Research Article: Antibacterial Hydrogels

Date Published: February 22, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Shuqiang Li, Shujun Dong, Weiguo Xu, Shicheng Tu, Lesan Yan, Changwen Zhao, Jianxun Ding, Xuesi Chen.

http://doi.org/10.1002/advs.201700527

Abstract

Antibacterial materials are recognized as important biomaterials due to their effective inhibition of bacterial infections. Hydrogels are 3D polymer networks crosslinked by either physical interactions or covalent bonds. Currently, hydrogels with an antibacterial function are a main focus in biomedical research. Many advanced antibacterial hydrogels are developed, each possessing unique qualities, namely high water swellability, high oxygen permeability, improved biocompatibility, ease of loading and releasing drugs, and structural diversity. Here, an overview of the structures, performances, mechanisms of action, loading and release behaviors, and applications of various antibacterial hydrogel formulations is provided. Furthermore, the prospects in biomedical research and clinical applications are predicted.

Partial Text

Since the first discovery of penicillin in 1928,1 antibiotics have been widely used in the antibacterial field. With the development of public hygiene and biomedical technology, many infections have been effectively suppressed or even conquered, and the quality of life for human beings has been significantly improved. However, a serious issue that still remains is that the use of antibiotics has led to the emergence of multidrug resistant microorganisms, which are very difficult to combat.2 This has led to over 13 million people dying per year from infectious diseases worldwide.3 What was the most disappointing was that the corresponding antibiotic‐resistant bacteria emerged almost immediately after the advanced antibiotics were approved, e.g., the fidaxomicin‐resistant Enterococci (K‐1476) and the methicillin‐resistant Staphylococcus aureus (S. aureus)(MRSA).4, 5, 6

Inorganic antibacterial materials mainly include metal ions and metallic oxide nanoparticles. Commonly used metal/metal ions include, but are not limited to, silver (Ag), gold (Au), and copper (Cu). Metallic oxide metal nanoparticles that are utilized include zinc oxide (ZnO), titanium dioxide (TiO2), and nickel oxide. Currently, the most widely used inorganic antibacterial materials are silver nanoparticles (Ag NPs) and ZnO NPs. Inorganic antibacterial material‐loaded hydrogels can not only enhance the antibacterial properties, but can also maintain antibacterial activity for a long period of time, which reduces the likelihood of bacterial resistance arising. Figure2 illustrates the possible antibacterial mechanisms of the metal and metallic oxide nanoparticles.12 To summarize, the nanoparticles cause damage to bacterial cell membranes or detrimental alterations to organelles. It should be emphasized, however, that some of these mechanisms are speculative and require further discussion and demonstration.

Although discovered after antibacterial metal agents, antibiotics are undoubtedly the most common and effective antibacterial agents.60 However, the drug‐resistant effect that bacteria possess has been the biggest obstacle in the development and applications of antibiotics. To overcome this, it is more promising and practical to minimize the dosage of conventional antibiotics rather than to explore new antibiotics.61 Local antibiotic administration, by delivering the adequate bactericidal dose of antibiotics directly into the infected site without significantly overtaking the systemic toxicity level, has drawn increasing attention in recent years.62 In biomedical research, fibers, beads, gels, and many other materials are used to deliver antibiotics. Hydrogels, a form of local administration matrix, offer a high surface area to volume ratio and structural controllability, such as porosity to mimic natural tissues. As a result, it is easy for hydrogels to selectively release their loaded drugs at desirable sites,63, 64 while maintaining high water content and biocompatibility.65 Some of the antibiotic‐loaded hydrogels are summarized in the following sections.

