ABSTRACT
Nitric oxide (NO) plays a critical role in a wide range of bodily functions, including vasodilation,
neurotransmission, wound healing, suppression of platelet activation, and modulation of ciliary beat frequency.
Further, inhaled gas phase NO is now routinely used to treat neonatal pulmonary hypertension. In infection,
NO released by neutrophils and macrophages functions as a potent antimicrobial/antiviral agent, and low nM
concentrations of NO efficiently disperse biofilm formed by a variety of bacterial strains. Recent clinical trials
have demonstrated its benefit in treating a variety of airway infections. In contrast, traditional antibiotics exhibit
reduced efficacy against established bacteria colonies, i.e., biofilms, and when used within a catheter lock
solution they do not mitigate other catheter dysfunction problems, including thrombotic complications related to
platelet activation along the outer surface of the catheter. Thus, the combined antimicrobial and antithrombotic
properties of NO make it an ideal candidate to prevent catheter-related blood stream infections (CRBSI) and
thrombotic complications for end stage renal disease (ESRD) patients with tunneled dialysis catheters (TDCs).
Recently, it has been shown that stabilized forms of NO, S-nitrosothiols (RSNOs), are a convenient way to
deliver therapeutic levels of NO for some of these medical applications.
NOTA Laboratories now proposes to use RSNO chemistry to develop two related disposable insert device
variants for use with TDCs that are capable of releasing significant NO fluxes for 3-4 days. One device variant
would be a catheter insert cap that bathes the extracorporeal portion, above the pinch clamp (the hub area) of
a TDC, to deliver bactericidal levels of NO in the catheter region most prone to bacterial intrusion. The second
product variant would be a longer insert that would extend to the distal tip and release NO through the entire
length of the TDC. These devices would consist of an appropriate narrow diameter polymeric tube packed with
the RSNO in a hydratable matrix. After each dialysis session the lumens of the TDC will be filled with saline
lock solution and the devices will be inserted into both lumens where they will spontaneously generate NO until
the next dialysis session, typically 3 days. If the TDC is composed of a NO permeable material, fibrin sheath
formation on the outer surface of the TDC should also be suppressed. Phase I research will focus on three
aims: 1) identifying the optimal RSNO chemistry and tubing to make the device; 2) evaluating the NO release
of the inserts within dual-lumen medical-grade TDC tubing; and 3) demonstrating the antimicrobial activity of
optimized disinfection inserts on the inner and outer surfaces of TDC catheter tubing.
