Management of oral biofilms by nisin delivery in adhesive microdevices.

Numerous beneficial microbes thrive in the oral cavity where they form biofilms on dental and mucosal surfaces to get access to nutrients, and to avoid being carried away with the saliva. However, biofilm formation is also a virulence factor as it also protects pathogenic bacteria, providing them with an environment for proliferation causing oral infections. Oral hygiene relies on mechanical removal of biofilms. Some oral care products also contain antimicrobials, but effective eradication of biofilms with antimicrobials requires both a high concentration and long exposure time. In the present communication, we investigate the potential of using miniaturized drug delivery devices, known as microcontainers (MCs), to deliver the antimicrobial peptide, nisin to an oral multi-species biofilm. MCs are loaded with nisin and X-ray micro-computed tomography reveals a full release of nisin through a chitosan lid within 15 min. Chitosan-coated MCs display substantial bioadhesion to the buccal mucosa compared to non-coated MCs (68.6 ± 14.3% vs 33.8 ± 5.2%). Confocal monitoring of multi-species biofilms reveals antibacterial effects of nisin-loaded chitosan-coated MCs with a faster onset (after 3 h) compared to solution-based delivery (after 9 h). Our study shows the potential of using MCs for treatment of multi-species oral biofilms and is encouraging for further design of drug delivery devices to treat oral diseases.

Enhanced Eradication of Mucin-Embedded Bacterial Biofilm by Locally Delivered Antibiotics in Functionalized Microcontainers.

Bacterial biofilm-related infections are difficult to eradicate and require repeated treatments with high doses of antibiotics. Thus, there is an urgent need for new treatment strategies that minimize the use of antibiotics while enhancing biofilm eradication. Functionalized reservoir-based microdevices, such as, microcontainers (MCs), offer, high drug loading capacity, mucus embedment, and tuneable drug release. Here, MCs are loaded with the antibiotic ciprofloxacin (CIP), and sealed with a lid consisting of chitosan (CHI) and a mucolytic agent, N-acetylcysteine (NAC). It is found that CHI and NAC work synergistically, showing improved mucoadhesive and mucolytic properties. To better mimic the in vivo habitat of Pseudomonas aeruginosa (P. aeruginosa), the biofilm is grown in a mucin-containing medium on a newly developed centrifugal microfluidic system. The CHI/NAC coated MCs improve eradication of biofilm (88.22 ± 2.89%) compared to CHI-coated MCs (72.68 ± 3.73%) or bolus injection (39.86 ± 13.28%). The findings suggest that MCs are significantly more efficient than a bolus treatment. Furthermore, CHI/NAC functionalized MCs kill most of the biomass already after 5 h (80.75 ± 3.50%), mainly due to a fast drug release. This is the first time that CHI/NAC has been combined as a coating to explore mucolytic properties on bacterial biofilms.

Polymeric nano- and microparticulate drug delivery systems for treatment of biofilms.

Now-a-days healthcare systems face great challenges with antibiotic resistance and low efficacy of antibiotics when combating pathogenic bacteria and bacterial biofilms. Administration of an antibiotic in its free form is often ineffective due to lack of selectivity to the infectious site and breakdown of the antibiotic before it exerts its effect. Therefore, polymeric delivery systems, where the antibiotic is encapsulated into a formulation, have shown great promise, facilitating a high local drug concentration at the site of infection, a controlled drug release and less drug degradation. All this leads to improved therapeutic effects and fewer systemic side effects together with a lower risk of developing antibiotic resistance. Here, we review and provide a comprehensive overview of polymer-based nano- and microparticles as carriers for antimicrobial agents and their effect on eradicating bacterial biofilms. We have a main focus on polymeric particulates containing poly(lactic-co-glycolic acid), chitosan and polycaprolactone, but also strategies involving combinations of these polymers are included. Different production techniques are reviewed and important parameters for biofilm treatment are discussed such as drug loading capacity, control of drug release, influence of particle size and mobility in biofilms. Additionally, we reflect on other promising future strategies for combating biofilms such as lipid-polymer hybrid particles, enzymatic biofilm degradation, targeted/triggered antibiotic delivery and future alternatives to the conventional particles.

Co-delivery of ciprofloxacin and colistin using microcontainers for bacterial biofilm treatment.

In many infected patients, bacterial biofilms represent a mode of growth that significantly enhances the tolerance to antimicrobials, leaving the patients with difficult-to-cure infections. Therefore, there is a growing need for effective treatment strategies to combat biofilm infections. In this work, reservoir-based microdevices, also known as microcontainers (MCs), are co-loaded with two antibiotics: ciprofloxacin hydrochloride (CIP) and colistin sulfate (COL), targeting both metabolically active and dormant subpopulations of the biofilm. We assess the effect of the two drugs in a time-kill study of planktonic P. aeruginosa and find that co-loaded MCs are superior to monotherapy, resulting in complete killing of the entire population. Biofilm consortia of P. aeruginosa grown in flow chambers were not fully eradicated. However, antibiotics in MCs work significantly faster than simple perfusion of antibiotics (62.5 ± 8.3% versus 10.6 ± 10.1% after 5 h) in biofilm consortia, showing the potential of the MC-based treatment to minimize the use of antimicrobials in future therapies.

Microcontainer Delivery of Antibiotic Improves Treatment of Pseudomonas aeruginosa Biofilms.

Biofilm-associated infections are difficult to treat effectively with antibiotics despite repeated treatments. Polymeric microdevices (microcontainers) have previously been shown to engulf in mucus layers and to provide tunable release. Such devices may overcome the challenge of delivering antibiotics into the biofilm, increasing the local drug concentration and hence improve local bacterial killing. In this work, microcontainers are loaded with the antibiotic, ciprofloxacin hydrochloride, and functionalized with polymeric lids of polyethylene glycol (PEG), chitosan, or Eudragit S100. The PEG lid gives rise to a drug release comparable to uncoated microcontainers showing complete release after 8 h, whereas chitosan and Eudragit S100 lids result in continuous release during the course of 24 h. All antibiotic-containing microcontainers inhibit planktonic growth of Pseudomonas aeruginosa (PAO1) cells, but the degree of inhibition depends on the coating. Microcontainers with ciprofloxacin hydrochloride kill about three times more biofilm-associated PAO1 cells compared with a single standard bolus. Moreover, the use of microcontainers in biofilm result in bacterial killing equal to a constant flow of a three times higher concentration of solubilized antibiotics. These studies suggest that microcontainers can be useful for antibiotic delivery in treatment of biofilm-associated infections, resulting in more effective treatment and reduced use of antibiotics.