Co-reporter:Stephen A. Ferguson and Mark E. Meyerhoff
ACS Sensors - New in 2016 October 27, 2017 Volume 2(Issue 10) pp:1505-1505
Publication Date(Web):September 1, 2017
DOI:10.1021/acssensors.7b00527
The detection of four different polyquaterniums (PQs) using a fully reversible potentiometric polyion sensor in three different detection modes is described. The polyion sensing “pulstrodes” serve as the detector for direct dose–response experiments, beaker titrations, and in a flow-injection analysis (FIA) system. Direct polycation response toward PQ-2, PQ-6, PQ-10, and poly(2-methacryloxyethyltrimethylammonium) chloride (PMETAC) yields characteristic information about each PQ species (e.g., relative charge densities, etc.) via syringe pump addition of each PQ species to a background electrolyte solution. Quantitative titrations are performed using a syringe pump to deliver heparin as the polyanion titrant to quantify all four PQs at μg/mL levels. Both the direct and indirect methods incorporate the use of a three-electrode system including counter, double junction reference, and working electrodes. The working electrode possesses a plasticized poly(vinyl chloride) (PVC) membrane containing the neutral lipophilic salt of dinonylnaphthalenesulfonate (DNNS–) tridodecylmethylammonium (TDMA+). Further, the titration method is shown to be useful to quantify PQ-6 levels in recreational swimming pool water collected in Ann Arbor, MI. Finally, a FIA system equipped with a pulstrode detector is used to demonstrate the ability to potentially quantify PQ levels via a more streamlined and semiautomated testing platform.Keywords: flow-injection analysis; polyquaternium; potentiometric titration; potentiometry; pulstrode;
Co-reporter:Yu Qin, Joanna Zajda, Elizabeth J. Brisbois, Hang Ren, John M. Toomasian, Terry C. Major, Alvaro Rojas-Pena, Benjamin Carr, Thomas Johnson, Jonathan W. Haft, Robert H. Bartlett, Andrew P. Hunt, Nicolai Lehnert, and Mark E. Meyerhoff
Molecular Pharmaceutics November 6, 2017 Volume 14(Issue 11) pp:3762-3762
Publication Date(Web):October 11, 2017
DOI:10.1021/acs.molpharmaceut.7b00514
A new portable gas phase nitric oxide (NO) generator is described for potential applications in inhaled NO (INO) therapy and during cardiopulmonary bypass (CPB) surgery. In this system, NO is produced at the surface of a large-area mesh working electrode by electrochemical reduction of nitrite ions in the presence of a soluble copper(II)-ligand electron transfer mediator complex. The NO generated is then transported into gas phase by either direct purging with nitrogen/air or via circulating the electrolyte/nitrite solution through a gas extraction silicone fiber-based membrane-dialyzer assembly. Gas phase NO concentrations can be tuned in the range of 5–1000 ppm (parts per million by volume for gaseous species), in proportion to a constant cathodic current applied between the working and counter electrodes. This new NO generation process has the advantages of rapid production times (5 min to steady-state), high Faraday NO production efficiency (ca. 93%), excellent stability, and very low cost when using air as the carrier gas for NO (in the membrane dialyzer configuration), enabling the development of potentially portable INO devices. In this initial work, the new system is examined for the effectiveness of gaseous NO to reduce the systemic inflammatory response (SIR) during CPB, where 500 ppm of NO added to the sweep gas of the oxygenator or to the cardiotomy suction air in a CPB system is shown to prevent activation of white blood cells (granulocytes and monocytes) during extracorporeal circulation with cardiotomy suction conducted with five pigs.Keywords: copper(II)-ligand electron transfer mediator; electrochemical reduction; inhaled nitric oxide therapy; nitric oxide;
Co-reporter:Xuewei Wang, Mollie Mahoney, and Mark E. Meyerhoff
Analytical Chemistry November 21, 2017 Volume 89(Issue 22) pp:12334-12334
Publication Date(Web):October 31, 2017
DOI:10.1021/acs.analchem.7b03352
The first paper-based polyion-sensitive optodes are reported. Dinonylnaphthalene sulfonic acid (a cation exchanger) and chromoionophore I (a lipophilic optical pH indicator) are printed on filter paper in the absence of any plasticizer and/or additional hydrophobic polymeric phase. The resulting optodes exhibit sensitive colorimetric response to polycations such as protamine but not to small inorganic cations because only polycations are able to form cooperative ion pairs with dinonylnaphthalenesulfonate adsorbed to the cellulose paper. The color change of the optode is recorded via an iPhone camera and analyzed by an iPhone App. The protamine-sensing optode platform is used to indirectly detect protease activity (trypsin) based on proteolytic digestion of protamine, and polyanions (pentosan polysulfate and heparin) based on the strong binding reaction of polyanions with protamine. The indirect sensing system is further simplified on a multilayer membrane device that consists of an optode paper site modified with buffer to prevent optode dependence on sample pH, and an underlying cellulose acetate filter membrane coated with protamine to eliminate addition of the indicator polycation into the sample. The detection of pentosan polysulfate concentrations in an undiluted urine sample is successfully demonstrated via this approach. Lastly, it is shown that plasticizer-free polyanion-sensitive optodes based on an adsorbed layer of quaternary ammonium type anion exchanger and a phenolic azo type proton chromoionophore can also be fabricated directly on cellulose paper strips.
Co-reporter:Yaqi Wo, Elizabeth J. Brisbois, Jianfeng Wu, Zi Li, Terry C. Major, Azmath Mohammed, Xianglong Wang, Alessandro Colletta, Joseph L. Bull, Adam J. Matzger, Chuanwu Xi, Robert H. Bartlett, and Mark E. Meyerhoff
ACS Biomaterials Science & Engineering March 13, 2017 Volume 3(Issue 3) pp:349-349
Publication Date(Web):January 22, 2017
DOI:10.1021/acsbiomaterials.6b00622
Nitric oxide (NO) has many important physiological functions, including its ability to inhibit platelet activation and serve as potent antimicrobial agent. The multiple roles of NO in vivo have led to great interest in the development of biomaterials that can deliver NO for specific biomedical applications. Herein, we report a simple solvent impregnation technique to incorporate a nontoxic NO donor, S-nitroso-N-acetylpenicillamine (SNAP), into a more biocompatible biomedical grade polymer, CarboSil 20 80A. The resulting polymer-crystal composite material yields a very stable, long-term NO release biomaterial. The SNAP impregnation process is carefully characterized and optimized, and it is shown that SNAP crystal formation occurs in the bulk of the polymer after solvent evaporation. LC-MS results demonstrate that more than 70% of NO release from this new composite material originates from the SNAP embedded CarboSil phase, and not from the SNAP species leaching out into the soaking solution. Catheters prepared with CarboSil and then impregnated with 15 wt % SNAP provide a controlled NO release over a 14 d period at physiologically relevant fluxes and are shown to significantly reduce long-term (14 day) bacterial biofilm formation against Staphylococcus epidermidis and Pseudonomas aeruginosa in a CDC bioreactor model. After 7 h of catheter implantation in the jugular veins of rabbit, the SNAP CarboSil catheters exhibit a 96% reduction in thrombus area (0.03 ± 0.01 cm2/catheter) compared to the controls (0.84 ± 0.19 cm2/catheter) (n = 3). These results suggest that SNAP impregnated CarboSil can become an attractive new biomaterial for use in preparing intravascular catheters and other implanted medical devices.Keywords: antimicrobial catheters; bactericidal; nitric oxide; S-nitroso-N-acetylpenicillamine (SNAP); solvent impregnation; thromboresistance;
Co-reporter:Stephen A. Ferguson;Mark E. Meyerhoff
ACS Sensors - New in 2016 February 24, 2017 Volume 2(Issue 2) pp:268-273
Publication Date(Web):January 10, 2017
DOI:10.1021/acssensors.6b00787
Two facile, robust, and universal methods by which various polymeric quaternary ammonium salts (polyquaterniums (PQs)) can be quantified and characterized using simple potentiometric polymeric membrane polyion-sensitive electrodes as detectors are described. The two methods are (a) direct detection with polycation sensitive membrane electrodes based on the sodium salt of dinonylnaphthalenesulfonate (NaDNNS), and (b) indirect detection using polyanion sensors based on tridodecylmethylammonium chloride (TDMAC) and dextran sulfate (DS) as a titrant to complex the various polyquaternary species (four different PQs: PQ-2, PQ-6, PQ-10, and poly(2-methacryloxyethyltrimethylammonium) chloride (PMETAC)). Direct detection yields information regarding the charge density of the polycationic species. For the titration method, a series of polyanion sensors doped with TDMAC are used to follow a potentiometric titration of a PQ species using a syringe pump to deliver the titrant. This indirect detection method is more reliable and yields limits of detection in the ppm range for the four PQs examined. The titration method is further explored for detecting excess levels of PQ-6, a common flocculating agent for municipal water supply systems, within the purified water emitted by the Ann Arbor, MI, drinking water treatment plant.Keywords: dextran sulfate; polyion; polyquaternary ammonium species; potentiometric titration; potentiometry;
Co-reporter:Dr. Xuewei Wang;Dr. Qi Zhang;Dr. Changwoo Nam; Dr. Michael Hickner;Mollie Mahoney; Dr. Mark E. Meyerhoff
Angewandte Chemie 2017 Volume 129(Issue 39) pp:11988-11992
Publication Date(Web):2017/09/18
DOI:10.1002/ange.201706147
AbstractA general anion-sensing platform is reported based on a portable and cost-effective ion-selective optode and a smartphone detector equipped with a color analysis app. In contrast to traditional anion-selective optodes using a hydrophobic polymer and/or plasticizer to dissolve hydrophobic sensing elements, the new optode relies on hydrophilic cellulose paper. The anion ionophore and a lipophilic pH indicator are inkjet-printed and adsorbed on paper and form a “dry” hydrophobic sensing layer. Porous cellulose sheets also allow the sensing site to be modified with dried buffer that prevents any sample pH dependence of the observed color change. A highly selective fluoride optode using an AlIII-porphyrin ionophore is examined as an initial example of this new anion sensing platform for measurements of fluoride levels in drinking water samples. Apart from Lewis acid–base recognition, hydrogen bonding recognition is also compatible with this sensing platform.
Co-reporter:Dr. Xuewei Wang;Dr. Qi Zhang;Dr. Changwoo Nam; Dr. Michael Hickner;Mollie Mahoney; Dr. Mark E. Meyerhoff
Angewandte Chemie International Edition 2017 Volume 56(Issue 39) pp:11826-11830
Publication Date(Web):2017/09/18
DOI:10.1002/anie.201706147
AbstractA general anion-sensing platform is reported based on a portable and cost-effective ion-selective optode and a smartphone detector equipped with a color analysis app. In contrast to traditional anion-selective optodes using a hydrophobic polymer and/or plasticizer to dissolve hydrophobic sensing elements, the new optode relies on hydrophilic cellulose paper. The anion ionophore and a lipophilic pH indicator are inkjet-printed and adsorbed on paper and form a “dry” hydrophobic sensing layer. Porous cellulose sheets also allow the sensing site to be modified with dried buffer that prevents any sample pH dependence of the observed color change. A highly selective fluoride optode using an AlIII-porphyrin ionophore is examined as an initial example of this new anion sensing platform for measurements of fluoride levels in drinking water samples. Apart from Lewis acid–base recognition, hydrogen bonding recognition is also compatible with this sensing platform.
Co-reporter:Yaqi Wo, Zi Li, Alessandro Colletta, Jianfeng Wu, Chuanwu Xi, Adam J. Matzger, Elizabeth J. Brisbois, Robert H. Bartlett, Mark E. Meyerhoff
Composites Part B: Engineering 2017 Volume 121(Volume 121) pp:
Publication Date(Web):15 July 2017
DOI:10.1016/j.compositesb.2017.03.027
Stable and long-term nitric oxide (NO) releasing polymeric materials have many potential biomedical applications. Herein, we report the real-time observation of the crystallization process of the NO donor, S-nitroso-N-acetylpenicillamine (SNAP), within a thermoplastic silicone-polycarbonate-urethane biomedical polymer, CarboSil 20 80A. It is demonstrated that the NO release rate from this composite material is directly correlated with the surface area that the CarboSil polymer film is exposed to when in contact with aqueous solution. The decomposition of SNAP in solution (e.g. PBS, ethanol, THF, etc.) is an apparent first-order reaction proportional to the SNAP concentration. Further, catheters fabricated with this novel NO releasing composite material are shown to exhibit significant effects on preventing biofilm formation on catheter surface by Pseudomonas aeruginosa and Proteus mirabilis grown in CDC bioreactor over 14 days, with a 2 and 3 log-unit reduction in the number of live bacteria on their surfaces, respectively. Therefore, the SNAP-CarboSil composite is a promising new material for antimicrobial catheters, as well as other biomedical devices.
