The Meyerhoff Group

From the PI

Photo of Professor MeyerhoffWelcome to the Meyerhoff Lab Website!!

Thanks for taking the time to view the contents of this site and learn about the exciting ongoing research activities in my group.

In a nutshell, my research interests are in the areas of bioanalytical chemistry, electrochemical and optical sensors, novel nitric oxide releasing/generating biomaterials, and immunoassays. Our current efforts are primarily focused on the following projects:

In the field of chemical sensors we investigate the use of various metal-ligand complexes (especially metalloporphyrins) as anion/gas recognition agents within thin polymeric films to create new electrochemical and optical anion and gas selective sensors.  Selective anion or gas molecule coordination to the metal ion center of these complexes can create large changes in membrane potentials (voltage across the polymeric films) and/or the optical absorbance or fluorescence spectra of the complexes  within the polymeric phase. Of particular interest is our recent discovery of interesting dimer-monomer equilibria of certain metalloporphyrins (In(III),  Ga(III), Zr(IV), Sn(IV) Al(III) and Sc(III) octaethyl- and tetraphenyl-porphyrins) within polymer films, and the use of such dimer-monomer chemistry as transduction for chemical sensing.  For example we discovered that Al(III) and Sc(III) porphyrins form dimeric structures in presence of fluoride ion, we used their selective interactions to develop both electrochemical and optical polymer film-based fluoride sensors that can be applied to monitor fluoride in drinking water and potentially detect fluorophosphate nerve agents.

We are also developing methods to improve the biocompatibility of implantable electrochemical/optical gas/ion sensors and other blood contacting medical devices (stents, vascular grafts, extracorporeal circuits, etc.) via novel use of nitric oxide (NO) release and generating polymers. Polymers such as polyurethane, poly(vinyl chloride), and polydimethylsiloxane are being  synthesized with pendant diazeniumdiolate functional  groups (adducts of NONO with secondary amines).  These groups slowly release NO as water is absorbed into the polymer. Owing to the potent anti-platelet aggregating activity of NO, the resulting polymers exhibit a dramatic decrease in platelet adhesion and surface clot formation (compared to blank films) during both in vitro and in vivo experiments.  New materials that contain immobilized Cu(II)-ligands, organoselenium (RSe) as well as organotellurium (RTe) sites are also being developed as biomimetic catalysts, to generate NO from endogenous nitrosothiols (RSNO) already present in blood.  These materials are also being used to develop novel RSNO selective chemical sensors that can be employed to assess the levels of endogenous RSNO species in blood.   Such measurements can confirm whether adequate levels of RSNO substrate are present to enable the NO generating polymers to effectively reduce clotting when in contact with flowing blood.  In addition, we believe that measurement of total RSNO species in blood may also be clinically important to predict the risk of thrombotic events (heart attacks, strokes, etc.) for patients, owing to the fact that RSNOs can be converted to NO locally at the surface of platelets.  Hence, levels of RSNO in blood likely control platelet function and thus serve as nature’s anti-platelet agent to prevent blood clots. 

Finally, we also have interests in developing new types of ultra-sensitive immuno- and DNA-binding assays using either electrochemical or optical readouts.  In our latest research, enzyme prosthetic groups are used as tracers (e.g. pyroloquinoline quinone (PQQ)), packed within liposomes or other nanosphere packages.  After binding, the prosthetic groups can be released from their nanosphere packages and assayed at extremely low levels (e.g., 10 pM) using appropriate apo-enzymes (e.g., glucose dehydrogenase (GDH)) that are reconstituted with the prosthetic groups. 

The projects described above are funded by four NIH grants, an Army grant, and several industrial grants/gifts to our lab.  My philosophy of training graduate students is to give considerable creative freedom, both in choosing the research project that best fits their interests and background, and also in their pursuit of that research. As a result, students in my group learn to be independent and highly motivated scientists who are ready for real-world challenges in industrial, government or academic laboratories.

Mark E. Meyerhoff (mmeyerho@umich.edu )

U-M Phillip J. Elving Professor of Chemistry

 

Monthly Lab Update- March/April 2007

The development of simple electrochemical sensor-based methods for detection of nitrosothiols (RSNOs; e.g., nitrosoglutathione, nitrosocysteine, etc.) in blood samples is becoming a potentially more important research avenue than we had initially envisioned. We started work in this direction (See Anal. Chem.,77(11), 3516-3524 (2005); and Langmuir, 22(25), 10830-10836 (2006).) primarily to detect the nitric oxide (NO)-generating ability in blood of new catalytic polymers that possess immobilized Cu(II) or organoselenium species (RSe). The idea is that we can prepare more biocompatible polymers (reduce clotting on polymer surface) by local catalytic generation of NO from endogenous RSNOs in blood, but we need to make sure there are adequate levels of RSNO substrates present and hence the need to detect RSNO concentrations in blood. However, above and beyond the need to measure RSNOs to assess whether our new catalytic polymer coatings will reduce thrombosis of biomedical devices, there is another major reason to devise simple sensor methods for detecting RSNOs. Indeed, RSNOs may well be an important biomarker to predict the risk of natural thrombotic events in patients (e.g., heart attack, stroke, deep vein thrombosis, etc.). Low levels of RSNO mean that you have dysfunctional endothelium and are not producing adequate levels of NO from the endothelial cells that line the inner walls of all healthy blood vessels. This would increase the risk of a thombotic event. Further, since it has been suggested in the literature that platelets (key cells that need to be activated to cause clotting) have proteins on their surface that convert RSNO to NO (catalytically), and since NO is potent inhibitor of platelet activation, decreased levels of RSNOs in blood would mean that platelets can more easily become activated, causing a clotting event. Thus, one goal for our group in the future will be to explore how we can simplify the measurements of RSNO levels using our sensor-based method so that collaborations with clinicians in our Medical School will enable a study of a large population of human subjects to assess whether there is indeed a clear link between RSNO levels in blood and risk of thrombotic events. If this is the case, measurement of RSNO levels in blood could eventually become a routine blood test to screen patients for the potential risk of heart attack, stroke and other life-threatening thrombotic episodes.

 

Monthly Lab Update- February 2007

Congratulations to our latest Ph.D. students who graduated recently. Dr. Wansik Cha defended his thesis titled “Catalytic Generation of Nitric Oxide from S-Nitrosothiols Using Organoselenium Species and Development of Amperometric S-Nitrosothiol Sensors"  in mid- December and is now a post-doc in our lab for 6 months before he joins Dr. Takayama’s laboratory in the Department of Biomedical Engineering at the University of Michigan.  Dr. Hairong Zhang defended her thesis titled “Gold/Conduction Polymer Coatings for Solid Phase Immunoassays” in mid-January and is now employed at BioVaris Inc. in Gaithersburg MD, working with electrogenerated luminescence based immunoassays.

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