Thromboresistant/anti-biofilm catheters via electrochemically modulated nitric oxide release

Abstract

Inexpensive nitric oxide (NO) release strategies to prevent thrombosis and bacterial infections are desirable for implantable medical devices. Herein, we demonstrate the utility of electrochemically modulated NO release from a catheter model using an inner copper wire working electrode and an inorganic nitrite salt solution reservoir. These catheters generate NO surface fluxes of >1.0×10−10 mol min−1 cm−2 for more than 60 h. Catheters with an NO flux of 1.1×10−10 mol min−1 cm−2 are shown to significantly reduce surface thrombus formation when implanted in rabbit veins for 7 h. Further, the ability of these catheters to exhibit anti-biofilm properties against bacterial species commonly causing bloodstream and urinary catheter infections is examined. Catheters releasing NO continuously during the 2 d growth of S. aureus exhibit a 6 log-unit reduction in viable surface bacteria. We also demonstrate that catheters generating NO for only 3 h at a flux of 1.0×10−10 mol min−1 cm−2 lower the live bacterial counts of both 2 d and 4 d pre-formed E. coli biofilms by >99.9%. Overall, the new electrochemical NO-release devices could provide a cost-effective strategy to greatly enhance the biocompatibility and antimicrobial properties of intravascular and urinary catheters, as well as other implantable medical devices.

Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO)

“…pathways. 132 Recently, it was demonstrated that nitrite can also be used to generate NO via electrochemical reduction at an electrode surface with either Cu(I) ion generated from oxidation of Cu 0 145,146 or via the use of Cu(II)-ligand complexes that mimic the active site of nitrite reductase (e.g., Cu(II)-tri(2-pyridylmethyl)amine, Cu(II)TPMA). 147 …”

“…The Cu + ion is generated from oxidation of a copper wire 145,146 or the reduction of copper(II)-tri(2-pyridylmethyl)amine (Cu(II)TPMA) complex. 147 The electrochemically generated NO can be modulated by changing the potentials applied to the electrodes and can achieve between 0.5 and 3.5 × 10 −10 mol cm −2 min −1 , which is in the range of physiological relevant levels of NO released by the endothelial cells.…”

“…Meyerhoff and coworkers have conducted many experiments where the antibacterial properties of NO releasing polymer were evaluated against mature biofilm, developed in CDC bioreactors prior to contacting with NO. 145,147 Electrochemical NO generating catheters using inner copper wire working electrode and inorganic nitrite salt solution can generate NO through the walls of the catheters with a flux > 1.0 × 10 −10 mol cm −2 min −1 for more than 60 h. 146 First, the catheters were mounted in a drip-flow bioreactor, which is a standardized model that allows growth of high biomass-biofilm of E. coli at the air liquid interface when incubated with in LB (Luria Bertani) broth for 2 d and 4 d without the NO turned on. After allowing biofilm to form on catheter surfaces, the electrochemical NO release was “turned on” for only 3 h at the end of the experiments.…”

Nitric Oxide Sensors for Biological Applications

“…Some more notable accomplishments utilizing NO include a reversal of hypoxic pulmonary vasoconstriction using inhaled NO, the development of an antimicrobial sol-gel for coating biomaterials used in implants, and an electrochemical oxygen probe which uses NO as an anticlotting agent [42][43][44].…”

Nitric oxide release for improving performance of implantable chemical sensors – A review

“…To avoid the leaching of NO donors and/or byproducts into the bloodstream, and to produce very controllable NO generation over prolonged time, Ren et al [67] reported improvement in in vivo analytical performance of intravascular analytical sensors by coupling them with a new electrochemical method of NO generation. This method involves electrochemical reduction of inorganic nitrite ions catalyzed by a copper(II)-ligand complex, copper(II)-tri(2-pyridylmethyl)amine (Cu(II)TPMA; see structure in Figure 2).…”