Co-reporter:Alex R. Ketchum, Michael P. Kappler, Jianfeng Wu, Chuanwu Xi and Mark E. Meyerhoff
Journal of Materials Chemistry A 2016 vol. 4(Issue 3) pp:422-430
Publication Date(Web):07 Dec 2015
DOI:10.1039/C5TB01664A
Recently, considerable research efforts have focused on increasing the biocompatibility and bactericidal activity of biomedical polymeric devices (e.g., catheters, etc.) through incorporation of nitric oxide (NO) releasing molecules. NO is an important endogenous molecule that is well known for enhancing blood flow via its vasodilatory activity, but it also exhibits potent antithrombotic and antimicrobial properties. In this work, we demonstrate that silicone rubber tubing can be impregnated with a tertiary S-nitrosothiol (RSNO), S-nitroso-tert-dodecylmercaptan, via a simple solvent swelling method. We further characterize the NO release and RSNO leaching from the tubing over time via use of chemiluminescence and UV/Vis spectroscopy, respectively. The tubing is shown to maintain an NO flux above the physiological levels released by endothelial cells, 0.5–4.0 × 10−10 mol cm−2 min−1, for more than 3 weeks while stored at 37 °C and exhibit minimal leaching. Finally, the RSNO impregnated tubing exhibits significant antimicrobial activity over a 21 d period (vs. controls) during incubation in a CDC bioreactor after inoculation of media with S. aureus bacteria. The use of such lipophilic RSNO impregnated silicone rubber tubing could dramatically reduce the risk of catheter-related infections, which are a common problem associated with placement of intravascular or urinary catheters.
Co-reporter:Elizabeth J. Brisbois, Maria Kim, Xuewei Wang, Azmath Mohammed, Terry C. Major, Jianfeng Wu, Jessica Brownstein, Chuanwu Xi, Hitesh Handa, Robert H. Bartlett, and Mark E. Meyerhoff
ACS Applied Materials & Interfaces 2016 Volume 8(Issue 43) pp:29270
Publication Date(Web):October 13, 2016
DOI:10.1021/acsami.6b08707
Blood-contacting devices, such as intravascular catheters, suffer from challenges related to thrombus formation and infection. Nitric oxide (NO) is an endogenous antiplatelet and antimicrobial agent. Exogenous release of NO from various polymer matrices has been shown to reduce thrombosis and infection of/on implantable medical devices. However, the clinical applications of such materials have been hindered due to factors such as NO donor leaching and thermal instability. In this study, a novel approach is demonstrated in which one lumen of commercial dual lumen catheters is dedicated to the NO release chemistry, allowing the other lumen to be available for clinical vascular access. A composite consisting of poly(ethylene glycol) (PEG) and S-nitroso-N-acetylpenicillamine (SNAP) is used to fill the NO-releasing lumen of commercial 7 French silicone catheters. Physiological levels of NO are released from the SNAP-PEG catheters for up to 14 d, as measured by chemiluminescence NO analyzer (in PBS buffer at 37 °C). PEG facilitates the NO release from SNAP within the lumen by increasing the water absorption and slowly dissolving the solid SNAP-PEG composite. In a CDC biofilm bioreactor, the SNAP-PEG catheters are found to reduce >97% bacterial adhesion as compared to the PEG controls for single bacterial species including E. coli and S. aureus. SNAP-PEG and PEG control catheters were implanted in rabbit veins for 7 h (single lumen) and 11 d (dual lumen) to evaluate their hemocompatibility properties. Significant reductions in thrombus formation on the SNAP-PEG vs PEG controls were observed, with ca. 85% reduction for 7 h single lumen catheters and ca. 55% reduction for 11 d dual lumen catheters.Keywords: antimicrobial; catheters; hemocompatibility; nitric oxide; poly(ethylene glycol); S-nitrosothiols
Co-reporter:Gergely Lautner, Mark E. Meyerhoff, Steven P. Schwendeman
Journal of Controlled Release 2016 Volume 225() pp:133-139
Publication Date(Web):10 March 2016
DOI:10.1016/j.jconrel.2015.12.056
Nitric oxide (NO) is a fascinating and important endogenous free-radical gas with potent antimicrobial, vasodilating, smooth muscle relaxant, and growth factor stimulating effects. However, its wider biomedical applicability is hindered by its cumbersome administration, since NO is unstable especially in biological environments. In this work, to ultimately develop site-specific controlled release vehicles for NO, the NO donor S-nitroso-N-acetyl-D-penicillamine (SNAP) was encapsulated within poly(lactic-co-glycolic acid) 50:50 (PLGA) microspheres by using a solid-in-oil-in-water emulsion solvent evaporation method. The highest payload was 0.56(± 0.01) μmol SNAP/mg microspheres. The in vitro release kinetics of the donor were controlled by the bioerosion of the PLGA microspheres. By using an uncapped PLGA (Mw = 24,000–38,000) SNAP was slowly released for over 10 days, whereas by using the ester capped PLGA (Mw = 38,000–54,000) the release lasted for over 4 weeks. The presence of copper ions and/or ascorbate in solution was necessary to efficiently decompose the released NO donor and obtain sustained NO release. It was also demonstrated that light can be used to induce rapid NO release from the microspheres over several hours. SNAP exhibited excellent storage stability when encapsulated in the PLGA microspheres. These new microsphere formulations may be useful for site-specific administration and treatment of pathologies associated with dysfunction in endogenous NO production, e.g. treatment of diabetic wounds, or in diseases involving other biological functions of NO including vasodilation, antimicrobial, anticancer, and neurotransmission.
Co-reporter:Yaqi Wo, Elizabeth J. Brisbois, Robert H. Bartlett and Mark E. Meyerhoff
Biomaterials Science 2016 vol. 4(Issue 8) pp:1161-1183
Publication Date(Web):26 May 2016
DOI:10.1039/C6BM00271D
Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO's therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo applications of the two most promising types of NO donors studied thus far, N-diazeniumdiolates (NONOates) and S-nitrosothiols (RSNOs).
Co-reporter:Stephen A. Ferguson, Xuewei Wang and Mark E. Meyerhoff
Analytical Methods 2016 vol. 8(Issue 29) pp:5806-5811
Publication Date(Web):04 Jul 2016
DOI:10.1039/C6AY01748G
Polymeric quaternary ammonium salts (polyquaterniums) have found increasing use in industrial and cosmetic applications in recent years. More specifically, polyquaternium-10 (PQ-10) is routinely used in cosmetic applications as a conditioner in personal care product formulations. Herein, we demonstrate the use of potentiometric polyion-sensitive polymeric membrane-based electrodes to quantify PQ-10 levels. Mixtures containing both PQ-10 and sodium lauryl sulfate (SLS) are used as model samples to illustrate this new method. SLS is often present in cosmetic samples that contain PQ-10 (e.g., shampoos, etc.) and this surfactant species interferes with the polyion sensor detection chemistry. However, it is shown here that SLS can be readily separated from the PQ-10/SLS mixture by use of an anion-exchange resin and that the PQ-10 can then be titrated with dextran sulphate (DS). This titration is monitored by potentiometric polyanion sensors to provide equivalence points that are directly proportional to PQ-10 concentrations.
Co-reporter:Hang Ren, Joseph L. Bull, and Mark. E. Meyerhoff
ACS Biomaterials Science & Engineering 2016 Volume 2(Issue 9) pp:1483
Publication Date(Web):July 27, 2016
DOI:10.1021/acsbiomaterials.6b00215
Nitric oxide (NO) releasing polymers are promising in improving the biocompatibility of medical devices. Polyurethanes are commonly used to prepare/fabricate many devices (e.g., catheters); however, the transport properties of NO within different polyurethanes are less studied, creating a gap in the rational design of new NO releasing devices involving polyurethane materials. Herein, we study the diffusion and partitioning of NO in different biomedical polyurethanes via the time-lag method. The diffusion of NO is positively correlated with the PDMS content within the polyurethanes, which can be rationalized by effective media theory considering various microphase morphologies. Using catheters as a model device, the effect of these transport properties on the NO release profiles and the distribution around an asymmetric dual lumen catheter are simulated using finite element analysis and validated experimentally. This method can be readily applied in studying other NO release medical devices with different configurations.Keywords: distribution; finite element analysis; mass transport; medical devices; nitric oxide; polyurethanes
Co-reporter:Woong Hee Lee, Hang Ren, Jianfeng Wu, Ondrej Novak, Richard B. Brown, Chuanwu Xi, and Mark E. Meyerhoff
ACS Biomaterials Science & Engineering 2016 Volume 2(Issue 9) pp:1432
Publication Date(Web):July 25, 2016
DOI:10.1021/acsbiomaterials.6b00360
Herein, we report a novel design and the antimicrobial efficacy of a flexible nitric oxide (NO) releasing patch for potential wound healing applications. The compact sized polydimethylsiloxane (PDMS) planar patch generates NO via electrochemical reduction of nitrite ions mediated by a copper(II)-ligand catalyst using a portable power system and an internal gold coated stainless steel mesh working electrode. Patches are fabricated via soft lithography and 3-D printing. The devices can continuously release NO over 4 days and exhibit potent bactericidal effects on both Escherichia coli and Staphylococcus aureus. The device may provide an effective, safe, and less costly alternative for treating chronic wounds.Keywords: 3D printing; antimicrobial patch; electrochemical devices; nitric oxide release; portable planar NO generation
Co-reporter:Elizabeth J. Brisbois, Ryan P. Davis, Anna M. Jones, Terry C. Major, Robert H. Bartlett, Mark E. Meyerhoff and Hitesh Handa
Journal of Materials Chemistry A 2015 vol. 3(Issue 8) pp:1639-1645
Publication Date(Web):12 Jan 2015
DOI:10.1039/C4TB01839G
Thrombosis and infection are two common problems associated with blood-contacting medical devices such as catheters. Nitric oxide (NO) is known to be a potent antimicrobial agent as well as an inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5–4 × 10−10 mol cm−2 min−1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, NO-releasing catheters were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in the Elast-eon E2As polymer. The SNAP/E2As catheters release physiological levels of NO for up to 20 days, as measured by chemiluminescence. Furthermore, SNAP is stable in the E2As polymer, retaining 89% of the initial SNAP after ethylene oxide (EO) sterilization. The SNAP/E2As and E2As control catheters were implanted in sheep veins for 7 days to examine the effect on thrombosis and bacterial adhesion. The SNAP/E2As catheters reduced the thrombus area when compared to the control (1.56 ± 0.76 and 5.06 ± 1.44 cm2, respectively). A 90% reduction in bacterial adhesion was also observed for the SNAP/E2As catheters as compared to the controls. The results suggest that the SNAP/E2As polymer has the potential to improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other blood-contacting medical devices (e.g., vascular grafts, extracorporeal circuits).
Co-reporter:Xuewei Wang, Yu Qin and Mark E. Meyerhoff
Chemical Communications 2015 vol. 51(Issue 82) pp:15176-15179
Publication Date(Web):25 Aug 2015
DOI:10.1039/C5CC06770G
An ionophore-based ion-selective optode platform on paper is described for the first time with a sodium optode as the example. Cellulose paper is shown to be an excellent substrate for adsorption of the required chromoionophore, ionophore, and ion-exchanger species. These adsorbed components form a hydrophobic phase that enables heterogeneous optical ion sensing in the absence of any plasticizer or organic polymer phase.
Co-reporter:Hang Ren, Megan A. Coughlin, Terry C. Major, Salvatore Aiello, Alvaro Rojas Pena, Robert H. Bartlett, and Mark E. Meyerhoff
Analytical Chemistry 2015 Volume 87(Issue 16) pp:8067
Publication Date(Web):July 23, 2015
DOI:10.1021/acs.analchem.5b01590
A novel electrochemically controlled release method for nitric oxide (NO) (based on electrochemical reduction of nitrite ions) is combined with an amperometric oxygen sensor within a dual lumen catheter configuration for the continuous in vivo sensing of the partial pressure of oxygen (PO2) in blood. The on-demand electrochemical NO generation/release method is shown to be fully compatible with amperometric PO2 sensing. The performance of the sensors is evaluated in rabbit veins and pig arteries for 7 and 21 h, respectively. Overall, the NO releasing sensors measure both venous and arterial PO2 values more accurately with an average deviation of −2 ± 11% and good correlation (R2 = 0.97) with in vitro blood measurements, whereas the corresponding control sensors without NO release show an average deviation of −31 ± 28% and poor correlation (R2 = 0.43) at time points >4 h after implantation in veins and >6 h in arteries. The NO releasing sensors induce less thrombus formation on the catheter surface in both veins and arteries (p < 0.05). This electrochemical NO generation/release method could offer a new and attractive means to improve the biocompatibility and performance of implantable chemical sensors.
