# Novel Approaches to Combat Medical Device-Associated BioFilms
## 1 Introduction  
A biofilm is a special existence state with a three-dimensional tower structure formed by a microbial community attached to a biological or nonbiological surface and embedded in the matrix of an extracellular polymeric substance (EPS). An EPS is secreted by attached cells and is mainly composed of polysaccharides, extracellular DNA (eDNA), proteins, and other secreted substances (Figure 1) [1, 2, 3]. These substances act as a shield that often makes microorganisms resistant to physical removal, host immune responses, and antimicrobial treatments [1, 2, 3]. The development of biofilms is linked to quorum sensing  
(QS), which is a cell-to-cell communication mechanism that regulates a variety of physiological and biochemical functions [4, 5]. It can influence the biological cycle of biofilms by targeting matrix compounds and regulate the production of multiple virulence factors to resist phagocytosis [4, 6, 7]. Biofilms have their own properties that change dynamically, and their biological cycle involves four stages, namely, adhesion, sessile growth, maturation, and dispersal [1, 8]. The adhesion and sessile growth stages are reversible, wherein the cells aggregate loosely, but can also become detached and return to a free-floating state [3, 8, 9]. The maturation of biofilms is related to the production of EPS, which encapsulates cells in a thick and stable layer of complex biomolecules. This stage is irreversible [3, 8, 10, 11]. Cells in the dispersion stage can secrete destruction factors to promote detachment of the biofilm and the colonization of surrounding sites [3, 8, 10, 12]. Biofilms exhibit spatial heterogeneity [10, 13]. The concentrations of various chemical substances in the biofilm, such as metabolic products, signal molecules, and nutrients, change stepwise from the surface to the inside, which makes the physiological activities of bacteria different in different parts of the biofilm [10, 13]. The outer-layer cells remain metabolically active, while the inner-layer cells are persister bacteria, which are usually dormant [14]. Because of the uneven metabolism of bacteria in biofilms, regardless ofthe metabolic link that the antibacterial factors act on, some bacteria that are not in this metabolic state can survive, leading to difficulties in the elimination of infection or repeated outbreaks of infection. Up to 80% of microbial infections in the human body involve biofilm formation, especially in hospital settings, which greatly promotes the incidence rate and mortality [15; 16]. With the high standards for the quality of life of patients, the improvement of medical standards, and the widespread application of medical devices, medical device-associated biofilms pose a serious threat to human health, and these biofilms are the most important source of nosocomial infections, despite the comprehensive prevention and control measures taken, such as disinfection and hygiene monitoring. According to statistics, about 2 million nosocomial infection cases occurred in the United States each year at the beginning of the 21 st century, of which 50%-70% of nosocomial infections were related to indwelling medical devices [17; 18; 19]. Given the challenges associated with medical device-associated biofilm control, new strategies are urgently needed for the treatment of these biofilm-specific infections. Several novel approaches have been developed and identified as effective and promising treatment strategies. Although previous reviews have already summarized novel approaches to combat medical device-associated biofilms [20; 21; 22; 23], we briefly summarize the challenges associated with the treatment of medical device-associated biofilm infections and provide a more comprehensive summary of strategies that can be employed to combat medical device-associated biofilms. In particular, we discuss the progress and limitations of the latest studies on antimicrobial peptides (AMPs) and nanotechnology in detail.