal agent for bacterial elimination under irradiation of near-infrared (NIR) laser, and (iii) as a potent linker for immobilization of PEG with inherent antifouling property to inhibit adhesion and accumulation of bacteria. The resulted hybrid film shows negligible cytotoxicity and good histocompatibility and could prevent biofilm formation for at least 15 days in vitro and suppress bacterial infection in vivo, showing great potential for practical applications to solve the biofilm-associated problems of biomedical materials and devices.

Dual-Functional Surfaces Based on an Antifouling Polymer and a Natural Antibiofilm Molecule: Prevention of Biofilm Formation without Using Biocides.

Pathogenic biofilms formed on the surfaces of implantable medical devices and materials pose an urgent global healthcare problem. Although conventional antibacterial surfaces based on bacteria-repelling or bacteria-killing strategies can delay biofilm formation to some extent, they usually fail in long-term applications, and it remains challenging to eradicate recalcitrant biofilms once they are established and mature. From the viewpoint of microbiology, a promising strategy may be to target the middle stage of biofilm formation including the main biological processes involved in biofilm development. In this work, a dual-functional antibiofilm surface is developed based on copolymer brushes of 2-hydroxyethyl methacrylate (HEMA) and 3-(acrylamido)phenylboronic acid (APBA), with quercetin (Qe, a natural antibiofilm molecule) incorporated via acid-responsive boronate ester bonds. Due to the antifouling properties of the hydrophilic poly(HEMA) component, the resulting surface is able to suppress bacterial adhesion and aggregation in the early stages of contact. A few bacteria are eventually able to break through the protection of the anti-adhesion layer leading to bacterial colonization. In response to the resulting decrease in the pH of the microenvironment, the surface could then release Qe to interfere with the microbiological processes related to biofilm formation. Compared to bactericidal and anti-adhesive surfaces, this dual-functional surface showed significantly improved antibiofilm performance to prevent biofilm formation involving both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus for up to 3 days. In addition, both the copolymer and Qe are negligibly cytotoxic, thereby avoiding possible harmful effects on adjacent normal cells and the risk of bacterial resistance. This dual-functional design approach addresses the different stages of biofilm formation, and (in accordance with the growth process of the biofilm) allows sequential activation of the functions without compromising the viability of adjacent normal cells. A simple and reliable solution may thus be provided to the problems associated with biofilms on surfaces in various biomedical applications.