Co-reporter:Anant S. Balijepalli; Adam T. Comstock; Xuewei Wang; Gary C. Jensen; Marc B. Hershenson; Mark A. Zacharek; Umadevi S. Sajjan;Mark E. Meyerhoff
Molecular Pharmaceutics 2015 Volume 12(Issue 7) pp:2396-2405
Publication Date(Web):May 15, 2015
DOI:10.1021/acs.molpharmaceut.5b00110
Nitric oxide (NO) is a key immune defense agent that is produced from l-arginine in the airways by leukocytes and airway epithelial cells, primarily via inducible nitric oxide synthase (iNOS). Deficiencies in nasal NO levels have been associated with diseases such as primary ciliary dyskinesia and chronic rhinosinusitis. Herein, we demonstrate a proof-of-concept regarding a potential new therapeutic approach for such disorders. We show that arginine-rich low molecular weight peptides (LMWPs) derived from the FDA-approved protamine (obtained from salmon sperm) are effective at significantly raising NO production in both RAW 264.7 mouse macrophage and LA4 mouse epithelial cell lines. LMWP is produced using a stable, easily produced immobilized thermolysin gel column followed by size-exclusion purification. Monomeric l-arginine induces concentration-dependent increases in NO production in stimulated RAW 264.7 and LA4 cells, as measured by stable nitrite in the cell media. In stimulated RAW 264.7 cells, LMWP significantly increases iNOS expression and total NO production 12–24 h post-treatment compared to cells given equivalent levels of monomeric l-arginine. For stimulated LA4 cells, LMWPs are effective in significantly increasing NO production compared to equivalent l-arginine monomer concentrations over 24 h but do not substantially enhance iNOS expression. The use of the arginase inhibitor S-boronoethyl-l-cysteine in combination with LMWPs results in even higher NO production by stimulated RAW 264.7 cells and LA4 cells. Increases in NO due to LMWPs, compared to l-arginine, occur only after 4 h, which may be due to iNOS elevation rather than increased substrate availability.
Co-reporter:Alexander K. Wolf, Yu Qin, Terry C. Major, Mark E. Meyerhoff
Chinese Chemical Letters 2015 Volume 26(Issue 4) pp:464-468
Publication Date(Web):April 2015
DOI:10.1016/j.cclet.2015.03.002
In this work, nitric oxide (NO) release coatings designed for intravenous amperometric glucose sensors are optimized through the use of a polylactic acid (PLA) layer doped with a lipophilic diazeniumdiolated species that releases NO through a proton-driven mechanism. An Elast-Eon E2As polyurethane coating is used to both moderate NO release from the sensor surface and increase the sensor's linear detection range toward glucose. These sensors were evaluated for thromboresistance and in vivo glucose performance through implantation in rabbit veins. By maintaining NO flux on a similar scale to endogenous endothelial cells, implanted glucose sensors exhibited reduced surface clot formation which enables more accurate quantitative glucose measurements continuously. An in vivo time trace of implanted venous sensors demonstrated glucose values that correlated well with the discrete measurements of blood samples on a benchtop point-of-care sensor-based instrument. The raw measured currents from the implanted glucose sensors over 7 h time periods were converted to glucose concentration through use of both a one-point in vivo calibration and a calibration curve obtained in vitro within a bovine serum solution. Control sensors, assembled without NO release functionality, exhibit distinctive surface clotting over the 7 h in vivo implantation period.In this work, intravenous amperometric glucose sensors demonstrate improved in vivo performance by utilizing nitric oxide (NO) release coatings and an Elast-Eon E2As polyurethane top coat. An in vivo time trace obtained with sensors implanted within rabbit jugular veins demonstrated glucose values that correlated well with the discrete measurements of blood samples on a benchtop point-of-care sensor-based instrument.
Co-reporter:Hang Ren, Alessandro Colletta, Dipankar Koley, Jianfeng Wu, Chuanwu Xi, Terry C. Major, Robert H. Bartlett, Mark E. Meyerhoff
Bioelectrochemistry 2015 Volume 104() pp:10-16
Publication Date(Web):August 2015
DOI:10.1016/j.bioelechem.2014.12.003
•Electrochemical NO release from a nitrite reservoir is demonstrated in a catheter.•NO release from the catheter surface can be turned “on” and “off”.•These catheters reduce surface thrombus in vivo by up to 67%.•The NO release catheters reduce S. aureus and E. coli biofilm formation by > 99.9%.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 Staphylococcus 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 Escherichia 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.
Co-reporter:Hitesh Handa, Terry C. Major, Elizabeth J. Brisbois, Kagya A. Amoako, Mark E. Meyerhoff and Robert H. Bartlett
Journal of Materials Chemistry A 2014 vol. 2(Issue 8) pp:1059-1067
Publication Date(Web):07 Jan 2014
DOI:10.1039/C3TB21771J
Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation. Nitric oxide releasing (NOrel) materials can be prepared by doping an NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2), within a polymer coating. The inherent hemocompatibility properties of the base polymer can also influence the efficiency of such NO release coatings. In this study, four biomedical grade polymers were evaluated in a 4 h rabbit model of thrombogenicity for their effects on extracorporeal circuit thrombus formation and circulating platelet count. At the end of 4 h, Elast-Eon E2As was found to preserve 58% of baseline platelets versus 48, 40, and 47% for PVC/DOS, Tecophilic SP-60D-60, and Tecoflex SG80A, respectively. Elast-Eon also had significantly lower clot area of 5.2 cm2 compared to 6.7, 6.1, and 6.9 cm2 for PVC/DOS, SP-60D-60, and SG80A, respectively. Based on the results obtained for the base polymer comparison study, DBHD/N2O2-doped E2As was evaluated in short-term (4 h) rabbit studies to observe the NO effects on prevention of clotting and preservation of platelet function. Platelet preservation for this optimal NO release formulation was 97% of baseline after 4 h, and clot area was 0.9 cm2 compared to 5.2 cm2 for controls, demonstrating that combining E2As with NO release provides a truly advanced hemocompatible polymer coating for extracorporeal circuits and potentially other blood contacting applications.
Co-reporter:Hang Ren, Jianfeng Wu, Chuanwu Xi, Nicolai Lehnert, Terry Major, Robert H. Bartlett, and Mark E. Meyerhoff
ACS Applied Materials & Interfaces 2014 Volume 6(Issue 6) pp:3779
Publication Date(Web):March 10, 2014
DOI:10.1021/am406066a
A controllable and inexpensive electrochemical nitric oxide (NO) release system is demonstrated to improve hemocompatibility and reduce bacterial biofilm formation on biomedical devices. Nitric oxide is produced from the electrochemical reduction of nitrite using a copper(II)-tri(2-pyridylmethyl)amine (Cu(II)TPMA) complex as a mediator, and the temporal profile of NO release can be modulated readily by applying different cathodic potentials. Single lumen and dual lumen silicone rubber catheters are employed as initial model biomedical devices incorporating this novel NO release approach. The modified catheters can release a steady, physiologically-relevant flux of NO for more than 7 days. Both single and dual lumen catheters with continuous NO release exhibit greatly reduced thrombus formation on their surfaces after short-term 7-h intravascular placement in rabbit veins (p < 0.02, n = 6). Three day in vitro antimicrobial experiments, in which the catheters are “turned on” for only 3 h of NO release each day, exhibit more than a 100-fold decrease in the amount of surface attached live bacteria (n = 5). These results suggest that this electrochemical NO generation system could provide a robust and highly effective new approach to improving the thromboresistance and antimicrobial properties of intravascular catheters and potentially other biomedical devices.Keywords: anti-biofilm; antimicrobial catheters; electrochemical reduction of nitrite; modulated NO release; nitric oxide; thromboresistant catheters;
Co-reporter:Kyoung Ha Cha, Gary C. Jensen, Anant S. Balijepalli, Bruce E. Cohan, and Mark E. Meyerhoff
Analytical Chemistry 2014 Volume 86(Issue 3) pp:1902
Publication Date(Web):January 15, 2014
DOI:10.1021/ac4040168
Tear glucose measurements have been suggested as a potential alternative to blood glucose monitoring for diabetic patients. While previous work has reported that there is a correlation between blood and tear glucose levels in humans, this link has not been thoroughly established and additional clinical studies are needed. Herein, we evaluate the potential of using commercial blood glucose test strips to measure glucose in tears. Of several blood glucose strips evaluated, only one brand exhibits the low detection limit required for quantitating glucose in tears. Calibration of these strips in the range of 0–100 μM glucose with an applied potential of 150 mV to the working electrode yields a sensitivity of 0.127 nA/μM and a limit of quantitation (LOQ) of 9 μM. The strips also exhibit ≤13% error (n = 3) for 25, 50, and 75 μM glucose in the presence of 10 μM acetaminophen, 100 μM ascorbic acid, and 100 μM uric acid. Measurements of glucose in tears from nine normal (nondiabetic) fasting human subjects using strips yielded glucose values within the range of 5–148 μM (mean = 47 μM, median = 43 μM), similar to those for human tears reported by others with more complex LC–MS methods. The glucometer strip method could facilitate more clinical studies to determine whether tear glucose and blood glucose levels sufficiently correlate for application to routine measurements in tears to supplement blood glucose testing. This would be especially helpful for children, adolescents, other Type 1 diabetics, and also for Type 2 diabetics who require treatment with insulin and cannot tolerate multiple finger sticks per day.
Co-reporter:Andrea K. Bell-Vlasov, Joanna Zajda, Ayman Eldourghamy, Elzbieta Malinowska, and Mark E. Meyerhoff
Analytical Chemistry 2014 Volume 86(Issue 8) pp:4041
Publication Date(Web):March 20, 2014
DOI:10.1021/ac500567g
A method for the detection of polyions using fully reversible polyion selective polymeric membrane type pulstrodes as detectors in a flow-injection analysis (FIA) system is examined. The detection electrode consists of a plasticized polymeric membrane doped with 10 wt % of tridodecylmethylammonium-dinonylnaphthalene sulfonate (TDMA/DNNS) ion-exchanger salt. The pulse sequence used involves a short (1 s) galvanostatic pulse, an open-circuit pulse (0.5 s) during which the EMF of the cell is measured, and a longer (15 s) potentiostatic pulse to return the membrane to its original chemical composition. It is shown that total pulse sequence times can be optimized to yield reproducible real-time detection of injected samples of protamine and heparin at up to 20 samples/h. Further, it is shown that the same membrane detector can be employed for FIA detection of both polycations at levels ≥10 μg/mL and polyanions at levels of ≥40 μg/mL by changing the direction of the galvanostatic pulse. The methodology described may also be applicable in the detection of polyionic species at low levels in other flowing configurations, such as in liquid chromatography and capillary electrophoresis.
Co-reporter:Elizabeth J. Brisbois, Jill Bayliss, Jianfeng Wu, Terry C. Major, Chuanwu Xi, Stewart C. Wang, Robert H. Bartlett, Hitesh Handa, Mark E. Meyerhoff
Acta Biomaterialia 2014 Volume 10(Issue 10) pp:4136-4142
Publication Date(Web):October 2014
DOI:10.1016/j.actbio.2014.06.032
Abstract
Nitric oxide (NO) has many biological roles (e.g. antimicrobial agent, promoter of angiogenesis, prevention of platelet activation) that make NO releasing materials desirable for a variety of biomedical applications. Localized NO release can be achieved from biomedical grade polymers doped with diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) and poly(lactic-co-glycolic acid) (PLGA). In this study, the optimization of this chemistry to create film/patches that can be used to decrease microbial infection at wound sites is examined. Two polyurethanes with different water uptakes (Tecoflex SG-80A (6.2 ± 0.7 wt.%) and Tecophilic SP-60D-20 (22.5 ± 1.1 wt.%)) were doped with 25 wt.% DBHD/N2O2 and 10 wt.% of PLGA with various hydrolysis rates. Films prepared with the polymer that has the higher water uptake (SP-60D-20) were found to have higher NO release and for a longer duration than the polyurethane with the lower water uptake (SG-80A). The more hydrophilic polymer enhances the hydrolysis rate of the PLGA additive, thereby providing a more acidic environment that increases the rate of NO release from the NO donor. The optimal NO releasing and control SG-80A patches were then applied to scald burn wounds that were infected with Acinetobacter baumannii. The NO released from these patches applied to the wounds is shown to significantly reduce the A. baumannii infection after 24 h (∼4 log reduction). The NO release patches are also able to reduce the level of transforming growth factor-β in comparison to controls, which can enhance re-epithelialization, decrease scarring and reduce migration of bacteria. The combined DBHD/N2O2 and PLGA-doped polymer patches, which could be replaced periodically throughout the wound healing process, demonstrate the potential to reduce risk of bacterial infection and promote the overall wound healing process.
