# Novel Approaches to Combat Medical Device-Associated BioFilms
## 3 Novel Approaches to Combat Medical Device-Associated Biofilms
### Agents for Degradation of the Extracellular Matrix of Biofilms  
The extracellular matrix plays an important role in the formation, development, and survival of biofilms. It is not only a protective barrier against external factors, but also a source of nutrients and enzymes, as well as connectors between cells [232]. Degradation of the matrix is a way to weaken biofilms, and several strategies have been proposed (Figure 1). First, enzymes can degrade various EPS components. The bacterial extracellular polysaccharide poly8-1,6-N-acetylglucosamine (PNAG) is the main extracellular matrix component of the biofilms of Gram-positive bacteria and Gram-negative bacteria [233]. Dispersin B, which is a \(\beta\)-N-acetylglucosamine monovidase produced by the Gram-negative species _Actinobacillus actinomycetemcomitants_, shows great potential for hydrolyzing PNAG to disperse biofilms formed by various bacteria, but does not kill the bacteria [234; 235]. Due to the biofilm dispersal activity of dispersin B, it is used to generate specific probes for monitoring the production and localization of PNAG in the process of biofilm formation and elucidating the early stages of PNAG-dependent biofilm formation [233]. eDNA contributes to the structural integrity of the matrix [236]. Deoxyribonuclease (DNase) can degrade the eDNA present in the matrix, thus disrupting the stability of the biofilm. The antibiofilm effect of DNase has been studied for several kinds of microorganisms, such as _S. aureus, P. aeruginosa, E. coli, A. baumanmi, Haenophilus influenzae_, and _K. pneumoniae_[237; 238]. DNase I immobilized on a titanium surface can prevent the adhesion and biofilm formation of _S. mutans_ and _S. aureus_ and exhibits good biocompatibility [160]. DNase I added to mature biofilms can also degrade biofilms. DNase I was further found to be less effective against mixed-species biofilms than individual biofilms [238]. Many other enzymes, such as proteinase K, lysozyme [239], \(\alpha\) amylase [240], and the glycoside hydrolases PelAh and PslGh [241], have been proven to have promising antibiofilm activity. Second, cation chelators can not only breakdown the extracellular matrix and eradicate biofilms, but also act as enhancers for antimicrobial agents, thereby disabling resistance mechanisms. For example, branched polyethylenimine (BPEI) is a cationic polymer with a low molecular weight of 600 Da. A recent study on treatment with BPEI combined with oxacillin demonstrated that this combination therapy could eradicate methicillin-resistant _Staphylococcus epidermidis_ (MRSE) biofilms and reduce the cell density of the biofilms by 100,000-fold. The strong synergistic effect between BPEI and lactam antibiotics is because BPEI can neutralize the anionic character of the biofilm, resulting in rupture of the EPS matrix, as well as destruction of the hydrophobic barrier, which prevents the permeation of hydrophilic antibiotics, allowing the antibiotics to enter and kill the bacteria [14]. Ethylene diamine tetraacetic acid (EDTA), which is a cationic chelating agent, has been shown to affect the structural integrity of biofilms through the chelation of calcium, iron, and magnesium in staphylococci and _Candida_ spp. [242]. A study revealed that EDTA alone significantly decreased fungal metabolic activity in preformed _C. albicans_ biofilms. Additionally, EDTA combined with fluconazole significantly reduced the growth of biofilms compared with fluconazole alone. In addition, the study also showed that the cell density decreased when biofilm cells were treated with EDTA alone or in combination with fluconazole [243]. In addition, a few compounds, such as ambroxol and N-acetylcysteine, have been reported to have active matrix destruction properties and can be used for antibiofilm purposes [232]. Therefore, matrix disruptive agents such as enzymes, cationic chelators, and compounds provide us with another effective treatment strategy against biofilm-associated infections.