The implementation of nanotechnology to develop efficient antimicrobial systems has a significant impact on the prospects of the biomedical field. Nanogels are soft polymeric particles with an internally cross-linked structure, which behave as hydrogels and can be reversibly hydrated/dehydrated (swollen/shrunken) by the dispersing solvent and external stimuli. Their excellent properties, such as biocompatibility, colloidal stability, high water content, desirable mechanical properties, tunable chemical functionalities, and interior gel-like network for the incorporation of biomolecules, make them fascinating in the field of biological/biomedical applications. In this review, various approaches will be discussed and compared to the newly developed nanogel technology in terms of efficiency and applicability for determining their potential role in combating infections in the biomedical area including implant-associated infections.

Staphylococcus aureus is commonly associated with biofilm-related infections and contributes to the large financial loss that accompany nosocomial infections. The micrococcal nuclease Nuc1 enzyme limits biofilm formation via cleavage of eDNA, a structural component of the biofilm matrix. Solid surface hydrophobicity influences bacterial adhesion forces and may as well influence eDNA production. Therefore, it is hypothesized that the impact of Nuc1 activity is dependent on surface characteristics of solid surfaces. For this reason, this study investigated the influence of solid surface hydrophobicity on S. aureus Newman biofilms where Nuc1 is constitutively produced. To this end, biofilms of both a wild-type and a nuc1 knockout mutant strain, grown on glass, salinized glass and Pluronic F-127-coated silanized glass were analysed. Results indicated that biofilms can grow in the presence of Nuc1 activity. Also, Nuc1 and solid surface hydrophobicity significantly affected the biofilm 3D-architecture. In particular, biofilm densities of the wild-type strain on hydrophilic surfaces appeared higher than of the mutant nuc1 knockout strain. Since virulence is related to bacterial cell densities, this suggests that the virulence of S. aureus Newman biofilms is increased by its nuclease production in particular on a hydrophilic surface. In general, bacteria prefer living in communities at a surface rather than as single individuals in their aqueous surroundings. It is therefore not surprising that the biofilm mode of growth is paramount to the survival of microorganism in both industrial and medical settings. Biofilms are notorious for causing food-borne diseases due to their formation on food and food factory equipments 1 but on the other hand can be beneficial in waste water treatments 2. Biofilms and in particular biofilms of Staphylococcus aureus that establish on medical implants still remain the underlying factor for infection recurrence and refractory response to conventional antibiotic treatments 3-5. A biofilm is described as a bacterial community wrapped in a self-produced matrix of extracellular polymeric substances (EPS). EPS generally consist of polysaccharide intercellular adhesin (PIA) or poly-N-acetylglucosamine (PNAG), proteins, RNA, lipids and extracellular DNA (eDNA), depending on the bacterial strain 6,7. eDNA on the surface of planktonic S. aureus has been shown to improve adhesion as well as stabilize S. aureus biofilm structure at low pH 8. During the early stages of S. aureus biofilm formation, a short period of heightened micrococcal nuclease production occurs which has been described to result in a first round of bacterial dispersal 9. As the biofilm matures, bacteria continue to grow and produce EPS. This is accompanied by a second round of cell detachment through the peripheral and in-depth expression of the accessory gene regulator (agr) quorum sensing system once a critical mass is reached 10,11. Staphylococcus aureus independently expresses two forms of micrococcal nucleases, the excreted Nuc1...

Advancements in contemporary medicine have led to an increasing life expectancy which has broadened the application of biomaterial implants. As each implant procedure has an innate risk of infection, the number of biomaterial-associated infections keeps rising. Staphylococcus aureus causes 34% of such infections and is known as a potent biofilm producer. By secreting micrococcal nuclease S. aureus is able to escape neutrophil extracellular traps by cleaving their DNA-backbone. Also, micrococcal nuclease potentially limits biofilm growth and adhesion by cleaving extracellular DNA, an important constituent of biofilms. This study aimed to evaluate the impact of micrococcal nuclease on infection persistence and biofilm formation in a murine biomaterial-associated infection-model with polyvinylidene-fluoride mesh implants inoculated with bioluminescent S. aureus or its isogenic micrococcal nuclease deficient mutant. Supported by results based on in-vivo bioluminescence imaging, ex-vivo colony forming unit counts, and histological analysis it was found that production of micrococcal nuclease enables S. aureus bacteria to evade the immune response around an implant resulting in a persistent infection. As a novel finding, histological analysis provided clear indications that the production of micrococcal nuclease stimulates S. aureus to form biofilms, the presence of which extended neutrophil extracellular trap formation up to 13 days after mesh implantation. Since micrococcal nuclease production appeared vital for the persistence of S. aureus biomaterial-associated infection, targeting its production could be a novel strategy in preventing biomaterial-associated infection.

Coatings are essential for biomedical applications antifouling and antimicrobial properties, supporting cell adhesion and tissue integration and particularly interesting in this field are nanogel (nGel)-based coatings. Since biomaterials differ in physiochemical properties, specific nGel-coating strategies need to be developed for every distinct material, leading to complex coating strategies. Hence, the solution lies in adopting a universal strategy to apply the same nGel coating with the same function on a wide range of implant surfaces. To this end, a universal nGel-based coating approach provides the same coating using a single method on implant materials including stiff polymer materials, metals, ceramics, glass, and elastomers. The coating formation is achieved by electrostatic interactions between oxygen plasma-activated surfaces and positively charged nGels using a spray-deposition method. Fluorescent labels are introduced into the nGels as a model for post-modification capabilities to increase the functionality of the coating. The coating is highly stable under in vitro physiological conditions with the retention of its function on different clinically relevant materials. Meanwhile, the in vivo study indicates that the nGel coating on a polyvinylidene fluoride hernia mesh is stable and biocompatible, therefore, making the coating and the coating strategy, a highly impactful approach for future clinical developments.

Biomaterials have diverse physicochemical properties and to apply a functional nanogel-based coating on these different materials, a unified approach is ideal which is independent of the material composition. In article number 2200141, Patrick Van Rijn and co-workers report a universal nGel spray coating strategy that is applied to metals, ceramics, elastomers, and (fluorinated) polymers.