Co-reporter:Si Yang, Yaqi Wo, Mark E. Meyerhoff
Analytica Chimica Acta 2014 Volume 843() pp:89-96
Publication Date(Web):16 September 2014
DOI:10.1016/j.aca.2014.06.041
•We examine cobalt(III) corroles and rhodium(III) porphyrins as ionophores in polymeric films for optical sensors to detect nitrite.•Different types of proton chromoionophores are evaluated to optimize nitrite response.•Selectivity over lipophilic anions such as perchlorate and thiocyanate is observed.•Both ionophores yield optical sensors that are fully reversible.•The cobalt(III) corrole based sensor is employed to determine nitric oxide emission rates from NO donor doped polymers with good accuracy.Cobalt(III) 5,10,15-tris(4-tert-butylphenyl) corrole with a triphenylphosphine axial ligand and rhodium(III) 5,10,15,20-tetra(p-tert-butylphenyl) porphyrin are incorporated into plasticized poly(vinyl chloride) films to fabricate nitrite-selective bulk optodes via absorbance measurements. The resulting films yield sensitive, fast and fully reversible response toward nitrite with significantly enhanced nitrite selectivity over other anions including lipophilic anions such as thiocyanate and perchlorate. The selectivity patterns differ greatly from the Hofmeister series based on anion lipophilicity and are consistent with selectivity obtained with potentiometric sensors based on the same ionophores. The optical nitrite sensors are shown to be useful for detecting rates of emission of nitric oxide (NO) from NO releasing polymers containing S-nitroso-N-acetyl-DL-penicillamine.
Co-reporter:Dakota J. Suchyta, Hitesh Handa, and Mark E. Meyerhoff
Molecular Pharmaceutics 2014 Volume 11(Issue 2) pp:645-650
Publication Date(Web):January 14, 2014
DOI:10.1021/mp400501c
Heparin is a widely used anticoagulant due to its ability to inhibit key components in the coagulation cascade such as Factor Xa and thrombin (Factor IIa). Its potential to preferentially bind to antithrombin (ATIII) results in a conformational change and activation that leads to the prevention of fibrin formation from fibrinogen and ultimately obstructs a hemostatic plug from forming. Nitric oxide (NO) exhibits potent antiplatelet activity attributed to its capacity to increase the amount of cyclic guanosine monophosphate (cGMP) within platelets, which decreases the Ca2+ concentration required for platelet activation. Currently there is no single agent that combines the functions of both antiplatelet and anticoagulant (anti-Xa and anti-IIa) activities to effectively block both the extrinsic and the intrinsic coagulation pathways. The research reported herein demonstrates the ability to combine the physiological capabilities of both heparin and NO into one functional compound via use of a spermine derivative of heparin, thus enabling formation of a novel diazeniumdiolate (NONOate). The heparin–spermine NONOate has a half-life of 85 min at 25 °C (pH 7.4). The heparin backbone of the conjugate maintains its anticoagulant activity as demonstrated via an anti-Xa assay, providing an anticoagulant conversion of 3.6 μg/mL of the heparin–spermine–NONO conjugate being equivalent to 2.5 μg/mL (0.50 IU/mL) of underivatized heparin in terms of anti-Xa activity. Using standard platelet aggregometry, it is shown that the functionality of the NO release portion of the heparin conjugate prevents (nearly 100%) platelet aggregation in the presence of adenosine diphosphate (ADP, platelet agonist).Keywords: combined antiplatelet/anticoagulant agent; diazeniumdiolated heparin; nitric oxide release;
Co-reporter:Hitesh Handa, Elizabeth J. Brisbois, Terry C. Major, Lahdan Refahiyat, Kagya A. Amoako, Gail M. Annich, Robert H. Bartlett and Mark E. Meyerhoff
Journal of Materials Chemistry A 2013 vol. 1(Issue 29) pp:3578-3587
Publication Date(Web):03 Jun 2013
DOI:10.1039/C3TB20277A
Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7 and 18 × 10−10 mol cm−2 min−1 NO for 14 days at 37 °C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing lipophilic diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating.
Co-reporter:Gary C. Jensen, Zheng Zheng, and Mark E. Meyerhoff
Analytical Chemistry 2013 Volume 85(Issue 21) pp:10057
Publication Date(Web):September 25, 2013
DOI:10.1021/ac402633t
An improved planar amperometric nitric oxide (NO) sensor with enhanced selectivity over carbon monoxide (CO), which represents a volatile interfering species for NO sensors that has been largely overlooked until recently, is described. Formation of an oxide film on the inner platinum working electrode via anodic polarization using an inner alkaline electrolyte solution provides the basis for improved selectivity. Cyclic voltammetry reveals that formation of an oxidized Pt film inhibits adsorption of CO to the electrode surface, which is a necessary initial step in the electrocatalytic oxidation of CO on Pt. Previous NO gas sensors that employ internal electrolyte solutions have been assembled using acidic internal solutions that inhibit the formation of a dense platinum oxide film on the working electrode surface. It is demonstrated herein that increasing the internal electrolyte pH promotes oxidized platinum film formation, resulting in improved selectivity over CO. Selectivity coefficients (log KNO,j) for sensors assembled with internal solutions at various pH values range from −0.08 at pH 2.0 to −2.06 at pH 11.7, with average NO sensitivities of 1.24 nA/μM and a limit of detection (LOD) of <1 nM.
Co-reporter:Bo Peng, Jing Lu, Anant S. Balijepalli, Terry C. Major, Bruce E. Cohan, Mark E. Meyerhoff
Biosensors and Bioelectronics 2013 Volume 49() pp:204-209
Publication Date(Web):15 November 2013
DOI:10.1016/j.bios.2013.05.014
•Miniature electrochemical biosensors are used to measure glucose levels in rabbit tear fluid.•The coulometric sensor has a lower detection limit and faster response at elevated temperature.•A positive correlation between the tear and blood glucose levels is found in the rabbit model.•Electrochemical tear glucose sensors may provide an added tool for blood glucose monitoring.Miniature enzyme-based amperometric and coulometric glucose sensors were fabricated and applied to measure tear glucose concentrations in anesthetized rabbits. Without perturbing the eyeball, 3 µL of tear fluid was sampled from the marginal conjunctiva under the lower eyelid of anesthetized rabbits at various time points via a microliter glass capillary tube, and the miniature sensors were then inserted into the volume of collected tear fluids within the capillaries for detection. Intravenous bolus doses of insulin were administrated to the rabbits to lower the elevated blood glucose concentrations caused by anesthesia over the 7 h test periods. A significant correlation was found between tear and blood glucose levels for multiple rabbits, suggesting that electrochemical sensor-based tear glucose measurements may be a potential supplementary method for point-of-care glucose monitoring.
Co-reporter:Elizabeth J. Brisbois, Hitesh Handa, Terry C. Major, Robert H. Bartlett, Mark E. Meyerhoff
Biomaterials 2013 34(28) pp: 6957-6966
Publication Date(Web):
DOI:10.1016/j.biomaterials.2013.05.063
Co-reporter:Kun Liu and Mark E. Meyerhoff
Journal of Materials Chemistry A 2012 vol. 22(Issue 36) pp:18784-18787
Publication Date(Web):03 Aug 2012
DOI:10.1039/C2JM32726K
A new, stable and highly efficient Cu2+–cyclen–polyurethane material is described and shown to exhibit an improved performance compared to that of prior materials for the catalytic decomposition of S-nitrosothiols to physiologically active nitric oxide.
Co-reporter:Lajos Höfler, Dipankar Koley, Jianfeng Wu, Chuanwu Xi and Mark E. Meyerhoff
RSC Advances 2012 vol. 2(Issue 17) pp:6765-6767
Publication Date(Web):12 Jul 2012
DOI:10.1039/C2RA20853A
Herein, we report a new approach to electromodulate the release of NO at physiological levels through polymeric materials from a stable nitrite electrolyte reservoir, with potential application in controlling biofilm formation and clotting on intravascular catheters. The NO flux can be turned ‘on’ and ‘off’ electrochemically, on demand.
Co-reporter:Wenyi Cai, Jianfeng Wu, Chuanwu Xi, Mark E. Meyerhoff
Biomaterials 2012 33(32) pp: 7933-7944
Publication Date(Web):
DOI:10.1016/j.biomaterials.2012.07.027
Co-reporter:Qinyi Yan, Bo Peng, Gang Su, Bruce E. Cohan, Terry C. Major, and Mark E. Meyerhoff
Analytical Chemistry 2011 Volume 83(Issue 21) pp:8341
Publication Date(Web):September 30, 2011
DOI:10.1021/ac201700c
An amperometric needle-type electrochemical glucose sensor intended for tear glucose measurements is described and employed in conjunction with a 0.84 mm i.d. capillary tube to collect microliter volumes of tear fluid. The sensor is based on immobilizing glucose oxidase on a 0.25 mm o.d. platinum/iridium (Pt/Ir) wire and anodically detecting the liberated hydrogen peroxide from the enzymatic reaction. Inner layers of Nafion and an electropolymerized film of 1,3-diaminobenzene/resorcinol greatly enhance the selectivity for glucose over potential interferences in tear fluid, including ascorbic acid and uric acid. Further, the new sensor is optimized to achieve very low detection limits of 1.5 ± 0.4 μM of glucose (S/N = 3) that is required to monitor glucose levels in tear fluid with a glucose sensitivity of 0.032 ± 0.02 nA/μM (n = 6). Only 4–5 μL of tear fluid in the capillary tube is required when the needle sensor is inserted into the capillary. The glucose sensor was employed to measure tear glucose levels in anesthetized rabbits over an 8 h period while also measuring the blood glucose values. A strong correlation between tear and blood glucose levels was found, suggesting that measurement of tear glucose is a potential noninvasive substitute for blood glucose measurements, and the new sensor configuration could aid in conducting further research in this direction.
Co-reporter:Kebede L. Gemene, Mark E. Meyerhoff
Analytical Biochemistry 2011 Volume 416(Issue 1) pp:67-73
Publication Date(Web):1 September 2011
DOI:10.1016/j.ab.2011.04.036
A novel electrochemical method, termed flash chronopotentiometry (FCP), is used to develop a rapid and sensitive method for detecting protease activities. In this method, an appropriate current pulse is applied across a polycation-selective polymer membrane to induce a strong flux of the polycationic peptides from the sample phase into the organic membrane of the electrode. During this current pulse, the cell potential (EMF) is monitored continuously, and is a function of the polypeptide concentration. The imposed current causes a local depletion of the polypeptide at the sample/membrane interface, which yields a drastic potential change in the observed chronopotentiogram at a characteristic time, called the transition time (τ). For a given magnitude of current, the square root of τ is directly proportional to the concentration of the polypeptide. Proteases cleave polypeptides into smaller fragments that are not favorably extracted into the membrane of the sensor. Therefore, a decrease in the transition time is observed during the proteolysis process. The degree of change in the transition time can be correlated to protease activity. To demonstrate this approach, the activities of trypsin and α-chymotrypsin are detected using protamine and synthetic polycationic oligopeptides that possess specific cleavage sites that are recognized by these proteases.
