# Novel Approaches to Combat Medical Device-Associated BioFilms
## 2 Medical Device-Related Biofilm Infection and the Challenges of Treatment
coli_[34], _Pseudomonas aeruginosa_[35], _Klebsiella pneumoniae_[36], _Acinetobacter baumannii_[37], and _Enterococcus faecalis_[38]. We have listed the main microorganisms involved in the formation of biofilms at the level of various medical implants in Table 1. Biofilms can be formed by a single bacterial strain. However, biofilms are usually formed by a variety of microorganisms in nature, and such mixed-species biofilms represent the actual lifestyles of microbes, including bacteria, fungi, and/or protozoa [39]. Bacterial species extensively interact with each other and these interactions (such as adhesin-mediated coaggregation, bacterial surface pili, and flagella, and their mediated motilities, competition, and cooperation) determine the structure development and functional dynamics of multi-speciesbiofilms [40]. The oral biofilm formation process is initiated by an early colonizer, such as _S. gordoni_, _S. sanguinis_, and _S. oligofermentans_, which provides further attachment sites for later colonizers, such as _S. mutans_. The succession of biofilm development involves the coaggregation and coadherence of oral bacteria, and if undisturbed, develops into a stratified, complex biofilm [41]. The resistance of bacteria in biofilms to antibiotics can be 10-1000 times that of the corresponding planktonic cells [88]. The mechanisms of biofilm resistance to conditional antimicrobial agents have been studied carefully and can be summarized as follows. The presence of biofilms enhances the drug resistance of bacteria, which is different from the mechanism of drug resistance of planktonic cells. As mentioned above, the large amounts of EPSs, such as exopolysaccharide and eDNA, in biofilms form molecular and charge barriers to prevent and delay drug penetration [89; 90]. Extracellular DNA can also induce the expression of drug resistance genes by chelating cations to increase the drug resistance [91]. In addition, some high-concentration hydrolases are present in biofilms; these hydrolases inactive antibacterial drugs that enter the biofilm. The biofilm matrix provides shelter and physical and chemical barriers for cells (Figure 1). Due to the heterogeneity of biofilms, such as those in cell metabolism, nutrients, and oxygen, bacterial cells in low-metabolism and slow-growth states are not sensitive to most antimicrobial agents. Cells in biofilms also acquire a resistance phenotype by altering their DNA, which has been associated with increased oxidative stress in biofilms [92; 93], leading to, for example, increased \(\beta\)-lactamase expression, the activation of multidrug efflux pumps, or the downregulation of outer membrane proteins [94; 95; 96; 97; 98]. Biofilms are considered ideal reaction chambers for horizontal gene transfer. Cells can acquire antibiotic resistance through the horizontal transfer of antibiotic resistance genes due to the high cell density of bacteria in biofilms [99]. Horizontal gene transfer promotes biofilm formation and heightens pathogens' host direct fitness. Furthermore, it can enforce pathogens to maintain stable social interactions [100]. Cells communicate through signal transduction pathways (e.g., QS or two-component systems), leading to global changes in gene expression by conjugation, transformation, and transduction, enhancing the virulence and expediting the acquisition of antibiotic resistance [101]. Among them, conjugation is certainly the most commonly studied. [PERSON] et al. have demonstrated that the biofilm growth of _S. aureus_ dramatically increases the horizontal transfer of plasmid-borne antibiotic resistance determinants by conjugation/mobilization [102]. It has also been reported that the horizontal transfer of antibiotic resistance genes between cells occurs efficiently in early biofilms and multiresistant gene transfer is heavily suppressed in dense biofilms [103]. Researchers have paid more attention to the risk of the development and dissemination of horizontal