## 5 Other Therapeutic Approaches
### Biomaterials and Nanoparticles  
Pathogenic biofilms formed on implantable medical devices (IMDs) or human tissues have caused a huge risk in global healthcare. Functionalized biomaterials could be a novel approach to combat and eradicate pre-existing biofilms. Adherence of bacteria is the initial stage of IMD-associated infections that enables bacteria to colonize in the implants. The inhibition of biofilms could be achieved by coating the implants with biomaterials with antifouling and antibacterial properties. Biofilm eradication could be achieved by using nanoparticle (NP)-coated drugs to disperse biofilms [148]. NPs are regarded as a substitute for antibiotics for combating multidrug-resistant and biofilm-associated infections [149]. The biofilm-NP interaction is a three-step process: (1) transport of NPs around the biofilm, (2) attachment of NPs to the biofilm EPS, and (3) penetration of NPs into the EPS and migration within the biofilm through diffusion which might be dependent on the biofilm pore sizes, the charges, hydrophobicity, and the EPS chemical gradient [150]. Drawbacks of antibiotic therapy, such as reduced penetration into the biofilm, could be overcome easily through their nano-formulations that can cross the biological barrier. Naturally forming and engineered NPs could differ largely in their physicochemical properties including size, shape, and charge [150]. For the last few years, different types of NPs have been used as antibiofilm and antimicrobial metal NPs, organic NPs, green NPs, and their combinations [151]. Several reports exist on NP-based eradication of biofilm communities [152; 153; 154]. [PERSON] et al. found the inhibitory effect of CaF2-NPs on genes related to _S. mutans_ virulence (_gtF_C, _vicR, comDE, ff_, and _spaP_). The study also proposed that CaF2-NPs could also suppress the enzymatic activities related to cell adhesion, glucan synthesis, acid production and tolerance, and quorum sensing that result in biofilm inhibition [141]  
NPs such as AuNPs (gold NPs) were also developed in combination with hardening. Hordenine-AuNPs displayed greater antibiofilm properties on _P. aeruginosa_ PAO1, which suggests NPs-delivered natural compounds can be efficiently used in biofilm-related infection [155]. Most recently, [PERSON] et al., constructed catalytic antimicrobial robots (CARs) that accurately, effectively, and controllably killed, damaged, and detached biofilms [138]. CARs utilizing iron oxide NPs with dual catalytic-magnetic functionality (1) formed free radicals, (2) disrupted biofilm EPS, and (3) eradicated the scrapy biofilm debris using magnetic field-driven robotic assemblies [138]. Nitric oxide-releasing nanoparticles (NO NPs) employ various simultaneous antimicrobial mechanisms, so the chances that microbes will develop resistance to NO NPs is low [149]. [PERSON] et al. compared hydrogel/glass composite NO NP with systemic vancomycin for treating MRSA-infected intramuscular abscess in a mouse model and found that NO NPs led to a more significant decrease in bacterial survival than vancomycin treatedones [139]. Drug-delivery NPs with targeting ligands have the potential for promoting improved proximity between the individual biofilm cells within the EPS and the nanocarrier. Lipid and polymer NPs are gaining attraction due to their versatility, biocompatibility, targeted/triggered release, and ability to incorporate lipophilic as well as hydrophilic drugs. Many liposomal formulations for biofilm treatment are under development, yet such products are not available on the market. A liposomal formulation containing the antibiotic amikacin, Arikayce(tm) (Transave, Inc., Monmouth Junction, NJ, USA) is in Phase III clinical trials, Similarly, Fluidsomes(tm), containing tobramycin, is in a Phase II trial for the treatment of cystic fibrosis-associated respiratory infections. Although there are some examples of antimicrobial catheters, implants, and wound dressings containing AgNPs available for clinical use, antibiofilm strategies are still underdeveloped.