Co-reporter:Laura B. Zimmerman, Brittany V. Worley, Edmund F. Palermo, Jeffrey R. Brender, Kyung-Dall Lee, Kenichi Kuroda, Ayyalusamy Ramamoorthy, Mark E. Meyerhoff
Analytical Biochemistry 2011 Volume 411(Issue 2) pp:194-199
Publication Date(Web):15 April 2011
DOI:10.1016/j.ab.2011.01.009
A simple homogeneous assay for the detection of membrane permeabilization by antimicrobial peptides and synthetic copolymers is described. Liposomes encapsulating pyrroloquinoline quinone (PQQ), the prosthetic group of the apoenzyme glucose dehydrogenase (GDH), are used to detect membrane permeabilization by the antimicrobial peptides MSI-594 and MSI-78 as well as various synthetic antimicrobial copolymers in an optical microwell assay. PQQ-loaded liposomes and the peptide or copolymer are added to wells of a 96-well microtiter plate. If the integrity of the liposome is compromised, the PQQ encapsulated in the liposomes is released and available for activating the apoenzyme. The release of PQQ catalyzes a color change in the presence of apo-GDH, glucose, and the redox dye 1,6-dichlorophenol indophenol (DCPIP) that can be evaluated through a visual color change. For more quantitative measurements, the absorbance change over a 30 min period was measured. The absorbance change is related to the activity and concentration for a given antimicrobial agent. Furthermore, by varying liposome compositions to include cholesterol, the potential toxicity of the peptide or polymer toward mammalian cells can be readily evaluated. The assay is simple and sensitive and will be useful for analyzing the membrane permeation/disruption properties of a host of antimicrobial peptides and synthetic polymers.
Co-reporter:Wenyi Cai, Jianfeng Wu, Chuanwu Xi, Arthur J. Ashe III, Mark E. Meyerhoff
Biomaterials 2011 32(31) pp: 7774-7784
Publication Date(Web):
DOI:10.1016/j.biomaterials.2011.06.075
Co-reporter:Qinyi Yan, Terry C. Major, Robert H. Bartlett, Mark E. Meyerhoff
Biosensors and Bioelectronics 2011 Volume 26(Issue 11) pp:4276-4282
Publication Date(Web):15 July 2011
DOI:10.1016/j.bios.2011.04.026
Intravenous amperometric needle-type enzymatic glucose/lactate sensors intended for continuous monitoring are prepared with a novel nitric oxide (NO) releasing layer to improve device hemocompatibility. To create an underlying NO release coating, the sensors with immobilized enzymes (either glucose oxidase or lactate oxidase) are prepared with a thin layer of poly(lactide-co-glycolide) (PLGA) loaded with lipophilic diazeniumdiolate species that slowly release NO via a proton driven reaction. An outer thin layer (ca. 30 μm) of PurSil (polyurethane/dimethylsiloxane copolymer) limits the flux of glucose and lactate to the inner layer of enzyme, to provide the desired linear amperometric response. A 30 μm coating of PLGA containing 33 wt% of the appropriate NO donor (N-diazeniumdiolated dibutylhexanediamine, DBHD/N2O2) can release NO at a physiologically relevant rate >1 × 10−10 mol min−1 cm−2 for at least 7 days without influencing the analytical performance of the glucose/lactate sensors. In vitro, the sensors exhibit relatively stable amperometric response over a one-week period with high selectivity over interferences (e.g., ascorbic acid) required for blood monitoring applications. Glucose sensors implanted in the veins of rabbits for 8 h exhibit significantly enhanced hemocompatibility for the NO release sensors vs. corresponding controls (without NO release in same animals), with greatly reduced thrombus formation on their surfaces. Further, the analytical performance of the NO release glucose sensors are superior to controls placed in the veins of the same animals, with a greater accuracy in measuring blood glucose levels as evaluated using a Clarke error grid type analysis.
Co-reporter:Melissa M. Reynolds, Joseph E. Saavedra, Brett M. Showalter, Carlos A. Valdez, Anna P. Shanklin, Bong K. Oh, Larry K. Keefer and Mark E. Meyerhoff
Journal of Materials Chemistry A 2010 vol. 20(Issue 15) pp:3107-3114
Publication Date(Web):05 Mar 2010
DOI:10.1039/C000152J
Nitric oxide (NO) has been shown to exhibit significant anti-platelet activity and its release from polymer matrices has been already utilized to increase the biocompatibility of various blood-contacting devices. Herein, the details of a new synthetic approach for preparing NO-releasing diazeniumdiolated polyurethanes (PUs) are described. The method's utility is demonstrated by the incorporation of methoxymethyl- or sugar-protected pre-formed diazeniumdiolate moieties directly into chain extender diols which are then incorporated into the polyurethane backbone. This approach provides the ability to control the number of diazeniumdiolate groups incorporated into the polymer backbone, and hence the surface flux of NO that can ultimately be liberated from polymeric films prepared from the new PU materials. The method provides a means of covalently attaching diazeniumdiolate groups to polyurethanes in a form that resists dissociation of NO during processing but can be activated for spontaneous NO release via hydrolysis of the carbohydrate or methoxymethyl moieties under basic and acidic conditions, respectively.
Co-reporter:Kebede L. Gemene and Mark E. Meyerhoff
Analytical Chemistry 2010 Volume 82(Issue 5) pp:1612
Publication Date(Web):February 1, 2010
DOI:10.1021/ac902836e
The first fully reversible polymeric membrane-based sensor for the anticoagulant heparin and other polyanions using a pulsed chronopotentiometry (pulstrode) measurement mode is reported. Polymeric membranes containing a lipophilic inert salt of the form R+R− (where R+ and R− are tridodecylmethylammonium (TDMA+) and dinonylnaphthalene sulfonate (DNNS−), respectively) are used to suppress unwanted spontaneous ion extractions under zero-current equilibrium conditions. An anodic galvanostatic current pulse applied across the membrane perturbs the equilibrium lipophilic ion distribution within the membrane phase in such a way that anions/polyanions are extracted into the membrane from the sample. The membrane is then subjected to an open-circuit zero current state for a short period, and finally a 0 V vs reference electrode potentiostatic pulse is applied to restore the membrane to its initial full equilibrium condition. Potentials are sampled as average values during the last 10% of the 0.5 s open circuit phase of the measurement cycle. Fully reversible and reproducible electromotive force (emf) responses are observed for heparin, pentosan polysulfate (PPS), chondroitin sulfate (CS), and oversulfated chondroitin sulfate (OSCS), with the magnitude of the potentiometric response proportional to charge density of the polyanions. The sensor provides an emf response related to heparin concentrations in the range of 1−20 U/mL. The responses to variations in heparin levels and toward other polyanions of the pulstrode configuration are analogous to the already established single-use, nonreversible potentiometric polyion sensors based on membranes doped only with the lipophilic anion exchanger TDMA+.
Co-reporter:Wansik Cha, Yi-Chung Tung, Mark E. Meyerhoff and Shuichi Takayama
Analytical Chemistry 2010 Volume 82(Issue 8) pp:3300
Publication Date(Web):March 23, 2010
DOI:10.1021/ac100085w
This article describes a thin amperometric nitric oxide (NO) sensor that can be microchannel embedded to enable direct real-time detection of NO produced by cells cultured within the microdevice. A key for achieving the thin (∼1 mm) planar sensor configuration required for sensor-channel integration is the use of gold/indium−tin oxide patterned electrode directly on a porous polymer membrane (pAu/ITO) as the base working electrode. The electrochemically deposited Au−hexacyanoferrate layer on pAu/ITO is used to catalyze NO oxidation to nitrite at lower applied potentials (0.65−0.75 V vs Ag/AgCl) and stabilize current output. Furthermore, use of a gas-permeable membrane to separate internal sensor compartments from the sample phase imparts excellent NO selectivity over common interfering agents (e.g., nitrite, ascorbate, ammonia, etc.) present in culture media and biological fluids. The optimized sensor design reversibly detects NO down to the ∼1 nM level in stirred buffer and <10 nM in flowing buffer when integrated within a polymeric microfluidic device. We demonstrate utility of the channel-embedded sensor by monitoring NO generation from macrophages cultured within non-gas-permeable microchannels, as they are stimulated with endotoxin.
Co-reporter:Laura B. Zimmerman, Kyung-Dall Lee, Mark E. Meyerhoff
Analytical Biochemistry 2010 Volume 401(Issue 2) pp:182-187
Publication Date(Web):15 June 2010
DOI:10.1016/j.ab.2010.02.041
The preparation of DNA-tagged liposomes containing an encapsulated prosthetic group tracer, pyrroloquinoline quinone (PQQ), and their application to the development of a sandwich-type hybridization assay for the visual detection of single-stranded DNA are described. Capture DNA is conjugated to the surface of microtiter plate wells through a biotin–streptavidin interaction. Target DNA is incubated with the plate in high salt concentrations. The reporter DNA-tagged liposomes encapsulating PQQ, the prosthetic group of the apo-enzyme glucose dehydrogenase (GDH), are used as the label to probe for bound target DNA. After washing away unbound liposomes and subsequent lysis of the bound fraction by surfactant, PQQ is released and available to activate the apo-enzyme. In the presence of glucose and a redox dye, 2,6-dichlorophenol indophenol (DCPIP), the dye is reduced to yield an optical color change from blue to colorless. This transition is observed visually or spectrophotometrically. The degree of optical change is proportional to the amount of PQQ present, which directly relates to the number of liposomes and, thus, the total amount of target DNA. An arbitrary target DNA sequence is used as a model system, and a limit of detection of 62 fmol is achieved.
Co-reporter:Dongxuan Shen and Mark E. Meyerhoff
Analytical Chemistry 2009 Volume 81(Issue 4) pp:1564
Publication Date(Web):January 22, 2009
DOI:10.1021/ac8023153
The preparation and analytical characteristics of novel prosthetic group loaded polymeric nanospheres for use in high-sensitivity bioaffinity assays is reported. Pyrroloquinoline quinone (PQQ), a prosthetic group for apoglucose dehydrogenase (apo-GDH), is loaded into poly(methyl methacrylate) (PMMA) nanospheres in the presence of methanol. PQQ released from the nanospheres in the presence of 40% acetonitrile is capable of reconstituting apo-GDH and triggers the enzymatic reaction with excess glucose. The two electrons generated are transferred from a reduced PQQ to a redox dye reagent, e.g., 2,6-dichloroindolphenol (DCPIP). The decrease in absorbance of DCPIP is observed visually or spectrophotometrically to assess the number of particles present. As initial model systems, this concept is applied to develop a microtiter plate assay to detect biotin (as a model for low molecular weight species) and C-reactive protein (CRP). For the CRP assay, neutravidin-coated PQQ-doped PMMA nanospheres are used to bind with a biotinylated reporter antibody directed toward CRP. Detection limits to CRP at subnanogram per milliliter levels are demonstrated. The advantage of this type of assay is that excess apoenzyme can be added, with detection capability dependent on the number of encapsulated PQQ species that can be readily released from the surface-bound nanospheres (ca. 20 000 PQQ molecules/PMMA particle).
Co-reporter:Mariusz Pietrzak and Mark E. Meyerhoff
Analytical Chemistry 2009 Volume 81(Issue 9) pp:3637
Publication Date(Web):April 2, 2009
DOI:10.1021/ac900092f
Several porphyrin and salophen complexes with Rh(III) are examined as ionophores to prepare nitrite selective polymeric membrane electrodes. All ionophores tested exhibit preferred selectivity toward nitrite anion. Enhanced potentiometric nitrite selectivity is observed in the presence of either lipophilic anionic as well as cationic sites within the membranes, suggesting that the ionophores can function via either a charged or a neutral carrier response mechanism. Among a range of complexes and membrane formulations examined, optimal nitrite selectivity and reversible response down to 5 × 10−6 M is achieved using Rh(III)-tetra(t-butylphenylporphyrin) as the ionophore in the presence of lipophilic cationic sites in plasticized poly(vinyl chloride) membrane. Response times are substantially longer than typical membrane electrodes apparently because of a slow nitrite ligation reaction with Rh(III); however, a significant improvement in dynamic EMF response can be realized by optimizing the membrane formulation and increasing the temperature. The selectivity observed with these membranes is greater than the best nitrite selective electrodes reported to date in the literature based on lipophilic Co(III)-corrin complexes, allowing the new nitrite electrodes to be utilized to determine the level of nitrite in meats with good correlation to the colorimetric Griess assay method.