Biological extracts include extracts from plants and animals.92 Seaweed extract‐based hydrogel was reported as an antibacterial wound dressing.93 PVA composite hydrogels based on combinations of agar and carrageenan have been proved to be useful as wound dressings in the treatments of burns, nonhealing ulcers of diabetes, and other external wounds.94 Although some studies have stated that SA does not display antibacterial properties, it can be an ideal material for wound dressings due to its morphology, fiber size, porosity, degradation, and swelling ratio.93, 95 Allicin–CS complexes were proved to be active against bacteria involved in spoilage and can be used as an antibacterial agent in foods.96 Curcumin (CUR), a nontoxic and bioactive agent found in turmeric, has been applied for centuries as a remedy to various ailments.97 However, its applications were limited by its low aqueous solubility and poor bioavailability. As a result, hydrogels incorporated by CUR nanoparticles were developed. Ag NP–CUR loaded hydrogels utilized for wound dressings were reported to exhibit good antibacterial property and sustained release, which indicated enormous therapeutic values.98, 99 SA hydrogels encapsulated with essential oils, such as lavender, thyme oil, peppermint, tea tree, rosemary, cinnamon eucalyptus, and lemongrass, were reported to be qualified as disposable wound dressings due to the distinctive antibacterial properties of essential oils.100

Synthetic antibacterial drugs discussed here refer to the nitroimidazoles, sulfanilamide groups, and other frequently used drugs, but do not include semisynthetic antibiotics nor biological extracts. Although the special chemical structures benefit synthetic drugs significantly, they carry risks and damages to the normal tissues as well. A stable and safe delivery system for them is necessary.

Some carbon materials combined with hydrogels were developed for inhibition of bacteria. Venkatesan et al. prepared CT–carbon nanotube hydrogels by freeze‐lyophilization method, which exhibited antimicrobial activity against S. aureus, E. coli, and Candidatropicalis.127 Composite CT/active carbon hydrogels prepared by ammonia vapor treatment showed an potential application to be used as wound dressings.128 Graphene oxide (GO) also has immense potential in the antibacterial field. A facile one‐pot method was used to synthesize GO‐based hydrogels (i.e., benzalkonium bromide/GO hydrogel and benzalkonium bromide/polydopamine/reduced GO hydrogel), which exhibited strong antibacterial activity against G+ and G− bacteria.129 Zeng et al. prepared an Ag/reduced GO hydrogel by a facile hydrothermal reaction, which consisted of two parts: (i) a controlled porous reduced GO network and (ii) well‐dispersed Ag NPs.130 The antibacterial hydrogels were generated by crosslinking the Ag/graphene composites with acrylic acid and N,N′‐methylene bisacrylamide, which exhibited good antibacterial abilities against E. coli and S. aureus. The excellent biocompatibility, high swelling ratio, and good extensibility were also found in this hydrogel system.131

Hydrogels with inherent antibacterial activity discussed here refer to the hydrogels that contain antibacterial components.132 These hydrogels, with inherent antibacterial activity, were developed in recent years as effective antibacterial agents with little or even no side effects compared to the traditional ones. The main forms of these hydrogels are discussed below.

Hydrogels with synergetic effects refers to hydrogels containing two or more antibacterial agents, which can enhance antibacterial effects. Metal nanoparticles and antibiotics are commonly reported to be incorporated into hydrogels together to obtain synergetic effects. In addition, as described above, the combined utilization of Ag NPs and reduced GO is also a common mechanism to enhance antibacterial effects.130, 131

Hydrogels as antibacterial biomaterials can be an alternative and amenable solution to traditional antibiotic treatments. Controlled and prolonged release, local administration, stimulated switch on–off release, enhanced mechanical strength, and improved biocompatibility are all important advantages that a broad diversity of hydrogels can provide and that is exactly what antibacterial biomaterials currently require. Antibacterial hydrogels can be widely applied in the field of wound dressings, urinary tract coatings, catheter‐associated infections, gastrointestinal infections, osteomyelitis, and contact lens. Based on current research regarding the development and application of antibacterial hydrogels, most researchers have been investigating hydrogels composed of polysaccharides, PEG, or other hydrophilic polymers in combination with a variety of bactericidal substances. For hydrogels to be utilized therapeutically, biocompatibility and biodegradability are the utmost important requirements. Furthermore, as a drug carrier, hydrogels should have high DLE. In regards to the side effects, there was no inflammation in the adjacent connective tissue after biodegradation of the hydrogels. Based on the above factors, intelligent hydrogel platforms should be exploited to overcome the challenges of local antibacterial drugs.

The authors declare no conflict of interest.

 

Source:

http://doi.org/10.1002/advs.201700527

 

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