# Treatment of Biofilm Communities: An Update on New Tools from the Nanosized World
## 4 Nanotechnology as a Tool to Counteract Biofilm Infections: A Still Preclinical Issue  
The relevance of biofilm in clinical settings arose in the 1980s when medical implants were found contaminated by bacteria upon analysis with electron microscopy [69; 70; 71].  
As reported in Figure 3, the main sites of initial infections are either sites where medical manipulation occurred (prosthesis or catheter implantation) or areas where bacteria can gain easy access to bloodstream (periodontal or \"gum\" disease--as previously said, dental plaque is a form of biofilm-). The contamination at these sites enables access to bloodstream, that allows dispersion of single cells or biofilm clumps in the entire body, therefore reaching even deeper tissues (e.g., endocarditis). The adherence to a substratum and its localization in a specific site (with sporadic bacteremia) are among the four characteristics that [PERSON] and [PERSON] proposed for biofilm-related infectious diseases [72]. The other two features are presence of a matrix-embedded biofilm upon microscopic observation and increased resistance to antibiotics despite antibiotic sensitivity of the constituent planktonic organisms. The latter is particularly relevant since it claims for alternative or complementary approaches for the reduction of the infection burden, since in many cases infection persists even after long-term aggressive antibiotic therapy, after which prosthesis or implant removal is necessary [73]. This implies higher costs in many different aspects, both from the patient side and the healthcare providers.  
Figure 3: Schematic representation of biofilm-associated infection disseminations, indicated by arrows. For more details, see main text. (With permission, from [24]).  
The design of nanomaterials that are anti-infective by-design may help the field to improve not only medical treatments, but also environmental applications. The development of nanoparticles and nanomaterials in general is more focused on cancer and cardiovascular treatment and diagnostic purposes, in which these nanostructured materials have reached successful clinical applications (for extensive reviews, see [8; 74; 75]). In the field of antimicrobials, the application of nanotechnology is still at a pre-clinical or academic research level [76; 77], with only some examples of wound-dressing, catheters, bone cements and cardiovascular implants containing silver as antimicrobial already available for clinical use [78]. As shown in Table 1, a simple search of the main US literature and clinical trial databases (PubMed and Clinicaltrail.gov, respectively) demonstrates that substantial effort is invested in academic research on nanoparticles in general, with minor attention to infections (166.221 vs. 2.604 hits) and biofilm (166.221 vs. 1.135 hits).  
The clinical research and application are already a major barrier to most of the nanoparticle preparations, especially for infectious diseases, as reflected by the paucity of clinical trials involving nanoparticles. Clinical applications of nanosystems as antimicrobials are almost absent to the best of our knowledge. Therefore, we will focus on the preclinical research that has been conducted in this field.