Co-reporter:Mariusz Pietrzak and Mark E. Meyerhoff
Analytical Chemistry 2009 Volume 81(Issue 14) pp:5961
Publication Date(Web):June 12, 2009
DOI:10.1021/ac900776d
Recent studies suggest that the measurement of intracellular potassium concentrations in red blood cells (RBC-K) can be a marker for assessing the risk, development, and treatment of hypertension. In this work, the combined use of miniature potassium- and sodium-selective membrane electrodes is evaluated as a simple means to determine RBC-K. The proposed method requires two separate sets of electrode measurements: (i) potassium and sodium concentrations in the plasma phase of an unmeasured volume of a whole blood sample, and (ii) determination of potassium and sodium concentrations in the same sample of blood after complete hemolysis by ultrasonic disruption of the RBC membranes. The dilution of sodium concentration after hemolysis can be used to determine hematocrit (Hct) (volume of red cells per unit volume of blood) of the blood. The concentration of potassium within the red blood cells (RBCs) is then calculated using the measured change in potassium levels before and after RBCs lysis and the hematocrit level determined from the sodium electrode measurements and/or a conventional centrifugation method. Good correlation for RBC-K between the proposed method and traditional flame photometry is observed for animal blood samples that possess the range of potassium levels found within human RBCs (80−120 mM). However, when potassium is much lower than that found in human RBCs (known to occur for certain animal species), the Hct measured by the sodium electrode method is falsely low, compared to traditional spun hematocrit values, because of an increased level of sodium within the RBCs, necessitating use of spun Hct levels to assess RBC-K accurately. It is envisioned that this new approach could be further miniaturized into a single-use disposable cartridge type electrode system that would enable rapid point-of-care screening of RBC-K levels in human subjects.
Co-reporter:Wansik Cha, Meredith R. Anderson, Fenghua Zhang, Mark E. Meyerhoff
Biosensors and Bioelectronics 2009 Volume 24(Issue 8) pp:2441-2446
Publication Date(Web):15 April 2009
DOI:10.1016/j.bios.2008.12.022
A new S-nitrosothiol (RSNO) detection strategy based on an electrochemical sensor is described for rapidly estimating levels of total RSNOs in blood and other biological samples. The sensor employs a cellulose dialysis membrane covalently modified with an organoselenium catalyst that converts RSNOs to NO at the distal tip of an amperometric NO sensor. The sensor is characterized by very low detection limits (<20 nM), good long-term stability, and can be employed for the rapid detection of total low-molecular-weight (LMW) RSNO levels in whole blood samples using a simple standard addition method. A strategy for detecting macromolecular RSNOs is also demonstrated via use of a transnitrosation reaction with added LMW thiols allowing the estimation of total RSNO levels in blood. The sensor is shown to exhibit high selectivity over nitrosamines and nitrite. Such RSNO detection is potentially useful to reveal correlation between blood RSNO levels and endothelial cell dysfunction, which often is associated with cardiovascular diseases.
Co-reporter:Sangyeul Hwang and Mark E. Meyerhoff
Journal of Materials Chemistry A 2008 vol. 18(Issue 15) pp:1784-1791
Publication Date(Web):26 Feb 2008
DOI:10.1039/B715523A
An organoditelluride (RTeTeR) species (5,5′-ditelluro-2,2′-dithiophenecarboxylic acid, DTDTCA) that catalytically decomposes endogenous S-nitrosothiols (RSNOs) to nitric oxide (NO) in the presence of free thiols (RSHs) is used to prepare new types of NO generating polymers (NOGPs). In this work, DTDTCA is covalently linked to poly(allylamine hydrochloride) (PAH) to form a water soluble NOGP (polymer 2). This polymer is further crosslinked within a cellulose membrane to yield an interpenetrating polymer network (IPN) (polymer 3). The catalytic NO generation ability of these NOPGs is clearly observed viachemiluminescence detection of liberated NO. The observed NO fluxes of the IPNs in the presence of given concentrations of RSNOs and reducing thiols can be tuned by adjusting the DTDTCA loading of polymer 2 crosslinked within the cellulose support. Polymer 3 is shown to spontaneously generate NO when in contact with fresh blood via amperometric sensor measurements. Hence, these new types of NOGPs are potentially useful as catalytic layers to create new amperometric RSNO sensors and possibly blood contacting medical devices that exhibit improved hemocompatiblity.
Co-reporter:Lin Wang, Stacey Buchanan and Mark E. Meyerhoff
Analytical Chemistry 2008 Volume 80(Issue 24) pp:9845
Publication Date(Web):November 14, 2008
DOI:10.1021/ac801879t
A very simple and inexpensive method to detect oversulfated chondroitin sulfate (OSCS) or other high-charge density polyanionic structures as contaminants in heparin products using potentiometric polyanion sensors is described. In the potentiometric measurement, a greater change in the phase boundary equilibrium potential of polymeric membranes formulated with tridodecylmethylammonium (TDMA) anion exchange sites is observed for the contaminated heparin than for the untainted heparin due to the higher charge density of OSCS or other impurities compared to that of porcine heparin. Detection of 0.5 wt % OSCS impurity is readily achieved using only 1 mg/mL of final polyion concentration. Even lower detection limits for OSCS contamination may be possible if higher final concentrations of heparin preparations can be employed in the test procedure.
Co-reporter:Lin Wang, Mark E. Meyerhoff
Analytica Chimica Acta 2008 Volume 611(Issue 1) pp:97-102
Publication Date(Web):17 March 2008
DOI:10.1016/j.aca.2008.01.070
The synthesis and characterization of a novel polymethacylate polymer with covalently linked Al(III)-tetraphenylporphyrin (Al(III)-TPP) groups is reported. The new polymer is examined as a potential macromolecular ionophore for the preparation of polymeric membrane-based potentiometric and optical fluoride selective sensors. To prepare the polymer, an Al(III) porphyrin monomer modified with a methacrylate functionality is synthesized, allowing insertion into a polymethacrylate block copolymer (methyl methacrylate and decyl methacrylate) backbone. The resulting polymer can then be incorporated, along with appropriate additives, into conventional plasticized poly(vinyl chloride) films for testing electrochemical and optical fluoride response properties. The covalent attachment of the Al(III)-TPP ionophore to the copolymer matrix provides potentiometric sensors that exhibit significant selectivity for fluoride ion with extended lifetimes (compared to ion-selective membrane electrodes formulated with conventional free Al(III)-TPP structure). However, quite surprisingly, the attachment of the ionophore to the polymer does not eliminate the interaction of Al(III)-TPP structures to form dimeric species within the membrane phase in the presence of fluoride ion. Such interactions are confirmed by UV/visible spectroscopy of the blended polymeric films. Use of the new polymer-Al(III)-TPP conjugates to prepare optical fluoride sensors by co-incorporating a lipophilic pH indicator (4′,5′-dibromofluorescein octadecyl ester; ETH7075) is also examined and the resulting optical sensing films are shown to exhibit excellent selectivity for fluoride, with the potential for prolonged operational lifetime.
Co-reporter:Yiduo Wu, Mark E. Meyerhoff
Talanta 2008 Volume 75(Issue 3) pp:642-650
Publication Date(Web):15 May 2008
DOI:10.1016/j.talanta.2007.06.022
The development of reliable in vivo chemical sensors for real-time clinical monitoring of blood gases, electrolytes, glucose, etc. in critically ill and diabetic patients remains a great challenge owing to inherent biocompatibility problems that can cause errant analytical results upon sensor implantation (e.g., cell adhesion, thrombosis, inflammation). Nitric oxide (NO) is a well-known inhibitor of platelet activation and adhesion, and also a potent inhibitor of smooth muscle cell proliferation. In addition, NO mediates inflammatory response and promotes angiogenesis. Polymers that release or generate NO at their surfaces have been shown to exhibit greatly enhanced thromboresistance in vivo when in contact with flowing blood, as well as reduce inflammatory response when placed subcutaneously, and thus have the potential to improve the biocompatibility of implanted chemical sensors. Locally elevated NO levels at the surface of implanted devices can be achieved by using polymers that incorporate NO donor species that can decompose and release NO spontaneously when in contact with physiological fluids, or NO-generating polymers that possess an immobilized catalyst that decompose endogenous S-nitrosothiols to generate NO in situ. The potential use of such NO-releasing/generating materials for preparing in vivo sensors implanted either intravascularly or subcutaneously, is examined in this review.
Co-reporter:Jun Yang, Jenna L. Welby and Mark E. Meyerhoff
Langmuir 2008 Volume 24(Issue 18) pp:10265-10272
Publication Date(Web):August 19, 2008
DOI:10.1021/la801466e
A universal nitric oxide (NO) generating surface is assembled via Layer-by-Layer (LbL) deposition of sodium alginate (Alg) and organoselenium modified polyethyleneimine (SePEI) on quartz and polymeric substrates. The immobilized SePEI species is capable of catalytically decomposing S-nitrosothiol species (RSNO) to NO in the presence of thiol reducing agents (e.g., glutathione, cysteine, etc.). The stepwise buildup of the multilayer films is monitored by UV−vis spectroscopy, SEM and surface contact angle measurements. X-ray photoelectron spectroscopy is used to study the stoichiometry between the polyanion and polycation, and also the presence of Se in the catalytic LbL film. A reductive annealing process is necessary to improve the stability of freshly coated multilayer films via chain rearrangement. Chemiluminescence measurements illustrate the ability of the LbL films to generate NO from S-nitrosoglutathione (GSNO) in the presence of glutathione (GSH). Enhanced NO fluxes can be achieved by increasing the number of catalytic (SePEI/Alg) bilayers coated on the substrates. Nitric oxide generation is observed even after prolonged contact with sheep whole blood. Preliminary applications of this LbL on silicone rubber tubings and polyurethane catheters reveal similar NO generation behavior from these biomedical grade polymeric substrates.
Co-reporter:Sangyeul Hwang and Mark E. Meyerhoff
Journal of Materials Chemistry A 2007 vol. 17(Issue 15) pp:1462-1465
Publication Date(Web):06 Mar 2007
DOI:10.1039/B700375G
An organoditelluride (5,5′-ditelluro-2,2′-dithiophenecarboxylic acid) and a polymeric derivative thereof are shown to exhibit catalytic decomposition of S-nitrosothiols such as S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CySNO).
Co-reporter:Zhengrong Zhou;Yiduo Wu;Mark E. Meyerhoff
Journal of Biomedical Materials Research Part A 2007 Volume 81A(Issue 4) pp:956-963
Publication Date(Web):24 JAN 2007
DOI:10.1002/jbm.a.31105
Nitric oxide (NO) is released by endothelial cells that line the inner walls of healthy blood vessels at fluxes ranging from 0.5 × 10−10 to 4.0 × 10−10 mol cm−2 min−1, and this continuous NO release contributes to the extraordinary thromboresistance of the intact endothelium. To improve the biocompatibility of blood-contacting devices, a biomimetic approach to release/generate NO at polymer/blood interfaces has been pursued recently (with NO donors or NO generating catalysts doped within polymeric coatings) and this concept has been shown to be effective in preventing platelet adhesion/activation via several in vivo animal studies. However, there are no reports to date describing any quantitative in vitro assay to evaluate the blood compatibilities of such NO release/generating polymers with controlled NO fluxes. Such a methodology is desired to provide a preliminary assessment of any new NO-releasing material, in terms of the effectiveness of given NO fluxes and NO donor amounts on platelet activity before the more complex and costly in vivo testing is carried out. In this article, we report the use of a lactate dehydrogenase assay to study in vitro platelet adhesion on such NO-releasing polymer surfaces with varying NO fluxes. Reduced platelet adhesion was found to correlate with increasing NO fluxes. The highest NO flux tested, 7.05 (±0.25) × 10−10 mol cm−2 min−1, effectively reduced platelet adhesion to nearly 20% of its original level (from 14.0 (±2.1) × 105 cells cm−2 to 2.96 (±0.18) × 105 cells cm−2) compared to the control polymer coating without NO release capability. © 2007 Wiley Periodicals, Inc. J Biomed Mater Res, 2007
Co-reporter:Hisham S.M. Abd-Rabboh, Mark E. Meyerhoff
Talanta 2007 Volume 72(Issue 3) pp:1129-1133
Publication Date(Web):15 May 2007
DOI:10.1016/j.talanta.2007.01.023
The determination of glucose in beverages is demonstrated using newly developed fluoride selective optical sensing polymeric film that contains aluminum (III) octaethylporphyrin (Al[OEP]) ionophore and the chromoionophore ETH7075 cast at the bottom of wells of a 96-well polypropylene microtiter plate. The method uses a dual enzymatic reaction involving glucose oxidase enzyme (GOD) and horseradish peroxidase (HRP), along with an organofluoro-substrate (4-fluorophenol) as the source of fluoride ions. The concentration of fluoride ions after enzymatic reaction is directly proportional to the glucose level in the sample. The method has a detection limit of 0.8 mmol L−1, a linear range of 0.9–40 mmol L−1 and a sensitivity of 0.125 absorbance/decade of glucose concentration. Glucose levels in several beverage samples determined using the proposed method correlate well with a reference spectrophotometric enzyme method based on detection of hydrogen peroxide using bromopyrogallol red dye (BPR). The new method can also be used to determine H2O2 concentrations in the 0.1–50 mmol L−1 range using a single enzymatic reaction involving H2O2 oxidation of 4-fluorophenol catalyzed by HRP. The methodology could potentially be used to detect a wide range of substrates for which selective oxidase enzymes exist (to generate H2O2), with the high throughput of simple microtiter plate detection scheme.
