David W. Schmidtke

Research Interests

The development of new medical devices and materials to replace damaged or worn tissues and organs is becoming increasingly important as the average age of our population increases. In view of this demand, my research interests are in the design and development of new analytical devices and technologies for medical therapy, and lie at the interface of medicine and engineering. My current research can be divided into three research directions: 1. Cell Adhesion; 2. Microfabrication; and 3. Biosensors.

CELL ADHESION
During inflammation and thrombosis, the initial interaction and rolling adhesion of leukocytes on activated endothelial cells and platelets and on other leukocytes, is mediated by the interaction of the selectin adhesion molecule family and their respective ligands. Leukocytes express L-selectin, whereas activated platelets and/or endothelial cells express P- and E-selectin. Leukocyte rolling allows regional sampling of chemokines and other mediators, which leads to integrin-dependent arrest and emigration of leukocytes into the underlying tissue. Rolling requires the rapid formation and rapid dissociation of selectin-ligand bonds that are subjected to tensile forces applied by wall shear stress. Our group has been able to demonstrate that during neutrophil rolling on selectin coated surfaces or platelets, thin membrane tether structures are formed at the trailing edge of neutrophils. A current focus of my research group is to investigate the physiological role that membrane tether’s play during rolling. Utilizing high-resolution differential interference contrast video microscopy my lab recently discovered that membrane tether formation is a dynamic process that appears to be regulated by the shear stress level. At high shear stress (6-8 dynes/cm2) multiple tethers are formed, while at low shear (2 dynes/cm2) a single membrane tether is normally pulled. Furthermore it appears that the formation of membrane tethers results in a reduction and stabilization in the cell’s rolling velocity.

MICROFABRICATION
The current practice to study the adhesive interactions of cells (e.g. platelets and neutrophils) under flow is to coat substrates with adhesive ligands by simple protein adsorption or incorporation into a phospholipid bilayer and then perfuse isolated cells over the coated substrate in a flow perfusion assay. Although these methods have led to a wealth of knowledge on the molecular interactions that mediate leukocyte adhesion and rolling under flow, potential drawbacks include (a) protein molecules are randomly distributed on the surface; (b) only a single protein concentration can be studied at a time; and (c) normally only a single protein can be studied. Many studies could benefit from the use of substrates in which adhesion proteins are patterned into well-defined microenvironments, and multiple proteins or protein concentrations are patterned simultaneously. Recently we have developed microfluidic patterning techniques for controlling cell adhesion and rolling under flow.

BIOSENSORS
As the need and desire to monitor our health and environment in real time increases, correspondingly the demand for reliable miniature sensors which can detect a wide range of molecules also increases. Although there have been many new biosensing technologies developed over the last thirty years, for these to be useful outside the laboratory they must be small, portable, and reliably report measurements in real time. In view of these demand, my group is developing amperometric biosensors for metabolic monitoring based on redox polymers that electrically “wire” the redox centers of enzymes to electrode surfaces. We have chosen to use redox polymers as our detection method since (a) they exhibit high current densities (1 mA/cm2) (a must for miniaturization), (b) their operating potential can be tuned by the appropriate chemistry, and (c) they can be used with several different enzymes. Currently my research in the field of biosensors is focused in the following areas 1. In vivo glucose sensing; 2. Carbon Nanotube Based Biosensors; and 3. Development of Novel Redox Polymers.

Selected Publications

Cell Adhesion

Schmidtke DW and Diamond SL. Direct observation of membrane tethers formed during neutrophil attachment to platelets or P-selectin under physiological flow. Journal of Cell Biology, 149:719-729, 2000.

Diamond SL, Tandon P, Schmidtke D, and Laurenzi I. Cellular Aggregation in Blood Flow. Comments on Theoretical Biology, 5:413-435, 2000.

Park EYH, Smith MJ, Stropp ES, Snapp KR, DiVietro JA, Walker WF, Schmidtke DW, Diamond SL, and Lawrence MB. Comparison of PSGL-1 Microbead and Neutrophil Rolling: Microvillus Elongation Stabilizes P-Selectin Bond Clusters. Biophysical Journal, 82:1835-1847, 2002.

Doggett TA, Girdhar G, Lawshe A, Schmidtke DW, Laurenzi IJ, Diamond SL, Diacovo TG. Selectin-like kinetics and biomechanics promote rapid platelet adhesion in flow: the GpIb-vWF Tether Bond. Biophysical Journal, 83:194-205, 2002.

Ramachandran V, Williams W, Yago T, Schmidtke DW, McEver RP. Dynamic alterations of membrane tethers stabilize leukocyte rolling on P-selectin. Proceedings of the National Academy of Science, 101:13519-13524, 2004.

Carbon Nanotube Based Biosensors

Joshi PP, Merchant SA, Wang Y, and Schmidtke DW, Amperometric Biosensors Based on Redox Polymer-Carbon Nanotube-Enzyme Composites, Analytical Chemistry. 77:3183-3188, 2005.

Chen T, Schmidtke DW, Heller A. Defining the period of recovery of the glucose concentration after its local perturbation by the implantation of a miniature sensor. Clin. Chem. Lab. Med. 40:786-789, 2002

Schmidtke DW, Freeland AC, Heller A, and Bonnecaze RT. Measurement and Modeling of the Transient Difference Between Blood and Subcutaneous Glucose Concentrations in the Rat Following Injection of Insulin. Proceedings of the National Academy of Science, 95:294-299, 1998.

Schmidtke DW, and Heller A. Accuracy of the One-Point In Vivo Calibration of "Wired" Glucose Oxidase Electrodes Implanted in Jugular Veins of Rats. Analytical Chemistry, 70:2149-2155, 1998.

Wagner JG, Schmidtke DW, Quinn CP, Fleming TF, Bernacky B, and Heller A. Continuous Amperometric Monitoring of Glucose in a Brittle Diabetic Chimpanzee with a Miniature Electrode. Proceedings of the National Academy of Science, 95:6379-6382, 1998.

Ishikawa M, Schmidtke DW, Raskin P, and Quinn CP. Initial evaluation of a 290 m diameter subcutaneous glucose sensor: Glucose monitoring with a biocompatible, flexible wire, enzyme-based amperometric microsensor in diabetic and non-diabetic humans. Journal of Diabetes and Its Complications, 12:295-301, 1998.