Co-reporter:Sangyeul Hwang;Wansik Cha
Angewandte Chemie International Edition 2006 Volume 45(Issue 17) pp:
Publication Date(Web):20 MAR 2006
DOI:10.1002/anie.200503588
In the matrix: A new cross-linked hydrogel polymer, poly(2-hydroxyethyl methacrylate) (pHEMA), containing appended CuII–cyclen sites (cyclen=1,4,7,10-tetraazacyclododecane) was prepared and shown to generate nitric oxide from endogenous S-nitrosothiol species (RSNO) typically found in circulating whole blood.
Co-reporter:Sangyeul Hwang;Wansik Cha
Angewandte Chemie 2006 Volume 118(Issue 17) pp:
Publication Date(Web):20 MAR 2006
DOI:10.1002/ange.200503588
In der Matrix: Ein vernetztes Hydrogelpolymer, Poly(2-hydroxyethylmethacrylat) (pHEMA) mit CuII(Cyclen)-Seitengruppen, setzt Stickstoffoxid aus endogenen S-Nitrosothiol-Spezies (RSNO) frei, die im Blutkreislauf auftreten. Cyclen=1,4,7,10-Tetraazacyclododecan.
Co-reporter:Ibrahim H.A. Badr, Mark E. Meyerhoff
Analytica Chimica Acta 2005 Volume 553(1–2) pp:169-176
Publication Date(Web):30 November 2005
DOI:10.1016/j.aca.2005.08.037
A highly selective optical sensor for fluoride ion based on the use of an aluminum(III)-salen complex as an ionophore within a thin polymeric film is described. The sensor is prepared by embedding the aluminum(III)-salen ionophore and a suitable lipophilic pH-sensitive indicator (ETH-7075) in a plasticized poly(vinyl chloride) (PVC) film. Optical response to fluoride occurs due to fluoride extraction into the polymer via formation of a strong complex with the aluminum(III)-salen species. Co-extraction of protons occurs simultaneously, with protonation of the indicator dye yielding the optical response at 529 nm. Films prepared using dioctylsebacate (DOS) are shown to exhibit better response (e.g., linear range, detection limit, and optical signal stability) compared to those prepared using ortho-nitrophenyloctyl ether (o-NPOE). Films formulated with aluminum(III)-salen and ETH-7075 indicator in 2 DOS:1 PVC, exhibit a significantly enhanced selectivity for fluoride over a wide range of lipophilic anions including salicylate, perchlorate, nitrate, and thiocyanate. The optimized films exhibit a sub-micromolar detection limit, using glycine-phosphate buffer, pH 3.00, as the test sample. The response times of the fluoride optical sensing films are in the range of 1–10 min depending on the fluoride ion concentration in the sample. The sensor exhibits very poor reversibility owing to a high co-extraction constant (log K = 8.5 ± 0.4), indicating that it can best be employed as a single-use transduction device. The utility of the aluminum(III)-salen based fluoride sensitive films as single-use sensors is demonstrated by casting polymeric films on the bottom of standard polypropylene microtiter plate wells (96 wells/plate). The modified microtiter plate optode format sensors exhibit response characteristics comparable to the classical optode films cast on quartz slides. The modified microtiter is utilized for the analysis of fluoride in diluted anti-cavity fluoride rinse samples and the results obtained are shown to correlate well with the analysis performed using the LaF3 single crystal ion-selective electrode.
Co-reporter:Megan C. Frost;Mark E. Meyerhoff
Journal of Biomedical Materials Research Part A 2005 Volume 72A(Issue 4) pp:409-419
Publication Date(Web):28 JAN 2005
DOI:10.1002/jbm.a.30275
A new type of nitric oxide (NO)-releasing material is described that utilizes S-nitrosothiols anchored to tiny fumed silica (FS) particles as the NO donor system. The synthetic procedures suitable for tethering three different thiol species (cysteine, N-acetylcysteine, and N-acetylpenicillamine) to the surface of FS polymer filler particles are detailed. The thiol-derivatized particles are converted to their corresponding S-nitrosothiols by reaction with t-butylnitrite. The total NO loading on the resulting particles range from 21–138 nmol/mg for the three different thiol-derivatized materials [S-nitrosocysteine-(NO-Cys)-FS, S-nitroso-N-acetylcysteine (SNAC)-FS, and S-nitroso-N-acetylpenicillamine (SNAP)-FS], with SNAP-FS yielding the highest NO loading. NO can be generated from these particles when suspended in solution via the addition of copper(II) ions, ascorbate, or irradiation with visible light. The SNAC-FS and SNAP-FS particles can be blended in polyurethane and silicone rubber matrixes to create films that release NO at controlled rates. Polyurethane films containing SNAC-FS submerged in phosphate-buffered saline (pH 7.4) generate NO surface fluxes ∼0.1–0.7 × 10−10 mol cm−2 min−1 and SNAP-FS films generate NO fluxes of ∼0–7.5 × 10−10 mol cm−2 min−1 upon addition of increasing amounts of copper ions. Silicone rubber films containing SNAC-FS or SNAP-FS do not liberate NO upon exposure to copper ions or ascorbate in phosphate-buffered saline solution. However, such films are shown to release NO at rates proportional to increasing intensities of visible light impinging on the films. Such photoinitiated NO release from these composite materials offers the first NO-releasing hydrophobic polymers with an external on/off trigger to control NO generation. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res 72A: 409–419, 2005
Co-reporter:Stacey A. Buchanan, Thomas P. Kennedy, Robert B. MacArthur, Mark E. Meyerhoff
Analytical Biochemistry 2005 Volume 346(Issue 2) pp:241-245
Publication Date(Web):15 November 2005
DOI:10.1016/j.ab.2005.08.035
O-Desulfated heparin (ODSH) is a promising new anti-inflammatory agent for the prevention of reperfusion injury following myocardial infarction or stroke. This partially desulfated heparin derivative has less anticoagulant activity than unfractionated heparin but retains the inherent anti-inflammatory properties of heparin. Thus, ODSH could be administered at the high doses needed to achieve desired anti-inflammatory function without risk of hemorrhage. However, given the very low anticoagulant activity of this species, traditional methods for heparin determination in clinical samples might not be well suited for ODSH measurements. In this article, a novel titrimetric method for detection of ODSH in buffer and plasma is described using a protamine-sensitive polymer membrane electrode as the detector. Titrations of ODSH with the heparin antagonist protamine yield sharp endpoints with sensitivity to ODSH in the micrograms per milliliter range for plasma samples. The stoichiometry for protamine interaction with ODSH is determined to average 1.39 μg protamine/μg ODSH in plasma. This technology is further applied to a toxicokinetic study of ODSH in an animal model, demonstrating the ability to detect the changes in ODSH concentrations in biological samples.
Co-reporter:Megan C. Frost, Melissa M. Batchelor, Youngmi Lee, Huiping Zhang, Youngjea Kang, Bongkyun Oh, George S. Wilson, Raeann Gifford, Steven M. Rudich, Mark E. Meyerhoff
Microchemical Journal 2003 Volume 74(Issue 3) pp:277-288
Publication Date(Web):June 2003
DOI:10.1016/S0026-265X(03)00033-X
The widespread use of miniaturized chemical sensors to monitor clinically important analytes such as PO2, PCO2, pH, electrolytes, glucose and lactate in a continuous, real-time manner has been seriously hindered by the erratic analytical results often obtained when such devices are implanted in vivo. One major factor that has influenced the analytical performance of indwelling sensors is the biological response they elicit when in contact with blood or tissue (e.g. thrombus formation on the device surface, inflammatory response, encapsulation, etc.). Nitric oxide (NO) has been shown to be a potent inhibitor of platelet adhesion and activation as well as a promoter of wound healing in tissue. Herein, we review recent work aimed at the development of hydrophobic NO-releasing polymers that can be employed to coat catheter-type amperometric oxygen sensors without interfering with the analytical performance of these devices. Such modified sensors are shown to exhibit greatly enhanced hemocompatibility and improved analytical performance when implanted within porcine carotid and femoral arteries for up to 16 h. Further, results from preliminary studies also demonstrate that prototype fluorescent oxygen sensors, catheter-style potentiometric carbon dioxide sensors and subcutaneous needle-type enzyme-based amperometric glucose sensors can also be fabricated with new NO-release outer coatings without compromising the analytical response characteristics of these devices. The NO-release strategy may provide a solution to the lingering biocompatibility problems encountered when miniature chemical sensors are implanted in vivo.
Co-reporter:Paweł G Parzuchowski, Jeff W Kampf, Ewa Roźniecka, Yevgeniy Kondratenko, Elżbieta Malinowska, Mark E Meyerhoff
Inorganica Chimica Acta 2003 Volume 355() pp:302-313
Publication Date(Web):20 November 2003
DOI:10.1016/S0020-1693(03)00267-6
The synthesis and single-crystal X-ray structures of the hydroxo-bridged complexes (μ-hydroxo)-bis(octaethylporphinato)gallium(III)perchlorate {[Ga(OEP)]2OH}ClO4 and (μ-hydroxo)-bis(octaethylporphinato)indium(III)tetrakis[3,5-bis-(trifluoromethyl)phenyl]borate {[In(OEP)]2OH}TFPB are reported. These complexes are prepared by the titration of monomeric metalloporphyrin species in dichloromethane with diluted perchloric acid or by the addition of stoichiometric amounts of the tetraphenylborate derivative salt. The structures show that complexes of two metalloporphyrins are joined by a single protonated metaloxygenmetal bridge with a nearly 150° bridge angle. The porphyrin rings of the dimers form dihedral angles of 15° Ga(III) and 23° In(III). In contrast to previously reported analogous dimeric Mn(III) and Fe(III) structures, the porphyrin rings of the present dimers are twisted by a much greater torsion angle of nearly 22°. In dichloromethane, high stability of the dimers is observed in the presence of perchlorate, but dissociation of the dimer species to monomers is found with increasing concentrations of halogen anions. This corresponds well with the observed anion selectivities recently reported for both electrochemical and optical anion sensors prepared with the respective Ga(III) and In(III) octaethylporphyrins in polymeric films.The synthesis and single-crystal X-ray structures of the hydroxo-bridged complexes (μ-hydroxo)-bis(octaethylporphinato)gallium(III)perchlorate and (μ-hydroxo)-bis(octaethylporphinato)indium(III)tetrakis[3,5-bis-(trifluoromethyl)phenyl]borate are reported. The dissociation of the dimer species to monomers is found with increasing concentrations of halogen anions. This corresponds well with the observed anion selectivities recently reported for both electrochemical and optical sensors prepared in polymeric films.
Co-reporter:Huiping Zhang, Gail M. Annich, Judiann Miskulin, Kathryn Osterholzer, Scott I. Merz, Robert H. Bartlett, Mark E. Meyerhoff
Biomaterials 2002 Volume 23(Issue 6) pp:1485-1494
Publication Date(Web):March 2002
DOI:10.1016/S0142-9612(01)00274-5
Nitric oxide (NO) releasing silicone rubbers (SR) are prepared via a three-step reaction scheme. A diamino/triamino-alkyltrimethoxysilane crosslinker is used to vulcanize hydroxyl terminated polydimethylsiloxane (PDMS) in the presence of ambient moisture and a dibutyltin dilaurate catalyst so that the respective diamine/triamine groups are covalently linked to the cured SR structure. These amine sites are then diazeniumdiolated, in situ, when the cured SR is reacted with NO at elevated pressure (80 psi). Although nitrite species are also formed during the NO addition reaction, in most cases the diazeniumdiolated polymer is the major product within the final SR matrix. Temperature appears to be the major driving force for the dissociation of the attached diazeniumdiolate moieties, whereas the presence of bulk water bathing the SR materials has only minimal effect on the observed NO release rate owing to the low water uptake of the SR matrices. The resulting SR films/coatings release NO at ambient or physiological temperature for up to 20 d with average fluxes of at least 4×10−10 mol·cm−2·min−1 (coating thickness ⩾600 μm) over first 4 h, comparable to the NO fluxes observed from stimulated human endothelial cells. The NO loading and concomitant NO release flux of the SR material are readily adjustable by altering the diamine/triamine loading and film/coating thickness. The new NO releasing SR materials are shown to exhibit improved thromboresistance in vivo, as demonstrated via reduced platelet activation on the surface of these polymers when used to coat the inner walls of SR tubings employed for extracorporeal circulation in a rabbit model.
Co-reporter:Kelly A. Mowery, Mark H. Schoenfisch, Joseph E. Saavedra, Larry K. Keefer, Mark E. Meyerhoff
Biomaterials 2000 Volume 21(Issue 1) pp:9-21
Publication Date(Web):January 2000
DOI:10.1016/S0142-9612(99)00127-1
The preparation of hydrophobic polymer films (polyurethane and poly(vinyl chloride)) containing nitric oxide (NO)-releasing diazeniumdiolate functions is reported as a basis for improving the thromboresistivity of such polymeric materials for biomedical applications. Several different approaches for preparing NO-releasing polymer films are presented, including: (1) dispersion of diazeniumdiolate molecules within the polymer matrix; (2) covalent attachment of the diazeniumdiolate to the polymer backbone; and (3) ion-pairing of a diazeniumdiolated heparin species to form an organic soluble complex that can be blended into the polymer. Each approach is characterized in terms of NO release rates and in vitro biocompatibility. Results presented indicate that the polymer films prepared by each approach release NO for variable periods of time (10–72 h), although they differ in the mechanism, location and amount of NO released. In vitro platelet adhesion studies demonstrate that the localized NO release may prove to be an effective strategy for improving blood compatibility of polymer materials for a wide range of medical devices.
Co-reporter:Elizabeth J. Brisbois, Ryan P. Davis, Anna M. Jones, Terry C. Major, Robert H. Bartlett, Mark E. Meyerhoff and Hitesh Handa
Journal of Materials Chemistry A 2015 - vol. 3(Issue 8) pp:NaN1645-1645
Publication Date(Web):2015/01/12
DOI:10.1039/C4TB01839G
Thrombosis and infection are two common problems associated with blood-contacting medical devices such as catheters. Nitric oxide (NO) is known to be a potent antimicrobial agent as well as an inhibitor of platelet activation and adhesion. Healthy endothelial cells that line the inner walls of all blood vessels exhibit a NO flux of 0.5–4 × 10−10 mol cm−2 min−1 that helps prevent thrombosis. Materials with a NO flux that is equivalent to this level are expected to exhibit similar anti-thrombotic properties. In this study, NO-releasing catheters were fabricated by incorporating S-nitroso-N-acetylpenicillamine (SNAP) in the Elast-eon E2As polymer. The SNAP/E2As catheters release physiological levels of NO for up to 20 days, as measured by chemiluminescence. Furthermore, SNAP is stable in the E2As polymer, retaining 89% of the initial SNAP after ethylene oxide (EO) sterilization. The SNAP/E2As and E2As control catheters were implanted in sheep veins for 7 days to examine the effect on thrombosis and bacterial adhesion. The SNAP/E2As catheters reduced the thrombus area when compared to the control (1.56 ± 0.76 and 5.06 ± 1.44 cm2, respectively). A 90% reduction in bacterial adhesion was also observed for the SNAP/E2As catheters as compared to the controls. The results suggest that the SNAP/E2As polymer has the potential to improve the hemocompatibility and bactericidal activity of intravascular catheters, as well as other blood-contacting medical devices (e.g., vascular grafts, extracorporeal circuits).
Co-reporter:Hitesh Handa, Terry C. Major, Elizabeth J. Brisbois, Kagya A. Amoako, Mark E. Meyerhoff and Robert H. Bartlett
Journal of Materials Chemistry A 2014 - vol. 2(Issue 8) pp:NaN1067-1067
Publication Date(Web):2014/01/07
DOI:10.1039/C3TB21771J
Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion/activation. Nitric oxide releasing (NOrel) materials can be prepared by doping an NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2), within a polymer coating. The inherent hemocompatibility properties of the base polymer can also influence the efficiency of such NO release coatings. In this study, four biomedical grade polymers were evaluated in a 4 h rabbit model of thrombogenicity for their effects on extracorporeal circuit thrombus formation and circulating platelet count. At the end of 4 h, Elast-Eon E2As was found to preserve 58% of baseline platelets versus 48, 40, and 47% for PVC/DOS, Tecophilic SP-60D-60, and Tecoflex SG80A, respectively. Elast-Eon also had significantly lower clot area of 5.2 cm2 compared to 6.7, 6.1, and 6.9 cm2 for PVC/DOS, SP-60D-60, and SG80A, respectively. Based on the results obtained for the base polymer comparison study, DBHD/N2O2-doped E2As was evaluated in short-term (4 h) rabbit studies to observe the NO effects on prevention of clotting and preservation of platelet function. Platelet preservation for this optimal NO release formulation was 97% of baseline after 4 h, and clot area was 0.9 cm2 compared to 5.2 cm2 for controls, demonstrating that combining E2As with NO release provides a truly advanced hemocompatible polymer coating for extracorporeal circuits and potentially other blood contacting applications.
Co-reporter:Sangyeul Hwang and Mark E. Meyerhoff
Journal of Materials Chemistry A 2007 - vol. 17(Issue 15) pp:NaN1465-1465
Publication Date(Web):2007/03/06
DOI:10.1039/B700375G
An organoditelluride (5,5′-ditelluro-2,2′-dithiophenecarboxylic acid) and a polymeric derivative thereof are shown to exhibit catalytic decomposition of S-nitrosothiols such as S-nitrosoglutathione (GSNO) and S-nitrosocysteine (CySNO).
Co-reporter:Sangyeul Hwang and Mark E. Meyerhoff
Journal of Materials Chemistry A 2008 - vol. 18(Issue 15) pp:NaN1791-1791
Publication Date(Web):2008/02/26
DOI:10.1039/B715523A
An organoditelluride (RTeTeR) species (5,5′-ditelluro-2,2′-dithiophenecarboxylic acid, DTDTCA) that catalytically decomposes endogenous S-nitrosothiols (RSNOs) to nitric oxide (NO) in the presence of free thiols (RSHs) is used to prepare new types of NO generating polymers (NOGPs). In this work, DTDTCA is covalently linked to poly(allylamine hydrochloride) (PAH) to form a water soluble NOGP (polymer 2). This polymer is further crosslinked within a cellulose membrane to yield an interpenetrating polymer network (IPN) (polymer 3). The catalytic NO generation ability of these NOPGs is clearly observed viachemiluminescence detection of liberated NO. The observed NO fluxes of the IPNs in the presence of given concentrations of RSNOs and reducing thiols can be tuned by adjusting the DTDTCA loading of polymer 2 crosslinked within the cellulose support. Polymer 3 is shown to spontaneously generate NO when in contact with fresh blood via amperometric sensor measurements. Hence, these new types of NOGPs are potentially useful as catalytic layers to create new amperometric RSNO sensors and possibly blood contacting medical devices that exhibit improved hemocompatiblity.
Co-reporter:Melissa M. Reynolds, Joseph E. Saavedra, Brett M. Showalter, Carlos A. Valdez, Anna P. Shanklin, Bong K. Oh, Larry K. Keefer and Mark E. Meyerhoff
Journal of Materials Chemistry A 2010 - vol. 20(Issue 15) pp:NaN3114-3114
Publication Date(Web):2010/03/05
DOI:10.1039/C000152J
Nitric oxide (NO) has been shown to exhibit significant anti-platelet activity and its release from polymer matrices has been already utilized to increase the biocompatibility of various blood-contacting devices. Herein, the details of a new synthetic approach for preparing NO-releasing diazeniumdiolated polyurethanes (PUs) are described. The method's utility is demonstrated by the incorporation of methoxymethyl- or sugar-protected pre-formed diazeniumdiolate moieties directly into chain extender diols which are then incorporated into the polyurethane backbone. This approach provides the ability to control the number of diazeniumdiolate groups incorporated into the polymer backbone, and hence the surface flux of NO that can ultimately be liberated from polymeric films prepared from the new PU materials. The method provides a means of covalently attaching diazeniumdiolate groups to polyurethanes in a form that resists dissociation of NO during processing but can be activated for spontaneous NO release via hydrolysis of the carbohydrate or methoxymethyl moieties under basic and acidic conditions, respectively.
Co-reporter:Kun Liu and Mark E. Meyerhoff
Journal of Materials Chemistry A 2012 - vol. 22(Issue 36) pp:NaN18787-18787
Publication Date(Web):2012/08/03
DOI:10.1039/C2JM32726K
A new, stable and highly efficient Cu2+–cyclen–polyurethane material is described and shown to exhibit an improved performance compared to that of prior materials for the catalytic decomposition of S-nitrosothiols to physiologically active nitric oxide.
Co-reporter:Hitesh Handa, Elizabeth J. Brisbois, Terry C. Major, Lahdan Refahiyat, Kagya A. Amoako, Gail M. Annich, Robert H. Bartlett and Mark E. Meyerhoff
Journal of Materials Chemistry A 2013 - vol. 1(Issue 29) pp:NaN3587-3587
Publication Date(Web):2013/06/03
DOI:10.1039/C3TB20277A
Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7 and 18 × 10−10 mol cm−2 min−1 NO for 14 days at 37 °C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing lipophilic diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating.
Co-reporter:Alex R. Ketchum, Michael P. Kappler, Jianfeng Wu, Chuanwu Xi and Mark E. Meyerhoff
Journal of Materials Chemistry A 2016 - vol. 4(Issue 3) pp:NaN430-430
Publication Date(Web):2015/12/07
DOI:10.1039/C5TB01664A
Recently, considerable research efforts have focused on increasing the biocompatibility and bactericidal activity of biomedical polymeric devices (e.g., catheters, etc.) through incorporation of nitric oxide (NO) releasing molecules. NO is an important endogenous molecule that is well known for enhancing blood flow via its vasodilatory activity, but it also exhibits potent antithrombotic and antimicrobial properties. In this work, we demonstrate that silicone rubber tubing can be impregnated with a tertiary S-nitrosothiol (RSNO), S-nitroso-tert-dodecylmercaptan, via a simple solvent swelling method. We further characterize the NO release and RSNO leaching from the tubing over time via use of chemiluminescence and UV/Vis spectroscopy, respectively. The tubing is shown to maintain an NO flux above the physiological levels released by endothelial cells, 0.5–4.0 × 10−10 mol cm−2 min−1, for more than 3 weeks while stored at 37 °C and exhibit minimal leaching. Finally, the RSNO impregnated tubing exhibits significant antimicrobial activity over a 21 d period (vs. controls) during incubation in a CDC bioreactor after inoculation of media with S. aureus bacteria. The use of such lipophilic RSNO impregnated silicone rubber tubing could dramatically reduce the risk of catheter-related infections, which are a common problem associated with placement of intravascular or urinary catheters.
Co-reporter:Xuewei Wang, Yu Qin and Mark E. Meyerhoff
Chemical Communications 2015 - vol. 51(Issue 82) pp:NaN15179-15179
Publication Date(Web):2015/08/25
DOI:10.1039/C5CC06770G
An ionophore-based ion-selective optode platform on paper is described for the first time with a sodium optode as the example. Cellulose paper is shown to be an excellent substrate for adsorption of the required chromoionophore, ionophore, and ion-exchanger species. These adsorbed components form a hydrophobic phase that enables heterogeneous optical ion sensing in the absence of any plasticizer or organic polymer phase.
Co-reporter:Yaqi Wo, Elizabeth J. Brisbois, Robert H. Bartlett and Mark E. Meyerhoff
Biomaterials Science (2013-Present) 2016 - vol. 4(Issue 8) pp:NaN1183-1183
Publication Date(Web):2016/05/26
DOI:10.1039/C6BM00271D
Biomedical devices are essential for patient diagnosis and treatment; however, when blood comes in contact with foreign surfaces or homeostasis is disrupted, complications including thrombus formation and bacterial infections can interrupt device functionality, causing false readings and/or shorten device lifetime. Here, we review some of the current approaches for developing antithrombotic and antibacterial materials for biomedical applications. Special emphasis is given to materials that release or generate low levels of nitric oxide (NO). Nitric oxide is an endogenous gas molecule that can inhibit platelet activation as well as bacterial proliferation and adhesion. Various NO delivery vehicles have been developed to improve NO's therapeutic potential. In this review, we provide a summary of the NO releasing and NO generating polymeric materials developed to date, with a focus on the chemistry of different NO donors, the polymer preparation processes, and in vitro and in vivo applications of the two most promising types of NO donors studied thus far, N-diazeniumdiolates (NONOates) and S-nitrosothiols (RSNOs).
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